Recent ucsd_postprints items

Simultaneous optimization of lignocellulosic sugar catabolism via systematic laboratory evolution under complex selection pressure

Tue, 13 Oct 2026 00:00:00 +0000

Efficient co-utilization of hexose and pentose sugars from lignocellulose is essential for microbial bioconversion, yet engineered catabolic pathways can be unstable or suboptimal in complex resource environments. Here, we use a Pseudomonas putida strain engineered to catabolize xylose and arabinose to examine how resource abundance, temporal availability, and subculturing shape evolutionary outcomes. Using an automated adaptive laboratory evolution (ALE) platform, we evolve the strain under simple single-substrate and complex multi-substrate selection pressures. These environments drive divergence between catabolic specialists and generalists. Weak or absent selection for xylose frequently leads to loss of xylose catabolism, whereas carbon-limited mixed-sugar environments promote stable retention and coordinated optimization of multiple catabolic pathways, enhancing growth and substrate utilization. Genomic, proteomic, and biochemical analyses show that pathway-specific fitness...

Combination of ATLAS and CMS Searches for Higgs Boson Pair Production at s=13 TeV

Tue, 13 Oct 2026 00:00:00 +0000

This Letter presents a combination of searches for Higgs boson pair ( ) production performed by the ATLAS and CMS Collaborations using proton-proton collision datasets recorded at during the Large Hadron Collider Run 2, corresponding to integrated luminosities ranging between 126 and . The upper limit at the 95% confidence level on the total signal strength, defined as the ratio of the measured cross section to the standard model (SM) prediction, corresponds to 2.5, with an expected value of 1.7 (2.8) assuming the absence (presence) of the SM signal. The strength of the signal is measured to be relative to the SM prediction. The observed significance is found to be 1.1 standard deviations whereas 1.3 are expected for the SM signal. Constraints are set on the Higgs boson trilinear self-coupling and on the couplings of two Higgs bosons to two vector bosons, both normalized to the SM predictions and denoted as and , respectively. The observed individual constraints at the...

Interplanetary scintillation (IPS) analyses during LOFAR campaign mode periods that include the first three Parker Solar Probe close passes of the Sun

Mon, 12 Oct 2026 00:00:00 +0000

The University of California, San Diego (UCSD) time-dependent three-dimensional (3-D) reconstruction technique provides volumetric maps of density, velocity, and solar surface extrapolated magnetic fields by iteratively fitting our kinematic 3-D model to interplanetary scintillation (IPS) observations. While we currently use data from the Institute for Space-Earth Environmental Research (ISEE), Japan, we have also integrated this system adding data from Worldwide IPS Stations (WIPSS) network groups to increase both spatial and temporal coverage when these data are available. Some of these stations, especially the LOw Frequency ARray (LOFAR), centered in the Netherlands, currently operate in “campaign” mode only during periods of interest when the Parker Solar Probe (PSP) makes close passes to the Sun. The UCSD 3-D iterative reconstruction technique is unique in its ability to yield a low-resolution seamless extension of density and velocity parameters measured in situ, going outward...

Volumetric mapping of total, bound and pore water as well as collagen protons in cortical bone using 3D ultrashort echo time (UTE) MR imaging techniques allows accurate diagnosis of osteopenia and osteoporosis

Sun, 11 Oct 2026 00:00:00 +0000

Volumetric mapping of total, bound and pore water as well as collagen protons in cortical bone using 3D ultrashort echo time (UTE) MR imaging techniques allows accurate diagnosis of osteopenia and osteoporosis

Ultrashort echo time magnetization transfer imaging of myelin in APP knock-in mice

Sun, 11 Oct 2026 00:00:00 +0000

PURPOSE: Myelin integrity is increasingly recognized as a potential factor in Alzheimer's disease (AD) pathology, making accurate quantification of myelin essential for elucidating its role in the progression of the disease. This study aims to evaluate the potential of ultrashort echo time magnetization transfer (UTE-MT) imaging for assessing myelin-related alterations in an APP knock-in mouse model of AD (hereafter referred to as APPKI mice). METHOD: Eighteen APPKI mice (∼14 months; 9 females/9 males) and fourteen age-matched wild-type C57BL/6 (WT) (8 females/6 males) were scanned on a 3T Bruker scanner. Two sets of UTE-MT data (TR=80 ms, TE=0.026 ms) were acquired with an MT pulse power of 1500° (θ=1500°) and frequency offset of 2 kHz (Δf = 2 kHz) (MT_on), and with θ=500° and Δf = 50 kHz (MT_off), respectively. UTE-MT ratio (UTE-MTR) maps, calculated as (MT_off - MT_on)/MT_off, were generated for comparing APPKI and WT mice....

Quantitative ultrashort echo time (UTE) magnetic resonance imaging of femoral trabecular bone in aging and osteoporosis

Sun, 11 Oct 2026 00:00:00 +0000

ObjectiveTo evaluate quantitative ultrashort echo time (UTE) magnetic resonance imaging (MRI) biomarkers, pore-to-matrix ratio (PMR), and matrix index (MI) for assessing trabecular bone in the proximal femur across aging and osteoporosis-related bone status.Materials and methodsIn this prospective study, 92 female subjects (20–83 years) were classified into four groups based on age and DXA-derived T-scores: Young Normal (n = 19), Old Normal (n = 14), Osteopenia (n = 44), and Osteoporosis (n = 15). All participants underwent 3-T hip MRI using 3D dual-echo proton-density-weighted UTE (PD-UTE) and short TR adiabatic inversion recovery UTE (STAIR-UTE) sequences. Measurements were performed in the femoral head and neck by two readers. Interobserver agreement was assessed via intraclass correlation coefficients (ICC). Group differences were analyzed with the Kruskal–Wallis test and Holm-adjusted post hoc tests. Spearman correlation analysis and receiver operating characteristic (ROC)...

Therapeutic Efficacy of NSI-189 against Diabetic Neuropathy and Encephalopathy in Mice

Fri, 9 Oct 2026 00:00:00 +0000

Therapeutic Efficacy of NSI-189 against Diabetic Neuropathy and Encephalopathy in Mice

Murine model and mechanisms of treatment-induced painful diabetic neuropathy

Fri, 9 Oct 2026 00:00:00 +0000

Diabetes mellitus represents a group of metabolic diseases that are characterized by hyperglycemia caused by either lack of insulin production or a reduced ability to respond to insulin. It is estimated that there were 347 million people worldwide who suffered from diabetes in 2008 and incidence is predicted to double by 2050. Neuropathy is the most common complication of long-term diabetes and approximately 30% of these subjects develop chronic neuropathic pain. A distinct acute, severe form of neuropathic pain, called insulin neuritis or treatment-induced painful neuropathy of diabetes (TIND), may also occur shortly after initiation of intensive glycemic control, with an incidence rate of up to 10.9%. The pathological mechanisms leading to TIND, which is mostly unresponsive to analgesics, are not yet understood, impeding the development of therapies. Studies to date have been clinical and with limited cohorts of patients. In the current study, we developed chronic and acute...

Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous CarcinomaTargeting RNR Induces Synthetic Lethality in USC

Fri, 9 Oct 2026 00:00:00 +0000

Uterine serous carcinoma (USC) is a highly aggressive endometrial cancer subtype with limited therapeutic options and a lack of targeted therapies. While mutations to PPP2R1A, which encodes the predominant protein phosphatase 2A (PP2A) scaffolding protein Aα, occur in 30% to 40% of USC cases, the clinical actionability of these mutations has not been studied. Using a high-throughput screening approach, we showed that mutations in Aα results in synthetic lethality following treatment with inhibitors of ribonucleotide reductase (RNR). In vivo, multiple models of Aα mutant uterine serous tumors were sensitive to clofarabine, an RNR inhibitor (RNRi). Aα-mutant cells displayed impaired checkpoint signaling upon RNRi treatment and subsequently accumulated more DNA damage than wild-type (WT) cells. Consistently, inhibition of PP2A activity using LB-100, a catalytic inhibitor, sensitized WT USC cells to RNRi. Analysis of The Cancer Genome Atlas data indicated that inactivation of PP2A,...

Redundant mispair excision mechanisms in eukaryotic DNA mismatch repair.

Fri, 9 Oct 2026 00:00:00 +0000

DNA mismatch repair (MMR) corrects DNA replication errors, some forms of chemical damage to DNA bases, and acts in processes such as heteroduplex rejection, triplet repeat expansion, antibody maturation and cytotoxicity of alkylating agents. During MMR, the newly synthesized DNA strand containing the error must be removed and resynthesized to prevent mutations. In bacteria, this strand is displaced by the UvrD DNA helicase. In eukaryotes, this strand is excised by redundant pathways. In the first excision pathway identified, Saccharomyces cerevisiae Msh2-Msh6 (or Msh2-Msh3) and/or Mlh1-Pms1 (human MLH1-PMS2) recruit Exo1 to 5' nicks, and 5'-to-3' excision by Exo1 excises the daughter strand containing the mispair to generate a single-stranded gap. The Mlh1-Pms1 endonuclease also mediates excision through extensive nicking of the daughter strand to generate single-stranded gaps. In coupled strand-displacement synthesis coordinated by Msh2-Msh6 (or Msh2-Msh3), DNA polymerase delta...

DNA mismatch repair mediated by Mlh1–Pms1 endonuclease-catalyzed mispair excision

Fri, 9 Oct 2026 00:00:00 +0000

Eukaryotic DNA mismatch repair (MMR) involves several excision pathways, including those mediated by exonuclease 1 (Exo1) and by the flap endonuclease Rad27 (human FEN1) coupled with DNA polymerase δ. Simultaneous inactivation of both excision mechanisms causes an MMR defect that is at most 5 to 13% of that caused by complete inactivation of MMR. Here, we reconstituted nicked-strand-specific MMR with the Saccharomyces cerevisiae proteins Msh2-Msh6 or Msh2-Msh3, DNA polymerase ε, RFC, PCNA, RPA, and Mlh1-Pms1 (human Mlh1-Pms2) under conditions lacking Exo1, Rad27, or strand-displacement synthesis by DNA polymerase δ. These reactions required the Mlh1-Pms1 endonuclease activity, its activation by RFC and PCNA, and its recruitment by Msh2-Msh6 or Msh2-Msh3. MMR was mediated by nicked-strand-specific excision by Mlh1-Pms1 through formation of single-strand DNA gaps having a broad range of sizes. This reaction is consistent with genetic data demonstrating redundancy between...

