Miracle-dz/UniFAR-FTUs huggingface dataset:
Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes

The gut microbiome of vertebrates is capable of numerous biotransformations of bile acids, which are responsible for intestinal lipid digestion and function as key nutrient-signaling molecules. The human liver produces bile acids from cholesterol predominantly in the A/B-trans orientation in which the sterol rings are “kinked”, as well as small quantities of A/B-cis oriented “flat” stereoisomers known as “primary allo-bile acids”. While the complex multi-step bile acid 7α-dehydroxylation pathway has been well-studied for conversion of “kinked” primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, the enzymatic basis for the formation of “flat” stereoisomers allo-deoxycholic acid (allo-DCA) and allo-lithocholic acid (allo-LCA) by Firmicutes has remained unsolved for three decades. Here, we present a novel mechanism by which Firmicutes generate the “flat” bile acids allo-DCA and allo-LCA. The BaiA1 was shown to catalyze the final reduction from 3-oxo-allo-DCA to allo-DCA and 3-oxo-allo-LCA to allo-LCA. Phylogenetic and metagenomic analyses of human stool samples indicate that BaiP and BaiJ are encoded only in Firmicutes and differ from membrane-associated bile acid 5α-reductases recently reported in Bacteroidetes that indirectly generate allo-LCA from 3-oxo-Δ4-LCA. We further map the distribution of baiP and baiJ among Firmicutes in human metagenomes, demonstrating an increased abundance of the two genes in colorectal cancer (CRC) patients relative to healthy individuals. SIGNIFICANCE STATEMENT Bile acid synthesis by vertebrates is central to digestion and nutrient signaling. Gut bacteria have evolved enzymes capable of converting primary bile acids to hundreds of secondary bile acids. While bile acid microbiology has been focused on the metabolism of ring hydroxyl groups and the carboxylated side-chain, very little is known about how bacteria alter the shape of the steroid ring system. Here, we describe enzymes expressed by Firmicutes that convert the “kinked” primary bile acid into “flat” secondary bile acids. Decades of research indicate that increased levels of secondary bile acids are risk factors for colorectal cancer. Hidden Markov Models developed from the BaiP and BaiJ enzyme sequences revealed significant enrichment in metagenomes of subjects with colorectal cancer.
Genetic variation associated with relative resistance in teak (Tectona grandis L. f.) against the leaf skeletonizer, Eutectona machaeralis Walker

Background Photosynthesizing tissue of teak (Tectona grandis L. f.) foliage is damaged by a host-specific insect pest called leaf skeletonizer (Eutectona machaeralis Walker) that severely eclipses annual growth increment and carbon sequestration of natural populations and plantation of teak. Gene-assisted selection of relatively resistant teak clones may efficiently control the damage in the populations and plantations. The present investigation aimed to identify genetic variation associated with relative resistance in teak against the pest. Method The investigation was carried out on 106 teak plus tree clones assembled at the National Teak Germplasm Bank from the Indian meta-population of teak. Resistance data were obtained recording the ocular damage caused by the pest to teak accessions for four years. Genotyping of the teak accessions was performed with 21 co-dominant markers and marker-trait association mapping was performed confirming the genetic structure of the germplasm bank and linkage disequilibrium (LD) among the marker loci. Results The sampled teak accessions exhibited a low albeit highly admixed genetic structure (FST=0.07) and low level of LD (16.66%) among loci, making them suitable for high-resolution association analysis. A significant correlation (p≤0.01, R2=0.67) was obtained between intra-specific heterozygosity and the relative resistance against the pest. A marker locus CCoAMT-1 representing the enzyme caffeoyl-CoA O-methyltransferase of phenylpropanoid pathway was also found significantly (p≤0.05) associated with the relative resistance against the pest explaining 6.6% of the phenotypic variation (R2=0.066) through positive effect (0.57) on the trait. Conclusions The present work exhibited a significant correlation of intra-specific heterozygosity with relative resistance in teak against a pest. It is the first report on teak identifying genetic markers associated with relative resistance against the pest. The marker can be applied for the selection of resistant planting stock for breeding and commercial plantation. Further investigation can be performed to understand the expression level polymorphism linked with the resistance applying next-generation sequencing approaches.
E-cadherin/HMR-1 and PAR-3 break symmetry at stable cell contacts in a developing epithelium

