Miracle-dz/UniFAR-FTUs huggingface dataset:
Limbic cortico-striato-thalamo-cortical functional connectivity in drug-naïve patients of obsessive-compulsive disorder

Abstract Background The pathophysiology of obsessive-compulsive disorder (OCD) remains unclear despite extensive neuroimaging work on the disorder. Exposure to medication and comorbid mental disorders can confound the results of OCD studies. The goal of this study was to explore differences in brain functional connectivity (FC) within the cortico-striato-thalamo-cortical (CSTC) loop of drug-naïve and drug-free OCD patients and healthy controls (HCs). Methods A total of 29 drug-naïve OCD patients, 22 drug-free OCD patients, and 25 HCs matched on age, gender and education level underwent functional magnetic resonance imaging scanning at resting state. Seed-based connectivity analyses were conducted among the three groups. The Yale Brown Obsessive Compulsive Scale and clinical inventories were used to assess the clinical symptoms. Results Compared with HCs, the drug-naïve OCD patients had reduced FC within the limbic CSTC loop. In the drug-naïve OCD participants, we also found hyperconnectivity between the supplementary motor area and ventral and dorsal putamen (p < 0.05, corrected for multiple comparisons). Conclusions Exposure to antidepressants such as selective serotonin reuptake inhibitors may affect the function of some brain regions. Future longitudinal studies could help to reveal the pharmacotherapeutic mechanisms in these loops.
Prognostic Implication of pAMPK Immunohistochemical Staining by Subcellular Location and Its Association with SMAD Protein Expression in Clear Cell Renal Cell Carcinoma

Although cytoplasmic AMP-activated protein kinase (AMPK) has been known as a tumor-suppressor protein, nuclear AMPK is suggested to support clear cell renal cell carcinoma (ccRCC). In addition, pAMPK interacts with TGF-β/SMAD, which is one of the frequently altered pathways in ccRCC. In this study, we investigated the prognostic significance of pAMPK with respect to subcellular location and investigated its interaction with TGF-β/SMAD in ccRCC. Immunohistochemical staining for pAMPK, pSMAD2 and SMAD4 was conducted on tissue microarray of 987 ccRCC specimens. Moreover, the levels of pSMAD2 were measured in Caki-1 cells treated with 5-aminoimidazole-4-carboxamide ribonucleotide. The relationship between AMPK/pAMPK and TGFB1 expression was determined using the TCGA database. As a result, pAMPK positivity, either in the cytoplasm or nuclei, was independently associated with improved ccRCC prognosis, after adjusting for TNM stage and WHO grade. Furthermore, pAMPK-positive ccRCC displayed increased pSMAD2 and SMAD4 expression, while activation of pAMPK increased pSMAD2 in Caki-1 cells. However, AMPK/pAMPK expression was inversely correlated with TGFB1 expression in the TCGA database. Therefore, pAMPK immunostaining, both in the cytoplasm and nuclei, is a useful prognostic biomarker for ccRCC. pAMPK targets TGF-β-independent phosphorylation of SMAD2 and activates pSMAD2/SMAD4, representing a novel anti-tumoral mechanism of pAMPK in ccRCC.
An optimised STAPUT method for the purification of mouse spermatocyte and spermatid populations.

The purification of individual male germ cell populations is integral for molecular and biochemical characterisation of specific spermatogenic phases. Although a number of more contemporary techniques have been developed, velocity sedimentation using the STAPUT method remains as a gold standard for this purpose. The gentle nature of the technique, wherein germ cell sub-populations are separated by sedimentation at unit gravity, results in the isolation of viable and high-purity cells. We provide an updated and simplified step-by-step version of the STAPUT protocol for the purification of mouse male germ cells. As per the original method, the protocol described herein allows for the purification of mouse spermatocyte and round spermatids, however it also allows for successful purification of elongating, and elongated spermatid populations, and is optimised for the preservation of cellular ultrastructure. This method yields sufficient numbers of high purity cells from one adult mouse for RNA or protein extraction or for immunolocalisation studies.
Exploring Conformational Transitions and Free Energy Profiles of Proton Coupled Oligopeptide Transporters