Time-resolved functional genomics using deep learning reveals global hierarchical control of autophagy

Fri, 9 Oct 2026 00:00:00 +0000

Recycling of cellular components through autophagy maintains homeostasis in changing nutrient environments. Although its core mechanisms are extensively studied, understanding of its systems-wide dynamic regulation remains limited, particularly regarding how autophagy is inactivated once nutrients are restored. Here we mapped the genetic network that controls activation and inactivation of autophagy during nitrogen changes by combining time-resolved high-content imaging, deep learning and latent feature analysis. This dataset, termed AutoDRY, categorizes 5,919 mutants based on nutrient response kinetics and their contributions to autophagosome formation and clearance. Integrating these profiles with functional and genetic network data uncovered hierarchical and multilayered control of autophagy and revealed multiple new regulatory pathways. Notably, we identified the retrograde pathway as a pivotal time-varying modulator that tunes the expression of core autophagy genes and plays...

Tumor FAK supports fibrillar collagen expression in ovarian cancer ascites

Fri, 9 Oct 2026 00:00:00 +0000

High-grade serous ovarian cancer (HGSOC) is a lethal malignancy where matrix proteins enhance ascites-associated recurrent tumor growth. Elevated focal adhesion kinase (FAK/PTK2) and collagen protein expression support tumor survival, chemoresistance, and immune evasion. However, the sources and regulation of collagen production within HGSOC tumorspheres is unclear. Using CRISPR-mediated FAK knockout and FAK re-expression in two syngeneic HGSOC models (MOVCAR and KMF), FAK loss impaired tumorsphere growth in vitro and in vivo while reducing collagen expression, as determined by RNA sequencing, quantitative RT-PCR, and protein mass spectrometry. FAK re-expression promoted spontaneous metastatic ovarian tumor dissemination. Integrated bioinformatic analyses of MOVCAR, KMF, and HGSOC patient datasets identified 56 common mRNAs co-elevated with PTK2, including COL3A1 and COL5A2. Single-cell RNA sequencing of murine KMF ascites revealed a subset of tumor cells expressing Col3a1 and...

Robust, randomized preconditioning for kernel ridge regression

Fri, 9 Oct 2026 00:00:00 +0000

We investigate preconditioned conjugate gradient methods for kernel ridge regression (KRR) problems with a moderate to large number of data points (104≤N≤107$$10^4 \le N \le 10^7$$). We develop and analyze two randomized preconditioners with complementary guarantees. For full-data KRR, RPCholesky preconditioning requires O(N2)$$\mathcal {O}(N^2)$$ arithmetic operations for fixed accuracy under sufficiently rapid eigenvalue decay of the kernel matrix. For restricted KRR with k≪N$$k\ll N$$ centers, KRILL preconditioning requires O((N+k2)klogk)$$\mathcal {O}((N+k^2)k\log k)$$ operations with no eigenvalue-decay assumption. Experiments on benchmark and scientific data sets demonstrate the robustness of both methods relative to existing preconditioners.

Disarming cancer resistance: FAK as a therapeutic target

Fri, 9 Oct 2026 00:00:00 +0000

The FDA recently granted accelerated approval of the small-molecule focal adhesion kinase (FAK) inhibitor (FAKi, defactinib) in combination with a RAF-MEK clamp inhibitor (avutometinib) for KRAS-mutated low-grade serous ovarian cancer developed by Verastem Inc. This milestone moment represents a long journey in FAKi development, from initial findings of limited single-agent activity to orally delivered FAKi effects that can sensitize solid tumors to chemotherapy, radiotherapy, and immunotherapy treatments. In this study, we review a short history of FAK, summarize ongoing combinatorial clinical trials, discuss potential mechanisms of action, and highlight studies showing that FAK activation is a chemo- and mechano-sensitive signaling hub driving tumor adaptive changes. Targeting FAK disarms tumor resistance through multiple mechanisms, which supports new biological insights and future clinical combinations.

Pirenzepine Reverses Chemotherapy-Induced Peripheral Neuropathy in Mice

Fri, 9 Oct 2026 00:00:00 +0000

Background/Objectives: Mitochondrial dysfunction is a common feature of many peripheral neuropathies and agents that enhance mitochondrial function have potential as pan-neuropathy therapeutics. M1 receptor (M1R) antagonists enhance mitochondrial function and reverse multiple indices of neuropathy in rodents and humans with diabetic neuropathy. The present studies extend evaluation of the M1R-selective antagonist pirenzepine to mouse models of chemotherapy-induced peripheral neuropathy (CIPN), with a primary focus on pain relief. Results: Oxaliplatin-exposed mice developed allodynia to light touch that persisted for months before resolution. Systemic pirenzepine (1 mg/kg/day) starting prior to chemotherapy did not prevent allodynia but accelerated recovery. Topical delivery (4% pirenzepine in hydrogel) to the paw, beginning after onset of allodynia, also accelerated recovery, with efficacy persisting weeks after treatment cessation and accompanied by normalization of paw responses...

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Indices of Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes

Fri, 9 Oct 2026 00:00:00 +0000

Topical Delivery of Muscarinic Receptor Antagonists Prevents and Reverses Indices of Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes

Mutant PP2A Induces IGFBP2 Secretion to Promote Development of High-Grade : Uterine Cancer

Fri, 9 Oct 2026 00:00:00 +0000

Uterine serous carcinoma (USC) and uterine carcinosarcoma (UCS) tumors are uniquely aggressive, suggesting that the primary tumor is intrinsically equipped to disseminate and metastasize. Previous work identified mutational hotspots within PPP2R1A, which encodes the Aα scaffolding subunit of protein phosphatase 2A (PP2A), a heterotrimeric serine/threonine phosphatase. Two recurrent heterozygous PPP2R1A mutations, P179R and S256F, occur exclusively within high-grade subtypes of uterine cancer and can drive tumorigenesis and metastasis. Elucidation of the mechanisms by which PP2A Aα mutants promote tumor development and progression could help identify therapeutic opportunities. Here, we showed that expression of these mutants in USC/UCS cell lines enhanced tumor-initiating capacity, drove a hybrid epithelial-to-mesenchymal plasticity phenotype, and elevated secretion of the tumorigenic cytokine insulin growth factor (IGF) binding protein 2 (IGFBP2). Therapeutic targeting of the...

Biased holoenzyme assembly of protein phosphatase 2A (PP2A): From cancer to small molecules

Fri, 9 Oct 2026 00:00:00 +0000

Protein phosphatase 2A (PP2A) is a family of serine threonine phosphatases responsible for regulating protein phosphorylation, thus opposing the activity of cellular kinases. PP2A is composed of a catalytic subunit (PP2A Cα/β) and scaffolding subunit (PP2A Aα/β) and various substrate-directing B regulatory subunits. PP2A biogenesis is regulated at multiple levels. For example, the sequestration of the free catalytic subunit during the process of biogenesis avoids promiscuous phosphatase activity. Posttranslational modifications of PP2A C direct PP2A heterotrimeric formation. Additionally, PP2A functions as a haploinsufficient tumor suppressor, where attenuated PP2A enzymatic activity creates a permissive environment for oncogenic transformation. Recent work studying PP2A in cancer showed that its role in tumorigenesis is more nuanced, with some holoenzymes being tumor suppressive, while others are required for oncogenic transformation. In cancer biology, PP2A function...

Rare variants of DNA ligase 1 show distinct mechanisms of deficiency

Fri, 9 Oct 2026 00:00:00 +0000

Human DNA ligase 1 (LIG1) performs the final step in DNA repair and recombination pathways by sealing DNA breaks, and it functions as the main replicative ligase. Hypomorphic LIG1 variants R771W and R641L cause immune deficiencies in LIG1 Syndrome patients. In vitro these LIG1 variants have decreased catalytic efficiency and increased abortive ligation and it is not known if either biochemical defect is sufficient on its own to cause immune deficiency. We investigated the enzymatic activity of several new candidate LIG1 Syndrome variants chosen based on their structural proximity to known clinical variants, low minor allele frequency (MAF), high level of conservation, and concurrence in patients with similar symptoms as LIG1 Syndrome patients. The R305Q substitution is in the DNA binding domain, R768W is in the OB-fold domain, and R641S is in the nucleotidyltransferase domain. Biochemical characterization confirmed deficiencies in ligase activity for all three variants, but...

Seasonal Shift in the Dominant Pathway Energizing Mesoscale Eddies in the California Current

Thu, 8 Oct 2026 00:00:00 +0000

Abstract Mesoscale eddies are the dominant reservoir of kinetic energy in the ocean, yet the mechanisms that generate and maintain them in eastern boundary current systems remain incompletely assessed. Here we use a 1-km resolution simulation of the California Current System (CCS) to diagnose and quantify the processes that supply kinetic energy to the mesoscale band. A pronounced seasonal transition is evident in surface vorticity, kinetic energy spectra, and mixed-layer depth. In winter and spring, the mixed layer deepens during periods of strong wind work. Once the forcing relaxes, the mixed layer restratifies, generating submesoscale eddies and filaments. These features merge and transfer energy upscale, supplying the mesoscale through an inverse cascade. These mixed-layer restratification events occur most frequently when the mixed layer is deep (∼50 m) and highly variable. In contrast, during summer when the mixed layer is shallow, a mixed-layer-averaged geostrophic kinetic...

Author Correction: DREAM repressive activity links somatic mutation, lifespan and disease

Thu, 8 Oct 2026 00:00:00 +0000

Author Correction: DREAM repressive activity links somatic mutation, lifespan and disease

Impactful Datasets in Earth, Space, and Environmental Sciences: Highlighting the Data That Transform Research

Thu, 8 Oct 2026 00:00:00 +0000

Abstract The American Geophysical Union (AGU) announces the new living collection “Impactful Datasets in Earth, Space, and Environmental Sciences” which recognizes the creation and curation of datasets enabling research, analysis, and decision making beyond what is captured by traditional academic impact metrics. The collection highlights datasets through the dimensions of People, Planet, and Prosperity, and includes a curated set of nominated datasets and accompanying special collection of data papers. Developed with the Earth Science Information Partners (ESIP) community, the nomination and review process initially invites contributors from across research, operations, and public service, to nominate datasets important to their work, and then submit a data paper that expands upon the nomination text for inclusion in the special collection. This commentary highlights the rationale for the living collection, and the process of nomination. The collection serves as a living...

