Miracle-dz/UniFAR-FTUs huggingface dataset:
A Novel Subset of CD95+ Pro-Inflammatory Macrophages Overcome miR155 Deficiency and May Serve as a Switch From Metabolically Healthy Obesity to Metabolically Unhealthy Obesity

Metabolically healthy obesity (MHO) accounts for roughly 35% of all obese patients. There is no clear consensus that has been reached on whether MHO is a stable condition or merely a transitory period between metabolically healthy lean and metabolically unhealthy obesity (MUO). Additionally, the mechanisms underlying MHO and any transition to MUO are not clear. Macrophages are the most common immune cells in adipose tissues and have a significant presence in atherosclerosis. Fas (or CD95), which is highly expressed on macrophages, is classically recognized as a pro-apoptotic cell surface receptor. However, Fas also plays a significant role as a pro-inflammatory molecule. Previously, we established a mouse model (ApoE-/-/miR155-/-; DKO mouse) of MHO, based on the criteria of not having metabolic syndrome (MetS) and insulin resistance (IR). In our current study, we hypothesized that MHO is a transition phase toward MUO, and that inflammation driven by our newly classified CD95+CD86- macrophages is a novel mechanism for this transition. We found that, with extended (24 weeks) high-fat diet feeding (HFD), MHO mice became MUO, shown by increased atherosclerosis. Mechanistically, we found the following: 1) at the MHO stage, DKO mice exhibited increased pro-inflammatory markers in adipose tissue, including CD95, and serum; 2) total adipose tissue macrophages (ATMs) increased; 3) CD95+CD86- subset of ATMs also increased; and 4) human aortic endothelial cells (HAECs) were activated (as determined by upregulated ICAM1 expression) when incubated with conditioned media from CD95+-containing DKO ATMs and human peripheral blood mononuclear cells-derived macrophages in comparison to respective controls. These results suggest that extended HFD in MHO mice promotes vascular inflammation and atherosclerosis via increasing CD95+ pro-inflammatory ATMs. In conclusion, we have identified a novel molecular mechanism underlying MHO transition to MUO with HFD. We have also found a previously unappreciated role of CD95+ macrophages as a potentially novel subset that may be utilized to assess pro-inflammatory characteristics of macrophages, specifically in adipose tissue in the absence of pro-inflammatory miR-155. These findings have provided novel insights on MHO transition to MUO and new therapeutic targets for the future treatment of MUO, MetS, other obese diseases, and type II diabetes.
Cognitive Functioning and Schizotypy: A Four-Years Study

Although there is ample evidence from cross-sectional studies indicating cognitive deficits in high schizotypal individuals that resemble the cognitive profile of schizophrenia-spectrum patients, there is still lack of evidence by longitudinal/follow-up studies. The present study included assessments of schizotypal traits and a wide range of cognitive functions at two time points (baseline and 4-years assessments) in order to examine (a) their stability over time, (b) the predictive value of baseline schizotypy on cognition at follow-up and (c) differences in cognition between the two time points in high negative schizotypal and control individuals. Only high negative schizotypal individuals were compared with controls due to the limited number of participants falling in the other schizotypal groups at follow-up. Seventy participants (mean age: 36.17; 70% females) were assessed at baseline and follow-up. Schizotypal traits were evaluated with the Schizotypal Personality Questionnaire. We found that schizotypal traits decreased over time, except in a sub-group of participants (“schizotypy congruent”) that includes individuals who consistently meet normative criteria of inclusion in either a schizotypal or control group. In these individuals, negative schizotypy and aspects of cognitive-perceptual and disorganized schizotypy remained stable. The stability of cognitive functioning also varied over time: response inhibition, aspects of cued attention switching, set-shifting and phonemic/semantic verbal fluency improved at follow-up. High negative schizotypy at baseline predicted poorer response inhibition and semantic switching at follow-up while high disorganized schizotypy predicted poorer semantic processing and complex processing speed/set-shifting. The between-group analyses revealed that response inhibition, set-shifting and complex processing speed/set-shifting were poorer in negative schizotypals compared with controls at both time points, while maintaining set and semantic switching were poorer only at follow-up. Taken together, the findings show differential stability of the schizotypal traits over time and indicate that different aspects of schizotypy predict a different pattern of neuropsychological task performance during a 4-years time window. These results are of significant use in the formulation of targeted early-intervention strategies for high-risk populations.
Mechanisms for Development of Ciprofloxacin Resistance in a Clinical Isolate of Pseudomonas aeruginosa

