Miracle-dz/UniFAR-FTUs huggingface dataset:
The Scaffold Proteins Paxillin B and α-Actinin Regulate Septation in Aspergillus nidulans via Control of Actin Ring Contraction

Cytokinesis, as the final step of cell division, plays an important role in fungal growth and proliferation. In the filamentous fungus Aspergillus nidulans, defective cytokinesis is able to induce abnormal multinuclear or nonnucleated cells and then result in reduced hyphal growth and abolished sporulation. Previous studies have reported that a conserved contractile actin ring (CAR) protein complex and the septation initiation network (SIN) signaling kinase cascade are required for cytokinesis and septation; however, little is known about the role(s) of scaffold proteins involved in these two important cellular processes. In this study, we show that a septum-localized scaffold protein paxillin B (PaxB) is essential for cytokinesis/septation in A. nidulans. The septation defects observed in a paxB deletion strain resemble those caused by the absence of another identified scaffold protein, α-actinin (AcnA). Deletion of α-actinin (AcnA) leads to undetectable PaxB at the septation site, whereas deletion of paxB does not affect the localization of α-actinin at septa. However, deletion of either α-actinin (acnA) or paxB causes the actin ring to disappear at septation sites during cytokinesis. Notably, overexpression of α-actinin acnA partially rescues the septum defects of the paxB mutant but not vice versa, suggesting AcnA may play a dominant role over that of PaxB for cytokinesis and septation. In addition, PaxB and α-actinin affect the septal dynamic localization of MobA, a conserved component of the SIN pathway, suggesting they may affect the SIN protein complex function at septa. Protein pull-down assays combined with liquid chromatography–mass spectrometry identification indicate that α-actinin AcnA and PaxB likely do not directly interact, but presumably belong to an actin cytoskeleton protein network that is required for the assembly and contraction of the CAR. Taken together, findings in this study provide novel insights into the roles of conserved scaffold proteins during fungal septation in A. nidulans.
Mitochondrial Protection by PARP Inhibition

Inhibitors of the nuclear DNA damage sensor and signalling enzyme poly(ADP-ribose) polymerase (PARP) have recently been introduced in the therapy of cancers deficient in double-strand DNA break repair systems, and ongoing clinical trials aim to extend their use from other forms of cancer non-responsive to conventional treatments. Additionally, PARP inhibitors were suggested to be repurposed for oxidative stress-associated non-oncological diseases resulting in a devastating outcome, or requiring acute treatment. Their well-documented mitochondria- and cytoprotective effects form the basis of PARP inhibitors’ therapeutic use for non-oncological diseases, yet can limit their efficacy in the treatment of cancers. A better understanding of the processes involved in their protective effects may improve the PARP inhibitors’ therapeutic potential in the non-oncological indications. To this end, we endeavoured to summarise the basic features regarding mitochondrial structure and function, review the major PARP activation-induced cellular processes leading to mitochondrial damage, and discuss the role of PARP inhibition-mediated mitochondrial protection in several oxidative stress-associated diseases.
Factors Associated with Incidental Neuroimaging Abnormalities in New Primary Headache Patients

Background and Purpose Deciding whether or not to perform neuroimaging in primary headache is a dilemma for headache physicians. The aim of this study was to identify clinical predictors of incidental neuroimaging abnormalities in new patients with primary headache disorders. Methods This cross-sectional study was based on a prospective multicenter headache registry, and it classified 1,627 consecutive first-visit headache patients according to the third edition (beta version) of the International Classification of Headache Disorders (ICHD-3β). Primary headache patients who underwent neuroimaging were finally enrolled in the analysis. Serious intracranial pathology was defined as serious neuroimaging abnormalities with a high degree of medical urgency. Univariable and multivariable logistic regression analyses were conducted to identify factors associated with incidental neuroimaging abnormalities. Results Neuroimaging abnormalities were present in 170 (18.3%) of 927 eligible patients. In multivariable analysis, age ≥40 years [multivariable-adjusted odds ratio (aOR)=3.37, 95% CI=2.07–6.83], male sex (aOR=1.61, 95% CI=1.12–2.32), and age ≥50 years at headache onset (aOR=1.86, 95% CI=1.24–2.78) were associated with neuroimaging abnormalities. In univariable analyses, age ≥40 years was the only independent variable associated with serious neuroimaging abnormalities (OR=3.37, 95% CI=1.17–9.66), which were found in 34 patients (3.6%). These associations did not change after further adjustment for neuroimaging modality. Conclusions Incidental neuroimaging abnormalities were common and varied in a primary headache diagnosis. A small proportion of the patients incidentally had serious neuroimaging abnormalities, and they were predicted by age ≥40 years. These findings can be used to guide the performing of neuroimaging in primary headache disorders.
Familial clustering of hepatitis C virus in a Pakistani population