Tissue-wide patterning is essential to multicellular development, requiring cells to individually generate polarity axes and coordinate them in space and time with neighbors. Using the C. elegans intestinal epithelium, we identified a patterning mechanism informed by stabilized cell/cell contact and executed via the scaffolding protein PAR-3 and the transmembrane protein E-cadherin/HMR-1. Intestinal cells break symmetry as PAR-3 and HMR-1 recruit apical determinants into micron-scale ‘local polarity complexes’ (LPCs) at homotypic contacts. LPCs undergo a HMR-1-based migration to a common tissue midline, thereby establishing tissue-wide polarity. Thus, symmetry breaking results from PAR-3-dependent intracellular polarization coupled to HMR-1-based tissue-level communication that occurs through a non-adhesive signaling role for HMR-1. Intestinal cells gain initial asymmetry from differential contact duration as homotypic contacts last longer than heterotypic contacts, thus providing stable platforms for LPC assembly and offering a logical and likely conserved framework for how internal epithelia with no obvious pre-existing asymmetries can polarize.
Membrane remodeling properties of the Parkinson’s disease protein LRRK2

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are responsible for late-onset autosomal dominant Parkinson’s disease (PD). LRRK2 has been implicated in a wide range of physiological processes including membrane repair in the endolysosomal system. Here, using cell free systems, we report that purified LRRK2 directly binds acidic lipid bilayers with a preference for highly curved bilayers. While this binding is nucleotide independent, LRRK2 can also deform low curvature liposomes into narrow tubules in a guanylnucleotide-dependent but ATP-independent way. Moreover, assembly of LRRK2 into scaffolds at the surface of lipid tubules can constrict them. We suggest that an interplay between the membrane remodeling and signaling properties of LRRK2 may be key to its physiological function. LRRK2, via its kinase activity, may achieve its signaling role at sites where membrane remodeling occurs. Significance Statement LRRK2 is one of the most frequently mutated gene in familial Parkinson’s disease. While much has been learned about its molecular properties, upstream regulators and protein substrates of its kinase activity, its precise function remains unclear. Recent evidence has pointed to a role of LRRK2 in membrane repair in the endo/lysosomal system. Here we show that purified LRRK2 has membrane remodeling properties. We suggest that its ability to sense and induce membrane curvature may be key to its function in membrane dynamics. These properties may help coordinate a direct role of LRRK2 at the membrane interface with its the signaling role of its kinase domain.
FGF21 Counteracts Alcohol Intoxication by Activating Noradrenergic Neurons

Animals that consume fermenting fruit or nectar are exposed to ethanol, thus increasing their risk of injury or predation. This risk is heightened in humans, who have actively imbibed alcohol for thousands of years. In this report, we show that the hormone FGF21, which is strongly induced by ethanol in murine and human liver, exerts sobering or “amethystic” effects on both arousal and motor coordination without changing ethanol catabolism. Mice lacking FGF21 take longer than wild-type littermates to recover their righting reflex and balance following ethanol exposure. Conversely, pharmacologic FGF21 administration reduces the time needed for mice to recover from ethanol-induced unconsciousness and ataxia. FGF21 mediates it amethystic effects by directly activating the noradrenergic nervous system, which regulates arousal and alertness. These results indicate that this FGF21 liver-brain pathway evolved to protect against ethanolinduced intoxication and that it might be targeted pharmaceutically for treating acute alcohol poisoning.
CRIC-seq reveals positional rule of PTBP1-mediated long-range RNA looping in splicing regulation

