UC San Diego

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.

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.

Amazon Mechanical Turk Workers lack accountability and redress when they are managed at scale, and by code. Report compiled by Amazon Mechanical Turk workers and academic collaborators, submitted to White House Office of Science and Technology Policy.

INTRODUCTION: The authors of this study sought to (1) describe the prevalence of social needs and (2) determine whether social needs were associated with closure of care gaps among patients aged ≥65 years seeking dental care. METHODS: In this retrospective cross-sectional study, the authors identified 754 Kaiser Permanente Northwest patients aged ≥65 years who completed an index dental visit; had at least 1 of 23 preventive care gaps (e.g., flu vaccination) or disease management care gaps (e.g., diabetes HbA1c screening test) documented in their medical record; and had completed a social needs assessment through survey evaluating financial strain, food insecurity, housing needs, social isolation, and transportation needs. The authors described the prevalence of social needs at the index visit and then used logistic regression to evaluate the association between the number of social needs (0, 1, ≥2) and closure of all care gaps over the following 60 days (yes versus no), adjusting for patient characteristics. Identification and closure of care gap were assessed through Kaiser Permanente Northwests Panel Support Tool. RESULTS: Approximately 28% of patients reported ≥1 social needs. The prevalence of social needs was as follows: social isolation, 13.7%; financial strain, 11.3%; food insecurity, 7.7%; transportation needs, 5.4%; and housing needs, 3.3%. Those with 1 social need were more likely to close care gaps than those with no social needs (OR=1.82, 95% CI=1.17, 2.85). No significant association was found with care gap closure among those with ≥2 versus zero social needs. CONCLUSIONS: The prevalence of social needs was nearly 30% among patients aged ≥65 years with dental and medical coverage. Patients with 1 social need were more likely than those with no social needs to close all care gaps after their visit.

Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M₁ sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

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What is the connection between the cultural evolution of a language and the rapid processing response to that language in the brains of individual learners? In an iterated communication study that was conducted previously, participants were asked to communicate temporal concepts such as "tomorrow," "day after," "year," and "past" using vertical movements recorded on a touch screen. Over time, participants developed simple artificial 'languages' that used space metaphorically to communicate in nuanced ways about time. Some conventions appeared rapidly and universally (e.g., using larger vertical movements to convey greater temporal durations). Other conventions required extensive social interaction and exhibited idiosyncratic variation (e.g., using vertical location to convey past or future). Here we investigate whether the brain's response during acquisition of such a language reflects the process by which the language's conventions originally evolved. We recorded participants' EEG as they learned one of these artificial space-time languages. Overall, the brain response to this artificial communication system was language-like, with, for instance, violations to the system's conventions eliciting an N400-like component. Over the course of learning, participants' brain responses developed in ways that paralleled the process by which the language had originally evolved, with early neural sensitivity to violations of a rapidly-evolving universal convention, and slowly developing neural sensitivity to an idiosyncratic convention that required slow social negotiation to emerge. This study opens up exciting avenues of future work to disentangle how neural biases influence learning and transmission in the emergence of structure in language.

Schwann cells (SCs) undergo phenotypic transformation and then orchestrate nerve repair following PNS injury. The ligands and receptors that activate and sustain SC transformation remain incompletely understood. Proteins released by injured axons represent important candidates for activating the SC Repair Program. The low-density lipoprotein receptor-related protein-1 (LRP1) is acutely up-regulated in SCs in response to injury, activating c-Jun, and promoting SC survival. To identify novel LRP1 ligands released in PNS injury, we applied a discovery-based approach in which extracellular proteins in the injured nerve were captured using Fc-fusion proteins containing the ligand-binding motifs of LRP1 (CCR2 and CCR4). An intracellular neuron-specific protein, Protein Kinase C and Casein Kinase Substrate in Neurons (PACSIN1) was identified and validated as an LRP1 ligand. Recombinant PACSIN1 activated c-Jun and ERK1/2 in cultured SCs. Silencing Lrp1 or inhibiting the LRP1 cell-signaling co-receptor, the NMDA-R, blocked the effects of PACSIN1 on c-Jun and ERK1/2 phosphorylation. Intraneural injection of PACSIN1 into crush-injured sciatic nerves activated c-Jun in wild-type mice, but not in mice in which Lrp1 is conditionally deleted in SCs. Transcriptome profiling of SCs revealed that PACSIN1 mediates gene expression events consistent with transformation to the repair phenotype. PACSIN1 promoted SC migration and viability following the TNFα challenge. When Src family kinases were pharmacologically inhibited or the receptor tyrosine kinase, TrkC, was genetically silenced or pharmacologically inhibited, PACSIN1 failed to induce cell signaling and prevent SC death. Collectively, these studies demonstrate that PACSIN1 is a novel axon-derived LRP1 ligand that activates SC repair signaling by transactivating TrkC.

The adenosine monophosphate (AMP)-activated protein kinase (AMPK) sits at a central node in the regulation of energy metabolism and tumor progression. AMPK is best known to sense high cellular ADP or AMP levels, which indicate the depletion of energy stores. Previous studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic cancer. In this study, we report that AMPK is also highly sensitive to extracellular matrix (ECM) stiffness. We found that AMPK is activated in cells when cultured under low ECM stiffness conditions and is functionally required for the metabolic switch induced by ECM stiffness. This regulation of AMPK requires the Hippo kinases but not LKB1/CaMKKβ. Hippo kinases directly phosphorylate AMPKα at Thr172 to activate AMPK at low ECM stiffness. Furthermore, we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma (PDAC) with high ECM stiffness and is associated with a poor survival outcome. The activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC growth. Together, these findings establish a novel model for AMPK regulation by the mechanical properties of ECMs and provide a rationale for simultaneously targeting the ECM stiffness-Hippo kinases-AMPK signaling and low glucose-LKB1-AMPK signaling pathways as an effective therapeutic strategy against PDAC.