Miracle-dz/UniFAR-FTUs huggingface dataset:
Cumulus expansion is impaired with advanced reproductive age due to loss of matrix integrity and reduced hyaluronan

Reproductive aging is associated with ovulatory defects. Age‐related ovarian fibrosis partially contributes to this phenotype as short‐term treatment with anti‐fibrotic compounds improves ovulation in reproductively old mice. However, age‐dependent changes that are intrinsic to the follicle may also be relevant. In this study, we used a mouse model to demonstrate that reproductive aging is associated with impaired cumulus expansion which is accompanied by altered morphokinetic behavior of cumulus cells as assessed by time‐lapse microscopy. The extracellular matrix integrity of expanded cumulus–oocyte complexes is compromised with advanced age as evidenced by increased penetration of fluorescent nanoparticles in a particle exclusion assay and larger open spaces on scanning electron microscopy. Reduced hyaluronan (HA) levels, decreased expression of genes encoding HA‐associated proteins (e.g., Ptx3 and Tnfaip6), and increased expression of inflammatory genes and matrix metalloproteinases underlie this loss of matrix integrity. Importantly, HA levels are decreased with age in follicular fluid of women, indicative of conserved reproductive aging mechanisms. These findings provide novel mechanistic insights into how defects in cumulus expansion contribute to age‐related infertility and may serve as a target to extend reproductive longevity.
Nonadditive functional interactions between ligand-binding sites of the multidrug efflux pump AdeB from Acinetobacter baumannii

ABSTRACT Multidrug efflux is one of the major mechanisms of antibiotic resistance identified in clinical isolates of the human pathogen Acinetobacter baumannii. The multiple antibiotic resistance in this species is often enabled by the overproduction of the tripartite efflux pump AdeABC. In this pump, AdeB is the inner membrane transporter from the resistance-nodulation-division (RND) superfamily of proteins, which is responsible for the recognition and efflux of multiple structurally unrelated compounds. Like other RND transporters, AdeB is a trimeric protein with ligand-binding sites located in the large periplasmic domains. Previous structural studies, however, highlighted the uniqueness of AdeB interactions with ligands. Up to three ligand molecules were bound to one protomer of AdeB, mapping its substrate translocation path. In this study, we introduced single and double substitutions in the identified ligand-binding sites of AdeB. Our results show that the mechanism of substrate translocation by AdeB is different from that of other characterized RND transporters and that the functional interactions between the sites are nonadditive. We identified AdeB mutants with both the loss and the gain of antibiotic susceptibility phenotypes, as well as AdeB mutations making A. baumannii cells overproducing such pump variants even more susceptible to multiple antibiotics than efflux-deficient cells. IMPORTANCE Multidrug efflux pumps of the resistance-nodulation-division superfamily of proteins are important contributors to various aspects of bacterial physiology and antibiotic resistance. Studies of the best-characterized model transporter AcrB from Escherichia coli suggested that these transporters operate by a functional rotation mechanism in which various substrates bind to at least two different binding sites. This study suggests that the mechanism of AdeB is distinct and that the binding sites in this transporter are functionally linked. Multidrug efflux pumps of the resistance-nodulation-division superfamily of proteins are important contributors to various aspects of bacterial physiology and antibiotic resistance. Studies of the best-characterized model transporter AcrB from Escherichia coli suggested that these transporters operate by a functional rotation mechanism in which various substrates bind to at least two different binding sites. This study suggests that the mechanism of AdeB is distinct and that the binding sites in this transporter are functionally linked.
Adipose Mesenchymal Stem Cell-Derived Exosomes Promote the Regeneration of Corneal Endothelium Through Ameliorating Senescence