RNA-binding proteins bind at different positions of pre-mRNA molecules to promote or reduce the usage of a particular exon. Seeking to understand the working principle of these positional effects, we develop a CRIC-seq method to enrich single RBP-mediated in situ RNA-RNA spatial interacting fragments for deep sequencing. We determine hnRNPA1- and PTBP1-mediated RNA-RNA interactions and regulatory mechanisms in HeLa cells. Unexpectedly, 3D RNA map analysis shows that PTBP1-mediated loops in introns preferably promote cassette exon splicing by accelerating asymmetric intron removal, whereas the loops spanning across cassette exon primarily repress splicing. This “positional rule” can faithfully predict PTBP1-regulated splicing outcomes. We further demonstrate that cancer-related splicing quantitative trait loci can disrupt RNA loops by reducing PTBP1 binding on pre-mRNAs to cause aberrant splicing in tumors. Our study presents a powerful method for exploring the functions of RBP-mediated RNA-RNA interactions in gene regulation and disease.
Selective Nigrostriatal Dopamine Excess Impairs Behaviors Linked to the Cognitive and Negative Symptoms of Psychosis

BACKGROUND Excess dopamine release in the dorsal striatum (DS) is linked to psychosis. Antipsychotics are thought to work for positive symptoms by blocking striatal D2 dopamine receptors, but they lack efficacy for the negative and cognitive symptoms. Further, broadly increasing dopamine release improves cognitive function. These observations fueled the dogma that excess dopamine is not involved in negative and cognitive symptoms, but this has never been tested with dopamine pathway specificity. METHODS We selectively re-expressed excitatory TRPV1 receptors in DS-projecting dopamine neurons of male and female Trpv1 knockout mice. We treated these mice with capsaicin (TRPV1 agonist) to selectively activate these neurons, validated this approach with fiber photometry, and assessed its effects on social and cognitive function. We combined this manipulation with antipsychotic treatment (haloperidol) and compared the pathway-specific manipulation to treatment with the non-selective dopamine releaser amphetamine. RESULTS Selectively activating DS-projecting dopamine neurons increased DS (but not cortical) dopamine release and increased locomotor activity. Surprisingly, this manipulation also impaired behavioral processes linked to negative and cognitive symptoms (social drive and working memory). Haloperidol normalized locomotion, only partially rescued working memory, and had no effect on social interaction. By contrast, amphetamine increased locomotion but did not impair social interaction or working memory. CONCLUSIONS Excess dopamine release, when restricted to the DS, causes behavioral deficits linked to negative and cognitive symptoms. Previous studies using non-selective approaches to release dopamine likely overlooked these contributions of excess dopamine to psychosis. Future therapies should address this disregarded role for excess striatal dopamine in the treatment-resistant symptoms of psychosis.
Prognostic implications of coronary artery disease and stress tests in patients with elevated left ventricular filling pressure and preserved ejection fraction

Background The prognostic role of myocardial ischemia in patients with heart failure with preserved ejection fraction (HFpEF) has not been fully elucidated. Therefore, we investigated the change in echocardiographic parameters and clinical outcomes based on the presence of epicardial coronary artery disease (CAD) and positive stress tests in HFpEF patients. Methods Symptomatic patients with left ventricular end diastolic pressure ≥15 mmHg who underwent coronary angiography were analyzed between January 2000 and August 2019 after exclusion of patients with acute coronary syndrome. Results A total of 555 HFpEF patients were invasively confirmed, 285 (51%) had angiographically-proven CAD. HFpEF patients with CAD displayed greater deterioration in left ventricular ejection fraction (p = 0.002) over time but this was not observed in those without CAD (p = 0.99) on follow-up echocardiography; however, the mitral annulus early diastolic velocity (e') was significantly decreased in both groups (p < 0.001 and p = 0.003, respectively). Among 274 patients that received stress tests, those with positive stress tests showed a decline in e' (p 0.001), but this was not found in subjects with negative stress tests (p = 0.44). There was no significant difference in all-cause mortality between patients with CAD and without CAD (p = 0.26) with a median follow-up of 10.6 years. Conclusion In HFpEF patients, CAD was associated with greater deterioration in the left ventricular systolic function but not with mortality during the follow-up. In addition, myocardial ischemia with a positive stress test may contribute to greater deterioration of diastolic dysfunction.
Cellular basis of learning and memory in the carotid body