Proteins involved in peptide uptake and transport belong to the proton-coupled oligopeptide transporter (POT) family. Crystal structures of POT family members reveal a common fold consisting of two domains of six transmembrane α helices that come together to form a “V” shaped transporter with a central substrate binding site. Proton coupled oligopeptide transporters operate through an alternate access mechanism, where the membrane transporter undergoes global conformational changes, alternating between inward-facing (IF), outward-facing (OF) and occluded (OC) states. Conformational transitions are promoted by proton and ligand binding, however, due to the absence of crystallographic models of the outward-open state, the role of H+ and ligands are still not fully understood. To provide a comprehensive picture of the POT conformational equilibrium, conventional and enhanced sampling molecular dynamics simulations of PepTst in the presence or absence of ligand and protonation were performed. Free energy profiles of the conformational variability of PepTst were obtained from microseconds of adaptive biasing force (ABF) simulations. Our results reveal that both, proton and ligand, significantly change the conformational free energy landscape. In the absence of ligand and protonation, only transitions involving IF and OC states are allowed. After protonation of the residue Glu300, the wider free energy well for Glu300 protonated PepTst indicates a greater conformational variability relative to the apo system, and OF conformations becames accessible. For the Glu300 Holo-PepTst, the presence of a second free energy minimum suggests that OF conformations are not only accessible, but also, stable. The differences in the free energy profiles demonstrate that transitions toward outward facing conformation occur only after protonation and, probably, this should be the first step in the mechanism of peptide transport. Our extensive ABF simulations provide a fully atomic description of all states of the transport process, offering a model for the alternating access mechanism and how protonation and ligand control the conformational changes. Graphical TOC Entry
Activity-induced SUMOylation of Neuronal Nitric Oxide Synthase is Associated with Plasticity of Synaptic Transmission and ERK1/2 Signaling.

AIMS Neuronal nitric oxide synthase (nNOS) and NO signaling have been implicated in learning, memory, and underlying long-lasting synaptic plasticity. In this study, we aimed at detecting whether nNOS is a target protein of SUMOylation in the hippocampus and its contributions to hippocampal long-term potentiation (LTP) of synaptic transmission. RESULTS We showed that N-methyl-D-aspartate receptors (NMDARs)-dependent neuronal activity enhancement induced the attachment of small ubiquitin-like modifier 1 (SUMO1) to nNOS. Protein inhibitor of activated STAT3 (PIAS3) promoted SUMO1 conjugation at K725 and K739 on nNOS, which upregulated NO production and nNOS S1412 phosphorylation (activation). In addition, the N-terminus (amino acids 43-86) of PIAS3 bound nNOS directly. Tat-PIAS3(43-86), a cell-permeable peptide containing PIAS3 residues 43-86, suppressed activity-induced nNOS SUMOylation by disrupting PIAS3-nNOS association. It also decreased LTP-related expression of Arc and brain-derived neurotrophic factor and blocked signaling via extracellular signal-regulated kinase (ERK) 1/2 and Elk-1 in the hippocampus. More importantly, PIAS3-mediated nNOS SUMOylation was required for activity-regulated ERK1/2 activation in nNOS-positive neurons and hippocampal LTP induction. Innovation and Conclusion. These findings indicated that network activity-regulated nNOS SUMOylation underlies excitatory synaptic LTP by facilitating nNOS-NO-ERK1/2 signal cascades.
Facilities that service economically advantaged neighborhoods perform surgical metastasectomy more often for patients with colorectal liver metastases

Metastasectomy of isolated colorectal liver metastases (CRLM) requires significant clinical expertise and may not be readily available or offered. The authors hypothesized that hospitals that treat a greater percentage of patients from higher income catchment areas are more likely to perform metastasectomies regardless of patient or tumor characteristics.
Medication histories documentation at the community pharmacy setting: A study from Jordan

