Miracle-dz/UniFAR-FTUs huggingface dataset:
Tumor-Specific T Cells Exacerbate Mortality and Immune Dysregulation during Sepsis

Key Points Tumor-specific CD8+ T cells worsen mortality in a mouse model of polymicrobial sepsis. This effect is linked to increased apoptosis of non–tumor-specific CD8+ T cells. This is linked to increased expression of 2B4 on non–tumor-specific CD8+ T cells. Visual Abstract Sepsis induces significant immune dysregulation characterized by lymphocyte apoptosis and alterations in the cytokine milieu. Because cancer patients exhibit a 10-fold greater risk of developing sepsis compared with the general population, we aimed to understand how pre-existing malignancy alters sepsis-induced immune dysregulation. To address this question, we assessed the impact of tumor-specific CD8+ T cells on the immune response in a mouse model of cecal ligation and puncture (CLP)–induced sepsis. Tumor-bearing animals containing Thy1.1+ tumor–specific CD8+ T cells were subjected to CLP, and groups of animals received anti-Thy1.1 mAb to deplete tumor-specific CD8+ T cells or isotype control. Results indicated that depleting tumor-specific T cells significantly improved mortality from sepsis. The presence of tumor-specific CD8+ T cells resulted in increased expression of the 2B4 coinhibitory receptor and increased apoptosis of endogenous CD8+ T cells. Moreover, tumor-specific T cells were not reduced in number in the tumors during sepsis but did exhibit impaired IFN-γ production in the tumor, tumor draining lymph node, and spleen 24 h after CLP. Our research provides novel insight into the mechanisms by which pre-existing malignancy contributes to increased mortality during sepsis.
Exosomes: Isolation, characterization, and biomedical applications

Exosomes are nano‐sized bioactive vesicles of 30–150 nm in diameter. They are secreted by exocytosis of nearly all type of cells in to the extracellular fluid. Thereby, they can be found in many biological fluids. Exosomes regulate intracellular communication between cells via delivery of their cargo which include lipids, proteins, and nucleic acid. Many desirable features of exosomes made them promising candidates in several therapeutic applications. In this review, we discuss the use of exosomes as diagnostic tools and their possible biomedical applications. Additionally, current techniques used for isolation, purification, and characterization of exosomes from both biological fluids and in vitro cell cultures were discussed.
ANGPTL8 protein-truncating variant associated with lower serum triglycerides and risk of coronary disease

Protein-truncating variants (PTVs) affecting dyslipidemia risk may point to therapeutic targets for cardiometabolic disease. Our objective was to identify PTVs that were associated with both lipid levels and the risk of coronary artery disease (CAD) or type 2 diabetes (T2D) and assess their possible associations with risks of other diseases. To achieve this aim, we leveraged the enrichment of PTVs in the Finnish population and tested the association of low-frequency PTVs in 1,209 genes with serum lipid levels in the Finrisk Study (n = 23,435). We then tested which of the lipid-associated PTVs were also associated with the risks of T2D or CAD, as well as 2,683 disease endpoints curated in the FinnGen Study (n = 218,792). Two PTVs were associated with both lipid levels and the risk of CAD or T2D: triglyceride-lowering variants in ANGPTL8 (-24.0[-30.4 to -16.9] mg/dL per rs760351239-T allele, P = 3.4 × 10−9) and ANGPTL4 (-14.4[-18.6 to -9.8] mg/dL per rs746226153-G allele, P = 4.3 × 10−9). The risk of T2D was lower in carriers of the ANGPTL4 PTV (OR = 0.70[0.60–0.81], P = 2.2 × 10−6) than noncarriers. The odds of CAD were 47% lower in carriers of a PTV in ANGPTL8 (OR = 0.53[0.37–0.76], P = 4.5 × 10−4) than noncarriers. Finally, the phenome-wide scan of the ANGPTL8 PTV showed that the ANGPTL8 PTV carriers were less likely to use statin therapy (68,782 cases, OR = 0.52[0.40–0.68], P = 1.7 × 10−6) compared to noncarriers. Our findings provide genetic evidence of potential long-term efficacy and safety of therapeutic targeting of dyslipidemias.
Inhibitors of Coronavirus 3CL Proteases Protect Cells from Protease-Mediated Cytotoxicity