Treatment of infections by Pseudomonas aeruginosa is difficult due to its high intrinsic and acquired antibiotic resistance. Upon colonization in the human hosts, P. aeruginosa accumulates genetic mutations that confer the bacterium antibiotic resistance and ability to better live in the host environment. Characterizing the evolutionary traits would provide important insights into the development of effective combinatory antibiotic therapies to cure P. aeruginosa infections. In this work, we performed a detailed analysis of the molecular mechanisms by which a clinical isolate (CSP18) yields a ciprofloxacin-resistant derivative (CRP42). Genomic DNA re-sequencing and RNAseq were carried out to compare the genomic mutational signature and transcriptional profiles between the two isolates. The results indicated that D87G mutation in GyrA, together with MexEF-OprN hyper-expression caused by F7S mutation in MexS, was responsible for the increased resistance to ciprofloxacin in the isolate CRP42. Further simulation of CRP42 by gene editing in CSP18 demonstrated that D87G mutation in GyrA rendered CSP18 a fourfold increase in minimum inhibitory concentration against ciprofloxacin, while F7S mutation in MexS conferred an additional eightfold increase. Our experimental results demonstrate for the first time that the clinically relevant F7S point mutation in MexS results in hyper-expression of the mexEF-oprN and thus confers P. aeruginosa resistance to ciprofloxacin.
Comparison of Outcomes Between Transperitoneal and Retroperitoneal Robotic Partial Nephrectomy: A Meta-Analysis Based on Comparative Studies

Background To compare perioperative, functional and oncological outcomes between transperitoneal robotic partial nephrectomy (TRPN) and retroperitoneal robotic partial nephrectomy (RRPN). Methods A literature searching of Pubmed, Embase, Cochrane Library and Web of Science was performed in August, 2020. Pooled odds ratios (ORs) or weighted mean differences (WMDs) with 95% conﬁdence intervals (CIs) were estimated using ﬁxed-effect or random-effect model. Publication bias was evaluated with funnel plots. Only comparative studies with matched design or similar baseline characteristics were included. Results Eleven studies embracing 2,984 patients were included. There was no signiﬁcant difference between the two groups regarding conversion to open (P = 0.44) or radical (P = 0.31) surgery, all complications (P = 0.06), major complications (P = 0.07), warm ischemia time (P = 0.73), positive surgical margin (P = 0.87), decline in eGFR (P = 0.42), CKD upstaging (P = 0.72), and total recurrence (P = 0.66). Patients undergoing TRPN had a significant higher minor complications (P = 0.04; OR: 1.39; 95% CI, 1.01–1.91), longer operative time (P < 0.001; WMD: 21.68; 95% CI, 11.61 to 31.76), more estimated blood loss (EBL, P = 0.002; WMD: 40.94; 95% CI, 14.87 to 67.01), longer length of hospital stay (LOS, P < 0.001; WMD: 0.86; 95% CI, 0.35 to 1.37). No obvious publication bias was identified. Conclusion RRPN is more favorable than TRPN in terms of less minor complications, shorter operative time, less EBL, and shorter LOS. Methodological limitations of the included studies should be considered while interpreting these results.
Familiarity for Serious Mental Illness in Help-Seeking Adolescents at Clinical High Risk of Psychosis

