Miracle-dz/UniFAR-FTUs huggingface dataset:
Design and Synthesis of Beta-Hairpin Peptidomimetics for Modulating Integrin Mediated Cell Adhesion, Abeta Fibrillogenesis and p53-MDM2 Protein-Protein Interactions

Inhibiting therapeutically important protein-protein interactions has been a tremendous challenge for medicinal chemists. The folded 3D structures of peptides and proteins, mainly comprise secondary structural elements i.e α-helices and β-sheet have created an opportunity to design small molecules and peptidomimetic inhibitors of protein-protein interaction (PPI). Hence, information about the formation and stabilization of these secondary structures is vital for designing future drugs. In this dissertation, several cyclic beta-hairpin peptidomimetics that mimic the recognition surface have been designed and synthesized as inhibitors for different targets such as integrin mediated extracellular matrix -cell adhesion in multiple myeloma, p53-MDM2 PPI, amyloid beta fibrillogenesis inhibitor. Cyclization of linear peptides to restrict the number of conformations available to the linear peptide can increase its affinity for the target as well as increase its proteolytic resistance. In this study, different beta turn promoters that increase the propensity of cyclic peptides to adopt beta-sheet structures have been designed and synthesized. Chapter two discusses the design and synthesis of several cyclic III (Integrin Interaction Inhibitor) peptides that block adhesion of integrins to extracellular matrix components in Multiple Myeloma tumor cells. These cyclic peptides, as assayed by
Site-specific incorporation of synthetic amino acids into functioning ion channels

Synthetic amino acids may be introduced into functioning proteins by means of nonsense suppression, using tRNA aminoacylated with unnatural amino acids. This technique can be extended to living cells through micro-injection of mRNA and tRNA into Xenopus laevis oocytes. Introduction of synthetic amino acids into proteins has been used, broadly, for three purposes. First, sensitive probes have been incorporated into proteins, using side chain chemistry unavailable to naturally encoded amino acids. Second, reactive side chains have been developed which can drive conformational rearrangements of the protein. Third, natural post-translational modifications of protein side chains have been mimicked. The work presented here applies all of these approaches to the study of ion channels. A series of fluorinated Trp residues was incorporated into the nicotinic acetylcholine receptor (nAChR) to probe electrostatic effects on cation-pi mediated binding of nicotine and other agonists. Site-specific protein backbone cleavage of the nicotinic acetylcholine and purinergic P2X2 receptors was undertaken, along with intersubunit photo-crosslinking in the nAChR. Caged tyrosine was employed to study tyrosine phosphorylation of an important modulatory site in the potassium channel Kir2.1. Finally, caged phosphoamino acid analogs were synthesized for further characterization of the effects of phosphorylation on ion channels.
Periglomerular afferent innervation of the mouse renal cortex

Recent studies using a novel method for targeted ablation of afferent renal nerves have demonstrated their importance in the development and maintenance of some animal models of hypertension. However, relatively little is known about the anatomy of renal afferent nerves distal to the renal pelvis. Here, we investigated the anatomical relationship between renal glomeruli and afferent axons identified based on transient receptor potential vanilloid 1 channel (TRPV1) lineage or calcitonin gene related peptide (CGRP) immunolabeling. Analysis of over 6,000 (10,000 was accurate prior to the removal of the TH data during the review process) glomeruli from wildtype C57BL/6J mice and transgenic mice expressing tdTomato in TRPV1 lineage cells indicated that approximately half of all glomeruli sampled were closely apposed to tdTomato+ or CGRP+ afferent axons. Glomeruli were categorized as superficial, midcortical, or juxtamedullary based on their depth within the cortex. Juxtamedullary glomeruli were more likely to be closely apposed by afferent axon subtypes than more superficial glomeruli. High-resolution imaging of thick, cleared renal slices and subsequent distance transformations revealed that CGRP+ axons closely apposed to glomeruli were often found within 2 microns of nephrin+ labeling of glomerular podocytes. Furthermore, imaging of thick slices suggested that CGRP+ axon bundles can closely appose multiple glomeruli that share the same interlobular artery. Based on their expression of CGRP or tdTomato, prevalence near glomeruli, proximity to glomerular structures, and close apposition to multiple glomeruli within a module, we hypothesize that periglomerular afferent axons may function as mechanoreceptors monitoring glomerular pressure. These anatomical findings highlight the importance of further studies investigating the physiological role of periglomerular afferent axons in neural control of renal function in health and disease.
Deciphering immune responses primed by a bacterial lipopeptide in wheat towards Zymoseptoria tritici