Multiple coronavirus pandemics have occurred over the last 2 decades. This has highlighted a need to be proactive in the development of therapeutics that can be readily deployed in the case of future coronavirus pandemics. ABSTRACT We describe a mammalian cell-based assay to identify coronavirus 3CL protease (3CLpro) inhibitors. This assay is based on rescuing protease-mediated cytotoxicity and does not require live virus. By enabling the facile testing of compounds across a range of 15 distantly related coronavirus 3CLpro enzymes, we identified compounds with broad 3CLpro-inhibitory activity. We also adapted the assay for use in compound screening and in doing so uncovered additional severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3CLpro inhibitors. We observed strong concordance between data emerging from this assay and those obtained from live-virus testing. The reported approach democratizes the testing of 3CLpro inhibitors by developing a simplified method for identifying coronavirus 3CLpro inhibitors that can be used by the majority of laboratories, rather than the few with extensive biosafety infrastructure. We identified two lead compounds, GC376 and compound 4, with broad activity against all 3CL proteases tested, including 3CLpro enzymes from understudied zoonotic coronaviruses. IMPORTANCE Multiple coronavirus pandemics have occurred over the last 2 decades. This has highlighted a need to be proactive in the development of therapeutics that can be readily deployed in the case of future coronavirus pandemics. We developed and validated a simplified cell-based assay for the identification of chemical inhibitors of 3CL proteases encoded by a wide range of coronaviruses. This assay is reporter free, does not require specialized biocontainment, and is optimized for performance in high-throughput screening. By testing reported 3CL protease inhibitors against a large collection of 3CL proteases with variable sequence similarity, we identified compounds with broad activity against 3CL proteases and uncovered structural insights into features that contribute to their broad activity. Furthermore, we demonstrated that this assay is suitable for identifying chemical inhibitors of proteases from families other than 3CL proteases.
IMPACT OF AGING IN THE SURGICAL OUTCOMES OF GASTRIC CANCER PATIENTS.

BACKGROUND As age advances, a higher burden of comorbidities and less functional reserve are expected, however, the impact of aging in the surgical outcomes of gastric cancer (GC) patients is unknown. OBJECTIVE The aim of this study is to evaluate surgical outcomes of GC patients according to their age group. METHODS Patients submitted to gastrectomy with curative intent due to gastric adenocarcinoma were divided in quartiles. Each group had 150 patients and age limits were: ≤54.8, 54.9-63.7, 63.8-72, >72. The outcomes assessed were: postoperative complications (POC), 90-day postoperative mortality, disease-free survival (DFS) and overall survival (OS). RESULTS Major surgical complications were 2.7% in the younger quartile vs 12% for the others (P=0.007). Major clinical complications raised according to the age quartile: 0.7% vs 4.7% vs 5.3% vs 7.3% (P<0.042). ASA score and age were independent risk factors for major POC. The 90-day mortality progressively increased according to the age quartile: 1.3% vs 6.0% vs 7.3% vs 14% (P<0.001). DFS was equivalent among quartile groups, while OS was significantly worse for those >72-year-old. D2 lymphadenectomy only improved OS in the three younger quartiles. Age >72 was an independent risk factor for worse OS (hazard ratio of 1.72). CONCLUSION Patients <55-year-old have less surgical complications. As age progresses, clinical complications and 90-day mortality gradually rise. OS is worse for those above age 72, and D2 lymphadenectomy should be individualized after this age.
DEAD-box helicases modulate dicing body formation in Arabidopsis

RH6, RH8, and RH12 are previously unidentified D-body components and drive the formation of D-bodies through LLPSs. Eukaryotic cells contain numerous membraneless organelles that are made from liquid droplets of proteins and nucleic acids and that provide spatiotemporal control of various cellular processes. However, the molecular mechanisms underlying the formation and rapid stress-induced alterations of these organelles are relatively uncharacterized. Here, we investigated the roles of DEAD-box helicases in the formation and alteration of membraneless nuclear dicing bodies (D-bodies) in Arabidopsis thaliana. We uncovered that RNA helicase 6 (RH6), RH8, and RH12 are previously unidentified D-body components. These helicases interact with and promote the phase separation of SERRATE, a key component of D-bodies, and drive the formation of D-bodies through liquid-liquid phase separations (LLPSs). The accumulation of these helicases in the nuclei decreases upon Turnip mosaic virus infections, which couples with the decrease of D-bodies. Our results thus reveal the key roles of RH6, RH8, and RH12 in modulating D-body formation via LLPSs.
The risk of hepatic adverse events of systemic medications for psoriasis: a prospective cohort study using the BIOBADADERM registry

