Miracle-dz/UniFAR-FTUs huggingface dataset:
ABPP-HT* - Deep meets fast for activity-based profiling of deubiquitylating enzymes using advanced DIA mass spectrometry methods

Activity-based protein profiling (ABPP) uses a combination of activity-based chemical probes with mass spectrometry (MS) to selectively characterise a particular enzyme or enzyme class. ABPP has proven invaluable for profiling enzymatic inhibitors in drug discovery. When applied to cell extracts and cells, challenging the ABP-enzyme complex formation with a small molecule can simultaneously inform on potency, selectivity, reversibility/binding affinity, permeability, and stability. ABPP can also be applied to pharmacodynamic studies to inform on cellular target engagement within specific organs when applied to in vivo models. Recently, we established separate high depth and high throughput ABPP (ABPP-HT) protocols for the profiling of deubiquitylating enzymes (DUBs). However, the combination of the two, deep and fast, in one method has been elusive. To further increase the sensitivity of the current ABPP-HT workflow we implemented state-of-the-art data-independent acquisition (DIA) and data-dependent acquisition (DDA) MS analysis tools. Hereby, we describe an improved methodology, ABPP-HT* (enhanced high-throughput-compatible activity-based protein profiling), that in combination with DIA MS methods allowed for the consistent profiling of 35-40 DUBs and provided a reduced number of missing values, whilst maintaining a throughput of 100 samples per day.
Dependence of diffusion in Escherichia coli cytoplasm on protein size, environmental conditions, and cell growth

Inside prokaryotic cells, passive translational diffusion typically limits the rates with which cytoplasmic proteins can reach their locations. Diffusion is thus fundamental to most cellular processes, but the understanding of protein mobility in the highly crowded and non-homogeneous environment of a bacterial cell is still limited. Here we investigated the mobility of a large set of proteins in the cytoplasm of Escherichia coli, by employing fluorescence correlation spectroscopy (FCS) combined with simulations and theoretical modeling. We conclude that cytoplasmic protein mobility could be well described by Brownian diffusion in the confined geometry of the bacterial cell and at the high viscosity imposed by macromolecular crowding. We observed similar size dependence of protein diffusion for the majority of tested proteins, whether native or foreign to E. coli, and, for the faster-diffusing proteins, it is well consistent with the Stokes-Einstein relation once taking into account the specific dumbbell shape of protein fusions. Pronounced subdiffusion and hindered mobility are only observed for proteins with extensive interactions within the cytoplasm. Finally, while protein diffusion becomes markedly faster in actively growing cells, at high temperature, or upon treatment with rifampicin, and slower at high osmolarity, all of these perturbations affect proteins of different sizes in the same proportions, which could thus be described as changes of a well-defined cytoplasmic viscosity.
Self-organization of songbird neural sequences during social isolation

Behaviors emerge via a combination of experience and innate predis-positions. As the brain matures, it undergoes major changes in cellular, network and functional properties that can be due to sensory experience as well as developmental processes. In normal birdsong learning, neural sequences emerge to control song syllables learned from a tutor. Here, we disambiguate the role of experience and development in neural sequence formation by delaying exposure to a tutor. Using functional calcium imaging, we observe neural sequences in the absence of tutoring, demonstrating that experience is not necessary for the formation of sequences. However, after exposure to a tutor, pre-existing sequences can become tightly associated with new song syllables. Since we delayed tutoring, only half our birds learned new syllables following tutor exposure. The birds that failed to learn were the birds in which pre-tutoring neural sequences were most ‘crystallized’, that is, already tightly associated with their (untutored) song.
Molecular characteristics and laminar distribution of prefrontal neurons projecting to the mesolimbic system