Plant immunity induction with natural biocontrol compounds is a valuable and promising ecofriendly tool that fits with sustainable agriculture and healthy food. Despite the agroeconomic significance of wheat, the mechanisms underlying its induced defense responses remain obscure. We reveal here, using combined transcriptomic, metabolomic and cytologic approach, that the lipopeptide mycosubtilin from the beneficial bacterium Bacillus subtilis, protects wheat against Zymoseptoria tritici through a dual mode of action (direct and indirect) and that the indirect one relies mainly on the priming rather than on the elicitation of plant defense-related mechanisms. Indeed, the molecule primes the expression of 80 genes associated with sixteen functional groups during the early stages of infection, as well as the accumulation of several flavonoids during the period preceding the fungal switch to the necrotrophic phase. Moreover, genes involved in abscisic acid (ABA) biosynthesis and ABA-associated signaling pathways are regulated, suggesting a role of this phytohormone in the indirect activity of mycosubtilin. The priming-based bioactivity of mycosubtilin against a biotic stress could result from an interaction of the molecule with leaf cell plasma membranes that may mimic an abiotic stress stimulus in wheat leaves. This study provides new insights into induced immunity in wheat and opens new perspectives for the use of mycosubtilin as a biocontrol compound against Z. tritici.
Coronary microvascular dysfunction: A review of recent progress and clinical implications

The coronary microcirculation plays a cardinal role in regulating coronary blood flow to meet the changing metabolic demands of the myocardium. Coronary microvascular dysfunction (CMD) refers to structural and functional remodeling of the coronary microcirculation. CMD plays a role in the pathogenesis of obstructive and non-obstructive coronary syndromes as well as myocardial diseases, including heart failure with preserved ejection fraction (HFpEF). Despite recent diagnostic advancements, CMD is often under-appreciated in clinical practice, and may allow for the development of novel therapeutic targets. This review explores the diagnosis and pathogenic role of CMD across a range of cardiovascular diseases, its prognostic significance, and the current therapeutic landscape.
Direct activation of endogenous Calcineurin A : biological impact of selective peptide aptamers

Therapeutic approaches leading to the stimulation of regeneration, and/or inhibition of degeneration processes in neuromuscular disorders are believed to offer valid therapeutic strategies that would preserve muscle tone and contribute to the quality of life while lengthening patient life span. Activation of CalcineurinA (CnA), a threonine-serine phosphatase, controls gene regulatory programs in skeletal muscle by stimulating slow muscle fiber (type I) gene expression. This phosphatase has been also identified as a key mediator in the hypertrophic response and in skeletal muscle regeneration. Activation of CnA is, therefore, considered as a potentially interesting means of stimulating muscle regeneration in myopathies. We have identified a peptide aptamer that activates CnA in vitro, in cells and in vivo. In a mouse model for denervation-induced muscle atrophy, CnA-activating peptide aptamers show significant positive impact. This is reflected in larger overall muscle cross-sectional surface area due to an increased number of fibers and larger individual fiber surface area. Insight into the biological mechanism is afforded by observation of increased levels of nuclear NFAT transcription factor in these fibers, in agreement with peptide aptamer-mediated activation of CnA. Furthermore, a significant increase in central nuclei, characteristic of the presence of new fibers, is observed in muscles treated with the peptide aptamers specifically activating CnA. Identification of the specific binding site of the peptide aptamer on CnA was achieved using several truncations of the phosphatase, offering insight into the molecular mechanism of action. Together, these studies offer the first proof that direct activation of endogenous CnA has a measureable impact on cellular responses resulting in stimulation of muscle regeneration and enhancement of pathophysiological state in selected animal models.
Evaluation and attribution of historical surface air temperature changes over China simulated by coupled and uncoupled models