Curvature regularization and dynamical vacuum structure in pseudo-complex general relativity

Thu, 8 Oct 2026 00:00:00 +0000

Whether classical spacetime remains well-defined at arbitrarily high curvature is a central question. In general relativity, singularities signal the breakdown of the classical description, motivating modifications of spacetime’s short-distance structure. Pseudo-complex general relativity (pcGR) extends spacetime geometry to pseudo-complex coordinates, naturally introducing two metric sectors, the physical metric gμν$$g_{\mu u }$$ and an auxiliary field fμν$$f_{\mu u }$$. The magnitude of the pseudo-imaginary component defines the invariant acceleration scale a0$$a_0$$, a direct consequence of the pseudo-complex structure. The simultaneity condition, requiring both idempotent sectors to satisfy the pseudo-complex Einstein equations independently, fixes the auxiliary field algebraically, with no new propagating degrees of freedom, and sets a lower bound on the lapse that regularizes curvature. The regularization is achieved through the combined effect of the lapse-gap condition...

Compression response of tire derived aggregate particles

Thu, 8 Oct 2026 00:00:00 +0000

Tire derived aggregate (TDA) is a recycled geosynthetic material that is often used in civil engineering applications as a lightweight fill. While TDA is typically modelled as a compressible porous media similar to soil, there haven’t been detailed investigations on the deformation response of individual particles or particle-particle interaction. TDA particles are approximately flat sheets of shredded tire, but their characteristics can vary based on where the shred is obtained from (tread or side-wall) and the direction of particle-particle loading. This study presents results from experiments focused on the deformation response of individual TDA particles under quasi-static and sustained normal stresses. This study is a first step toward defining contact relationships for discrete element modeling of TDA fills.

Fluorescent cAMP Analogs: Enzymatic Synthesis, Unexpected Photophysical Behavior and Protein Kinase A Recognition

Thu, 8 Oct 2026 00:00:00 +0000

ABSTRACT Cyclic adenosine monophosphate (cAMP) is a second messenger, regulating critical physiological processes. We report the enzymatic synthesis, unique photophysical features, and biological activity of novel emissive cAMP analogs (c th AMP and c tz AMP), comprised of thiopheno‐ and isothiazolo‐based families of isomorphic ribonucleotides. The unexpectedly high brightness of c th AMP compared to th ATP and th AMP, its precursor and hydrolysis products, respectively, driven by an anti ‐to‐ syn conformational shift upon cyclization, is employed for real‐time monitoring of the adenylyl cyclase (AC) mediated synthesis and phosphodiesterase (PDE) mediated hydrolysis. Importantly, these emissive analogs effectively activate protein kinase A (PKA). This study provides critical insights into the biomolecular recognition and catalytic mechanism of cAMP‐regulating enzymes, establishing these isomorphic analogs as potential tools for investigating cAMP‐dependent protein–ligand interaction...

Isothiazologuanosine (tzG) as Environmentally Sensitive Fluorescent Reporter in RNA

Thu, 8 Oct 2026 00:00:00 +0000

ABSTRACT Site‐specific labeling of RNA with emissive, structurally non‐perturbing nucleosides is critically needed for probing RNA structure, dynamics, and function. Isothiazolopyrimidine‐based nucleoside surrogates are leading examples of fluorescent RNA building blocks, with the C‐nucleosidic guanosine analogue tz G standing out due to its brightness. Here, we report the first synthesis of a tz G phosphoramidite and its incorporation into RNA via solid‐phase synthesis. Comprehensive biochemical and photophysical analyses demonstrate that tz G acts as an isomorphic and isofunctional substitute for guanosine, with fluorescence properties that are sensitive to local environmental changes. These features enable fluorescence‐based monitoring of RNA cleavage by deoxyribozymes and of site‐specific RNA methylation by a methyltransferase ribozyme. Our findings establish tz G as a valuable emissive nucleoside analog for the interrogation of RNA modifications at defined positions.

From phenomenon to mechanism in the circadian clock of Synechococcus elongatus

Thu, 8 Oct 2026 00:00:00 +0000

Creative and collaborative research in the early 21st century revealed the mechanistic secrets of the cyanobacterial circadian clock, a nanomachine whose function can be studied in vitro. The structural dynamics of the Synechococcus elongatus circadian oscillator, comprising KaiA, KaiB, and KaiC, establish a near 24 h cycle of activity of the global transcription regulator RpaA by rhythmically changing the interaction platform of kinases that control RpaA phosphorylation.

Divergent effects of hyperandrogenemia on the female reproductive neuroendocrine axis under different physiological conditions

Thu, 8 Oct 2026 00:00:00 +0000

The hypothalamic-pituitary-gonadal (HPG) axis coordinates reproductive function and incorporates gonadal sex steroid feedback to regulate gonadotropin secretion in a homeostatic manner. In females, ovarian estrogens and progestins act as the primary negative feedback signals to suppress luteinizing hormone (LH) release, whereas in males, androgens, such as testosterone (T), typically provide this feedback. However, androgens can also exert feedback effects on the female HPG axis, particularly in conditions where circulating T levels exceed that of the normal female physiological range. Three clinically relevant examples are anabolic substance abuse, testosterone therapy, and polycystic ovary syndrome (PCOS; recently renamed polyendocrine metabolic ovarian syndrome [PMOS]). Despite shared exposure to "androgen excess," these different hyperandrogenic states are associated with strikingly different neuroendocrine phenotypes. In testosterone therapy and anabolic substance abuse,...

Comprehensive Biophysical and Biochemical Characterization of Multi-Arm Maleimide-Poly(ethylene glycol) Conjugated Bovine and Human Hemoglobin as Potential Red Blood Cell Substitutes

Thu, 8 Oct 2026 00:00:00 +0000

Abstract: This study examines bench-scale synthesis and the physicochemical and functional properties of hemoglobin (Hb) formulations, including bovine (bHb), human (hHb), and pyridoxylated (PLP, pyridoxal-5′-phosphate) human Hb (PLP-hHb), along with their poly(ethylene glycol) (PEG)-conjugated counterparts. These PEGylated Hb constructs were synthesized via an inside-out strategy targeting the β-Cys93 residue of Hb using a four-arm PEG-maleimide molecule (MW = 20 kDa per arm; 80 kDa total), producing multi-arm PEG conjugated Hbs (MA-PEG-Hbs). The precursor Hbs exist as α2β2 tetramers (MW ∼64–65 kDa; diameter ∼5 nm), whereas MA-PEG-Hbs showed increased size (320–345 kDa; ∼14 nm), consistent with 3–4 Hb tetramers per PEG scaffold. This expansion reduced haptoglobin binding kinetics by ∼6–9-fold, potentially prolonging circulation and reducing renal clearance. Circular dichroism confirmed preservation of α-helical structure and heme integrity, while thermal stability...

TREM2⁺ tumor-associated macrophages in cancer: Context-dependent biology, biomarkers, and precision immunotherapy

Thu, 8 Oct 2026 00:00:00 +0000

Tumor-associated macrophages (TAMs) are abundant and functionally important components of the tumor microenvironment (TME), yet the molecular programs that distinguish pathogenic macrophage states from tissue-adaptive populations remain incompletely defined. Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a key marker of specialized immunoregulatory macrophage states across multiple solid tumors. Accumulating evidence links TREM2⁺ macrophages to metabolic adaptation, immune evasion, and impaired antitumor immunity, although their biological functions vary substantially across tumor types, tissue niches, and disease settings. In this review, we synthesize current understanding of TREM2-associated immunobiology, including ligand recognition, signaling architecture, immunometabolic adaptation, and macrophage functional heterogeneity. We critically evaluate conflicting findings across tumor types and discuss how tissue context, macrophage ontogeny, and microenvironmental...

Phantom-based evaluation of time-SLIP MRI for measuring spinal-canal Lagrangian drift

Thu, 8 Oct 2026 00:00:00 +0000

The pulsatile motion of cerebrospinal fluid (CSF) in the spinal canal includes a mean Lagrangian drift, representing the cumulative net displacement experienced by the fluid over each oscillatory cycle. Quantifying this motion in vivo is challenging because the associated velocities ($$\sim $$cm min$$\vphantom{0}^{-1})$$are much smaller than those of the dominant oscillatory flow ($$\sim $$ cm s$$\vphantom{0}^{-1}$$), limiting the applicability of conventional phase-contrast (PC) MRI. Here we assess the suitability of Time-Spatial Labeling Inversion Pulse MRI (Time-SLIP) for characterizing this motion using in vitro experiments in a spinal-canal phantom. The phantom consists of a flexible tube with a rigid insert forming an eccentric annular canal representative of the spinal subarachnoid space, driven by a 1 Hz sinusoidal flow mimicking cardiac-induced CSF pulsations. Oscillatory velocities were measured with PC-MRI, while net fluid displacement over successive...

Probing the Structure and Dynamics of Telomeric G‑Quadruplexes with Thienoguanosine, a Fluorescent Analogue of Guanosine

Thu, 8 Oct 2026 00:00:00 +0000

The potential of thienoguanosine (^thG), an isomorphic fluorescent analogue of guanosine, was evaluated as a reporter for probing the structure and dynamics of hTel22, a human telomeric G-quadruplex (G4) sequence. Nine of the 12 guanines directly participating in G-tetrads were individually substituted with ^thG, and their impact on the hTel22 structure was examined by circular dichroism, thermal melting, and ¹H NMR spectroscopy. In Na⁺ buffer, substitutions at external tetrads maintained the native antiparallel topology and thermal stability, while substitutions within the middle tetrad significantly disrupted the G4 structure. Molecular dynamics simulations supported that ^thG incorporation in external tetrads is well tolerated, whereas it alters base stacking and Na⁺ coordination in middle tetrad positions. In K⁺ buffer, external substitutions favored the antiparallel over the hybrid topology, resulting...

More Than Money: The Relative Importance of Cultural, Social, and Economic Capital for Highbrow Cultural Experiences

Tue, 6 Oct 2026 00:00:00 +0000

More Than Money: The Relative Importance of Cultural, Social, and Economic Capital for Highbrow Cultural Experiences

From Service Level to Maximum Considered Earthquake: Evaluating the Seismic Response of a Ten-Story Cold-Formed Steel-Framed Building

Tue, 6 Oct 2026 00:00:00 +0000

From Service Level to Maximum Considered Earthquake: Evaluating the Seismic Response of a Ten-Story Cold-Formed Steel-Framed Building

China’s power market reform for a high-renewable future: Key drivers, market design, and prospects

Mon, 5 Oct 2026 00:00:00 +0000

China’s rapid renewable expansion coincides with deep structural reforms to its power markets. Over the past decade, reform has drawn on international market design experience while making substantial institutional progress since 2015. Unlike developed markets adapting established frameworks to accommodate renewables, China must address high-renewable integration alongside conventional market liberalisation challenges. High renewable penetration creates several shared analytical challenges, including revenue adequacy under near-zero marginal costs, intensified price volatility, limited participation by emerging flexible resources, incomplete markets for new system attributes, and ambiguous planning–market interactions. In China, responses to these challenges are shaped by two foundational drivers: (1) using the market as an instrument of government policy and (2) hierarchical prioritisation of end-user price stability and socio-political acceptability of reform over allocative...