Purpose Human corneal endothelial cells (hCECs) have been considered unable to regenerate in vivo, resulting in corneal decompensation after significant loss of hCECs. adipose-derived mesenchymal stem cell (ASC)-derived exosomes can regenerate tissues and organs. In this study, we investigated whether ASC-derived exosomes could protect and regenerate CECs. Methods We performed cell viability and cell-cycle analyses to evaluate the effect of ASC-derived exosomes on the regeneration capacity of cultured hCECs. Transforming growth factor-β (TGF-β) and hydrogen peroxide (H2O2) were used to induce biological stress in CECs. The effect of ASC-derived exosomes on CECs was investigated in vivo. ASC-derived exosomes were introduced into rat CECs using electroporation, and rat corneas were injured using cryoinjury. Next-generation sequencing analysis was performed to compare the differentially expressed microRNAs (miRNAs) between ASC-derived and hCEC-derived exosomes. Results ASC-derived exosomes induced CEC proliferation and suppressed TGF-β- or H2O2-induced oxidative stress and senescence. ASC-derived exosomes protect hCECs against TGF-β- or H2O2-induced endothelial-mesenchymal transition and mitophagy. In an in vivo study, ASC-derived exosomes promoted wound healing of rat CECs and protected the corneal endothelium against cryoinjury-induced corneal endothelium damage. Next-generation sequencing analysis revealed differentially expressed miRNAs for ASC-derived and hCEC-derived exosomes. They are involved in lysine degradation, adherens junction, the TGF-β signaling pathway, the p53 signaling pathway, the Hippo signaling pathway, the forkhead box O (FoxO) signaling pathway, regulation of actin cytoskeleton, and RNA degradation based on Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Conclusions ASC-derived exosomes promoted wound healing and regeneration of endothelial cells by inducing a shift in the cell cycle and suppressing senescence and autophagy.
Posttreatment complications in pediatric cervical neuroblastoma: A retrospective case series at a tertiary cancer center

Neuroblastomas rarely occur as primary tumors in the cervical region. Therefore, very little has been reported regarding treatment strategies, complications, and outcomes of these cervical neuroblastomas. The goal of this study is to review the presentation, management, and outcomes of all primary cervical pediatric neuroblastoma cases at a single tertiary care center.
Pupillary Light Reflex and Multimodal Imaging in Patients With Central Serous Chorioretinopathy

Purpose The purpose of this study was to investigate and compare the corresponding alterations of the pupillary response between acute and chronic central serous chorioretinopathy (CSC) and between different disease categories. Methods We recruited patients with unilateral acute and chronic CSC. An eye tracker was applied to determine the pupillary light reflex (PLR) and evaluate the following PLR metrics in healthy eyes: pupil diameter, diameter changes, including relative constriction amplitude (AMP%), and re-dilation ratio (D1%). Baseline optical coherence tomography (OCT), and fluorescein and indocyanine green angiography (FA/ICGA) were performed to analyze the relationship between pupillary response and retinal/choroidal architecture. Results In total, 52 patients were enrolled, including 25 with acute CSC and 27 with chronic CSC. Compared to the chronic CSC group, the acute CSC group displayed a significantly larger baseline pupil diameter (BPD; of 5.51 mm, P = 0.015), lower AMP% (34.40%, P = 0.004), and higher D1% (93.01%, P = 0.002), indicating sympathetic overactivity. On OCT, the total macular volume was positively correlated with the D1% (r = 0.48, P = 0.005) and negatively with AMP (r = −0.47, P = 0.007). On ICGA, the intense choroidal vascular hyperpermeability (CVH) group displayed a greater BPD than the nonintense CVH group. Additionally, 9 cases with later recurrent episodes following therapy showed a lower AMP% and higher D1% than the nonrecurrent group. Conclusions The PLR revealed sympathetic excitation in patients with acute CSC. The stronger D1% was significantly associated with greater total macular volume, and it may be a potential biomarker for predicting the later recurrence of CSC.
Local Search and the Evolution of World Models.