Pakistan has the second‐highest burden of hepatitis C patients in the world. A total of 683 individuals, who visited the Liver Clinic during the study period, were screened for the presence of hepatitis C virus (HCV) infection. A total of 534 individuals who showed positive HCV infection were grouped into the case group and 149 individuals with HCV negative status were grouped into the control group. A detailed questionnaire was used to collect demographic, clinical, HCV risk factor, and familial clustering data. HCV familial clustering was found in 30.1% in the case group compared with 17.4% in the control group. We also found 17% of patients had spouses who were also infected with HCV compared to 4% spouse infection in the control group. Only 3.7% of patients had HCV positive mothers. These results were further expanded by regression analysis that showed that family history and sexual history are independent risk factors for transmission of hepatitis C infection and mother's history has no significance as a risk factor for transmission. The major risk factor for getting HCV infection are dental procedures, unsafe injections, surgery, and blood transfusions. There is a strong need to increase awareness about HCV transmission routes among positive patients to reduce the chances of HCV familial clustering.
Noninvasive Diagnosis of NAFLD and NASH

The aim of this review is to outline emerging biomarkers that can serve as early diagnostic tools to identify patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) and, among them, the subgroup of best candidates for clinical trials on emerging compounds. Regarding possible predictors of NAFLD, a number of studies evaluated a combination of serum biomarkers either available in routine practice (or investigational) or proprietary and expensive. So far, magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) appears to be the most accurate for fatty liver diagnosis. In clinical practice, the main question is how to diagnose NASH early. There are new promising biomarkers that can help in diagnosing early stages of NASH, yet they include variables not routinely tested. In the setting of NASH, most studies confirm that, in spite of several well-known limitations, transient elastography or point shear wave elastography can help in enriching the pool of patients that should be screened for investigational treatments. Newer multiomics biomarkers including those focusing on microbiota can be useful but require methods to be standardized and implemented. To date, one biomarker alone is not able to non- or minimally invasively identify patients with NASH and mild to moderate fibrosis.
Novel insights into serodiagnosis and epidemiology of Erysipelothrix rhusiopathiae, a newly recognized pathogen in muskoxen (Ovibos moschatus)

