Miracle-dz/UniFAR-FTUs huggingface dataset:
Evolutionary biology and development model of medicines: A necessary ‘pas de deux’ for future successful bacteriophage therapy

The increase in frequency of multidrug‐resistant bacteria worldwide is largely the result of the massive use of antibiotics in the second half of the 20th century. These relatively recent changes in human societies revealed the great evolutionary capacities of bacteria towards drug resistance. In this article, we hypothesize that the success of future antibacterial strategies lies in taking into account both these evolutionary processes and the way human activities influence them. Faced with the increasing prevalence of multidrug‐resistant bacteria and the scarcity of new antibacterial chemical molecules, the use of bacteriophages is considered as a complementary and/or alternative therapy. After presenting the evolutionary capacities of bacteriophages and bacteria, we show how the development model currently envisaged (based on the classification of bacteriophages as medicinal products similar to antibacterial chemical molecules) ignores the evolutionary processes inherent in bacteriophage therapy. This categorization imposes to bacteriophage therapy a specific conception of what a treatment and a therapeutic scheme should be as well as its mode of production and prescription. We argue that a new development model is needed that would allow the use of therapeutic bacteriophages fully adapted (after in vitro ‘bacteriophage training’) to the aetiologic bacteria and/or aimed at rendering bacteria either avirulent or antibiotic‐susceptible (‘bacteriophage steering’). To not repeat the mistakes made with antibiotics, we must now think about and learn from the ways in which the materialities of microbes (e.g. evolutionary capacities of both bacteriophages and bacteria) are intertwined with those of societies.
Peptide‐PAINT Enables Investigation of Endogenous Talin with Molecular Scale Resolution in Cells and Tissues

Talin is a cell adhesion molecule that is indispensable for the development and function of multicellular organisms. Despite its central role for many cell biological processes, suitable methods to investigate the nanoscale organization of talin in its native environment are missing. Here, we overcome this limitation by combining single‐molecule resolved PAINT (points accumulation in nanoscale topography) imaging with the IRIS (image reconstruction by integrating exchangeable single‐molecule localization) approach, enabling the quantitative analysis of genetically unmodified talin molecules in cells. We demonstrate that a previously reported peptide can be utilized to specifically label the two major talin isoforms expressed in mammalian tissues with a localization precision of <10 nm. Our experiments show that the methodology performs equally well as state‐of‐the‐art single‐molecule localization techniques, and the first applications reveal a thus far undescribed cell adhesion structure in differentiating stem cells. Furthermore, we demonstrate the applicability of this peptide‐PAINT technique to mouse tissues paving the way to single‐protein imaging of endogenous talin proteins under physiologically relevant conditions.
Mouse and Fly Sperm Motility Changes Differently under Modelling Microgravity

Sperm motility is essential for the natural fertilization process in most animal species. Despite the fact that evolution took place under conditions of constant gravity, the motility of spermatozoa of insects and mammals under microgravity conditions changes in different ways. In this work, an attempt was made to explain this effect. The sperm motility of the fruit fly Drosophila melanogaster and the mouse was evaluated after exposure to a random positioning machine for 6 h. Sodium fluoride was used to inhibit serine/threonine phosphatases, sodium orthovanadate was used to inhibit tyrosine phosphatases, and 6-(dimethylamino)purine was used to inhibit protein kinases. The results obtained indicate that simulated microgravity leads to an increase in the speed of movement of fly spermatozoa by 30% (p < 0.05), and this effect is blocked by sodium fluoride. In contrast, a 29% (p < 0.05) decrease in the speed of movement of mouse spermatozoa under simulated microgravity is prevented by 6-(dimethylamino)purine. Moreover, after 6 h of exposure, the content of tubulin cytoskeleton and actin proteins remains at the control level in the spermatozoa of flies and mice. However, the content of the actin-binding protein alpha-actinin in fly sperm decreases by 29% (p < 0.05), while in mouse sperm, the relative content of alpha-actinin1 increases by 94% (p < 0.05) and alpha-actinin4 by 121% (p < 0.05) relative to the control, as determined by 6 simulated microgravity tests. It can be assumed that the effect of simulated microgravity on the motility of mammalian spermatozoa is mediated through the regulation of phosphorylation and that of insects through the regulation of dephosphorylation of motor proteins; moreover, the development of a response to changes in external mechanical conditions has a different time scale.
Branched chain amino acid-inflammation relationship in youth with obesity: A randomized controlled intervention study.