Objectives The main objective of this study was to evaluate community pharmacists’ awareness and perception about medication reconciliation service and to assess the completeness of collecting patients’ medication histories in the community pharmacy setting. Methods A cross-sectional study was conducted between February to March 2018 in Amman-Jordan. During the study period, 150 community pharmacists were invited to participate in the study. Each pharmacist completed a validated structured questionnaire evaluating their awareness, current practice, perceived attitude and perceived barriers towards the implementation of medication reconciliation and the collection of medication histories at the community pharmacy setting. Results A total of 121 pharmacists agreed to participate and filled the questionnaire. Our results showed that only 13.2% of the pharmacists were able to define “medication reconciliation” correctly, and around 31% have a misconception that the medication reconciliation process should be performed only at the inpatient setting. Only 19.8% (n = 24) of the participating pharmacists stated that they ask all patients for a complete current medication list of medications when they arrive at the pharmacy site. Medication histories for most patients were lacking information about the dosage, route, frequency, and time of the last refill for each medication listed. “Patients lack of awareness about all the medications they are receiving” was the main barrier discouraging community pharmacists from collecting medication histories and participating in reconciliation service. Conclusion Community pharmacists in Jordan showed a low awareness about the medication reconciliation concept and demonstrated a modest role in obtaining medication histories in community pharmacies. But still, they showed a positive attitude towards their role in implementing the different steps of medication reconciliation. This suggests that educational workshops to increase pharmacists’ awareness about their role and responsibilities in collecting a complete and accurate medication history are warrented.
Functional dopaminergic neurons derived from human chorionic mesenchymal stem cells ameliorate striatal atrophy and improve behavioral deficits in Parkinsonian rat model

Human chorionic mesenchymal stem cells (HCMSCs) have been recognized as a desirable choice for cell therapy in neurological disorders such as Parkinson's disease (PD). Due to invaluable features of HCMSCs including their immunomodulatory and immunosuppressive properties, easily accessible and less differentiated compared to other types of MSCs, HCMSCs provide a great hope for regenerative medicine. Thus, the purpose of this study was to determine the in vitro and in vivo efficacy of HCMSCs‐derived dopaminergic (DA) neuron‐like cells with regard to PD. Initially, HCMSCs were isolated and underwent a 2‐week DA differentiation, followed by in vitro assessments, using quantitative real‐time polymerase chain reaction, immunocytochemistry, patch clamp recording, and high‐performance liquid chromatography. In addition, the effects of implanted HCMSCs‐derived DA neuron‐like cells on the motor coordination along with stereological alterations in the striatum of rat models of PD were investigated. Our results showed that under neuronal induction, HCMSCs revealed neuron‐like morphology, and expressed neuronal and DA‐specific genes, together with DA release. Furthermore, transplantation of HCMSCs‐derived DA neurons into the striatum of rat models of PD, augmented performance. Besides, it prevented reduction of striatal volume, dendritic length, and the total number of neurons, coupled with a diminished level of cleaved caspase‐3. Altogether, these findings suggest that HCMSCs could be considered as an attractive strategy for cell‐based therapies in PD.
Ex Situ Liver Machine Perfusion: The Impact of Fresh Frozen Plasma

The primary aim of this single‐center, phase 1 exploratory study was to investigate the safety, feasibility, and impact on intrahepatic hemodynamics of a fresh frozen plasma (FFP)–based perfusate in ex situ liver normothermic machine perfusion (NMP) preservation. Using an institutionally developed perfusion device, 21 livers (13 donations after brain death and 8 donations after circulatory death) were perfused for 3 hours 21 minutes to 7 hours 52 minutes and successfully transplanted. Outcomes were compared in a 1:4 ratio to historical control patients matched according to donor and recipient characteristics and preservation time. Perfused livers presented a very low resistance state with high flow during ex situ perfusion (arterial and portal flows 340 ± 150 and 890 ± 70 mL/minute/kg liver, respectively). This hemodynamic state was maintained even after reperfusion as demonstrated by higher arterial flow observed in the NMP group compared with control patients (220 ± 120 versus 160 ± 80 mL/minute/kg liver, P = 0.03). The early allograft dysfunction (EAD) rate, peak alanine aminotransferase (ALT), and peak aspartate aminotransferase (AST) levels within 7 days after transplantation were lower in the NMP group compared with the control patients (EAD 19% versus 46%, P = 0.02; peak ALT 363 ± 318 versus 1021 ± 999 U/L, P = 0.001; peak AST 1357 ± 1492 versus 2615 ± 2541 U/L, P = 0.001 of the NMP and control groups, respectively). No patient developed ischemic type biliary stricture. One patient died, and all other patients are alive and well at a follow‐up of 12‐35 months. No device‐related adverse events were recorded. In conclusion, with this study, we showed that ex situ NMP of human livers can be performed safely and effectively using a noncommercial device and an FFP‐based preservation solution. Future studies should further investigate the impact of an FFP‐based perfusion solution on liver hemodynamics during ex situ normothermic machine preservation.
Structural and biophysical characterizations of HIV-1 matrix trimer binding to lipid nanodiscs shed light on virus assembly