Background Muskoxen are a key species of Arctic ecosystems and are important for food security and socio-economic well-being of many Indigenous communities in the Arctic and Subarctic. Between 2009 and 2014, the bacterium Erysipelothrix rhusiopathiae was isolated for the first time in this species in association with multiple mortality events in Canada and Alaska, raising questions regarding the spatiotemporal occurrence of the pathogen and its potential impact on muskox populations. Materials and methods We adapted a commercial porcine E. rhusiopathiae enzyme-linked immunosorbent assay to test 958 blood samples that were collected from muskoxen from seven regions in Alaska and the Canadian Arctic between 1976 and 2017. The cut-off between negative and positive results was established using mixture-distribution analysis, a data-driven approach. Based on 818 samples for which a serological status could be determined and with complete information, we calculated trends in sample seroprevalences in population time-series and compared them with population trends in the investigated regions. Results Overall, 219/818 (27.8%, 95% Confidence Interval: 24.7–31.0) samples were classified as positive for exposure to E. rhusiopathiae. There were large variations between years and regions. Seropositive animals were found among the earliest serum samples tested; 1976 in Alaska and 1991 in Canada. In Alaskan muskoxen, sample seroprevalence increased after 2000 and, in two regions, peak seroprevalences occurred simultaneously with population declines. In one of these regions, concurrent unusual mortalities were observed and E. rhusiopathiae was isolated from muskox carcasses. In Canada, there was an increase in sample seroprevalence in two muskox populations following known mortality events that had been attributed to E. rhusiopathiae. Conclusion Our results indicate widespread exposure of muskoxen to E. rhusiopathiae in western Canada and Alaska. Although not new to the Arctic, we documented an increased exposure to the pathogen in several regions concurrent with population declines. Understanding causes for the apparent increased occurrence of this pathogen and its association with large scale mortality events for muskoxen is critical to evaluate the implications for wildlife and wildlife-dependent human populations in the Arctic.
Efficacy and Safety of Topical Clascoterone Cream, 1%, for Treatment in Patients With Facial Acne

Key Points Question What is the efficacy and safety of clascoterone cream, 1%, in the treatment of facial acne among patients older than 9 years? Findings Results of 2 phase 3 randomized clinical trials including 1440 patients demonstrated that patients with acne treated with clascoterone cream, 1%, experienced greater treatment success vs treatment with vehicle, with considerable reductions in absolute noninflammatory and inflammatory lesion counts. Adverse events with use of clascoterone cream, 1%, were predominantly mild and similar to those with use of vehicle. Meaning Clascoterone cream, 1%, a novel topical androgen receptor inhibitor, appears to demonstrate a favorable safety profile and improvement in efficacy for acne treatment.
HMGN5 promotes IL-6-induced epithelial-mesenchymal transition of bladder cancer by interacting with Hsp27

Bladder cancer (BC) is one of the most common cancers worldwide, with a high rate of recurrence and poor outcomes. High-mobility group nucleosome-binding domain 5 (HMGN5) is overexpressed in many cancers and could cause carcinogenesis in BC. By protein-protein-interaction (PPI) analysis, we found that heat shock protein 27 (Hsp27), also a crucial functional factor in BC carcinogenesis, is significantly related to HMGN5. Hsp27 is required for IL-6-mediated EMT via STAT3/Twist signaling in prostate cancer. Here, we hypothesize that HMGN5 may interact with Hsp27 to affect IL-6-induced EMT and invasion in BC via STAT3 signaling. In the present study, we found that HMGN5 and Hsp27 are highly expressed in BC tissues and positively correlated with each other. HMGN5 interacts with Hsp27 in vitro, to modulate the cell invasion and EMT in BC. Moreover, HMGN5 could modulate IL-6-Hsp27-induced EMT and invasion in BC cells by regulating STAT3 phosphorylation and STAT3 targeting of the Twist promoter. HMGN5 interacts with Hsp27 to promote tumor growth in a human BC xenograft model in nude mice. In summary, HMGN5 interacts with Hsp27 to promote IL-6-induced EMT, therefore promoting invasion in BC and contributing to the progression of BC.
Quantitative and qualitative analysis of autophagy flux using imaging

As an intracellular degradation system, autophagy is an essential and defensive cellular program required for cell survival and cellular metabolic homeostasis in response to various stresses, such as nutrient deprivation and the accumulation of damaged organelles. In general, autophagy flux consists of four steps: (1) initiation (formation of phagophore), (2) maturation and completion of autophagosome, (3) fusion of autophagosomes with lysosomes (formation of autolysosome), and (4) degradation of intravesicular components within autolysosomes. The number of genes and reagents that modulate autophagy is increasing. Investigation of their effect on autophagy flux is critical to understanding the roles of autophagy in many physiological and pathological processes. In this review, we summarize and discuss ways to analyze autophagy flux quantitatively and qualitatively with the use of imaging tools. The suggested imaging method can help estimate whether each modulator is an inhibitor or a promoter of autophagy and elucidate the mode of action of specific genes and reagents on autophagy processes.
Antibacterial Activities of Selected Pure Compounds Isolated from Gut Bacteria of Animals Living in Polluted Environments