CONTEXT Elevated concentrations of branched chain amino acids (BCAA) are strong predictors of type 2 diabetes mellitus (T2DM). Their association with cardiovascular disease (CVD) remains uncertain, particularly in youth. We investigated the role of BCAA and aromatic amino acids (AAA) in obesity, their relationships with novel biomarkers of CVD and response to a physical activity-based lifestyle intervention (PAL-I) in a randomized controlled study in youth with normal weight (NW) and obesity (OB). METHODS Age (14-18 years) and Tanner stage (≥IV) matched youth (OB, n=15 and NW, n=6) were studied; the 15 participants with OB underwent a 3-month randomized controlled PAL-I. Circulating amino acid profile, glucose, insulin, lipids, adiponectin, retinol binding protein-4 (RBP4), fibrinogen, high-sensitivity c-reactive protein (hs-CRP), interleukin-6 (IL-6) and 25-hydroxy vitamin-D, along with body composition (DXA) were measured at baseline and after PAL-I. Independent t-tests, analysis of covariance and mixed effect models were used for analysis of the data. RESULTS Compared to NW, the concentration of various amino acids including BCAA and AAA were altered in the OB (P<0.05). BCAA and AAA showed baseline correlations with body composition and novel biomarkers of CVD, particularly inflammatory factors (p<0.05 for all). The PAL-I produced only negligible effects (p>0.05) on BCAA and AAA. Glutamine, glycine, and aspartic acid decreased with PAL-I (p<0.05 for all). CONCLUSIONS The novel finding of the BCAA-inflammation relationship along with strong correlations with nontraditional biomarkers of CVD may evoke the prospect of BCAA as a biomarkers of CVD and a potential link between obesity, T2DM and CVD.
Physical Therapists’ Attitudes Are Associated with Their Confidence in and the Frequency with Which They Engage in Prescription Opioid Medication Misuse Management Practices with Their Patients. A Cross–Sectional Study

Background: In the US, prescription opioid medication misuse (POMM) necessitates engagement of physical therapists (PTs). We (1) evaluated the attitudes of (PT) related to their management of patients with POMM and (2) examined the association between these attitudes and PTs confidence in POMM–related management abilities and the frequency with which they engaged in POMM–related management practices. Methods: We conducted a national survey of PTs that included a modified Drug and Drug Problems Perception Questionnaire (DDPPQ). Confidence in POMM–related abilities and the frequency of engaging in POMM–related management practices were measured. Logistic regression evaluated the association between the DDPPQ subscales (role adequacy, role legitimacy, role self–esteem, role support, job satisfaction) and confidence and frequency outcomes. Results: The analysis included 402 respondents. Role adequacy and legitimacy subscales were associated with confidence and frequency outcomes (p<.05), indicating that more favorable role adequacy and legitimacy attitudes are associated with greater odds of having more confidence in POMM–related management abilities and of engaging in more frequent POMM–related management practices. Conclusions: PTs with a greater sense of preparedness to engage in POMM–related management were more likely to report greater confidence in POMM–related management abilities and engage in POMM–related management practices with greater frequency.
Phylogeny‐based conservation priorities for Australian freshwater fishes