Aim: Ultrahigh-risk (UHR) individuals have an increased vulnerability to psychosis because of accumulating environmental and/or genetic risk factors. Although original research examined established risk factors for psychosis in the UHR state, these findings are scarce and often contradictory. The aims of this study were (a) to investigate the prevalence of severe mental illness (SMI) in family members of distinct subgroups of adolescents identified through the UHR criteria [i.e., non-UHR vs. UHR vs. first-episode psychosis (FEP)] and (b) to examine any relevant associations of family vulnerability and genetic risk and functioning deterioration (GRFD) syndrome with clinical and psychopathological characteristics in the UHR group. Methods: Adolescents (n = 147) completed an ad hoc sociodemographic/clinical schedule and the Comprehensive Assessment of At-Risk Mental States to investigate the clinical status. Results: More than 60% UHR patients had a family history of SMI, and approximately a third of them had at least a first-degree relative with psychosis or other SMI. A GRFD syndrome was detected in ~35% of UHR adolescents. GRFD adolescents showed baseline high levels of positive symptoms (especially non-bizarre ideas) and emotional disturbances (specifically, observed inappropriate affect). Conclusions: Our results confirm the importance of genetic and/or within-family risk factors in UHR adolescents, suggesting the crucial need of their early detection, also within the network of general practitioners, general hospitals, and the other community agencies (e.g., social services and school).
Association of Caveolin-1 Expression With Prostate Cancer: A Systematic Review and Meta-Analysis

Purpose The prognostic value of caveolin-1 in prostate cancer remains uncertain. Hence, this meta-analysis was performed to evaluate the prognostic value of caveolin-1 in prostate cancer, as well as ascertain the relationship between caveolin-1 expression and clinicopathological characteristics of prostate cancer patients. Methods The PubMed, Embase, Chinese National Knowledge Infrastructure and Chinese Biology Medicine databases were electronically searched to retrieve published studies on caveolin-1 expression in prostate cancer. After study selection and data extraction, the meta-analysis was conducted using Review manager 5.3 software. Odds ratio (OR) with 95% confidence interval (CI) was used to estimate the pooled effect. Funnel plot was used to assess publication bias. Results A total of ten studies were enrolled, which included 3976 cases of prostate cancer, 72 cases of high-grade intraepithelial neoplasia (HGPIN), and 157 normal controls. Results of the meta-analysis showed that the positive rate of caveolin-1 expression in prostate cancer was 18.28 times higher than that in normal control (OR= 18.28, 95% CI: 9.02–37.04, p<0.01), and 4.73 times higher than that in HGPIN (OR= 4.73, 95% CI: 2.38–9.42, p<0.01). The relationship between caveolin-1 and clinicopathological characteristics of prostate cancer showed that the differences in caveolin-1 expression in patients with prostate-specific antigen (PSA) >10 vs. ≤ 10 (OR=2.09, 95% CI: 1.35–3.22, p<0.01), differentiation degree low vs. medium/high (OR=2.74, 95% CI: 1.84–4.08, p<0.01), TNM stage T3+T4 vs. T1+T2 (OR=2.77, 95% CI: 1.78–4.29, p<0.01), and lymph node metastasis present vs. absent (OR=2.61, 95% CI: 1.84–3.69, p<0.01) were statistically significant. The correlation analysis between caveolin-1 and the survival time of patients with prostate cancer demonstrated that caveolin-1 was closely related to the prognosis of prostate cancer patients (HR=1.50, 95% CI: 1.28–1.76, p<0.01). Conclusion Caveolin-1 is overexpressed in prostate cancer, which can serve as a risk factor and adverse clinicopathological feature of prostate cancer. Caveolin-1 can also predict poor survival in prostate cancer patients after radical prostatectomy.
Understanding the Better Than Average Effect on Altruism