Antibiotic resistance is a global threat to public health, further accelerated by the misuse of antibiotics in humans and animals. Our recent studies have shown that gut bacteria of animals living in polluted environments are a potential source of antibacterials. Gut bacteria of cockroaches, water monitor lizards and the turtle exhibited molecules such as curcumenol, docosanedioic acid, N-acyl-homoserine lactone, L-homotyrosine and Di-rhamnolipids. Using purified compounds, assays were performed to determine their antibacterial properties using serial dilution method, cytotoxic effects using lactate dehydrogenase release, and cell viability using MTT assay. The results revealed that the purified compounds exhibited significant antibacterial activities (p < 0.05) against selected Gram-negative (Pseudomonas aeruginosa) and Gram-positive bacteria (Streptococcus pyogenes) with effective MIC50 and MIC90 at µg concentrations, and with minimal effects on human cells as observed from LDH and MTT assays. These findings are significant and provide a basis for the rational development of therapeutic antibacterials. Future studies are needed to determine in vivo effects of the identified molecules together with their mode of action, which could lead to the development of novel antibacterial(s).
Current aspects of polycystic ovary syndrome I: definition, pathophysiology, clinical manifestations, diagnosis and complications

Abstract Polycystic ovary syndrome (PCOS) is the most frequent endocrine disease among women with childbearing potential, the best-known cause of hirsutism, with a hypothesized prevalence of 8-22%. The first part of the paper discusses the conceptional evolution of the syndrome, from its description in 1935 by Stein and Leventhal till today. It describes the changes in the criteria systems, emphasizing that the Rotterdam criteria, proposed in 2003 by the European Society for Human Reproduction and Embryology/American Society for Reproductive Medicine, are still valid today. This system basically differs from earlier (1990) NIH-criteria in one aspect: it introduced two newer phenotypes, one without hyperandrogenism and the other with ovulatory cycles, so it distinguishes 4 phenotypes. The etiology and pathogenesis of PCOS is heterogeneous, multifactorial, poorly understood. We present the 3 leading hypotheses (1 - hypothalamo-hypophyseal disturbances, 2 – primary enzyme disorders in ovarian, or ovarian/adrenal steroidogenesis, resulting primarily in hyperactivity of 17alpha-hydroxylase/17,20-lyase, 3 – insulin resistance-hyperinsulinism and other metabolic dysfunctions). We emphasize the role of genetically determined hyperandrogenism, that of insulin resistance-hyperinsulinism and the importance of reinforcing each other. Subsequently, the aggravating aspects of the frequently associated metabolic syndrome are discussed, and then the effects of the mentioned pathological processes on the endocrine and other organ structures participating in the regulation of sexual functions. We stress the hypothetical role of perinatal and pubertal androgen exposition in the pathogenesis of PCOS. The mechanisms of anovulation and those of the endometrial lesions are discussed, too. The clinical manifestations, the paraclinical and laboratory examinations, the positive and differential diagnosis and the complications are also presented. We intend to deal with the therapeutic aspects of PCOS in an upcoming paper.
Anuran limbs reflect microhabitat and distal, later‐developing bones are more evolutionarily labile *

Tetrapod limbs have been used as a model system to investigate how selective pressures and constraints shape morphological evolution. Anurans have had many independent transitions to various microhabitats, allowing us to dissect how these factors influence limb morphology. Furthermore, anurans provide a unique system to test the generality of developmental constraints proposed in mammals, namely that later‐developing limb bones are under less constraint and show more variation. We used microcomputed tomography scans of 236 species from 52 of 55 families, geometric morphometrics, and modern phylogenetic comparative methods to examine how limb bones are related to microhabitat, phylogeny, allometry, and developmental timing. Although there was significant phylogenetic signal, anuran limb shape showed a relationship with microhabitat and to a lesser extent, body size. We found that distal bones had higher evolutionary rates than proximal bones, providing evidence that developmental constraints are reduced in later‐developing bones. Distal bones also showed increased selection related to allometry and microhabitat, providing an additional explanation for higher evolutionary rates. By looking at the evolution of limb shape across a diverse clade, we demonstrated that multiple factors have shaped anuran limbs and that greater evolutionary lability in later‐developing limb bones is likely a general trend among tetrapods.
A Guide to Targeting the Endocannabinoid System in Drug Design