During the late phase of the HIV-1 replication cycle, the viral Gag polyproteins are targeted to the plasma membrane for assembly. The Gag-membrane interaction is mediated by binding of Gag's N-terminal myristoylated matrix (MA) domain to phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). The viral envelope (Env) glycoprotein is then recruited to the assembly sites and incorporated into budding particles. Evidence suggests that Env incorporation is mediated by interactions between Gag's MA domain and the cytoplasmic tail of the gp41 subunit of Env (gp41CT). MA trimerization appears to be an obligatory step for this interaction. Insufficient production of a recombinant MA trimer and unavailability of a biologically relevant membrane system have been barriers to detailed structural and biophysical characterization of the putative MA-gp41CT-membrane interactions. Here, we engineered a stable recombinant HIV-1 MA trimer construct by fusing a foldon domain (FD) of phage T4 fibritin to the MA C terminus. Results from NMR experiments confirmed that the FD attachment does not adversely alter the MA structure. Employing hydrogen–deuterium exchange MS, we identified an MA-MA interface in the MA trimer that is implicated in Gag assembly and Env incorporation. Utilizing lipid nanodiscs as a membrane mimetic, we show that the MA trimer binds to membranes 30-fold tighter than does the MA monomer and that incorporation of PI(4,5)P2 and phosphatidylserine enhances the binding of MA to nanodiscs. These findings advance our understanding of a fundamental mechanism in HIV-1 assembly and provide a template for investigating the interaction of MA with gp41CT.
A Scoping Review and Conceptual Model of Social Participation and Mental Health among Refugees and Asylum Seekers

Social participation plays a key role in the integration of refugees and asylum seekers into their host societies, and is also closely tied to the mental health of those populations. The aim of this scoping review was to study how the concept of social participation is described in empirical research, and how it is associated with mental health outcomes. Methods: In total, 64 studies were identified through searches in PubMed, PsycInfo, and Sociological Abstracts. These studies describe various forms of social participation among refugees and asylum seekers, and 33 of them also addressed various forms of mental health outcomes. Results: The identified studies described forms and conditions of social participation—both in the host country and transnationally—that could be synthesized into three broad dimensions: (1) Regulatory frameworks, conditions and initiatives; (2) Established societal organizations and social structures; and (3) Community organized groups. Each of these consisted of several sub-domains. The identified dimensions of social participation were also associated with psychosocial well-being and decreased psychological distress. Conclusions: There is a need for policies to enable and support the participation of refugees and asylum seekers in various dimensions of social structures in host societies. Social participation enhances resilience, re-establishes social lives, and acts as a protective factor against poor mental health outcomes.
Glaucoma management in the era of artificial intelligence

Glaucoma is a result of irreversible damage to the retinal ganglion cells. While an early intervention could minimise the risk of vision loss in glaucoma, its asymptomatic nature makes it difficult to diagnose until a late stage. The diagnosis of glaucoma is a complicated and expensive effort that is heavily dependent on the experience and expertise of a clinician. The application of artificial intelligence (AI) algorithms in ophthalmology has improved our understanding of many retinal, macular, choroidal and corneal pathologies. With the advent of deep learning, a number of tools for the classification, segmentation and enhancement of ocular images have been developed. Over the years, several AI techniques have been proposed to help detect glaucoma by analysis of functional and/or structural evaluations of the eye. Moreover, the use of AI has also been explored to improve the reliability of ascribing disease prognosis. This review summarises the role of AI in the diagnosis and prognosis of glaucoma, discusses the advantages and challenges of using AI systems in clinics and predicts likely areas of future progress.
Thinner bark increases sensitivity of wetter Amazonian tropical forests to fire.