Beyond the boundaries of the second law of thermodynamics: Intrinsic-nonequilibrium distribution of large ions in charged small nanopores

Sun, 4 Oct 2026 00:00:00 +0000

Beyond the boundaries of the second law of thermodynamics: Intrinsic-nonequilibrium distribution of large ions in charged small nanopores

Cities

Fri, 2 Oct 2026 00:00:00 +0000

This chapter surveys literary and critical modes of figuring, understanding, and analyzing the space of the city. It argues that, rather than see literary representation as a privileged mode of relating urban experience, literature might sit alongside a more expansive analysis of the many affective and narrative modes that attend to the built environment. After retracing some of the fundamental insights of cultural studies, the chapter asks how the city can be understood as an object of cultural knowledge. Along these lines, it interrogates the axiomatic association of the city with modernity, asking what is occluded or ignored in that association.

Dissipating the Political: Battersea Power Station and the Temporal Aesthetics of Development

Fri, 2 Oct 2026 00:00:00 +0000

Abstract This article analyses the idiom of “placemaking” in contemporary development, specifically considering the Battersea Power Station development in south London. It argues that the recourse to a highly aestheticised concept of place allows development to mediate the structural transformations they are enacting and create a narrative and discourse about development that deflects and dissipates political critique. In order for public-private “regeneration” to proceed as the default mode of urbanisation for contemporary London, developers need to not only create sound investments but also produce a hegemonic cultural narrative that articulates the stakes of their interventions in ways that make them not just compelling but inarguable and inevitable. Three modes of conceptualising the redeveloped city are considered: the concept of place, the aesthetic of the garden and rhetoric of sustainability, and the ethos of creativity. Together, these constitute a vision for the future...

Roy Fisher’s City and the Affective Landscapes of Modernization

Fri, 2 Oct 2026 00:00:00 +0000

abstract: This article considers Roy Fisher’s 1961 prose-poem City in the context of slum clearance and urban modernization in the postwar period. Modernization projects, like those in Fisher’s native Birmingham, sought to employ figures of destruction and ruin for the sake of constructing a literal and figurative new Britain after World War II. In doing so, it treated the process of clearing “slum” housing as necessary for the sake of progress. This article argues that City attempts to register the affective landscapes of the postwar city while not directing those affects to any particular political or representational project. Instead, Fisher is concerned with a nonrecuperative form of mourning for the environments and communities lost amid destruction and violence. The poem presents regional specificity of Britain’s postwar landscapes through a late-modernist, fragmentary form for the purpose of gathering together affects of loss, disappearance, and destruction without attempting...

NEOM’s elite dreaming: affective infrastructure and the aesthetics of global modernity

Fri, 2 Oct 2026 00:00:00 +0000

This article analyzes the development of NEOM, a regional megaproject of four cities currently being constructed along the Red Sea in Saudi Arabia. It argues that development for NEOM is speculative, not only in that it these megacities are being built absent of real need, but that the projects themselves are a form of “elite dreaming.” Here, a global elite of designers produce speculative visions for new cities, an imaginary in which these cities serve as technological fixes for problems of climate change and sustainable growth. In so doing, elite designers allow for particular futures while absenting others, namely the people displaced by new cities and the workers who construct and maintain these infrastructures. To this end, this article pays particular attention to the way that design leverages particular aesthetics, narratives, and affects in ways that nevertheless have the power to drive real investment, movement, and construction.

Future Circular Collider Feasibility Study Report

Wed, 30 Sep 2026 00:00:00 +0000

In response to the 2020 Update of the European Strategy for Particle Physics, the Future Circular Collider (FCC) Feasibility Study was launched as an international collaboration hosted by CERN. This report describes the FCC integrated programme, which consists of two stages: an electron-positron collider (FCC-ee) in the first phase, serving as a high-luminosity Higgs, top, and electroweak factory; followed by a proton-proton collider (FCC-hh) at the energy frontier in the second phase. The FCC-ee is designed to operate at four key centre-of-mass energies: the Z pole, the WW pair production threshold, the ZH production peak, and the top/anti-top production threshold—each delivering the highest possible luminosities to four experiments. Over 15 years of operation, FCC-ee will produce more than 6 trillion Z bosons, 200 million WW pairs, nearly 3 million Higgs bosons, and 2 million top anti-top pairs. Precise energy calibration at the Z pole and WW threshold will be achieved through...

Correction: Future Circular Collider Feasibility Study Report

Wed, 30 Sep 2026 00:00:00 +0000

The Image Sources and Credits information section was missing from this article and should have read ‘The FCC Project formally acknowledges and credits all organisations and contributors whose data and imagery form part of the basemaps used in this work. These include © Esri, Airbus DS, FAO, FEMA, GSA, NASA, NGA, NOAA, USGS, CGIAR, NCEAS, Rijkswaterstaat, SITG – State of Geneva (CH), swisstopo, Facebook, Garmin, Geoland, Geodatastyrelsen, Google, Intermap, Maxar, Microsoft, N Robinson, NLS, NMA, OS, Planet, TomTom, as well as © OpenStreetMap contributors, Esri Community Maps contributors, and the GIS User Community. Every effort has been made to correctly acknowledge all data providers and rights holders. Any omission is unintentional, and the FCC Project remains available to review and amend credits upon request from legitimate data owners.’ The original article has been corrected.

Combination of inclusive top-quark pair production cross-section measurements using ATLAS and CMS data at s = 7 and 8 TeV

Wed, 30 Sep 2026 00:00:00 +0000

A combination of measurements of the inclusive top-quark pair production cross-section performed by ATLAS and CMS in proton–proton collisions at centre-of-mass energies of 7 and 8 TeV at the LHC is presented. The cross-sections are obtained using top-quark pair decays with an opposite-charge electron–muon pair in the final state and with data corresponding to an integrated luminosity of about 5 fb−1 at s$$ \sqrt{s} $$ = 7 TeV and about 20 fb−1 at s$$ \sqrt{s} $$ = 8 TeV for each experiment. The combined cross-sections are determined to be 178.5 ± 4.7 pb at s$$ \sqrt{s} $$ = 7 TeV and 243.3−5.9+6.0$$ {243.3}_{-5.9}^{+6.0} $$ pb at s$$ \sqrt{s} $$ = 8 TeV with a correlation of 0.41, using a reference top-quark mass value of 172.5 GeV. The ratio of the combined cross-sections is determined to be R8/7 = 1.363 ± 0.032. The combined measured cross-sections and their ratio agree well with theory calculations using several parton distribution function (PDF) sets. The values of the top-quark...

Review of Particle Physics*

Wed, 30 Sep 2026 00:00:00 +0000

The Review summarizes much of particle physics and cosmology. Using data from previous editions, plus 3,200 new measurements from 903 papers, we list, evaluate, and average measured properties of gauge bosons and the recently discovered Higgs boson, leptons, quarks, mesons, and baryons. We summarize searches for hypothetical particles such as supersymmetric particles, heavy bosons, axions, dark photons, etc. Particle properties and search limits are listed in Summary Tables. We give numerous tables, figures, formulae, and reviews of topics such as Higgs Boson Physics, Supersymmetry, Grand Unified Theories, Neutrino Mixing, Dark Energy, Dark Matter, Cosmology, Particle Detectors, Colliders, Probability and Statistics. Most of the 118 reviews are updated, including many that are heavily revised. The Review is divided into two volumes. Volume 1 includes the Summary Tables and 96 review articles. Volume 2 consists of the Particle Listings and contains also 22 reviews that address...

Cowpea mosaic virus as a candidate for intratumoral immunotherapy: progress, challenges, and future directions

Wed, 30 Sep 2026 00:00:00 +0000

Immunotherapy has emerged as a new pillar of cancer therapeutics that utilizes the patients own immune system to target tumor cells, a particular advantage in the context of hard-to-treat cancers. Virus-based immunotherapies have shown great potential as cancer treatments, including oncolytic viruses, viral vectors and virus-like particles. Here, we discuss the development, applications, challenges, and future opportunities of cowpea mosaic virus (CPMV) as a plant virus-based candidate for intratumoral immunotherapy, focusing on the treatment of aggressive, metastatic and refractory solid tumors. Evidence of antitumor efficacy has been gathered from mouse tumor models and veterinary clinical trials involving canine cancer patients. CPMV is promising as a monotherapy and as part of combination therapies, including chemotherapy, radiation, checkpoint inhibitors, and cytokine therapies. The putative mechanism of action is described, highlighting key features such as the capsid proteins...

Future Circular Collider Feasibility Study Report

Wed, 30 Sep 2026 00:00:00 +0000

Volume 3 of the FCC Feasibility Report presents studies related to civil engineering, the development of a project implementation scenario, and environmental and sustainability aspects. The report details the iterative improvements made to the civil engineering concepts since 2018, taking into account subsurface conditions, accelerator and experiment requirements, and territorial considerations. It outlines a technically feasible and economically viable civil engineering configuration that serves as the baseline for detailed subsurface investigations, construction design, cost estimation, and project implementation planning. Additionally, the report highlights ongoing subsurface investigations in key areas to support the development of an improved 3D subsurface model of the region. The report describes the development of the project scenario based on the ‘avoid-reduce-compensate’ iterative optimisation approach. The reference scenario balances optimal physics performance with...

Feasibility and acceptability of remote smartphone cognitive testing in frontotemporal dementia research

Tue, 29 Sep 2026 00:00:00 +0000

Introduction: Remote smartphone assessments of cognition, speech/language, and motor functioning in frontotemporal dementia (FTD) could enable decentralized clinical trials and improve access to research. We studied the feasibility and acceptability of remote smartphone data collection in FTD research using the ALLFTD Mobile App (ALLFTD-mApp). Methods: A diagnostically mixed sample of 214 participants with FTD or from familial FTD kindreds (asymptomatic: CDR®+NACC-FTLD = 0 [N = 101]; prodromal: 0.5 [N = 49]; symptomatic ≥1 [N = 51]; not measured [N = 13]) were asked to complete ALLFTD-mApp tests on their smartphone three times within 12 days. They completed smartphone familiarity and participation experience surveys. Results: It was feasible for participants to complete the ALLFTD-mApp on their own smartphones. Participants reported high smartphone familiarity, completed ∼ 70% of tasks, and considered...