Prior research suggests that most people perceive themselves to be more altruistic than the average population, an observation known as the better-than-average (BTA) effect. Understanding the BTA effect carries significant public health implications, as self-perceived altruism is closely related to altruistic behaviors, which plays a significant role in individual and societal well-being. However, little is known about whether subpopulations with specific sociodemographic profiles are more likely to hold BTA altruistic self-perceptions, making it difficult to design targeted programs based on multiple sociodemographic characteristics to promote altruistic behaviors. This study addresses this gap by identifying the sociodemographic profiles of populations who are more likely to exhibit BTA effects on trait altruism. Data were derived from a representative sample of Hong Kong citizens (n = 1,185) in the 2017 Hong Kong Altruism Survey. A latent class analysis was performed using four domains of sociodemographic characteristics: sex, age, religion, and socioeconomic status. Multivariate multinomial logistic regressions were conducted to examine associations between class membership, BTA effect, and altruistic behaviors. The results yielded four classes of sociodemographic profiles. Middle-aged, Christian/Catholic, highly educated, and high-income individuals (Class 4, 17.8%) were most likely to exhibit BTA effects and behave altruistically; Class 3 (14.0%) were older, male, no/other religious belief, low education, and least likely to exhibit BTA effects and behave altruistically. Findings improve the understanding of the sociodemographic profiles of people showing BTA effects and facilitate targeted policy development to effectively promote altruism.
A Hetero-Multimeric Chitinase-Containing Plasmodium falciparum and Plasmodium gallinaceum Ookinete-Secreted Protein Complex Involved in Mosquito Midgut Invasion

Malaria parasites are transmitted by Anopheles mosquitoes. During its life cycle in the mosquito vector the Plasmodium ookinete escapes the proteolytic milieu of the post-blood meal midgut by traversing the midgut wall. This process requires penetration of the chitin-containing peritrophic matrix lining the midgut epithelium, which depends in part on ookinete-secreted chitinases. Plasmodium falciparum ookinetes have one chitinase (PfCHT1), whereas ookinetes of the avian-infecting parasite, P. gallinaceum, have two, a long and a short form, PgCHT1 and PgCHT2, respectively. Published data indicates that PgCHT2 forms a high molecular weight (HMW) reduction-sensitive complex; and one binding partner is the ookinete-produced von Willebrand A-domain-containing protein, WARP. Size exclusion chromatography data reported here show that P. gallinaceum PgCHT2 and its ortholog, P. falciparum PfCHT1 are covalently-linked components of a HMW chitinase-containing complex (> 1,300 kDa). Mass spectrometry of ookinete-secreted proteins isolated using a new chitin bead pull-down method identified chitinase-associated proteins in P. falciparum and P. gallinaceum ookinete-conditioned culture media. Mass spectrometry of this complex showed the presence of several micronemal proteins including von Willebrand factor A domain-related protein (WARP), ookinete surface enolase, and secreted ookinete adhesive protein (SOAP). To test the hypothesis that ookinete-produced PfCHT1 can form a high molecular homo-multimer or, alternatively, interacts with P. berghei ookinete-produced proteins to produce an HMW hetero-multimer, we created chimeric P. berghei parasites expressing PfCHT1 to replace PbCHT1, enabling the production of large numbers of PfCHT1-expressing ookinetes. We show that chimeric P. berghei ookinetes express monomeric PfCHT1, but a HMW complex containing PfCHT1 is not present. A better understanding of the chitinase-containing HMW complex may enhance development of next-generation vaccines or drugs that target malaria transmission stages.
Research Progress Concerning Dual Blockade of Lymphocyte-Activation Gene 3 and Programmed Death-1/Programmed Death-1 Ligand-1 Blockade in Cancer Immunotherapy: Preclinical and Clinical Evidence of This Potentially More Effective Immunotherapy Strategy

Although various immunotherapies have exerted promising effects on cancer treatment, many patients with cancer continue to exhibit poor responses. Because of its negative regulatory effects on T cells and its biological functions related to immune and inflammatory responses, there has been considerable emphasis on a protein-coding gene named lymphocyte-activation gene 3 (LAG3). Recently, evidence demonstrated marked synergy in its targeted therapy with programmed death-1 and programmed death-1 ligand-1 (PD-1/PD-L1) blockade, and a variety of LAG3 targeted agents are in clinical trials, indicating the important role of LAG3 in immunotherapy. This mini-review discusses preclinical and clinical studies investigating PD-1 pathway blockade in combination with LAG3 inhibition as a potentially more effective immunotherapy strategy for further development in the clinic. This strategy might provide a new approach for the design of more effective and precise cancer immune checkpoint therapies.
Electrochemical Characterization of a Complex FeFe Hydrogenase, the Electron-Bifurcating Hnd From Desulfovibrio fructosovorans