Understory fires represent an accelerating threat to Amazonian tropical forests and can, during drought, affect larger areas than deforestation itself. These fires kill trees at rates varying from < 10 to c. 90% depending on fire intensity, forest disturbance history and tree functional traits. Here, we examine variation in bark thickness across the Amazon. Bark can protect trees from fires, but it is often assumed to be consistently thin across tropical forests. Here, we show that investment in bark varies, with thicker bark in dry forests and thinner in wetter forests. We also show that thinner bark translated into higher fire-driven tree mortality in wetter forests, with between 0.67 and 5.86 gigatonnes CO2 lost in Amazon understory fires between 2001 and 2010. Trait-enabled global vegetation models that explicitly include variation in bark thickness are likely to improve the predictions of fire effects on carbon cycling in tropical forests.
Direct Wideband Coherent Localization by Distributed Antenna Arrays

We address wideband direct coherent localization of a radio transmitter by a distributed antenna array in a multipath scenario with spatially-coherent line-of-sight (LoS) signal components. Such a signal scenario is realistic in small cells, especially indoors in the mmWave range. The system model considers collocated time and phase synchronized receiving front-ends with antennas distributed in 3D space at known locations connected to the front-ends via calibrated coaxial cables or analog radio frequency over fiber links. The signal model assumes spherical wavefronts. We propose two ML-type algorithms (for known and unknown transmitter waveforms) and a subspace-based SCM-MUSIC algorithm for wideband direct coherent position estimation. We demonstrate the performance of the methods by Monte Carlo simulations. The results show that even in multipath environments, it is possible to achieve localization accuracy that is much better (by two to three orders of magnitude) than the carrier wavelength. They also suggest that the methods that do not exploit knowledge of the waveform have mean-squared errors approaching the Cramér–Rao bound.
Optimism and depressive symptoms following a diabetes diagnosis: Results from the Health and Retirement Study

Depression is common among individuals with diabetes and contributes to poorer prognoses. Optimism is associated with enhanced mental health. Therefore, this study tested whether optimism buffered against increases in depressive symptoms following a diabetes diagnosis. Participants were drawn from the Health and Retirement Study (n = 328, Mage = 65.8). Optimism, assessed before diagnosis, was inversely associated with depressive symptoms within 2 (B = −.30, p = .004, ΔR2 = .02) and 6 (B = −.29, p = .008, ΔR2 = .02) years of a diabetes diagnosis. Results suggest that optimism is a protective factor for comorbid depressive symptoms.
Insights revealed by the co‐crystal structure of the Saccharomyces cerevisiae histidine phosphotransfer protein Ypd1 and the receiver domain of its downstream response regulator Ssk1

Two‐component signaling systems are the primary means by which bacteria, archaea, and certain plants and fungi react to their environments. The model yeast, Saccharomyces cerevisiae, uses the Sln1 signaling pathway to respond to hyperosmotic stress. This pathway contains a hybrid histidine kinase (Sln1) that autophosphorylates and transfers a phosphoryl group to its own receiver domain (R1). The phosphoryl group is then transferred to a histidine phosphotransfer protein (Ypd1) that finally passes it to the receiver domain (R2) of a downstream response regulator (Ssk1). Under normal conditions, Ssk1 is constitutively and preferentially phosphorylated in the phosphorelay. Upon detecting hyperosmotic stress, Ssk1 rapidly dephosphorylates and activates the high‐osmolarity glycerol (HOG) pathway, initiating a response. Despite their distinct physiological roles, both Sln1 and Ssk1 bind to Ypd1 at a common docking site. Co‐crystal structures of response regulators in complex with their phosphorelay partners are scarce, leaving many mechanistic and structural details uncharacterized for systems like the Sln1 pathway. In this work, we present the co‐crystal structure of Ypd1 and a near wild‐type variant of the receiver domain of Ssk1 (Ssk1‐R2‐W638A) at a resolution of 2.80 Å. Our structural analyses of Ypd1‐receiver domain complexes, biochemical determination of binding affinities for Ssk1‐R2 variants, in silico free energy estimates, and sequence comparisons reveal distinctive electrostatic properties of the Ypd1/Ssk1‐R2‐W638A complex that may provide insight into the regulation of the Sln1 pathway as a function of dynamic osmolyte concentration.