The ENIGMA Consortium: large-scale collaborative analyses of neuroimaging and genetic data

Tue, 29 Sep 2026 00:00:00 +0000

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium is a collaborative network of researchers working together on a range of large-scale studies that integrate data from 70 institutions worldwide. Organized into Working Groups that tackle questions in neuroscience, genetics, and medicine, ENIGMA studies have analyzed neuroimaging data from over 12,826 subjects. In addition, data from 12,171 individuals were provided by the CHARGE consortium for replication of findings, in a total of 24,997 subjects. By meta-analyzing results from many sites, ENIGMA has detected factors that affect the brain that no individual site could detect on its own, and that require larger numbers of subjects than any individual neuroimaging study has currently collected. ENIGMA’s first project was a genome-wide association study identifying common variants in the genome associated with hippocampal volume or intracranial volume. Continuing work is exploring genetic associations...

Dynamic activity in cis-regulatory elements of leukocytes identifies transcription factor activation and stratifies COVID-19 severity in ICU patients

Tue, 29 Sep 2026 00:00:00 +0000

Transcription factor programs mediating the immune response to coronavirus disease 2019 (COVID-19) are not fully understood. Capturing active transcription initiation from cis-regulatory elements such as enhancers and promoters by capped small RNA sequencing (csRNA-seq), in contrast to capturing steady-state transcripts by conventional RNA-seq, allows unbiased identification of the underlying transcription factor activity and regulatory pathways. Here, we profile transcription initiation in critically ill COVID-19 patients, identifying transcription factor motifs that correlate with clinical lung injury and disease severity. Unbiased clustering reveals distinct subsets of cis-regulatory elements that delineate the cell type, pathway-specific, and combinatorial transcription factor activity. We find evidence of critical roles of regulatory networks, showing that STAT/BCL6 and E2F/MYB regulatory programs from myeloid cell populations are activated in patients with poor disease outcomes...

The all-time maximum for branching Brownian motion with absorption conditioned on long-time survival

Sun, 27 Sep 2026 00:00:00 +0000

Nous considérons un mouvement brownien branchant dans lequel il y a initialement une particule à x, les particules produisent un nombre aléatoire de descendants avec une moyenne de m+1 au moment des événements de ramification, et chaque particule branche au taux β=1/2m. Les particules se déplacent indépendamment selon des mouvements browniens avec une dérive de −1 et sont tuées à l’origine. Il est bien connu que ce processus finit par s’éteindre avec une probabilité positive. Nous conditionnons ce processus à survivre pendant un temps inhabituellement grand t et nous étudions le comportement du processus à de petits temps s≪t en utilisant une décomposition épinale. Nous montrons en particulier que le temps où une particule s’éloigne le plus de l’origine est de l’ordre de t5/6.

A Gaussian particle distribution for branching Brownian motion with an inhomogeneous branching rate

Sun, 27 Sep 2026 00:00:00 +0000

A Gaussian particle distribution for branching Brownian motion with an inhomogeneous branching rate

Integrating Context and Emotions: Top-Down Effects of Intent on Mimicry and Contagion

Sun, 27 Sep 2026 00:00:00 +0000

Emotions are always expressed and perceived in context. Context can provide key information about the meaning of the emotional expression, such as cues regarding the expresser's intentions. We examined how contextually inferred intent (Study 1, N = 212) as well as explicitly stated intent (Study 2, N = 229) shape emotion perception (accuracy/bias), interpersonal closeness, emotional contagion, and emotional mimicry. A further goal was to assess whether mimicry and contagion are tightly coupled or can dissociate depending on how the expression is interpreted in context. In Study 1, adolescent avatars expressed happiness or sadness in scenarios wherein the context suggested that the expression was either normative (norm consistent) or nonnormative (norm challenging). In Study 2, videos of adult avatars in wedding/funeral scenes were paired with benevolent versus malicious intent captions that were explicitly normative or nonnormative. Across studies, nonnormative,...

Λ-coalescents arising in a population with dormancy

Sun, 27 Sep 2026 00:00:00 +0000

Consider a population evolving from year to year through three seasons: spring, summer and winter. Every spring starts with N dormant individuals waking up independently of each other according to a given distribution. Once an individual is awake, it starts reproducing at a constant rate. By the end of spring, all individuals are awake and continue reproducing independently as Yule processes during the whole summer. In the winter, N individuals chosen uniformly at random go to sleep until the next spring, and the other individuals die. We show that because an individual that wakes up unusually early can have a large number of surviving descendants, for some choices of model parameters the genealogy of the population will be described by a Λ-coalescent. In particular, the beta coalescent can describe the genealogy when the rate at which individuals wake up increases exponentially over time. We also characterize the set of all Λ-coalescents that can arise in this framework.

RoboTALES: Learning Reasoning-Guided Robot Policies via Task-Aligned Simulated Futures

Sat, 26 Sep 2026 00:00:00 +0000

Pretrained video generative models are promising backbones for visuomotor control, but their imagined futures often drift from task intent and are not reliably action-conditional. As a result, these models can be difficult to use for planning or policy extraction. To address these limitations, we propose RoboTALES, a single-stage framework that learns task-aligned simulated futures and uses them to train robot policies. Our approach introduces two key innovations: (1) a hierarchical LLM-based planner that breaks complex tasks into a sequence of subgoals to guide the model’s imagination; and (2) a VLM-based critic that evaluates these “imagined” futures and uses reward-based feedback to keep the model’s internal representations focused on the goal. By anchoring the video generator in abstract reasoning, we produce temporally consistent rollouts and more coherent actions. We evaluate RoboTALES on diverse manipulation tasks from RoboCasa and LIBERO10, and show that our method consistently...

MultiVirusConsensus: An accurate and efficient open-source pipeline for identification and consensus sequence generation of multiple viruses from mixed samples

Thu, 24 Sep 2026 00:00:00 +0000

Abstract Motivation Viral surveillance from mixed samples (e.g. wastewater) has become critical in public health efforts to track and contain pathogens. However, existing open-source bioinformatics tools for viral consensus sequence generation are optimized for individual viruses (rather than multiple potential viruses of interest). Results MultiVirusConsensus (MVC) is an accurate and efficient open-source pipeline for identification and consensus sequence generation of multiple viruses from mixed samples. It utilizes the memory-efficient ViralConsensus tool to simultaneously perform consensus sequence calling on all viruses of interest (1) completely in parallel, and (2) by piping datastreams between tools without writing/reading intermediate files (thus eliminating slowdowns related to slow disk accesses). Availability MultiVirusConsensus (MVC) is freely available as an open-source software project at: https://github.com/niemasd/MultiVirusConsensus Supplementary information...

Longitudinal Metabolic Trajectories in Diabetes Prevention Program Participants Reveal Subgroups With Varying Micro- and Macrovascular Complication Risks.

Thu, 24 Sep 2026 00:00:00 +0000

OBJECTIVE: Type 2 diabetes (T2D) and its associated complications develop heterogeneously over decades, but few studies span the progression from prediabetes to clinical events. We investigated whether long-term metabolic trajectories beginning in prediabetes delineate subgroups with differential complication risk. RESEARCH DESIGN AND METHODS: Clinical data from 1,732 Diabetes Prevention Program/Outcomes Study participants (follow-up 19 years) were analyzed across 12 phenotypes. Tensor decomposition was used to capture longitudinal patterns, and Gaussian mixture modeling was used to define longitudinal clusters. Cluster-specific complications were quantified with Cox and logistic regression. RESULTS: Four clusters emerged. Clusters 1 and 2 (73% of participants) maintained stable glycemia, blood pressure, and lipids. Although 49% and 71%, respectively, developed T2D, cumulative micro- and macrovascular events remained low. Cluster 3 (12%) showed the steepest rise in insulin resistance...

QPL-enabled HTSlib library: accelerating sequence file compression using Intel IAA

Thu, 24 Sep 2026 00:00:00 +0000

Summary: Sequence analysis workflows require the accessibility of large datasets, which require state-of-the-art compression tools. These compression tools, such as Samtools, often rely on HTSlib as a GZip implementation, but are still limited by throughput on time-intensive compression. QPL-HTSLib offers order of magnitude speedups for the compression and decompression of the SAM and BAM file formats commonly used in genomics workflows at the cost of a slightly larger compressed file, and is a drop-in replacement for HTSlib on Intel systems. Availability and implementation: QPL-HTSLib is freely available on Github as an open-source software project.

MED-DSLC: Multi-expert-Domain Classification via Domain Supervision and Logit Calibration

Thu, 24 Sep 2026 00:00:00 +0000

Vision-language models (VLMs) such as CLIP enable zero-shot classification by comparing image features with text prompts in a shared embedding space. A fundamental property underlying this capability is the global comparability of logits across arbitrary candidate classes. However, VLMs are often adapted to fine-grained domains using techniques such as LoRA. While this improves in-domain accuracy, out-of-domain accuracy degrades. This leads to a higly fragmented model ecosystem, with thousands of specialized models. Multi-Expert-Domain (MED) classification seeks to address this problem, by merging LoRAs trained independently on specialized domains. However, due to the independent training, the various domain experts no longer produce globally calibrated logits. As a result, when evaluating over the union of multiple domain-specific class sets, heterogeneous logit scales induce cross-domain interference and artificially high confidence for out-of-domain classes, inducing prediction...

Adapting Research Protocols During War: The ANCHOR (Analysis of Network Composition, Health Outcomes, and Resilience) Study

Thu, 24 Sep 2026 00:00:00 +0000

BackgroundConducting longitudinal infectious disease research during armed conflicts is important for understanding transmission dynamics and preventing outbreaks. War in Ukraine started in 2014, with the escalation to full-scale invasion in 2022, resulting in massive population displacement, infrastructure destruction, mobility restriction for men, and reduced access to healthcare. The ANCHOR (Analysis of Network Composition, Health Outcomes, and Resilience) study, launched in November 2024, examines how war- and displacement-driven changes affect social networks, HIV risks, and HIV care engagement. Here, we report implementation challenges and adaptations as practical lessons that may inform infectious disease surveillance and research in conflict settings.MethodsANCHOR is a cohort study conducted in Kyiv and Lviv in 2024–2026 that enrolled sexual minority men (SMM) using respondent-driven sampling, with 6- and 12-month follow up of participants testing positive for HIV. Data...