Hnd, an FeFe hydrogenase from Desulfovibrio fructosovorans, is a tetrameric enzyme that can perform flavin-based electron bifurcation. It couples the oxidation of H2 to both the exergonic reduction of NAD+ and the endergonic reduction of a ferredoxin. We previously showed that Hnd retains activity even when purified aerobically unlike other electron-bifurcating hydrogenases. In this study, we describe the purification of the enzyme under O2-free atmosphere and its biochemical and electrochemical characterization. Despite its complexity due to its multimeric composition, Hnd can catalytically and directly exchange electrons with an electrode. We characterized the catalytic and inhibition properties of this electron-bifurcating hydrogenase using protein film electrochemistry of Hnd by purifying Hnd aerobically or anaerobically, then comparing the electrochemical properties of the enzyme purified under the two conditions via protein film electrochemistry. Hydrogenases are usually inactivated under oxidizing conditions in the absence of dioxygen and can then be reactivated, to some extent, under reducing conditions. We demonstrate that the kinetics of this high potential inactivation/reactivation for Hnd show original properties: it depends on the enzyme purification conditions and varies with time, suggesting the coexistence and the interconversion of two forms of the enzyme. We also show that Hnd catalytic properties (Km for H2, diffusion and reaction at the active site of CO and O2) are comparable to those of standard hydrogenases (those which cannot catalyze electron bifurcation). These results suggest that the presence of the additional subunits, needed for electron bifurcation, changes neither the catalytic behavior at the active site, nor the gas diffusion kinetics but induces unusual rates of high potential inactivation/reactivation.
Health-Related Fitness in Adults From Eight European Countries—An Analysis Based on Data From the European Fitness Badge

Background There are conflicting reports about the fitness status of European adults, partly due to the lack of a standardized fitness test battery used across Europe. The European Fitness Badge (EFB) was developed in 2017 as an online-based tool to assess the health-related fitness of persons aged ≥ 18 years residing in European countries. We examined the demographic characteristics and fitness status of persons who completed the EFB between June 2017 and May 2019. Methods We conducted a multinational study in eight European countries. Participants completed the EFB which includes 11 validated motor tests to measure endurance, strength, coordination, and flexibility performance, under the supervision of an EFB instructor in different settings (e.g., sports club sessions, public events). Two different test batteries [test profiles (TPs)] are available to distinguish between less active (TP1) and active individuals (TP2). We calculated descriptive statistics and conducted analyses of variance to examine sample characteristics and a potential impact of sex, age, body mass index (BMI), physical activity, and posture on fitness as assessed by the EFB. Results The sample included 6,019 adults (68.7% females; mean age 52.7 years; age range 18–89 years). Participants who completed TP1 were older (TP1: 61.4 years; TP2: 44.2 years; p = 0.00), reported a lower level of physical activity (TP1: 3.8; TP2: 4.0; p = 0.00), had a higher BMI (TP1: 25.7; TP2: 24.3; p = 0.00) and a higher frequency of postural abnormalities (TP1: 43%; TP2: 33%; p = 0.00) than TP2 participants. Among 3,034 participants who completed TP2, males had higher performance in endurance, strength, and overall fitness, whereas females performed better in coordination and flexibility tests. In addition, younger age, lower BMI, and higher level of physical activity engagement were associated with better EFB test performance. Conclusion The EFB can be used to assess the health-related fitness status of individuals aged ≥ 18 years. Our results show that TP1 and TP2 were completed by persons from the respective target groups (i.e., less active vs. active), and also confirm findings from previous studies on potential determinants of fitness such as sex or age.