The endocannabinoid system (ECS) is one of the most crucial systems in the human organism, exhibiting multi-purpose regulatory character. It is engaged in a vast array of physiological processes, including nociception, mood regulation, cognitive functions, neurogenesis and neuroprotection, appetite, lipid metabolism, as well as cell growth and proliferation. Thus, ECS proteins, including cannabinoid receptors and their endogenous ligands’ synthesizing and degrading enzymes, are promising therapeutic targets. Their modulation has been employed in or extensively studied as a treatment of multiple diseases. However, due to a complex nature of ECS and its crosstalk with other biological systems, the development of novel drugs turned out to be a challenging task. In this review, we summarize potential therapeutic applications for ECS-targeting drugs, especially focusing on promising synthetic compounds and preclinical studies. We put emphasis on modulation of specific proteins of ECS in different pathophysiological areas. In addition, we stress possible difficulties and risks and highlight proposed solutions. By presenting this review, we point out information pivotal in the spotlight of ECS-targeting drug design, as well as provide an overview of the current state of knowledge on ECS-related pharmacodynamics and show possible directions for needed research.
A Comparative Analysis of Implants Presenting Different Diameters: Extra-Narrow, Narrow and Conventional

This study aimed at performing a comparative analysis of the fracture resistance of implants, evaluating extra-narrow, narrow, and regular implants. Four groups containing 15 implants each were evaluated. Group 1 (G1): single-piece extra-narrow implants; Group 2 (G2): single-piece narrow implants; Group 3 (G3): Morse taper narrow implants with solid abutments; Group 4 (G4): Morse taper conventional implants with solid abutments. The implants were tested using a universal testing machine for their maximum force limit and their maximum bending moment. After obtaining the data, the Shapiro–Wilk, ANOVA, and Tukey (p < 0.05) statistical tests were applied. Samples from all the groups were analyzed by scanning electron microscopy and Groups 3 and 4 were analyzed by profilometry. The means and the standard deviation values for the maximum force limit (N) and the maximum bending moment (Nmm) were respectively: G1:134.29 N (10.27); G2:300.61 N (24.26); G3:360.64 N (23.34); G4:419.10 N (18.87); G1:1612.02 Nmm (100.6); G2:2945 Nmm (237.97); G3:3530.38 Nmm (228.75); G4:4096.7 Nmm (182.73). The groups behaved statistically different from each other, showing that the smallest diameter implants provided less fracture resistance, both in the tensile strength tests and in the maximum bending moment between all groups. Furthermore, single-piece implants, with 2.5 mm and 3.0 mm diameters, deformed in the implant body region area, rather than in the abutment region.
First Insights into the Urinary Metabolome of Captive Giraffes by Proton Nuclear Magnetic Resonance Spectroscopy

The urine from 35 giraffes was studied by untargeted 1H-NMR, with the purpose of obtaining, for the first time, a fingerprint of its metabolome. The metabolome, as downstream of the transcriptome and proteome, has been considered as the most representative approach to monitor the relationships between animal physiological features and environment. Thirty-nine molecules were unambiguously quantified, able to give information about diet, proteins digestion, energy generation, and gut-microbial co-metabolism. The samples collected allowed study of the effects of age and sex on the giraffe urinary metabolome. In addition, preliminary information about how sampling procedure and pregnancy could affect a giraffe’s urinary metabolome was obtained. Such work could trigger the setting up of methods to non-invasively study the health status of giraffes, which is utterly needed, considering that anesthetic-related complications make their immobilization a very risky practice.