Assessment of Site Response and Building Damage Following the Mw 6.4 Copiapó Earthquake

Thu, 24 Sep 2026 00:00:00 +0000

On June 6, 2025, an inslab earthquake of Mw 6.4 occurred in the north‐central region of Chile, near the city of Copiapó, within the Atacama seismic gap. Despite its moderate magnitude, the event produced strong ground motions with recorded accelerations exceeding 0.4 g and widespread nonstructural damage. Due to these unusual consequences, we conducted a multidisciplinary field study, collecting in situ data, which provides an opportunity to characterize both local site conditions and structural behavior in a mature seismic gap region. Shallow shear‐wave velocity profiles and predominant site periods were derived from ambient‐vibration measurements to evaluate site amplification effects in Copiapó. Damage surveys revealed widespread nonstructural damage in designated evacuation zones, significantly impacting the functionality of numerous facilities. Finally, using ambient‐vibration measurements, we estimated the structural properties of nine buildings (five damaged and four undamaged)...

The use of acoustic doppler current profiler acoustic backscatter to develop a regional zooplankton indicator for temperate marine ecosystems

Thu, 24 Sep 2026 00:00:00 +0000

Zooplankton are important prey in ocean food webs, linking primary producers to higher trophic levels; understanding their biomass is important to understanding ecosystem state and managing commercial fisheries accordingly. Due to expense and necessary processing time, there are limited indicators of zooplankton that can be produced timely enough to be useful for real-time management needs. We analyzed and compared an 18-year dataset of zooplankton biomass of 21 different species/taxa groups from net samples and acoustic backscatter from Acoustic Doppler Current Profilers (ADCPs) deployed on underwater gliders in the California Current System. Results show positive linear relationships across multiple spatial and temporal scales with greater than 50% of the variance of the total zooplankton biomass explained by the acoustic backscatter when samples were collected within 24 h and 1 km of each other. Copepod species usually dominated the total net haul biomass and there...

Premature Battery Depletion of an Insertable Cardiac Monitor: A Two-Patient Case Series

Thu, 24 Sep 2026 00:00:00 +0000

Premature Battery Depletion of an Insertable Cardiac Monitor: A Two-Patient Case Series

Eating Disorders and Parkinson's Disease—2: Genetic Epidemiology and Shared Genomics

Thu, 24 Sep 2026 00:00:00 +0000

OBJECTIVE: Individuals with anorexia nervosa (AN) share premorbid traits with Parkinson's Disease (PD) (e.g., anxiety) and exhibit a two-fold relative risk of a reported family history of PD. Published estimates of intra- and inter-disorder genetic architecture were extracted and compared prior to conducting novel analyses to provide evidence for cross-disorder genetic risk. METHODS: National register or meta-analytic familial, twin, and common variant genome-wide studies were searched; estimates and findings were extracted and compared. Novel cross-disorder conditional and conjunctional false discovery rate analyses were performed. RESULTS: Sibling relative risks and additive genetic estimates of the two disorders were similar. AN had greater common variant heritability than PD whether measured via infinitesimal model (linkage disequilibrium score regression, LDSC) or causal mixture model (MiXeR). AN had greater polygenicity than PD (mean (SD) 2.50E-03 (1.64E-04) versus...

Harnessing the mental imprints of climate change for collective climate action

Thu, 24 Sep 2026 00:00:00 +0000

Harnessing the mental imprints of climate change for collective climate action

Seventy Seconds of Asystole Delayed Atrioventricular Block Post-TAVR From His-Bundle Injury and Phase 4 Block

Thu, 24 Sep 2026 00:00:00 +0000

BACKGROUND: Conduction system disturbance is a leading complication of transcatheter aortic valve replacement (TAVR). Conventional predictors of post-TAVR pacing include preexisting right bundle branch block, new left bundle branch block, and annular calcification. CASE SUMMARY: A 71-year-old woman with severe aortic stenosis and left bundle branch block (PR: 160 ms, QRS: 138 ms) underwent TAVR. The QRS paradoxically narrowed postprocedure (104 ms), and inpatient telemetry showed no high-grade atrioventricular block before discharge. Five days later, an outpatient real-time monitor captured 71 seconds of asystole due to complete heart block. She presented with syncope and underwent pacemaker implantation. DISCUSSION: The paradoxical QRS narrowing reflects His-bundle injury producing a proximal conduction delay in the His bundle, with recovery of conduction in the left bundle branch indicative of gap phenomenon. The recovery of conduction in the left bundle also highlights the...

The Spatiotemporal Evolution of Creep on the Southern San Andreas Fault Between 2015–2021

Thu, 24 Sep 2026 00:00:00 +0000

Abstract The Southern San Andreas fault (SSAF) in the Coachella Valley experiences shallow creep and slow slip events (SSE), which re‐distribute stresses in the seismogenic zone and affect the potential of future earthquakes. Although average creep rates are relatively well‐constrained, untangling the details of spatiotemporal variation in creep along the SSAF has been challenging due to limited data coverage. In this study, we use 7 years of Interferometric Synthetic Aperture Radar data from the dense Sentinel‐1 catalog to image and model the evolution of shallow creep along the SSAF. We generate time series of fault parallel displacements and isolate the signal associated with shallow creep. We apply a network inversion filter approach to invert the surface displacements for the full slip history on the shallow creeping part of the SSAF and simultaneously characterize model uncertainties. Although some quasi‐steady creep may have been occurring at the southern end of the...

Reflecting Process Expertise in Procedural Material Generation

Thu, 24 Sep 2026 00:00:00 +0000

Procedural material creation underpins applications in digital content creation, visual effects, and 3D asset design. Achieving high-quality results requires more than reproducing node graphs—it demands understanding the process by which experts construct materials. We formulate procedural material generation as retrieval-time process reasoning over expert demonstrations, elevating process to a first-class representation beyond graph-only synthesis. Concretely, we represent expert workflows as process traces: textual records of construction steps, parameters, and design intent. To instantiate this idea, we use a pretrained LLM-based ProcessSynthesizer to synthesize a process trace aligned with a user’s intent and a pretrained LLM-based Compiler to ground the process trace into an executable Blender material graph. Because procedural expertise is most naturally conveyed through demonstrations, we leverage tutorial videos as a source of process knowledge and extract textual, LLM-compatible...

3D epigenome of glial cell types in developing human cortex

Thu, 24 Sep 2026 00:00:00 +0000

The human cortex is complex and heterogeneous, undergoing extensive expansion during development1,2. Our prior study of neurogenesis, including radial glia (RG), intermediate progenitor cells, excitatory neurons and interneurons demonstrated that chromatin looping underlies transcriptional regulation for lineage-specific genes, shedding light on how non-coding genetic variants contribute to neuropsychiatric disorders by means of cell-type-specific gene regulation3. RG have a crucial role in generating cellular diversity through both neurogenesis and gliogenesis and can be further classified into ventricular RG (vRG) and outer RG (oRG)4,5. Given their significance in cortical development, we conducted a comprehensive three-dimensional (3D) epigenomic analysis of four main glial populations, including vRG, oRG, oligodendrocyte precursor cells and microglia, from the mid-gestational human neocortex. By integrating gene expression, chromatin accessibility, DNA methylation and...

Adapting Diffusion Models for Improved Prompt Compliance and Controllable Image Synthesis

Thu, 24 Sep 2026 00:00:00 +0000

Adapting Diffusion Models for Improved Prompt Compliance and Controllable Image Synthesis

The North Balearic Front as an ecological boundary: zooplankton fine-scale distribution patterns in late spring

Thu, 24 Sep 2026 00:00:00 +0000

Abstract. Observations, models and theory have suggested that ocean fronts are ecological hotspots, generally associated with higher diversity and biomass across many trophic levels. Nutrient injections are often associated with higher chlorophyll concentrations at fronts, but the response of the zooplankton community is still insufficiently understood. The present study investigates mesozooplankton stocks and composition during late spring, northeast of Menorca, along two north-south transects that crossed the North Balearic Front separating central waters of the Northwestern Mediterranean Sea gyre from peripheral waters originating from the Algerian basin. During the BioSWOT-Med campaign, vertical triple-net tows with 200 and 500 µm meshes were carried out at three depths (100, 200, and 400 m), and the samples were processed with ZooScan to classify organisms into eight taxonomic groups. Zooplankton distributions were analyzed for the surface layer (0–100 m), a mid-depth layer...

Optimizing adolescent brain development

Thu, 24 Sep 2026 00:00:00 +0000

Optimizing adolescent brain development

Kernel-SDF: An Open-Source Library for Real-Time Signed Distance Function Estimation using Kernel Regression

Thu, 24 Sep 2026 00:00:00 +0000

Accurate and efficient scene representation is crucial for robotic tasks such as motion planning, manipulation, and navigation. Signed distance functions (SDFs) have emerged as a powerful representation for encoding distance to obstacle boundaries, enabling efficient collision-checking and trajectory optimization. However, existing methods are limited for large-scale uncertainty-aware SDF estimation from streaming sensor data: voxel-based approaches have fixed resolution and lack uncertainty quantification, neural network methods require significant training time, and Gaussian process (GP) methods struggle with scalability, sign estimation, and uncertainty calibration. In this letter, we develop an open-source library, Kernel-SDF, using kernel regression to learn SDF with calibrated uncertainty in real-time. It combines a front-end learning a continuous occupancy field via kernel regression with a back-end that estimates accurate SDF via GP regression using samples from the front-end...

Judicial Opinions 133 and 134

Mon, 21 Sep 2026 00:00:00 +0000

Opinion 133 addresses the unusual situation of two genus names that are homonyms and are also considered heterotypic synonyms. Furthermore, it clarifies the meaning of the term 'homonym' in the International Code of Nomenclature of Prokaryotes, as well as the implications of the absence of the term 'isonym' from that code. Isonyms are homotypic synonyms with the same spelling and as such are adequately regulated by the code. The Judicial Commission agrees that the names Methylacidiphilum caldifontis Awala et al. 2023, Methylacidiphilum Awala et al. 2023, Methylacidiphilaceae Awala et al. 2023 and Methylacidiphilales Awala et al. 2023 are illegitimate. The possible actions to resolve this illegitimacy are outlined. The request to conserve Methylacidiphilum Awala et al. 2023 over Methylacidiphilum Ratnadevi et al. 2023 is not granted. However, Methylacidiphilaceae Awala et al. 2023...

Reconceiving merit and devotion at work, with evidence-based illustrations from academic STEM

Sat, 19 Sep 2026 00:00:00 +0000

This paper draws on research to argue that the cultural schema of work devotion – the cognitive, emotional and moral understanding of work as a calling and an ostensible marker of merit – promises a workplace community and a sense of purpose. These rewards are consistent with the biological propensity for social connections, which can help protect our physical and mental health. However, the benefits of work devotion are not equally available to all socio-demographic groups. Further, the work devotion mandate can feel coercive, justify overwork, deplete engagement with family and community, and lead to moral distress. The paper then considers evidence from the exemplar case of academic STEM to illustrate how small, employee-led changes in the workplace, framed as consistent with professional values of merit and devotion, could allow workers to benefit more equally from the work devotion schema while also mitigating some of its detriments.