The carotid body is the primary peripheral chemoreceptor in the body, and critical for respiration and cardiovascular adjustments during hypoxia. Yet considerable evidence now implicates the carotid body as a multimodal sensor, mediating the chemoreflexes of a wide range of physiological responses, including pH, temperature, and acidosis as well as hormonal, glucose and immune regulation. How does the carotid body detect and initiate appropriate physiological responses for these diverse stimuli? The answer to this may lie in the structure of the carotid body itself. We suggest that at an organ-level the carotid body is comparable to a miniature brain with compartmentalized discrete regions of clustered glomus cells defined by their neurotransmitter expression and receptor profiles, and with connectivity to defined reflex arcs that play a key role in initiating distinct physiological responses, similar in many ways to a switchboard that connects specific inputs to selective outputs. Similarly, within the central nervous system, specific physiological outcomes are co-ordinated, through signaling via distinct neuronal connectivity. As with the brain, we propose that highly organized cellular connectivity is critical for mediating co-ordinated outputs from the carotid body to a given stimulus. Moreover, it appears that the rudimentary components for synaptic plasticity, and learning and memory are conserved in the carotid body including the presence of glutamate and GABAergic systems, where evidence pinpoints that pathophysiology of common diseases of the carotid body may be linked to deviations in these processes. Several decades of research have contributed to our understanding of the central nervous system in health and disease, and we discuss that understanding the key processes involved in neuronal dysfunction and synaptic activity may be translated to the carotid body, offering new insights and avenues for therapeutic innovation.
Correlation between altered gut microbiota and elevated inflammation markers in patients with Crohn’s disease

Prior studies reported inconsistent results on the altered gut microbial composition in patients with Crohn’s disease (CD), likely under the influences of many confounding factors including genetic, life style and environmental variations among different study cohorts. This study aims to examine the gut microbiota of CD patients with particular efforts to minimize the impact of the confounding factors. For this purpose, the healthy relatives of the patients were enrolled as control subjects so that the paired study subjects may have similar genetic background, dietary habits, and household environment. The fecal microbiota of the study subjects were examined by 16S rRNA sequencing. After the identification of the differential bacterial genera, multivariate regression analysis was performed to adjust the results for the impact of confounding factors. We found that the microbiota of the CD patients were featured with reduced short chain fatty acid (SCFA) producing bacteria and elevated opportunistic pathogen Escherichia-Shigella. Correlation analysis indicated that the elevation in Escherichia-Shigella and the reduction in SCFA-producing bacteria usually occur simultaneously. These differential genera exhibited a high capacity in distinguishing between CD and healthy controls achieving an area under curve of 0.89, and were correlated with the changes in inflammation related blood biochemical markers. Consistent with the reduction in SCFA-producing bacteria in CD, metabolomics analysis revealed decreased blood level of SCFAs in the patients. The differential genera identified in this study demonstrated outstanding capability to serve as diagnosis markers for CD and are potential targets for intervention.
Are Most Published Research Findings False?

Summary In a provocative article Ioannidis (2005) argues that, in disciplines employing statistical tests of significance, professional journals report more wrong than true significant results. This short note sketches the argument and explores under what conditions the assertion holds. The “positive predictive value” (PPV) is lower than 1/2 if the a priori probability of the truth of a hypothesis is low. However, computation of the PPV includes only significant results. If both significant and non-significant results are taken into account the “total error ratio” (TER) will not exceed 1/2 provided no extremely large publication bias is present. Moreover, it is shown that theory-driven research may reduce the proportion of errors. Also, the role of replications is emphasized; replication studies of original research are so important because they drastically decrease the error ratio.
On beta-deformations and Noncommutativity

We elucidate the connection between the N=1 beta-deformed SYM theory and noncommutativity. Our starting point is the T-duality generating transformation involved in constructing the gravity duals of both beta-deformed and noncommutative gauge theories. We show that the two methods can be identified provided that a particular submatrix of the O(3,3,R) group element employed in the former case, is interpreted as the noncommutativity parameter associated with the deformation of the transverse space. It is then explained how to construct the matrix in question, relying solely on information extracted from the gauge theory Lagrangian and basic notions of AdS/CFT. This result may provide an additional tool in exploring deformations of the N=4 SYM theory. Finally we use the uncovered relationship between beta-deformations and noncommutativity to find the gravity background dual to a noncommutative gauge theory with beta-type noncommutativity parameter.
A call to action for blood flow restriction training in older adults with or susceptible to sarcopenia: A systematic review and meta-analysis