The increase in the average surface air temperature anomaly (SATA) over China is higher than the global average. However, the accurate simulation and attribution of regional SATA evolution remain challenging for current global climate models. This study simulates historical SATA variations over China using the coupled (FGOALS-g3) and uncoupled (atmospheric component, GAMIL3) models and examines their possible causes. Results show that both models reproduce the historical SATA variation with higher correlation coefficients (0.735 and 0.782) than many global climate models (0.25–0.56), although they overestimate or underestimate the changes of SATA to some extent in different periods. The results show that the cooling trend during 1941–1970 is well simulated with the coupled model while poorly presented with the uncoupled model; the coupled simulations particularly produce stronger long-term trends than the uncoupled ones during 1870–2014 considering full interaction among the atmosphere, ocean, and sea ice. In contrast, the uncoupled simulations reproduce better decadal and multi-decadal SATA variations owing to the constraints of the observed sea surface temperature (SST), such as the Atlantic multidecadal oscillation, and sea ice cover. Using Detection and Attribution Model Intercomparison Project (DAMIP) experiments, we found that the warming in the early 20th century and the recent 50 years is mainly driven by natural forcings and greenhouse gases (GHGs), whereas the cooling during 1941–1970 is caused by natural factors and anthropogenic aerosols. The cooling effects of anthropogenic aerosols are mainly attributed from the indirect SST-mediated responses through the atmosphere-ocean interactions in the coupled model.
The coexistence region in the Van der Waals fluid and the liquid-liquid phase transitions

Cellular membraneless organelles are thought to be droplets formed within the two-phase region corresponding to proteinaceous systems endowed with the liquid-liquid transition. However, their metastability requires an additional constraint—they arise in a certain region of density and temperature between the spinodal and binodal lines. Here, we consider the well-studied van der Waals fluid as a test model to work out criteria to determine the location of the spinodal line for situations in which the equation of state is not known. Our molecular dynamics studies indicate that this task can be accomplished by considering the specific heat, the surface tension and characteristics of the molecular clusters, such as the number of component chains and radius of gyration.
Replacing alfalfa hay with industrial hemp ethanol extraction byproduct and Chinese wildrye hay: Effects on lactation performance, plasma metabolites, and bacterial communities in Holstein cows

This trial was designed to investigate the effects of industrial hemp ethanol extraction byproduct (IHEEB) and Chinese wildrye hay (CWH) replacement of alfalfa hay (AH) on digestibility, and lactation performance, plasma metabolites, ruminal fermentation, and bacterial communities in Holstein dairy cows. Nine healthy multiparous Holstein cows (parity = 3) with similar body weights (584 ± 12.3 kg), days in milk (108 ± 11.4), and milk yields (30 ± 1.93 kg; all mean ± standard deviation) were used in a replicated 3 × 3 Latin square design with 3 periods of 21 d. During each period, each group consumed 1 of 3 diets: (1) 0% IHEEB (0IHEEB); (2) 6.0% IHEEB and 1.7% Chinese wildrye hay (6IHEEB); (3) 10.8% IHEEB and 4.3% Chinese wildrye hay (11IHEEB). The diets in each group were isocaloric and isonitrogenous, with similar contents of concentrate and silage but different ratios of IHEEB and CWH to replace AH. The results showed that increasing the substitute did not affect the total-tract apparent nutrient digestibility. There was no difference in lactation performance of dairy cows fed the three diets, except for the cows' somatic cell count (SCC), which decreased with the increase in the amount of the substitute. Cannabidiol and tetrahydrocannabinol were not detected in milk samples of dairy cows in the different treatment groups. 6IHEEB and 11IHEEB-fed cows showed a linear decrease in total volatile fatty acids (VFA) and butyrate compared to the 0IHEEB cows. Plasma IL-1β content quadratically decreased with feeding IHEEB and CWH, and other blood parameters were unaffected. The rumen fluid's relative abundances of Bacteroidota, Fibrobacterota, and Prevotellaceae quadratically increased, while Firmicutes tended to decrease quadratically as the substitution increased. Feeding IHEEB and CWH linearly increased the relative abundances of Firmicutes, Lachnospiraceae, Monoglobaceae, and Butyricicoccaceae in the feces. As the substitution increased, the cost of dairy farming was reduced. In summary, substituting AH with IHEEB and CWH in diets did not affect the total-tract apparent nutrient digestibility, improved milk composition, and plasma immune indices. It changed the bacterial composition in rumen fluid and feces and improved dairy farming benefits.
Comparative transcriptome profiling reveals the importance of GmSWEET15 in soybean susceptibility to Sclerotinia sclerotiorum