Prefrontal cortical influence over the mesolimbic system – including the nucleus accumbens (NAc) and the ventral tegmental area (VTA) - is implicated in various cognitive processes and behavioral malfunctions. The functional versatility of this system could be explained by an underlying anatomical complexity; however, the detailed characterization of the medial prefrontal cortical (mPFC) innervation of the NAc and VTA is still lacking. Therefore, combining classical retrograde and conditional viral tracing techniques with multiple fluorescent immunohistochemistry, we sought to deliver a precise, cell- and layer-specific anatomical description of the cortico-mesolimbic pathways. We demonstrated that NAc- (mPFCNAc) and VTA-projecting mPFC (mPFCVTA) populations show different laminar distribution (layers 2/3-5a and 5b-6, respectively) and express different molecular markers. Specifically, calbindin and Ntsr1 are specific to mPFCNAc neurons, while mPFCVTA neurons express high levels of Ctip2 and FoxP2, indicating that these populations are mostly separated at the cellular level. We directly tested this with double retrograde tracing and Canine adenovirus type 2-mediated viral labelling and found that there is indeed minimal overlap between the two populations. Furthermore, whole-brain analysis revealed that the projection patter of these populations is also different throughout the brain. Taken together, we demonstrated that the NAc and the VTA are innervated by two, mostly non-overlapping mPFC populations with different laminar distribution and molecular profile. These results can contribute to the advancement in our understanding of mesocorticolimbic functions and its disorders in future studies.
A Meta-Analysis of the Effect of Sodium Glucose Cotransporter-2 Inhibitors on Metabolic Parameters in Patients With Polycystic Ovary Syndrome

Objective Polycystic ovary syndrome (PCOS) is the most common endocrinopathy among women of childbearing age and is associated with multiple morbidities. However, treatment for this condition is mainly applied for symptomatic relief and does not address the complex pathophysiology of this condition. This meta-analysis was conducted on the usage of sodium-glucose cotransporter 2 inhibitors (SGLT-2is) in PCOS because this group of drugs presents an attractive strategy to address the metabolic and hormonal defects by managing the pathophysiological defects observed in this syndrome. Methods We included prospective trials that enrolled patients with established PCOS and compared an SGLT-2i group versus a control group with at least 2 weeks of follow-up. The standardized mean difference (SMD) was used for effect size estimation from individual studies and was pooled using the fixed effect model. Results We included four trials with a pooled population of 158 patients with documented PCOS who received either an SGLT-2i or standard management. From a metabolic perspective, significant improvements were observed in the reduction in body weight (SMD: -0.68, 95% CI -1.16 to -0.19, <0.01), fasting plasma glucose (FPG) (SMD: -0.59, 95% CI -0.99 to -0.19, P<0.01), and insulin resistance as assessed with the HOMA-IR (SMD: -0.39, 95% CI -0.76 to -0.03, P=0.03). In addition, a significant improvement was noted in dehydroepiandrosterone sulphate (DHEAS) levels (SMD: -0.55, 95% CI -0.94 to -0.16, P<0.01). Conclusion SGLT-2i use is associated with salutary outcomes of metabolic and anthropometric markers of PCOS and likely favourable hormonal effects. Clinical Trial Registration [https://www.crd. york.ac. uk/prospero/display_record. php? ID=CRD42021268564], PROSPERO 2021 CRD42021268564.
Is Douglas Fir [Pseudotsuga menziesii (Mirbel) Franco] Invasive in Central Europe? A Case Study From South-West Germany

Worldwide, forestry must face several challenges during the UN Decade on Ecosystem Restoration. The decline of biodiversity and ecosystem services, ongoing deforestation, climate change, and biological invasions must be mitigated with forest restoration and by applying sustainable forest management. Experiences with the integration of non-native tree species into forest management in many parts of the world show benefits but also trade-offs regarding sustainability. In Central Europe, Douglas fir [Pseudotsuga menziesii (Mirbel) Franco], originating from Northern America, has been introduced by forestry and managed for more than one and a half centuries. Growth characteristics, drought tolerance, and timber quality are major reasons which make this tree species attractive for forestry and wood industry. Whether Douglas fir might be invasive with potential trade-offs regarding biodiversity, uncontrolled regeneration, and spread is not yet fully understood and controversially debated. We investigated the regeneration of Douglas fir in the Spessart mountains, a vast woodland in south-western Germany which has a considerable cover of anthropogenic coniferous afforestations. We sampled the regeneration of Douglas fir by differentiating height growth classes in various forest-stand types, taking the distance from mature mother trees, abiotic site conditions (e.g., water balance and soil properties), light supply, forest-stand characteristics, ground vegetation, and browsing pressure into account. Also integrating the individual regeneration of the accompanying tree species, we applied multivariate analyses. Most of our investigated variables did not show a significant correlation with Douglas fir regeneration. However, results point to a positive relationship of spontaneous Douglas fir regeneration at moist and light sites as well as in close distance to potential seed trees. The analysis of the current invasion potential did not reveal a major risk under the given site conditions in the study area.
Structure-Activity Relationship Studies of 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine (FPMINT) Analogues as Inhibitors of Human Equilibrative Nucleoside Transporters

