The focus of this project is assessing the critical connections which may be viewedbetween the musical works of Black artists during the 1970’s and 1980’s which served as thegenesis of the genre of hardcore punk and the foundational theories which created the culturalphenomenon, aesthetic, and critical lens that is Afrofuturism. In doing so, this project highlightsforms of African American speculative thinking and defines Afrofuturism itself through theworks of these musicians. Furthermore, by pulling out these connections, this research begins theprocess of seeing the genre of hardcore punk—its uniquely African American form, sound, andpurpose integral in this—as a necessary strand in Afrofuturism, to be viewed in the larger streamof African American approaches towards speculativity in the 20th century. To achieve this goal,this essay will analyze primarily Jacques Attali’s Noise: The Political Economy of Music, afoundational text of sound studies, in relation to musical works by the bands Bad Brains, PureHell, and Death, among others. Additionally, this research seeks to draw upon a history ofscholarly approaches towards Afrofuturism itself through citing works by authors includingMark Dery, Stuart Hall, Stefano Harvey, and Fred Moten, alongside the necessary perspectives ofscholars and critics working in the proximity of music, including Daphne Brooks and JoséEsteban Muñoz. This research posits the work of these aforementioned musicians alongsidethese authors, providing through its totality a viewpoint into Afrofuturism altogether absent inscholarly works.

Prolonged pulmonary vasoconstriction and vascular remodeling cause idiopathic pulmonary arterial hypertension (IPAH). Pulmonary vasoconstriction is caused by pulmonary artery smooth muscle cell (PASMC) contraction, and enhanced proliferation of PASMC contributes to vascular remodeling. An increase in cytosolic Ca²⁺ concentration ([Ca²⁺ cyt) in PASMC triggers both contraction and proliferation. Inhibition of Ca²⁺ influx completely inhibits prolonged pulmonary vasoconstriction and stops PASMC proliferation. Store-operated Ca²⁺ entry (SOCE) is an important mechanism that mediates Ca²⁺ influx in PASMC and most other cell types. We previously reported that SOCE was significantly enhanced in PASMC exposed to hypoxia and in PASMC from IPAH patients. Stromal interaction molecule (STIM1/2) and Orai proteins (Orai1/2/ 3) were identified recently as essential components that mediate SOCE. We aim to examine whether the expression levels of STIM and Orai are altered in IPAH-PASMC compared to control PASMC, and whether these putative changes in expression level are responsible for the enhanced SOCE and proliferation observed in IPAH-PASMC. The protein expression level of STIM2 was increased in IPAH-PASMC, whereas STIM1 protein expression was decreased. Hypoxia (4% O₂, 5% CO₂, balance N₂) enhanced the protein expression level of STIM2, but not STIM1, in rat PASMC after 48 hours. In IPAH-PASMC knockdown of STIM2 decreased SOCE and proliferation, while knockdown of STIM2 in control PASMC had no effect on either SOCE or proliferation. Overexpression of STIM2 in control PASMC failed to enhance SOCE or proliferation. These data indicate that enhanced protein expression of STIM2 is necessary, but not sufficient, for enhanced SOCE and proliferation of IPAH-PASMC. Orai2 protein expression level was increased in IPAH-PASMC. Orai1 and Orai3 protein expression levels were not statistically significantly altered. Furthermore, 48 hours of hypoxia significantly increased protein expression of Orai1 and Orai2, but not Orai3. Overexpression of Orai2 alone in PASMC did not enhance SOCE. Co-overexpression of both STIM2 and Orai2, however, did augment SOCE in PASMC. In conclusion, upregulated protein expression of STIM2 is necessary, but insufficient, for augmented SOCE and enhanced proliferation in PASMC from IPAH patients. Increased expression of both STIM2 and Orai2 is sufficient to enhance SOCE in normal PASMC

Despite a prevailing view that advances in cancer therapy will come through selective targeting of enzymes encoded by mutated oncogenes responsible for the neoplastic phenotype, recent advances in the treatment of patients with chronic lymphocytic leukemia (CLL) have instead exploited knowledge of its biology. Indeed, CLL cells depend on interactions with cells and soluble factors present in the tumor microenvironment for proliferation and survival. B-cell receptor signaling and chemokine-receptor signaling play prominent roles. Elucidation of these signaling pathways has defined physiologic targets for drugs, such as ibrutinib, which inhibit Bruton tyrosine kinase and are therapeutically effective. The characteristic high-level expression of BCL2 in CLL that can enhance leukemia-cell survival has now become an Achilles heel targeted by clinically effective drugs such as venetoclax. Here we discuss advances in such targeted therapy and highlight other disease attributes, such as the distinctive expression of ROR1, which may be targeted for clinical benefit, alone or in combination with other targeted therapies.