Soybean sclerotinia stem rot (SSR) is a disease caused by Sclerotinia sclerotiorum that causes incalculable losses in soybean yield each year. Considering the lack of effective resistance resources and the elusive resistance mechanisms, we are urged to develop resistance genes and explore their molecular mechanisms. Here, we found that loss of GmSWEET15 enhanced the resistance to S. sclerotiorum, and we explored the molecular mechanisms by which gmsweet15 mutant exhibit enhanced resistance to S. sclerotiorum by comparing transcriptome. At the early stage of inoculation, the wild type (WT) showed moderate defense response, whereas gmsweet15 mutant exhibited more extensive and intense transcription reprogramming. The gmsweet15 mutant enriched more biological processes, including the secretory pathway and tetrapyrrole metabolism, and it showed stronger changes in defense response, protein ubiquitination, MAPK signaling pathway-plant, plant-pathogen interaction, phenylpropanoid biosynthesis, and photosynthesis. The more intense and abundant transcriptional reprogramming of gmsweet15 mutant may explain how it effectively delayed colonization by S. sclerotiorum. In addition, we identified common and specific differentially expressed genes between WT and gmsweet15 mutant after inoculation with S. sclerotiorum, and gene sets and genes related to gmsweet15_24 h were identified through Gene Set Enrichment Analysis. Moreover, we constructed the protein–protein interaction network and gene co-expression networks and identified several groups of regulatory networks of gmsweet15 mutant in response to S. sclerotiorum, which will be helpful for the discovery of candidate functional genes. Taken together, our results elucidate molecular mechanisms of delayed colonization by S. sclerotiorum after loss of GmSWEET15 in soybean, and we propose novel resources for improving resistance to SSR.
Cerebellar and basal ganglia structural connections in humans: Effect of aging and relation with memory and learning

Introduction The cerebellum and basal ganglia were initially considered anatomically distinct regions, each connected via thalamic relays which project to the same cerebral cortical targets, such as the motor cortex. In the last two decades, transneuronal viral transport studies in non-human primates showed bidirectional connections between the cerebellum and basal ganglia at the subcortical level, without involving the cerebral cortical motor areas. These findings have significant implications for our understanding of neurodevelopmental and neurodegenerative diseases. While these subcortical connections were established in smaller studies on humans, their evolution with natural aging is less understood. Methods In this study, we validated and expanded the previous findings of the structural connectivity within the cerebellum-basal ganglia subcortical network, in a larger dataset of 64 subjects, across diﬀerent age ranges. Tractography and fixel-based analysis were performed on the 3 T diﬀusion-weighted dataset using Mrtrix3 software, considering fiber density and cross-section as indicators of axonal integrity. Tractography of the well-established cerebello-thalamo-cortical tract was conducted as a control. We tested the relationship between the structural white matter integrity of these connections with aging and with the performance in diﬀerent domains of Addenbrooke’s Cognitive Examination. Results Tractography analysis isolated connections from the dentate nucleus to the contralateral putamen via the thalamus, and reciprocal tracts from the subthalamic nucleus to the contralateral cerebellar cortex via the pontine nuclei. Control tracts of cerebello-thalamo-cortical tracts were also isolated, including associative cerebello-prefrontal tracts. A negative linear relationship was found between the fiber density of both the ascending and descending cerebellum-basal ganglia tracts and age. Considering the cognitive assessments, the fiber density values of cerebello-thalamo-putaminal tracts correlated with the registration/learning domain scores. In addition, the fiber density values of cerebello-frontal and subthalamo-cerebellar (Crus II) tracts correlated with the cognitive assessment scores from the memory domain. Conclusion We validated the structural connectivity within the cerebellum-basal ganglia reciprocal network, in a larger dataset of human subjects, across wider age range. The structural features of the subcortical cerebello-basal ganglia tracts in human subjects display age-related neurodegeneration. Individual morphological variability of cerebellar tracts to the striatum and prefrontal cortex was associated with diﬀerent cognitive functions, suggesting a functional contribution of cerebellar tracts to cognitive decline with aging. This study oﬀers new perspectives to consider the functional role of these pathways in motor learning and the pathophysiology of movement disorders involving the cerebellum and striatum.
Potential mediators of improvement in painful chemotherapy-induced peripheral neuropathy via a web-based cognitive behavioural intervention.