Equilibrative nucleoside transporters (ENTs) play a vital role in nucleotide synthesis, regulation of adenosine function and chemotherapy. Current inhibitors of ENTs are mostly ENT1-selective. Our previous study has demonstrated that 4-((4-(2-fluorophenyl)piperazin-1-yl)methyl)-6-imino-N-(naphthalen-2-yl)-1,3,5-triazin-2-amine (FPMINT) is a novel inhibitor of ENTs, which is more selective to ENT2 than to ENT1. The present study aimed to screen a series of FPMINT analogues and study their structure-activity relationship. Nucleoside transporter-deficient cells transfected with cloned human ENT1 and ENT2 were used as in vitro models. The results of the [3H]uridine uptake study showed that the replacement of the naphthalene moiety with the benzene moiety could abolish the inhibitory effects on ENT1 and ENT2. The addition of chloride to the meta position of this benzene moiety could restore only the inhibitory effect on ENT1 but had no effect on ENT2. However, the addition of the methyl group to the meta position or the ethyl or oxymethyl group to the para position of this benzene moiety could regain the inhibitory activity on both ENT1 and ENT2. The presence of a halogen substitute, regardless of the position, in the fluorophenyl moiety next to the piperazine ring was essential for the inhibitory effects on ENT1 and ENT2. Among the analogues tested, compound 3c was the most potent inhibitor. Compound 3c reduced V max of [3H]uridine uptake in ENT1 and ENT2 without affecting K m. The inhibitory effect of compound 3c could not be washed out. Compound 3c did not affect cell viability, protein expression and internalization of ENT1 and ENT2. Therefore, similar to FPMINT, compound 3c was an irreversible and non-competitive inhibitor. Molecular docking analysis also showed that the binding site of compound 3c in ENT1 may be different from that of other conventional inhibitors. It is expected that structural modification may further improve its potency and selectivity and lead to the development of useful pharmacological agents.
Transfer Learning Approaches for Neuroimaging Analysis: A Scoping Review

Deep learning algorithms have been moderately successful in diagnoses of diseases by analyzing medical images especially through neuroimaging that is rich in annotated data. Transfer learning methods have demonstrated strong performance in tackling annotated data. It utilizes and transfers knowledge learned from a source domain to target domain even when the dataset is small. There are multiple approaches to transfer learning that result in a range of performance estimates in diagnosis, detection, and classification of clinical problems. Therefore, in this paper, we reviewed transfer learning approaches, their design attributes, and their applications to neuroimaging problems. We reviewed two main literature databases and included the most relevant studies using predefined inclusion criteria. Among 50 reviewed studies, more than half of them are on transfer learning for Alzheimer's disease. Brain mapping and brain tumor detection were second and third most discussed research problems, respectively. The most common source dataset for transfer learning was ImageNet, which is not a neuroimaging dataset. This suggests that the majority of studies preferred pre-trained models instead of training their own model on a neuroimaging dataset. Although, about one third of studies designed their own architecture, most studies used existing Convolutional Neural Network architectures. Magnetic Resonance Imaging was the most common imaging modality. In almost all studies, transfer learning contributed to better performance in diagnosis, classification, segmentation of different neuroimaging diseases and problems, than methods without transfer learning. Among different transfer learning approaches, fine-tuning all convolutional and fully-connected layers approach and freezing convolutional layers and fine-tuning fully-connected layers approach demonstrated superior performance in terms of accuracy. These recent transfer learning approaches not only show great performance but also require less computational resources and time.
HPV Vaccine Hesitancy Among Medical Students in China: A Multicenter Survey