Background: Venetoclax (Ven) is a BCL-2 inhibitor that produces deep responses with high rates of undetectable minimal residual disease (uMRD) for patients (pts) with chronic lymphocytic leukemia (CLL) (Al-Sawaf et al. 2020). Currently, ven is FDA approved as either monotherapy (mono) or in combination (combo) with rituximab (R) In patients with relapsed/refractory (R/R) CLL (Seymour et al. 2018). However, the optimal ven based treatment (tx) for pts with R/R CLL either as mono, or in combo with anti-CD20 monoclonal antibody (mab), or bruton tyrosine kinase inhibitor (BTKi) is uncertain. We performed a single institution retrospective analysis of pts with R/R CLL treated with ven based regimens evaluating efficacy of different ven based txs. Methods: 98 pts with R/R CLL treated between the years of 2012 and 2023 were evaluated. Ven based treatment consisted of ven mono or in combo with R, obinutuzumab (G), or ibrutinib (BTKi) with standard ven dose ramp up to a maximum dose of 400mg daily. R and G were administered per FDA standard dosing. Ibrutinib was administered as 420mg daily, as either fixed or continuous duration tx. Response assessment was performed using iwCLL criteria. Minimal residual disease (MRD) was assessed by multi-parametric peripheral blood flow cytometry with a sensitivity of 10 -4. Time-to-event analyses were performed with the Kaplan-Meier method, with log-rank test used to assess statistically significant differences between variables. Hazard ratios (HR) were calculated by use of Cox proportional modelling. Results: The pts had a median age of 68 years (range; 46-89). Rai stage at time of tx initiation with ven: I 14.2%; II 36.3%; III 8.8%; Stage IV 40.7%. The median number of previous txs was 4 (range; 1-14). Pts harbored the following cytogenetic abnormalities: del(13q) 50.5%; del(11q) 18.5%; trisomy 12 15.5%; normal 15.5%; del(17p)/TP53 mutation 24.7%; and complex in 33%. Seventy percent of pts harbored an unmutated immunoglobulin heavy chain. 25.5% of pts had genomic complexity, with ≥ 5 gene mutations. 43.9% of pts were treated with ven mono; 19.4% were treated with venR; 25.5% of pts were treated with venG; and 11.2% of pts were treated with ven + BTKi. The median number of months of ven based tx was 16.3 (range; 0.9-118.6). 14.3% of pts currently remain on ven. 60.8% of pts had progression after ven based tx; with 62.2% requiring additional tx. 15.3% of pts developed Richter's Transformation. The best overall response for the cohort was: CR 67%; PR 24.5%; SD 1.1%; and PD 7.4%. The best MRD response for the whole cohort was uMRD 76.8%; low MRD 19.5; and high MRD 3.6%. uMRD as best MRD response occurred in 66.7% of ven mono; 82.4% of venR; 86.4% of venG; and 70% of ven + BTKi treated pts. With a median follow-up of 52 months (mo), the median progression-free survival (PFS) for the whole cohort was 67.8 mo. Ven combo had superior PFS to ven mono; median PFS 76.6 vs 58.9 mo (p = 0.04; HR 0.5037; 95% CI 0.2583 - 0.9635). Among the combination treatment approaches, there was a trend for improved PFS for venG compared to ven mono; median PFS not reached (NR) vs 58.9 mo (p = 0.08; HR 0.4385; 95% CI 0.1608 - 1.0240). Similarly, there was also a trend to improved PFS for ven + BTKi compared to ven mono; median PFS NR vs 58.9 mo (p = 0.07; HR 0.2895; 95% CI 0.0462 - 0.9950). Both the presence of del17p/TP53 mutation; and the presence of MRD (+MRD) 12 months after stopping ven based tx were associated with inferior PFS. The median PFS for pts without del17p/TP53 mutation vs with del17p/TP53 mutation was 118 vs 39.7 mo (p < 0.0001; HR 0.2242; 95% CI 0.0533 - 0.8366). Median PFS for pts with uMRD vs +MRD 12 months after ven was NR vs 42.8 mo (p = 0.0001; HR 0.0689; 95% CI 0.0037 - 0.3810). Conclusions : In a high-risk population of pts with R/R CLL, we found that ven based tx leads to durable remissions, with high rates of uMRD. Combo approaches with the addition of either an anti-CD20mab or BTKi led to improved PFS. While venR is the current FDA approved combo regimen for pts with R/R CLL, we found that there was a trend for improved PFS with either venG or ven + BTKi compared to ven mono. Both the presence of a del17p/TP53 mutation and the presence of MRD 12 months after stopping ven based tx significantly adversely affected PFS. However, pts who maintained uMRD 12 months after completing ven, had exceptionally durable long-term remission. This has possible implications for employing MRD adapted txs for pts with CLL.