Purpose Preliminary evidence suggests that a self-guided cognitive and behaviourally-based pain management intervention (PROSPECT) is effective for chronic painful chemotherapy-induced peripheral neuropathy (CIPN), but its mechanism of action is unknown. The purpose of this secondary analysis was to explore if changes in anxiety, depression, sleep-related impairment, or fatigue mediated improvements in worst pain following PROSPECT in individuals with chronic painful CIPN. Methods Sixty participants were randomized to receive self-guided cognitive behavioural pain management (access for eight weeks) or treatment as usual. A seven-day worst CIPN pain diary and the PROMIS measures of anxiety, depression, fatigue, and sleep-related impairment were administered pre/posttest (eight-weeks). Causal mediation analysis was used to quantify mediators of worst pain improvement. Results None of the hypothesized mediators had a statistically significant effect on worst pain (n=38). Implications Further research is needed to identify potential mediators of pain intensity that can be targeted by specific cognitive behavioural strategies to improve painful CIPN severity.
DO PILATES AND YOGA AFFECT QUALITY OF LIFE AND PHYSICAL PERFORMANCE OF ELDERLY LIVING IN A NURSING HOME A PRELIMINARY STUDY

1 Gazi Üniversitesi T›p Fakültesi Fiziksel T›p ve Rehabilitasyon Anabilim Dal› ANKARA 2 Gazi Üniversitesi Beden E¤itimi ve Meslek Yüksekokulu ANKARA Özden ÖZYEM‹fiC‹ TAfiKIRAN1 ‹brahim C‹C‹O⁄LU2 Nasrin GOLMOGHAN‹-ZADEH2 Ayfle DEM‹R ATILGAN1 Emre BA⁄CI2 Mehmet GÜNAY2 Fatma ATALAY1 DO PILATES AND YOGA AFFECT QUALITY OF LIFE AND PHYSICAL PERFORMANCE OF ELDERLY LIVING IN A NURSING HOME A PRELIMINARY STUDY
Evidence for chronic mechanical irritation as a causative factor in oral cancer: application of Bradford Hill criteria

Chronic mechanical irritation (CMI) of the oral mucosa has been proposed as a risk factor for oral cancer (OC), but the available evidence is limited and controversial. One of the main limitations is the lack of proper criteria to define and classify CMI. The objective of this narrative review is to apply the Bradford Hill causality criteria to assess such an association based on the published literature. The level of evidence is not conclusive, mainly due to methodological shortcomings. Hence, to systematize future CMI research, we recommend the following items should be included: a clear definition for CMI, ascertaining any temporal association, recording all types of CMI: dental, prosthetic, and functional. Finally, it is important to emphasize that studies dealing with risk factors for OC should not only be restricted to established factors such as tobacco, alcohol, and areca nut consumption but should also consider other factors including the patient’s dental condition. In this regard, CMI, tooth loss, periodontal disease, and many others could be included. The causality criteria set out by Bradford Hill could be used for studying different controversial risk factors for OC.