A PKA-selective inhibitor captures an open but more ordered conformation of the PKA catalytic subunit

Fri, 18 Sep 2026 00:00:00 +0000

The structure of the catalytic subunit of cAMP-dependent protein kinase (PKA-C), a prototype for the protein kinase superfamily, laid the foundation for the development of targeted kinase inhibitors. Here we describe the structure and biophysical characterization of a PKA-C complex with BLU0588, a small PKA-selective inhibitor. The high-resolution crystal structure not only captures the inhibitor's unusual T-shaped geometry, but also shows how the four rings of BLU0588 serve as surrogates for ATP's adenosine and phosphate-organizing sites. Each site contains two subsites. BLU0588's planar azaindole and pyridine rings, which are buried beneath the glycine-rich loop in a hydrophobic shell at the base of the active site cleft, fill the adenine and ribose subsites. In contrast, BLU0588's indane and pyrrolidine rings fill the phosphate-organizing site. The indane ring occupies the α/β-phosphate organizing site while the pyrrolidine ring fills the Mg/γ-phosphate organizing site. The...

Kidiolects: How children perceive child speech

Mon, 14 Sep 2026 00:00:00 +0000

A longstanding assumption is that children acquire language mainly from adult models, but newer research suggests this cannot be correct. Children experience a great deal of child speech as well, particularly across a broader sample of cultures. They enjoy listening to child speech. They can comprehend and learn from child speech. This chapter discusses acoustic properties unique to child speech; argues for its prevalence and importance as an input source to other children; outlines an account that children recognize speech contingent on the speaker’s age and identity; and discusses some outstanding questions about children’s comprehension of and learning from child speech. The goal is to convince readers that there is an enormous gap in our knowledge of a major component of children’s language input, which shapes both child comprehension and production.

Muscle as Method

Sat, 12 Sep 2026 00:00:00 +0000

Muscle as Method

Building bioorthogonal click-release capable artificial receptors on cancer cell surface for imaging, drug targeting and delivery.

Fri, 11 Sep 2026 00:00:00 +0000

The current targeting drug delivery mainly relies on cancer cell surface receptors. However, in many cases, binding affinities between protein receptors and homing ligands is relatively low and the expression level between cancer and normal cells is not significant. Distinct from conventional targeting strategies, we have developed a general cancer targeting platform by building artificial receptor on cancer cell surface via a chemical remodeling of cell surface glycans. A new tetrazine (Tz) functionalized chemical receptor has been designed and efficiently installed on cancer cell surface as overexpressed biomarker through a metabolic glycan engineering. Different from the reported bioconjugation for drug targeting, the tetrazine labeled cancer cells not only locally activate TCO-caged prodrugs but also release active drugs via the unique bioorthogonal Tz-TCO click-release reaction. The studies have demonstrated that the new drug targeting strategy enables local...

The effects of transcranial random noise stimulation on excitation/inhibition balance in ADHD.

Fri, 11 Sep 2026 00:00:00 +0000

Background

Children with attention-deficit/hyperactivity disorder (ADHD) often show aberrant neural activity, including excitation/inhibition (E/I) imbalances, atypical event-related potentials (ERPs), and neural network dysfunction. Transcranial Random Noise Stimulation (tRNS) has shown promise in modulating neural activity in ADHD.

Methods

The current study examined differences in behavioral and EEG signals recorded during an inhibitory control task in children with (N = 23) and without (N = 33) ADHD. Changes in these signals were further assessed following a combined tRNS and cognitive training intervention targeting the right inferior frontal gyrus and left dorsolateral prefrontal cortex in a sham-controlled randomized trial within the ADHD group only (n = 11 and 12 for intervention and sham groups, respectively).

Results

At baseline, children with ADHD showed slower reaction times, and higher commission error rates compared...

What Dose of Methamphetamine Do Regular Consumers Use Daily? Estimating Oral Amphetamine Milligram Equivalents

Fri, 11 Sep 2026 00:00:00 +0000

OBJECTIVES: The purity, accessibility, and affordability of illicit methamphetamine have increased in recent decades, which has been linked to rising rates of methamphetamine-involved overdoses, psychosis, cardiovascular events, and other health consequences. Nevertheless, information about the quantity of methamphetamine used by regular consumers has been limited, despite the potential clinical utility of exposure quantification. METHODS: From August 2024 to April 2026, self-reported daily methamphetamine consumption was assessed among n = 94 individuals in Los Angeles County. Methamphetamine samples (n = 256) were analyzed for purity using liquid chromatography-mass spectrometry. Bioavailability by route of administration and stimulant equivalency were obtained from the literature. A simulation model leveraging bootstrapping with 1,000,000 draws was used to estimate oral amphetamine milligram equivalents (AME). RESULTS: The average reported methamphetamine consumption was 1.09...

Efficacy and Safety of Naloxegol in Patients with Chronic Non-Cancer Pain Who Experience Opioid-Induced Constipation: A Pooled Analysis of Two Global, Randomized Controlled Studies

Fri, 11 Sep 2026 00:00:00 +0000

Objective: This study evaluates the onset, magnitude, and consistency of improvement of opioid-induced constipation (OIC) symptoms with naloxegol treatment. Methods: This was a pooled analysis of two Phase 3, double-blind, randomized, placebo-controlled studies (KODIAC-04/05, NCT01309841/NCT01323790) in patients with chronic non-cancer pain and OIC treated with naloxegol 25mg or 12.5mg daily. This analysis assessed improvements in response rates, frequency of spontaneous bowel movement (SBM) and complete SBMs (CSBM), OIC constipation symptoms (straining, stool consistency), time to first post-dose SBM and CSBM, and onset of adverse events over the 12-week period. Subjects: The population of 1337 subjects had a mean age of 52 years and mean duration of opioid use of 3.6 years at baseline. Mean SBM frequency was 1.4/week. Results: Naloxegol 25mg and 12.5mg demonstrated significantly higher response rates vs placebo (PBO) [41.9% (P < 0.001), 37.8% (P = 0.008), 29.4% respectively]....

Reproductive Futures in Focus: Contraceptive Choices Among Individuals With Cystic Fibrosis-Patterns, Preferences, and Influencing Factors.

Fri, 11 Sep 2026 00:00:00 +0000

Introduction

Advancements in the care of people with cystic fibrosis (PwCF) have made discussions about reproductive health increasingly important. Rising rates of both intended and unintended pregnancies highlight the need for effective contraception counseling. Understanding current contraception use patterns and identifying priorities for contraception education amongst PwCF are therefore essential.

Methods

A web-based survey was developed in partnership with Community Voice, a virtual community of PwCF and their family members supported by the Cystic Fibrosis Foundation. The survey was distributed over a 5-week period (June-July 2025) to participants from Community Voice and Elevate. Females with cystic fibrosis aged 18 years and older were eligible to participate.

Results

Ninety-seven PwCF completed the survey, representing 27 U.S. states and four Canadian provinces. Among individuals currently using contraception, the most common methods were intrauterine...

Corrigendum to: Topical analgesics for neuropathic pain: an evidence-informed guide for the practicing clinician

Fri, 11 Sep 2026 00:00:00 +0000

Corrigendum to: Topical analgesics for neuropathic pain: an evidence-informed guide for the practicing clinician

Update on Treating Painful Diabetic Peripheral Neuropathy: A Review of Current US Guidelines with a Focus on the Most Recently Approved Management Options

Fri, 11 Sep 2026 00:00:00 +0000

Painful diabetic peripheral neuropathy (DPN) is a highly prevalent and disabling complication of diabetes that is often misdiagnosed and undertreated. The management of painful DPN involves treating its underlying cause via lifestyle modifications and intensive glucose control, targeting its pathogenesis, and providing symptomatic pain relief, thereby improving patient function and health-related quality of life. Four pharmacologic options are currently approved by the US Food and Drug Administration (FDA) to treat painful DPN. These include three oral medications (duloxetine, pregabalin, and tapentadol extended release) and one topical agent (capsaicin 8% topical system). More recently, the FDA approved several spinal cord stimulation (SCS) devices to treat refractory painful DPN. Although not FDA-approved specifically to treat painful DPN, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, gabapentinoids, and sodium channel blockers are common first-line...

S497 Naloxegol Accelerates Time to First Spontaneous Bowel Movement (SBM) and Complete SBM (CSBM) With Predictable Efficacy in Patients With Extreme Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Phase 3 Trials

Fri, 11 Sep 2026 00:00:00 +0000

S497 Naloxegol Accelerates Time to First Spontaneous Bowel Movement (SBM) and Complete SBM (CSBM) With Predictable Efficacy in Patients With Extreme Opioid-Induced Constipation (OIC): A Pooled Analysis of Two Phase 3 Trials

Combining photoredox catalysis and hydrogen atom transfer for dearomative functionalization of electron rich heteroarenes.

Fri, 11 Sep 2026 00:00:00 +0000

Reductive dearomatization has been a broadly explored means for rapid generation of sp³ complexity from simple planar arenes. Breaking the electron rich, stable aromatic systems requires strong reduction conditions. It has been notoriously challenging to dearomatize electron even richer heteroarenes. Herein we report an umpolung strategy enabling dearomatization of such structures under mild conditions. The reversal of the reactivity of these electron rich aromatics via photoredox mediated single electron transfer (SET) oxidation generates electrophilic radical cations, which can react with nucleophiles and break the aromatic structure to form a Birch type radical species. A crucial hydrogen atom transfer (HAT) is successfully engineered into the process to efficiently trap the dearomatic radical and minimize the formation of the overwhelmingly favorable, irreversible aromatization products. Particularly, a non-canonical dearomative ring-cleavage of thiophene/furan...

Frontline Perspectives on Buprenorphine for the Management of Chronic Pain

Fri, 11 Sep 2026 00:00:00 +0000

Due to the prevalence of chronic pain and high-impact chronic pain in the US, a significant percentage of the population is prescribed opioids for pain management. However, opioid use disorder is associated with reduced quality of life, along with fatal opioid overdoses, and is a significant burden on the US economy. Considering the clinical needs of patients with intractable chronic pain and the potential harms associated with prescribed and illicit opioids in our communities, having a deep understanding of current treatment options, supporting evidence, and clinical practice guidelines is essential for optimizing treatment selections. Buprenorphine is a Schedule III opioid with a unique mechanism of action, allowing effective and long-lasting analgesia at microgram doses with fewer negative side effects and adverse events, including respiratory depression, when compared with other immediate-release, long-acting, and extended-release prescription opioids. Due to its relatively...