Background: The extent to which exercise training with blood flow restriction (BFR) improves functional performance (FP) in people with sarcopenia remains unclear. We performed a comprehensive search of BFR training in subjects with sarcopenia or susceptible to sarcopenia hoping to perform a systematic review and meta-analysis on the effects of BFR on FP in older adults without medical disorders, but with or susceptible to sarcopenia. Methods: PubMed and the Cochrane library were searched through February 2022. Inclusion criteria were: 1) the study examined older adults (>55 years of age) with or susceptible to sarcopenia and free of overt acute or chronic diseases, 2) there was a random allocation of participants to BFR and active control groups, 3) BFR was the sole intervention difference between the groups, and 4) the study provided post-intervention measures of skeletal muscle and physical function which were either the same or comparable to those included in the revised European Working Group on Sarcopenia in Older People (EWGSOP) diagnostic algorithm. Results: No studies of BFR training in individuals with sarcopenia were found and no study included individuals with FP values below the EWGSOP criteria. However, four studies of BFR training in older adults in which FP was examined were found. BFR training significantly improved the timed up and go (MD = −0.46, z = 2.43, p = 0.02), 30-s chair stand (MD = 2.78, z = 3.72, p < 0.001), and knee extension strength (standardized MD = 0.5, z = 2.3, p = 0.02) in older adults. Conclusion: No studies of BFR exercise appear to have been performed in patients with or suspected sarcopenia based on latest diagnostic criteria. Despite the absence of such studies, BFR training was found to significantly improve the TUG, 30-s chair stand, and knee extension strength in older adults. Studies examining the effects of BFR in subjects below EWGSOP cut-off points are needed.
Sex differences in the therapeutic effect of unaltered versus NFκB sensing IL-4 over-expressing mesenchymal stromal cells in a murine model of chronic inflammatory bone loss

Wear particles from joint arthroplasties induce chronic inflammation associated with prolonged upregulation of nuclear factor kappa-B (NF-κB) signaling in macrophages and osteoclasts, which leads to osteolysis and implant loosening. Mesenchymal stromal cell (MSC)-based therapy showed great potential for immunomodulation and mitigation of osteolysis in vivo, especially in the chronic phase of inflammation. We previously generated genetically modified MSCs that secrete the anti-inflammatory cytokine interleukin 4 (IL-4) in response to NF-κB activation (NFκB-IL-4 MSCs). However, whether the impact of sexual difference in the internal environment can alter the therapeutic effects of IL-4 over-secreting MSCs that simultaneously mitigate prolonged inflammation and enhance bone formation remains unknown. This study investigated the therapeutic effects of unaltered MSCs versus NFκB-IL-4 MSCs in mitigating chronic inflammation and enhancing bone formation in male and female mice. The murine model was established by continuous infusion of polyethylene particles contaminated with lipopolysaccharide (cPE) into the medullary cavity of the distal femur for 6 weeks to induce chronic inflammation. Unaltered MSCs or NFκB-IL-4 MSCs were infused into the femoral intramedullary cavity in sex-matched groups beginning 3 weeks after primary surgery. Femurs were harvested at 6 weeks, and bone marrow density was measured with micro-computational tomography. Numbers of osteoclast-like cells, osteoblasts, and macrophages were evaluated with histochemical and immunofluorescence staining. cPE infusion resulted in severe bone loss at the surgery site, increased tartrate-resistant acid phosphatase positive osteoclasts and M1 pro-inflammatory macrophages, and decreased alkaline phosphatase expression. MSC-based therapy effectively decreased local bone loss and polarized M1 macrophages into an M2 anti-inflammatory phenotype. In females, unaltered MSCs demonstrated a larger impact in enhancing the osteogenesis, but they demonstrated similar anti-inflammatory effects compared to NFκB-IL-4 MSCs. These results demonstrated that local inflammatory bone loss can be effectively modulated via MSC-based treatments in a sexually dimorphic manner, which could be an efficacious therapeutic strategy for treatment of periprosthetic osteolysis in both genders.