Human papillomavirus (HPV) is the most common genital tract virus infection and can cause genital warts and cervical cancer. This multicenter study examined HPV information sources, vaccine hesitancy, and the association between the two variables. An online survey of HPV information sources and vaccine hesitancy was conducted among Chinese medical students. The World Health Organization (WHO) Vaccine Hesitancy 3Cs model was used to evaluate reasons for respondents' vaccine hesitancy. A probit model was used to investigate the association between vaccine information sources and vaccine hesitancy. The reported rate of vaccine hesitancy was 62.36%. Convenience was the primary factor for vaccine hesitancy in medical students, and 19% used a single source to obtain vaccine information. A multivariate analysis revealed that master degree and above were 33% less likely to be hesitant about the HPV vaccine than first grade students. Respondents receiving HPV information through doctor were 8% less likely to report vaccine hesitancy than those receiving information from other information channels. HPV vaccine hesitancy requires more attention. Future studies could examine whether increasing vaccination locations and dissemination of information about the safety and effectiveness of HPV vaccines as well as using Internet media would help reduce medical students' vaccine hesitancy and expand HPV vaccine coverage.
Association Between Atopic Dermatitis, Asthma, and Serum Lipids: A UK Biobank Based Observational Study and Mendelian Randomization Analysis

Background Both atopic diseases and dysregulation of serum lipids (SLs) add to significant health burden, but evidences about their association are inconsistent. Objective This work is to evaluate the association between asthma/atopic dermatitis (AD) and SLs and investigate the potential causal relationship. Methods A large-scale cross-sectional study based on the UK Biobank (UKB) and then examined the casual relationships between SLs with asthma/AD based on a Mendelian randomization (MR) analysis. Results A total of 502,505 participants were included in analysis. After full adjustment, AD was associated with lower TG (β = −0.006; 95%CI, −0.010 to −0.002; P = 0.006), lower LDL (β = −0.004; 95%CI, −0.006 to −0.002, P < 0.001), and lower TC (β = −0.004; 95%CI, −0.005 to −0.002; P < 0.001) but insignificantly correlated to HDL (P = 0.794). Asthma was also inversely correlated to TG (β = −0.005; 95%CI, = −0.007 to −0.003; < 0.001), LDL (β = −0.003; 95%CI, −0.004 to −0.002; P < 0.001), and TC (β = −0.002; 95%CI, −0.003 to −0.002; P < 0.001), but was positively correlated to HDL (β = 0.004; 95%CI, 0.003 to 0.005; P < 0.001), respectively. In subsequent MR analysis, both allergic diseases and asthma showed a protective effect on TC. Allergic diseases, asthma, and AD all showed a negative effect on LDL. Conclusion Collectively, we identify a protective causal effect of allergic diseases on serum lipids, as well as a potentially positive association of HDL with asthma. Owing to the largest sample size and the application of IVs in causal inference, this study will provide a robust evidence for the management of asthma and AD and the prevention of dyslipidemia.
Astragaloside IV Alleviates Infarction Induced Cardiomyocyte Injury by Improving Mitochondrial Morphology and Function

The protective effect of astragaloside IV (AS-IV) on myocardial injury after myocardial infarction has been reported. However, the underlying mechanism is still largely unknown. We established a myocardial infarction model in C57BL/6 mice and injected intraperitoneally with 10 mg/kg/d AS-IV for 4 weeks. The cardiac function, myocardial fibrosis, and angiogenesis were investigated by echocardiography, Masson's trichrome staining, and CD31 and smooth muscle actin staining, respectively. Cardiac mitochondrial morphology was visualized by transmission electron microscopy. Cardiac function, infarct size, vascular distribution, and mitochondrial morphology were significantly better in AS-IV-treated mice than in the myocardial infarction model mice. In vitro, a hypoxia-induced H9c2 cell model was established to observe cellular apoptosis and mitochondrial function. H9c2 cells transfected with silent information regulator 3 (Sirt3) targeting siRNA were assayed for Sirt3 expression and activity. Sirt3 silencing eliminated the beneficial effects of AS-IV and abrogated the inhibitory effect of AS-IV on mitochondrial division. These results suggest that AS-IV protects cardiomyocytes from hypoxic injury by maintaining mitochondrial homeostasis in a Sirt3-dependent manner.
High Immunogenicity of a T-Cell Epitope-Rich Recombinant Protein Rv1566c-444 From Mycobacterium tuberculosis in Immunized BALB/c Mice, Despite Its Low Diagnostic Sensitivity

