UC San Diego

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Aberration of the "gut-liver axis" contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.

Authorship and dissemination policies vary across NIH research consortia. We aimed to describe elements of real-life policies in use by eligible U01 clinical research consortia. Principal investigators of eligible, active U01 clinical research projects identified in the NIH Research Portfolio Online Reporting Tools database shared relevant policies. The characteristics of key policy elements, determined a priori, were reviewed and quantified, when appropriate. Twenty one of 81 research projects met search criteria and provided policies. K elements (e.g., in quotations): manuscript proposals reviewed and approved by committee (90%); guidelines for acknowledgements (86%); writing team formation (71%); process for final manuscript review and approval (71%), responsibilities for lead author (67%), guidelines for other types of publications (67%); draft manuscript review and approval (62%); recommendation for number of members per consortium site (57%); and requirement to identify individual contributions in the manuscript (19%). Authorship/dissemination policies for large team science research projects are highly variable. Creation of an NIH policies repository and accompanying toolkit with model language and recommended key elements could improve comprehensiveness, ethical integrity, and efficiency in team science work while reducing burden and cost on newly funded consortia and directing time and resources to scientific endeavors.

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Schizophrenia and bipolar disorder are associated with cognitive deficits that contribute significantly to disability. However, traditional in-lab cognitive assessments are time-consuming and not optimized for remote administration. Recent advancements in smartphone technology enable momentary cognitive assessments in a real-world context. This brief report reviews recent research in momentary cognitive assessments in individuals with schizophrenia and bipolar disorder through reviewing mobile platforms and cognitive assessments studied. A total of 14 experimental articles were reviewed, focusing on cognitive domains including visual working memory, processing speed, executive function, verbal fluency, verbal memory, social cognition, and typing patterns. The review highlights the feasibility of remote cognitive assessment with smartphones, and provides a layout of domains studied in this context, but illustrates a low volume of current research, the need for additional studies, and the potential for innovations like digital phenotyping.

OBJECTIVES: Tai Chi (TC) shows some beneficial effects in reducing pain in knee osteoarthritis (OA). However, the selection of criteria TC forms in previous studies were unclear and inconsistent, possibly accounting for the varying outcomes and rendering the training effects suboptimal. We have selected four optimal TC (OTC) forms based on the knee joint load and its association with pain. This pilot study sought to examine the effect of the OTC forms on reducing knee pain in individuals with knee OA. METHODS: Fifteen knee OA participants were recruited. Their knee joint pain level was rated by using the Visual Analogue Scale before and after two weeks of OTC training and compared between these two assessments. RESULTS: The two-week OTC training course was well accepted by our participants. The knee OA pain showed a significant reduction (median pain score: 5 ​cm before training and 1 ​cm post-training, Wilcoxon p ​< ​0.001) after the two-week training program. CONCLUSIONS: Our pilot results revealed that the 2-week four-form-based OTC program could significantly reduce the knee pain level in people with knee OA. Additionally, our OTC program appears to be about 50% more effective in reducing knee pain than the existing TC-based program, which uses 10 ​TC forms over 12 weeks (1.59 vs. 1.06 in Hedges g). The findings in this study may inform the development of OTC-based knee pain reduction programs and the design of relevant clinical trials to establish OTCs effectiveness, safety, and dose-response relationship in easing knee OA pain.

Protein translation initiation is a conserved process involving many proteins acting in concert. The 13 subunit eukaryotic initiation factor 3 (eIF3) complex is essential for assembly of the pre-initiation complex that scans mRNA and positions ribosome at the initiation codon. We previously reported that a gain-of-function (gf) mutation affecting the G subunit of the Caenorhabditis elegans eIF3 complex, eif-3.g(gf), selectively modulates protein translation in the ventral cord cholinergic motor neurons. Here, through unbiased genetic suppressor screening, we identified that the gene lin-66 mediates eif-3.g(gf)-dependent protein translation in motor neurons. LIN-66 is composed largely of low-complexity amino acid sequences with unknown functional domains. We combined bioinformatics analysis with in vivo functional dissection and identified a cold-shock domain in LIN-66 critical for its function. In cholinergic motor neurons, LIN-66 shows a close association with EIF-3.G in the cytoplasm. The low-complexity amino acid sequences of LIN-66 modulate its subcellular pattern. As cold-shock domains function broadly in RNA regulation, we propose that LIN-66 mediates stimulus-dependent protein translation by facilitating the interaction of mRNAs with EIF-3.G.

Pathogenic and likely pathogenic variants in the TECRL gene are known to be associated with recessive catecholaminergic polymorphic ventricular tachycardia 3, which can include prolonged QT intervals (MIM#614021). We report a case of cardiac arrest in a previously healthy adolescent male in the community. The patient was found to have a novel maternally inherited likely pathogenic variant in TECRL (c.915T>G [p.Tyr305Ter]) and an additional 19-kb duplication encompassing multiple exons of TECRL (chr4:65165944-65185287, dup [4q13.1]) not identified in the mother. Genetic results were revealed via rapid whole-genome sequencing, which allowed appropriate treatment and prognostication.

Given their dangerous effects on the nervous system, neurotoxins represent a significant threat to public health. Various therapeutic approaches, including chelating agents, receptor decoys, and toxin-neutralizing antibodies, have been explored. While prophylactic vaccines are desirable, it is oftentimes difficult to effectively balance their safety and efficacy given the highly dangerous nature of neurotoxins. To address this, we report here on a nanovaccine against neurotoxins that leverages the detoxifying properties of cell membrane-coated nanoparticles. A genetically modified cell line with constitutive overexpression of the α7 nicotinic acetylcholine receptor is developed as a membrane source to generate biomimetic nanoparticles that can effectively and irreversibly bind to α-bungarotoxin, a model neurotoxin. This abrogates the biological activity of the toxin, enabling the resulting nanotoxoid to be safely delivered into the body and processed by the immune system. When co-administered with an immunological adjuvant, a strong humoral response against α-bungarotoxin is generated that protects vaccinated mice against a lethal dose of the toxin. Overall, this work highlights the potential of using genetic modification strategies to develop nanotoxoid formulations against various biological threats.