Conservation scientists are increasingly interested in the question of how extinction prunes the tree of life. This question is particularly important for Australian freshwater fishes because there is a broad mix of ∼300 old and young species, many of which are severely threatened. We used a complete species‐level phylogeny of Australian freshwater fishes to examine phylogenetic nonrandomness of extinction risk. We computed the potential loss of phylogenetic diversity by simulating extinction across the tree under a pattern weighted based on International Union for Conservation of Nature extinction risk category and compared this loss to projected diversity loss under a random null model of extinction. Finally, we calculated EDGE (evolutionary distinctiveness, global endangerment) scores for 251 freshwater and 60 brackish species and compiled a list of high‐priority species for conservation actions based on their extinction risk and evolutionary uniqueness. Extinction risk was not random and was clustered in both diversity cradles (recently diversifying, species‐rich clades, such as Galaxiidae and Percichthyidae) and museums (older, species‐poor groups, such as freshwater chondrichthyans). Clustered extinction made little difference to the average expected loss of phylogenetic diversity. However, the upper bound of loss was higher under a selective model of extinction, particularly when the counts of species lost were low. Thus, the loss of highly threatened species would diminish the tree of life more than a null model of randomly distributed extinction. High priority species included both widely recognized and charismatic ones, such as the Queensland lungfish (Neoceratodus forsteri), river sharks, and freshwater sawfishes, and lesser‐known species that receive less public attention, including the salamanderfish (Lepidogalaxias salamandroides), cave gudgeons, and many galaxiids, rainbowfishes, and pygmy perches.
Enterochromaffin-like Cell Hyperplasia-Associated Gastric Neuroendocrine Tumors May Arise in the Setting of Proton Pump Inhibitor Use: The Need for a New Clinicopathologic Category.

CONTEXT. — Hypergastrinemia states such as achlorhydria from gastric mucosal atrophy or a gastrin-producing tumor in humans have been associated with the development of enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumors (GNETs). Whether drugs that can elevate serum gastrin levels, such as proton pump inhibitors (PPIs), can produce the same tissue effect is not known and there is no concrete evidence linking the use of PPIs to GNETs outside animal models and case reports. OBJECTIVE. — To explore the clinicopathologic association for GNETs of presumed ECL cell origin that cannot be reliably placed into any of the 3 established categories currently recognized by the World Health Organization. DESIGN. — This is a retrospective clinicopathologic study of GNETs in the body/fundus of a period of 15 years (2005-2019). RESULTS. — Of a total of 87 cases, 57 (65.5%) were associated with atrophic gastritis, 2 (2.3%) were associated with Zollinger-Ellison syndrome, and 28 (32.2%) were unclassified. Of the latter, 11 were consistent with true sporadic/type 3 GNETs, while 17 had background mucosal changes of parietal cell and ECL cell hyperplasia but without underlying detectable gastrinoma, and 88.2% (15 of 17) of patients from this group had documented long-term PPI use. This subtype of GNETs was more commonly multifocal, and of higher grade (P = .03) than "true" sporadic GNETs. CONCLUSIONS. — A subset of GNETs arises in the background of gastric mucosal changes suggestive of hypergastrinemia, but without underlying gastrinoma, and could be linked to long-term PPI use.
Alleviation of Oxidative Damage by Exogenous Application of Plant Growth Regulators on Medicinally Important Oil Yielding Plant Simarouba Glauca Dc. Under Water Stress Conditions.

Drought stress is one of the main environmental factor that causes oxidative damage and adversely affect plant growth and productivity. Strategies to minimize oxidative damage are a universal feature of plant de-fense responses. Plant growth regulators have antioxidative characteristic that can decrease drought effect. An attempt have been made to identify the response of PGRs like SA (salicylic acid), Putrescine, GABA (Gamma amino butyric acid) and Abscisic acid on ascorbate peroxidase, guaicol peroxidase and IIA oxidase activities of medicinally important oil yielding plant Simarouba glauca DC. under water stress conditions. Increased levels of ascorbate peroxidase, guaiacol peroxidase and IIA oxidase activity were noticed in stressed plants as compared to control plants. Exogenous applications of these PGRs also showed increase in the activities of these antioxidant enzymes as compared to unsprayed stressed plants. These results indicate that SA, Putrescine, GABA and Abscisic acid plays a vital role in drought tolerance by minimizing oxidative damage.
Frustration and Frustrated Crystal Structures of Polymers and Biopolymers

The manifestations of frustration are widespread in materials science. The more specific geometrical frustration in crystalline materials is created when physical interactions between nearest neighbors induce packing modes (e.g., the slight twist between neighboring DNA strands) that cannot propagate indefinitely throughout space. The structure is made of small domains separated by dislocation lines or other less ordered walls (e.g., in DNA blue phases). A second type of geometrical frustration, compatible with crystallographic symmetry, may arise in hexagonal close-packed crystals of helices with 3-fold symmetry. If favorable pair–pair interactions exist between helices, they can propagate only in a honeycomb pattern. The resulting unit cell is trigonal and contains three independent helices, one of which interacts less favorably with its neighbors—thus the frustration. Recognition of this type of geometrical frustration in polymer crystallography is relatively recent, although some crystal structures de.
Host-Like Conditions Are Required for T6SS-Mediated Competition among Vibrio fischeri Light Organ Symbionts