An open question regarding how people develop their models of the world is how new candidates are generated for consideration out of infinitely many possibilities. We discuss the role that evolutionary mechanisms play in this process. Specifically, we argue that when it comes to developing a global world model, innovation is necessarily incremental, involving the generation and selection among random local mutations and recombinations of (parts of) one's current model. We argue that, by narrowing and guiding exploration, this feature of cognitive search is what allows human learners to discover better theories, without ever grappling directly with the problem of finding a "global optimum," or best possible world model. We suggest this aspect of cognitive processing works analogously to how blind variation and selection mechanisms drive biological evolution. We propose algorithms developed for program synthesis provide candidate mechanisms for how human minds might achieve this. We discuss objections and implications of this perspective, finally suggesting that a better process-level understanding of how humans incrementally explore compositional theory spaces can shed light on how we think, and provide explanatory traction on fundamental cognitive biases, including anchoring, probability matching, and confirmation bias.
Plasma Rich in Growth Factors (PRGF) in the Treatment of Patients With Chronic Cervical and Lumbar Pain: A Prospective Observational Clinical Study.

BACKGROUND Chronic back pain is a long-lasting disorder, whose main source of pain is often the intervertebral disc that undergoes a degenerative process associated with low-grade inflammation, leading to a reduced quality of life. OBJECTIVES The aim of our study was to assess the efficacy of intradiscal and epidural injections of plasma rich in growth factors (PRGF) in patients with chronic clinical symptoms due to intervertebral disc (IVD) degeneration. STUDY DESIGN Prospective observational study. SETTING A single spine unit in a private clinic. METHODS Thirty-two patients with cervical and lumbar chronic pain due to IVD degeneration were treated with 2 or 3 series of intradiscal and epidural PRGF infiltrations with 2 weeks between each procedure. The procedures were performed under fluoroscopic guidance and grade 3 sedation in an operating theater. Treatment efficacy was evaluated using the Spine Tango Core Outcome Measure Index questionnaire, Numeric Rating Scale for back pain, and the Oswestry Disability Index questionnaire. In addition, the number of patients who successfully achieved the minimal clinically important change was also determined. These assessments were evaluated at pretreatment (baseline) and at one, 3, and 6 months posttreatment. RESULTS The Oswestry Disability Index, COMI Spine Tango Core Outcome Measure Index total score, and Numeric Rating Scale showed a statistically significant reduction from the baseline level to the posttreatment first month, third month, and sixth month (P < 0.001). Moreover, 78.1% of the patients reached a pain reduction superior to 30% one month posttreatment, and 87.5% at 6 months posttreatment, which is considered as a clinically significant improvement. LIMITATIONS This study was prospective and did not have a control group. Only patient-reported outcomes were evaluated. CONCLUSIONS This observational, prospective study of patients with chronic back pain showed that 2-3 intradiscal and epidural injections of PRGF significantly decreased pain and disability at one month posttreatment and this improvement was maintained, and in some patients even improved, at 3, and 6 months posttreatment.
A Staphylococcus capitis strain with unusual bacteriocin production

Staphylococcus capitis is a member of the human and mammal skin microbiomes and is considered less harmful than Staphylococcus aureus. S. capitis subsp. urealyticus BN2 was isolated from a cat and expressed strong antibacterial activity against a range of Gram‐positive species, most notably including S. aureus strains with resistance to methicillin (MRSA) and strains with intermediate resistance to vancomycin (VISA). These latter strains are normally relatively resistant to bacteriocins, due to cell wall and cell membrane modifications. Genomic sequencing showed that the strain harboured at least two complete gene clusters for biosynthesis of antagonistic substances. The complete biosynthetic gene cluster of the well‐known lantibiotic gallidermin was encoded on a large plasmid and the mature peptide was present in isopropanol cell extracts. In addition, a chromosomal island contained a novel non‐ribosomal peptide synthetase (NRPS) gene cluster. Accidental deletion of two NRPS modules and partial purification of the anti‐VISA activity showed that this novel bacteriocin represents a complex of differently decorated, non‐ribosomal peptides. Additionally, a number of phenol‐soluble modulins (PSMs) was detected by mass spectrometry of whole cells. Producing these compounds, the strain was able to outcompete several S. aureus strains, including MRSA and VISA, in tube cultures.
Issues on utilization of domestic organic fertilizer resources and its countermeasure