Multimodal Therapies for the Treatment of Neuropathic Pain: The Role of Lidocaine Patches in Combination Therapy: A Narrative Review

Fri, 11 Sep 2026 00:00:00 +0000

Neuropathic pain (NP) has a population presence of up to 10%. Both systemic agents and topical agents are recommended as first-line therapy for the treatment of NP but monotherapy provides adequate pain relief only in < 50% of the cases. This has created the need for multimodal combination therapy, a practice that is becoming more common. Combination therapy with multiple systemic agents has a risk for drug–drug interactions and adverse events (AEs), while add-on therapy with a topical agent such as lidocaine patches minimizes such risks. The focus of this review was to find if there is evidence from trials that combination therapy of the topical lidocaine patches with systemic agents will have better efficacy and/or less risk of AEs than the combination of two systemic agents. Since gabapentinoids are one of the most common systemic agents used in first-line NP therapy, the objective of this review was to summarize the safety and efficacy data and evaluate the benefit–risk...

Genome-wide alignment-free phylogenetic distance estimation under a no strand-bias model.

Fri, 11 Sep 2026 00:00:00 +0000

While alignment has been the dominant approach for determining homology prior to phylogenetic inference, alignment-free methods can simplify the analysis, especially when analyzing genome-wide data. Furthermore, alignment-free methods present the only option for emerging forms of data, such as genome skims, which do not permit assembly. Despite the appeal, alignment-free methods have not been competitive with alignment-based methods in terms of accuracy. One limitation of alignment-free methods is their reliance on simplified models of sequence evolution such as Jukes-Cantor. If we can estimate frequencies of base substitutions in an alignment-free setting, we can compute pairwise distances under more complex models. However, since the strand of DNA sequences is unknown for many forms of genome-wide data, which arguably present the best use case for alignment-free methods, the most complex models that one can use are the so-called no strand-bias models. We show how to calculate...

Founding the Pain Medicine Academy of Advanced Practice Providers

Fri, 11 Sep 2026 00:00:00 +0000

Founding the Pain Medicine Academy of Advanced Practice Providers

Topical analgesics for neuropathic pain: an evidence-informed guide for the practicing clinician

Fri, 11 Sep 2026 00:00:00 +0000

OBJECTIVE: To evaluate available evidence for the efficacy and safety of topical analgesics for neuropathic pain and to offer treatment guidance. METHODS: An expert panel searched PubMed (Medline) and reference lists of published articles for available literature assessing 8 categories of topical analgesics used to treat various neuropathic pain conditions. The panel rated the level of analgesic efficacy evidence for each treatment and considered safety, ease of use, and cost. The degree of consensus on the recommendations among the panelists was measured. RESULTS: There was strong evidence and high consensus that capsaicin 8% is effective for diabetic peripheral neuropathy and postherpetic neuralgia and that lidocaine is effective for postherpetic neuralgia. There was strong evidence and moderate consensus that capsaicin 8% could be effective for HIV-induced neuropathy. There was moderate evidence and high consensus that lidocaine is likely effective for diabetic peripheral neuropathy,...

Naloxegol (Movantik®) Provides Rapid and Sustained Improvement of Opioid-Induced Constipation Symptoms Irrespective of Opioid Dose

Fri, 11 Sep 2026 00:00:00 +0000

Aim Naloxegol (Movantik), an oral peripherally acting mu-opioid receptor antagonist has demonstrated rapid relief of opioid-induced constipation (OIC) in patients with chronic non-cancer pain in two phase 3 trials (KODIAC 4/5; NCT01309841/NCT01323790). This analysis aims to characterize the OIC symptom burden and evaluate the efficacy of naloxegol in treating symptoms of OIC based on daily opioid dosages. This is the first naloxegol analysis based on a lower opioid dose cutoff of 100 MEU/day. Methods Data were pooled from the KODIAC 4/5 intent-to-treat populations (N=1337). Subjects treated with placebo (PBO) and naloxegol (12.5mg, 25mg) QD were evaluated based on opioid dose ranges (lower dose, ≤100mg; higher dose, >100mg MEU/day). OIC symptoms assessed include number of spontaneous bowel movements (SBM/wk), complete evacuation (CSBM), straining (scale 1=not at all, 5=extreme) and stool consistency (Bristol Stool Scale: 1=hard, 7=watery). Results Baseline OIC symptom burden...

Characterization of Spirometric Response to Standard-of-care Treatment in Lung Allograft Recipients With Bronchiolitis Obliterans and the Utility of Spirometric Criteria for Rescue Therapy: Implications for the Design of Risk-stratified Clinical Trials

Fri, 11 Sep 2026 00:00:00 +0000

BACKGROUND: The spirometric response to standard-of-care (SOC) immunosuppressive therapy for the management of bronchiolitis obliterans syndrome (BOS) has been sparsely reported in the literature. Data from a Medicare-approved Registry were analyzed to characterize the effectiveness/durability of a wide range of SOC interventions to manage the decline of lung function and to validate the study spirometric criteria for initiation of rescue therapy. METHODS: Lung transplant recipients with refractory BOS at 21 US collaborating centers were enrolled in the Registry. Data included both nonspirometric (eg, demographic, Immunosuppressive Regimens for management of BOS) and spirometric parameters (ie, forced expiratory volume in 1 s [FEV 1 ] measurements and derived indices). The utility of study FEV 1 criteria for treatment (ie, statistically significant rate of FEV 1 decline >30 mL/mo) was evaluated by comparing the spirometric course between participants who met or did not meet...

Rational Urine Drug Monitoring in Patients Receiving Opioids for Chronic Pain: Consensus Recommendations

Fri, 11 Sep 2026 00:00:00 +0000

Objective: To develop consensus recommendations on urine drug monitoring (UDM) in patients with chronic pain who are prescribed opioids. Methods: An interdisciplinary group of clinicians with expertise in pain, substance use disorders, and primary care conducted virtual meetings to review relevant literature and existing guidelines and share their clinical experience in UDM before reaching consensus recommendations. Results: Definitive (e.g., chromatography-based) testing is recommended as most clinically appropriate for UDM because of its accuracy; however, institutional or payer policies may require initial use of presumptive testing (i.e., immunoassay). The rational choice of substances to analyze for UDM involves considerations that are specific to each patient and related to illicit drug availability. Appropriate opioid risk stratification is based on patient history (especially psychiatric conditions or history of opioid or substance use disorder), prescription drug monitoring...

Can a public information campaign increase trust in American elections?

Fri, 11 Sep 2026 00:00:00 +0000

Confidence in the conduct and results of American elections has declined and polarized along party lines in recent years. Can a nonpartisan public information campaign featuring election officials enhance trust in elections when delivered to skeptical voters during a contentious political contest? We analyze a preregistered, randomized field experiment conducted during the 2024 US presidential election in which conservative voters were randomly assigned to a control condition or to receive a multimodal messaging campaign designed by political professionals explaining protections on election integrity. In contrast to the large positive effects of informational messages found in recent survey experiments, we observed primarily null effects with respect to turnout (n = 147,488), general confidence in elections (n = 4740 to 4868), and perceptions of the frequency of fraud (n = 4925). We observed one hypothesized effect: an increase...

Carboxyhemoglobin and depletion of blood oxygen in sleeping elephant seals

Fri, 11 Sep 2026 00:00:00 +0000

An exceptionally large blood O2 store underlies the remarkable dive performance of elephant seals. However, elevated carboxyhemoglobin (COHb) concentrations in these seals complicate estimations of blood O2 content and O2 depletion rates, and may also affect monitoring of brain oxygenation in seals with new non-invasive near-infrared (NIR) recorders. Using hemoximetry analyses of blood samples during sleep apneas of juvenile northern elephant seals (Mirounga angustirostris), we constructed in vivo Hill plot equations and O2–Hb dissociation curves (ODCs). We found: (a) COHb and methemoglobin (both of which do not bind O2 and increase hemoglobin (Hb) affinity for O2) comprised 8% of Hb, (b) an in vivo P50 (partial pressure of O2 at 50% Hb saturation, an index of O2 affinity of Hb) of 27.1 mm Hg that was Hg 3.4 mm Hg less than that previously determined with an in vitro laboratory approach, and (c) when the in vivo and in vitro Hill plot equations were applied to arterial,...

Intrathecal pain management: a team-based approach

Fri, 11 Sep 2026 00:00:00 +0000

OBJECTIVE: Physician assistants (PAs), nurse practitioners (NPs), and registered nurses (RNs) provide professional services on pain management teams. This review provides an overview of the practical management of chronic pain with intrathecal (IT) therapy using an interprofessional approach (eg, physicians and other health care professionals), with a focus on the contributions of PAs, NPs, and RNs. METHODS: Narrative review based on literature searches of the Medline database and treatment guidelines on the use of IT therapy in the management of patients with chronic pain. RESULTS: The specific roles and responsibilities of PAs, NPs, and RNs in the management of patients receiving IT therapy vary by practice. In many pain treatment centers, PAs, NPs, and RNs are responsible for patient education, postimplant maintenance, and ongoing supportive care of patients receiving IT therapy. Topics that we address include patient selection, patient expectations and goal setting, medication...

A rare case report of decompensated cirrhosis from hereditary hemochromatosis following lung transplant in a person with cystic fibrosis

Fri, 11 Sep 2026 00:00:00 +0000

A 33-year-old woman with cystic fibrosis following bilateral sequential cadaveric lung transplantation experienced prolonged intermittent liver enzyme elevation. An abdominal ultrasound revealed increased hepatic echogenicity and cirrhotic features, warranting further investigation with iron studies and liver biopsy, which confirmed hereditary hemochromatosis. This rare case underscores the importance of considering hereditary hemochromatosis post lung transplantation irrespective of not receiving multiple blood products or iron replacement.

An overview of abuse-deterrent opioids and recommendations for practical patient care

Fri, 11 Sep 2026 00:00:00 +0000

Despite advances in the treatment of severe intractable pain, opioids remain a critical and appropriate component of treatment. However, abuse, misuse, and diversion of prescription opioids are significant public health concerns. Opioid abuse-deterrent formulations (ADFs) are one component of an opioid risk management plan to manage patient's pain relief and quality of life while offering some protection against potentially harmful consequences of opioids from misuse and abuse. Opioid ADFs are designed to make manipulation more difficult and administration via non-oral routes less appealing. There are currently nine extended-release and one immediate-release opioid pain medications with US Food and Drug Administration-approved ADF labeling. All use physical/chemical barriers or agonist/antagonist combinations to deter manipulation and abuse. Evidence suggests that opioid ADFs decrease rates of abuse and diversion of opioids in the USA; however, some opioid ADFs are not yet commercially...