A characteristic among many marine Gammaproteobacteria is the biosynthesis and incorporation of omega-3 polyunsaturated fatty acids into membrane phospholipids. The biosynthesis of eicosapentaenoic (EPA) and/or docosahexaenoic (DHA) acids is mediated by a polyketide/fatty acid synthase mechanism encoded by a set of five genes, pfaABCDE. This unique fatty acid synthesis pathway co-exists with the principal type II dissociated fatty acid synthesis pathway, which is responsible for the biosynthesis of core saturated, monounsaturated, and hydroxylated fatty acids used in phospholipid and lipid A biosynthesis. In this work, a genetic approach was undertaken to elucidate genetic regulation of the pfa genes in the model marine bacterium Photobacterium profundum SS9. Using a reporter gene fusion, we showed that expression of the pfa operon is down regulated in response to exogenous fatty acids, particularly long chain monounsaturated fatty acids. This regulation occurs independently of the canonical fatty acid regulators, FabR and FadR, present in P. profundum SS9. Transposon mutagenesis and screening of a library of mutants identified a novel transcriptional regulator, which we have designated pfaF, to be responsible for the observed regulation of the pfa operon in P. profundum SS9. Gel mobility shift and DNase I footprinting assays confirmed that PfaF binds the pfaA promoter and identified the PfaF binding site.Importance The production of long-chain omega-3 polyunsaturated fatty acids (PUFA) by marine Gammaproteobacteria, particularly those from deep-sea environments, has been known for decades. These unique fatty acids are produced by a polyketide-type mechanism and subsequently incorporated into the phospholipid membrane. While much research has focused on the biosynthesis genes, their products and the phylogenetic distribution of these gene clusters, no prior studies have detailed the genetic regulation of this pathway. This study describes how this pathway is regulated under various culture conditions and has identified and characterized a fatty acid responsive transcriptional regulator specific to PUFA biosynthesis.

High-throughput Sanger sequencing requires DNA to be inserted into bacterial vectors for biological amplification. Adapter or linker oligonucleotides may also be attached to target DNA fragments to facilitate insertion into the vector. These vector and adapter sequences are sequenced concomitantly with the target, or insert, sequence and represent contamination which must be removed from the dataset prior to analysis. Removal of such contamination can be accomplished by screening the dataset against the known sequence of the vector and adapter used to generate the data. However, often in the case of public or collaborator datasets, information regarding these contaminant sequences may be incorrect or absent, resulting in an incomplete screening.We've created a piece of software, VecFinder, which is able to identify the sequence of the vector and adapter from the read sequences alone and subsequently remove it. This alleviates the dependence on the library creators to provide the vector and adapter sequences used for the library. It also automates the previously manual task of identifying and screening the adapter or linker sequence, which can be tedious and time-consuming

Falciform ligament appendagitis (FLA) is a rare cause of intraperitoneal focal fat infarction (IFFI) characterized by the torsion of a fatty appendage related to the falciform ligament. FLA demonstrates characteristic features on computed tomography (CT), especially the hyperattenuating ring sign. Because of these characteristic features, a diagnosis of FLA can be achieved with CT alone. By recognizing the signs of FLA, radiologists can prevent unnecessary surgical intervention. We report two cases of FLA with associated images to assist radiologists in diagnosing this rare entity.

Many bacteria and archaea rely on chemotaxis signal transduction systems for optimal fitness. These complex, multiprotein signaling systems have core components found in all chemotactic microbes, as well as variable proteins found in only some species. We do not yet understand why these variations exist or whether there are specific niches that favor particular chemotaxis signaling organization. One variation is in the presence/absence of the chemotaxis methylation adaptation enzymes CheB and CheR. Genes for CheB and CheR are missing in the gastric pathogen Helicobacter pylori but present in related Helicobacter that colonize the liver or intestine. In this work, we asked whether there was a general pattern of CheB/CheR across multiple Helicobacter species. Helicobacter spp. all possess chemotactic behavior, based on the presence of genes for core signaling proteins CheA, CheW, and chemoreceptors. Genes for the CheB and CheR proteins, in contrast, were variably present. Niche mapping supported the idea that these genes were present in enterohepatic Helicobacter species and absent in gastric ones. We then analyzed whether there were differences between gastric and enterohepatic species in the CheB/CheR chemoreceptor target methylation sites. Indeed, these sites were less conserved in gastric species that lack CheB/CheR. Lastly, we determined that cheB and cheR could serve as markers to indicate whether an unknown Helicobacter species was of enterohepatic or gastric origin. Overall, these findings suggest the interesting idea that methylation-based adaptation is not required in specific environments, particularly the stomach. IMPORTANCE Chemotaxis signal transduction systems are common in the archaeal and bacterial world, but not all systems contain the same components. The rationale for this system variation remains unknown. In this report, comparative genomics analysis showed that the presence/absence of CheR and CheB is one main variation within the Helicobacter genus, and it is strongly associated with the niche of Helicobacter species: gastric Helicobacter species, which infect animal stomachs, have lost their CheB and CheR, while enterohepatic Helicobacter species, which infect the liver and intestine, retain them. This study not only provides an example that a chemotaxis system variant is associated with particular niches but also proposes that CheB and CheR are new markers distinguishing gastric from enterohepatic Helicobacter species.