Bacteria have evolved diverse strategies to compete for limited space and resources. Because these mechanisms can be costly to use, their expression and function are often restricted to specific environments where the benefits outweigh the costs. ABSTRACT Bacteria employ diverse competitive strategies to enhance fitness and promote their own propagation. However, little is known about how symbiotic bacteria modulate competitive mechanisms as they compete for a host niche. The bacterium Vibrio fischeri forms a symbiotic relationship with marine animals and encodes a type VI secretion system (T6SS), which is a contact-dependent killing mechanism used to eliminate competitors during colonization of the Euprymna scolopes squid light organ. Like other horizontally acquired symbionts, V. fischeri experiences changes in its physical and chemical environment during symbiosis establishment. Therefore, we probed both environmental and host-like conditions to identify ecologically relevant cues that control T6SS-dependent competition during habitat transition. Although the T6SS did not confer a competitive advantage for V. fischeri strain ES401 under planktonic conditions, a combination of both host-like pH and viscosity was necessary for T6SS competition. For ES401, high viscosity activates T6SS expression and neutral/acidic pH promotes cell-cell contact for killing, and this pH-dependent phenotype was conserved in the majority of T6SS-encoding strains examined. We also identified a subset of V. fischeri isolates that engaged in T6SS-mediated competition at high viscosity under both planktonic and host-like pH conditions. T6SS phylogeny revealed that strains with pH-dependent phenotypes cluster together to form a subclade within the pH-independent strains, suggesting that V. fischeri may have recently evolved to limit competition to the host niche. IMPORTANCE Bacteria have evolved diverse strategies to compete for limited space and resources. Because these mechanisms can be costly to use, their expression and function are often restricted to specific environments where the benefits outweigh the costs. However, little is known about the specific cues that modulate competitive mechanisms as bacterial symbionts transition between free-living and host habitats. Here, we used the bioluminescent squid and fish symbiont Vibrio fischeri to probe for host and environmental conditions that control interbacterial competition via the type VI secretion system. Our findings identify a new host-specific cue that promotes competition among many but not all V. fischeri isolates, underscoring the utility of studying multiple strains to reveal how competitive mechanisms may be differentially regulated among closely related populations as they evolve to fill distinct niches.
Sequential multiple mediation of cognitive fusion and experiential avoidance in the relationship between rumination and social anxiety among Chinese adolescents

ABSTRACT Background and Objectives The potential mechanism by which rumination influences social anxiety through cognitive fusion and experiential avoidance proposed by the Acceptance and Commitment Therapy model has not been well-documented. This study, therefore, aimed to examine the sequential multiple mediation of the two processes. Design A cross-sectional survey was conducted. Method A total of 233 Chinese adolescents (42.06% girls) completed a set of printed self-report questionnaires measuring rumination, cognitive fusion, experiential avoidance, and social anxiety. The SPSS macro PROCESS (model 6) was used to test a sequential mediating model. A 95% confidence interval (CI) was calculated with 5000 bootstrapping re-samples. Results Bootstrap analyses indicated that there were indirect effects of rumination on social anxiety mediated by cognitive fusion together with experiential avoidance (B = 0.098, BootSE = 0.032, CI = 0.045 to 0.170), or solely by experiential avoidance (B = 0.048, BootSE = 0.020, CI = 0.014 to 0.093). The mediation of cognitive fusion alone was not significant (B = 0.065, BootSE = 0.038, CI = –0.006 to 0.144). Conclusions The results indicated the sequential mediating role of cognitive fusion and experiential avoidance, and the relative prominence of the latter in the association between rumination and social anxiety.
The ependymal cell cytoskeleton in the normal and injured spinal cord of mice