In view of increasing application of chemical fertilizer and gradually decreasing proportion of organic fertilizer, the resource, utilization and issues of organic fertilizer in China are discussed, then the roles of organic fertilizer to soil and crop are also introduced, finally some countermeasures for development of domestic organic fertilizer are presented, such as extending balanced fertilization, utilizing civic resources of organic fertilizer, developing green manure, and changing straw and stalk to manure. The viewpoint is emphasized that the application of chemical fertilizer is still an important measure to replenish N, P K nutrients in soil, however utilization of organic fertilizer has an active significance to make good use of resource and protect environment.
Hydroxamate-based compounds are potent inhibitors of Toxoplasma gondii HDAC biological activity

ABSTRACT Toxoplasmosis is a critical health issue for immune-deficient individuals and the offspring of newly infected mothers. It is caused by a unicellular intracellular parasite called Toxoplasma gondii that is found worldwide. Although efficient drugs are commonly used to treat toxoplasmosis, serious adverse events are common. Therefore, new compounds with potent anti-T. gondii activity are needed to provide better suited treatments. We have tested compounds designed to target specifically histone deacetylase enzymes. Among the 55 compounds tested, we identified three compounds showing a concentration of drug required for 50% inhibition (IC50) in the low 100 nM range with a selectivity index of more than 100. These compounds are not only active at inhibiting the growth of the parasite in vitro but also at preventing some of the consequences of the acute disease in vivo. Two of these hydroxamate based compound also induce a hyper-acetylation of the parasite histones while the parasitic acetylated tubulin level remains unchanged. These findings suggest that the enzymes regulating histone acetylation are potent therapeutic targets for the treatment of acute toxoplasmosis.
Early-Life Temperamental Differences as Longitudinal Predictors of Unintentional Injuries

Abstract Objective Unintentional injuries are the leading cause of hospitalization and death among children. Compared to environmental factors, less attention in injury preventive efforts has been paid to how individual characteristics relate to the risk of injury. Using a large prospective cohort, the current study assessed the longitudinal impact of early-life temperament on the cumulative number of injuries until mid-adolescence. Methods The data came from the European Longitudinal Study of Pregnancy and Childhood (ELSPAC-CZ). Temperament was evaluated by mothers when children were 3 years old (N = 3,545). The main outcome was the pediatrician-reported sum of child’s injuries from age 3 to 15 (seven timepoints). Latent profile analysis (LPA) was used to determine classes based on temperamental dimensions and then extended to a mixture model with a distal count outcome. The covariates included maternal conflict and attachment, sex, family structure, and maternal education. Results The LPA determined the existence of three classes: shy children (8.1% of the sample; lowest activity/highest shyness), outgoing children (50.8%; highest activity/lowest shyness), and average: children (41.1%; middle values). Results from a mixture model showed that the outgoing temperament was associated with the highest longitudinal risk for injuries, as both average children (IRR = 0.89 [0.80, 0.99]), and the shy children (IRR = 0.80 [0.68, 0.95]) had lower risk. Conclusions Early childhood temperamental differences can have long-term effects on injury risk. Highly active children showed the highest risk for future injuries, suggesting that these characteristics make them more likely to be involved in novel and potentially dangerous situations.
Microbiota from Alzheimer’s patients induce deficits in cognition and hippocampal neurogenesis