The discovery of immunodominant antigens is of great significance for the development of new especially sensitive diagnostic reagents and effective vaccines in controlling tuberculosis (TB). In the present study, we targeted the T-Cell epitope-rich fragment (nucleotide position 109-552) of Rv1566c from Mycobacterium tuberculosis (MTB) and got a recombinant protein Rv1566c-444 and the full-length protein Rv1566c with Escherichia coli expression system, then compared their performances for TB diagnosis and immunogenicity in a mouse model. The results showed that Rv1566c-444 had similar sensitivity with Rv1566c (44.44% Vs 30.56%) but lower sensitivity than ESAT-6&CFP-10&Rv3615c (44.4% Vs. 94.4%) contained in a commercial kit for distinguishing TB patients from healthy donors. In immunized BALB/c mice, Rv1566c-444 elicited stronger T-helper 1 (Th1) cellular immune response over Rv1566c with higher levels of Th1 cytokine IFN-γ and IFN-γ/IL-4 expression ratio by ELISA; more importantly, with a higher proliferation of CD4+ T cells and a higher proportion of CD4+ TNF-α+ T cells with flow cytometry. Rv1566c-444 also induced a higher level of IL-6 by ELISA and a higher proportion of Rv1566c-444-specific CD8+ T cells and a lower proportion of CD8 + IL-4 + T cells by flow cytometry compared with the Rv1566c group. Moreover, the Rv1566c-444 group showed a high IgG secretion level and the same type of CD4+ Th cell immune response (both IgG1/IgG2a >1) as its parental protein group. Our results showed the potential of the recombinant protein Rv1566c-444 enriched with T-Cell epitopes from Rv1566c as a host T cell response measuring biomarker for TB diagnosis and support further evaluation of Rv1566c-444 as vaccine antigen against MTB challenge in animal models in the form of protein mixture or fusion protein.
Aberrant Functional Connectivity of Sensorimotor Network and Its Relationship With Executive Dysfunction in Bipolar Disorder Type I

Background The key pathophysiological mechanism of executive dysfunction in patients with bipolar disorder type I (BD-I) is still unclear. Previous studies have demonstrated that it may be related to the disbalance of the sensory motor network (SMN). Objective This study was designed to explore the aberrant functional connectivity (FC) of SMN in BD-I patients and its potential associations with executive dysfunction. Methods Eighteen BD-I patients and 20 healthy controls (HCs) underwent resting-state fMRI scans. The intranetwork and internetwork functional connectivities of SMN were extracted by independent component analysis (ICA). Clinical symptoms were assessed by the Bech–Rafaelsen Mania Rating Scale (BRMS) and Positive and Negative Syndrome Scale (PANSS). Executive function was measured by digit span tasks and a verbal fluency test. Finally, linear regression and correlation analyses were applied to measure the potential associations between clinical symptoms, intranetwork and internetwork functional connectivities, and executive function performance. Results (1) Patients with BD-I showed increased connectivity in the right paracentral lobule and the right postcentral gyrus within the SMN, and the increased connectivity value was positively correlated with the BRMS score (P < 0.05) but negatively correlated with digit span forward scores (P < 0.05). (2) Compared with HC, the connectivity value increased between the SMN and dorsal attention network (DAN) (P < 0.01) and between the default mode network (DMN) and DAN (P < 0.05) but decreased between the DAN and auditory network (AN) (P < 0.05) and between the SMN and DMN (P < 0.01) in patients with BD-I. (3) Digit span forward scores and education of all participants were negatively correlated with FC between SMN and DAN. Age of all subjects was positively correlated with FC between SMN and DMN. Conclusion Our findings suggest that the sensorimotor network of BD-I has abnormal functional connections within and between networks, and the abnormal FC value correlated with clinical symptoms and executive function, which provide new information for exploring the neural physiopathology of executive dysfunction in BD-I patients.