The cytoskeleton of ependymal cells is fundamental to organize and maintain the normal architecture of the central canal (CC). However, little is known about the plasticity of cytoskeletal components after spinal cord injury. Here, we focus on the structural organization of the cytoskeleton of ependymal cells in the normal and injured spinal cord of mice (both females and males) using immunohistochemical and electron microscopy techniques. We found that in uninjured animals, the actin cytoskeleton (as revealed by phalloidin staining) was arranged following the typical pattern of polarized epithelial cells with conspicuous actin pools located in the apical domain of ependymal cells. Transmission electron microscopy images showed microvilli tufts, long cilia, and characteristic intercellular membrane specializations. After spinal cord injury, F‐actin rearrangements paralleled by fine structural modifications of the apical domain of ependymal cells were observed. These changes involved disruptions of the apical actin pools as well as fine structural modifications of the microvilli tufts. When comparing the control and injured spinal cords, we also found modifications in the expression of vimentin and glial fibrillary acidic protein (GFAP). After injury, vimentin expression disappeared from the most apical domains of ependymal cells but the number of GFAP‐expressing cells within the CC increased. As in other polarized epithelia, the plastic changes in the cytoskeleton may be critically involved in the reaction of ependymal cells following a traumatic injury of the spinal cord.
Deciphering CAD: Structure and function of a mega‐enzymatic pyrimidine factory in health and disease

CAD is a 1.5 MDa particle formed by hexameric association of a 250 kDa protein divided into different enzymatic domains, each catalyzing one of the initial reactions for de novo biosynthesis of pyrimidine nucleotides: glutaminase‐dependent Carbamoyl phosphate synthetase, Aspartate transcarbamoylase, and Dihydroorotase. The pathway for de novo pyrimidine synthesis is essential for cell proliferation and is conserved in all living organisms, but the covalent linkage of the first enzymatic activities into a multienzymatic CAD particle is unique to animals. In other organisms, these enzymatic activities are encoded as monofunctional proteins for which there is abundant structural and biochemical information. However, the knowledge about CAD is scarce and fragmented. Understanding CAD requires not only to determine the three‐dimensional structures and define the catalytic and regulatory mechanisms of the different enzymatic domains, but also to comprehend how these domains entangle and work in a coordinated and regulated manner. This review summarizes significant progress over the past 10 years toward the characterization of CAD's architecture, function, regulatory mechanisms, and cellular compartmentalization, as well as the recent finding of a new and rare neurometabolic disorder caused by defects in CAD activities.
Dietary fat intake during early pregnancy is associated with cord blood DNA methylation at IGF2 and H19 genes in newborns

Maternal fat intake during pregnancy affects fetal growth, but mechanisms underlying this relationship are unclear. We performed an exploratory study of the associations of fat consumption during pregnancy with cord blood DNA methylation of the insulin‐like growth factor 2 (IGF2) and H19 genes. We used data from 96 uncomplicated full‐term pregnancies of mothers of whom majority had normal body mass index (BMI) (66%) in Project Viva, a prospective pre‐birth cohort. We assessed maternal diet with validated food frequency questionnaires during the first and second trimesters and measured DNA methylation in segments of the IGF2‐ and H19‐differentially methylated regions (DMRs) by pyrosequencing DNA extracted from umbilical cord blood samples. Mean (SD) age was 32.8 (4.1) years and prepregnancy BMI was 24.0 (4.4) kg/m2. Mean DNA methylation was 56.3% (3.9%) for IGF2‐DMR and 44.6% (1.9%) for H19‐DMR. Greater first trimester intake of omega‐6 polyunsaturated fat (effect per 1% of calories at the expense of carbohydrates) was associated with lower DNA methylation of IGF2‐DMR (−1.2%; 95% confidence interval [CI]: −2.2%, −0.2%) and higher DNA methylation at H19‐DMR (0.8%; 95% CI: 0.3%, 1.3%). On the other hand, greater first trimester intake of omega‐3 polyunsaturated fat was associated with lower DNA methylation of the H19‐DMR (−4.3%; 95% CI: −7.9%, −0.8%). We did not find significant associations of IGF2 and H19 methylation with IGF2 cord blood levels. Our findings suggest that early prenatal fat intake (omega‐3, omega‐6, and saturated fatty acids) may influence DNA methylation at the IGF2 and H19 locus, which could impact fetal development and long‐term health.