Abstract Alzheimer’s disease is a complex neurodegenerative disorder leading to a decline in cognitive function and mental health. Recent research has positioned the gut microbiota as an important susceptibility factor in Alzheimer’s disease by showing specific alterations in the gut microbiome composition of Alzheimer’s patients and in rodent models. However, it is unknown whether gut microbiota alterations are causal in the manifestation of Alzheimer’s symptoms. To understand the involvement of Alzheimer’s patient gut microbiota in host physiology and behaviour, we transplanted faecal microbiota from Alzheimer’s patients and age-matched healthy controls into microbiota-depleted young adult rats. We found impairments in behaviours reliant on adult hippocampal neurogenesis, an essential process for certain memory functions and mood, resulting from Alzheimer’s patient transplants. Notably, the severity of impairments correlated with clinical cognitive scores in donor patients. Discrete changes in the rat caecal and hippocampal metabolome were also evident. As hippocampal neurogenesis cannot be measured in living humans but is modulated by the circulatory systemic environment, we assessed the impact of the Alzheimer’s systemic environment on proxy neurogenesis readouts. Serum from Alzheimer’s patients decreased neurogenesis in human cells in vitro and were associated with cognitive scores and key microbial genera. Our findings reveal for the first time, that Alzheimer’s symptoms can be transferred to a healthy young organism via the gut microbiota, confirming a causal role of gut microbiota in Alzheimer’s disease, and highlight hippocampal neurogenesis as a converging central cellular process regulating systemic circulatory and gut-mediated factors in Alzheimer’s.
Skin Models Used to Define Mechanisms of Action of Sulfur Mustard

Abstract Sulfur mustard (SM) is a threat to both civilian and military populations. Human skin is highly sensitive to SM, causing delayed erythema, edema, and inflammatory cell infiltration, followed by the appearance of large fluid-filled blisters. Skin wound repair is prolonged following blistering, which can result in impaired barrier function. Key to understanding the action of SM in the skin is the development of animal models that have a pathophysiology comparable to humans such that quantitative assessments of therapeutic drugs efficacy can be assessed. Two animal models, hairless guinea pigs and swine, are preferred to evaluate dermal products because their skin is morphologically similar to human skin. In these animal models, SM induces degradation of epidermal and dermal tissues but does not induce overt blistering, only microblistering. Mechanisms of wound healing are distinct in these animal models. Whereas a guinea pig heals by contraction, swine skin, like humans, heals by re-epithelialization. Mice, rats, and rabbits are also used for SM mechanistic studies. However, healing is also mediated by contraction; moreover, only microblistering is observed. Improvements in animal models are essential for the development of therapeutics to mitigate toxicity resulting from dermal exposure to SM.
Industrial agglomeration in Costa Rica : a descriptive analysis

This paper investigates the current situation of industrial agglomeration in Costa Rica, utilizing firm-level panel data for the period 2008-2012. We calculated Location Quotient and Theil Index based on employment by industry and found that 14 cantons have the industrial agglomerations for 9 industries. The analysis is in line with the nature of specific industries, the development of areas of concentration around free zones, and the evolving participation of Costa Rica in GVCs.
Mechanistic aspects of IPTG (isopropylthio-β-galactoside) transport across the cytoplasmic membrane of Escherichia coli—a rate limiting step in the induction of recombinant protein expression

Abstract Coupling transcription of a cloned gene to the lac operon with induction by isopropylthio-β-galactoside (IPTG) has been a favoured approach for recombinant protein expression using Escherichia coli as a heterologous host for more than six decades. Despite a wealth of experimental data gleaned over this period, a quantitative relationship between extracellular IPTG concentration and consequent levels of recombinant protein expression remains surprisingly elusive across a broad spectrum of experimental conditions. This is because gene expression under lac operon regulation is tightly correlated with intracellular IPTG concentration due to allosteric regulation of the lac repressor protein (lacY). An in-silico mathematical model established that uptake of IPTG across the cytoplasmic membrane of E. coli by simple diffusion was negligible. Conversely, lacY mediated active transport was a rapid process, taking only some seconds for internal and external IPTG concentrations to equalize. Optimizing kcat and KM parameters by targeted mutation of the galactoside binding site in lacY could be a future strategy to improve the performance of recombinant protein expression. For example, if kcat were reduced whilst KM was increased, active transport of IPTG across the cytoplasmic membrane would be reduced, thereby lessening the metabolic burden on the cell and expediating accumulation of recombinant protein. The computational model described herein is made freely available and is amenable to optimize recombinant protein expression in other heterologous hosts. One-Sentence Summary A computational model made freely available to optimize recombinant protein expression in Escherichia coli other heterologous hosts.