Abstract Background Limited information is available regarding the risk of incident liver disease in patients with psoriasis receiving systemic therapies. Objectives To describe the liver safety findings of conventional and modern systemic therapies for moderate-to-severe psoriasis, and to compare the relative incidence rates of hepatic adverse events (AEs) for each drug. Methods All the patients on the BIOBADADERM registry were included. Crude and adjusted incidence rate ratios (cIRR and aIRR, respectively) of hepatic AEs, using anti-TNF drugs as reference, were determined. Outcomes of interest were hypertransaminasemia, nonalcoholic fatty liver disease (NADFLD) and a group of other, less represented, hepatic AEs. Results Our study included 3,171 patients exposed to systemic drugs (6279 treatment cycles). Incident hypertransaminasemia was the most frequent hepatic AE (incidence rate of 21 per 1000 patients-years [CI 95% 18–23]), followed by NAFLD (8 cases per 1000 patients-years [95% CI 6–10]). Methotrexate (aIRR 3.06 [2.31–4.4]; p = 0.000) and cyclosporine (aIRR 2.37 [1.05–5.35]; p = .0378) were associated with an increased risk for hypertransaminasemia when compared to anti-TNF-α agents. No differences were observed between different groups of biologics. Conventional therapies were not associated with new incident NAFLD. Conclusions Comparative information of the incidence of hepatic AEs could facilitate drug selection in moderate-to-severe psoriasis.
Threespine Stickleback: A Model System For Evolutionary Genomics.

The repeated adaptation of oceanic threespine sticklebacks to fresh water has made it a premier organism to study parallel evolution. These small fish have multiple distinct ecotypes that display a wide range of diverse phenotypic traits. Ecotypes are easily crossed in the laboratory, and families are large and develop quickly enough for quantitative trait locus analyses, positioning the threespine stickleback as a versatile model organism to address a wide range of biological questions. Extensive genomic resources, including linkage maps, a high-quality reference genome, and developmental genetics tools have led to insights into the genomic basis of adaptation and the identification of genomic changes controlling traits in vertebrates. Recently, threespine sticklebacks have been used as a model system to identify the genomic basis of highly complex traits, such as behavior and host-microbiome and host-parasite interactions. We review the latest findings and new avenues of research that have led the threespine stickleback to be considered a supermodel of evolutionary genomics. Expected final online publication date for the Annual Review of Genomics and Human Genetics Volume 22 is August 2021. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
Evaluation of ganglion cell-inner plexiform layer thickness in the diagnosis of preperimetric glaucoma and comparison to retinal nerve fiber layer

Purpose: The aim of this study was to evaluate the diagnostic ability of optic nerve head (ONH), RNFL, and GC-IPL parameters in differentiating eyes with PPG from normals. Methods: This was a retrospective, cross-sectional, observational study. We studied 73 eyes of 41 patients and compared them to 65 eyes of 34 normal persons. Each patient underwent detailed ocular examination, standard automated perimetry, GC-IPL, ONH, and RNFL analysis. PPG was defined as eyes with normal visual field results and one or more localized RNFL defects that were associated with a glaucomatous disc appearance (e.g., notching or thinning of neuroretinal rim) and IOP more than 21 mm Hg. Diagnostic abilities of GC-IPL, ONH, and RNFL parameters were computed using area under receiver-operating curve (AUROC), sensitivity and specificity, and likelihood ratios (LRs). Results: All GC-IPL parameters differed significantly from normal. The ONH, RNFL, and GC-IPL parameters with best area under curves (AUCs) to differentiate PPG were vertical cup to disc ratio (0.76), inferior quadrant RNFL thickness (0.79), and inferotemporal quadrant GC-IPL thickness (0.73), respectively. Similarly, best LRs were found for clock hour 5, 6, and 12 thicknesses among RNFL; inferior sector and inferotemporal sector thicknesses among GC-IPL parameters. Conclusion: Diagnostic abilities of GC-IPL parameters were comparable to RNFL parameters in differentiating PPG patients from normals. The likelihood of ruling in a disease was greater with GC-IPL parameters.
Wettability of vertically-oriented graphenes with different intersheet distances

Vertically-oriented graphenes (VGs), i.e., graphene nanosheets arranged perpendicularly to the substrate surface, possess great promise as electrode materials for supercapacitors, mainly due to the vertical orientation on the substrate, open intersheet space, and exposed sharp edges. In this work, the dependence of VGs' wettability on their surface morphologies is investigated with experiments and numerical simulations. VGs with different intersheet distances are fabricated with plasma-enabled methods employing different plasma sources. The results show that the contact angle of VGs changes from 111° to 34.5° with a decreasing intersheet distance from ∼306.2 to ∼14.5 nm, indicating that the graphene intersheet distance plays an critical role on the wettability of VGs. Lattice Boltzmann (LB) simulation is further conducted to explore the mechanism on the flow and transport of electrolytes within VG channels. The behavior of electrolyte flow and its permeation into VG interiors is found to be strongly dominated by the capillary force across the air–liquid interface, while the gravity of the bulk electrolyte and the viscous force produced by the graphene surface could be ignored. A 3-fold improvement in the accessible surface area of VGs is achieved with reducing intersheet distance. Electrochemical results indicate that the hydrophilic VG electrode with a small intersheet distance of 14.5 nm exhibits a high specific capacitance (up to 147 F g−1) at a high cyclic voltammetry scan rate of 500 mV s−1, due to the effective wetting and utilization of VG surfaces. The results of the current work could provide instructive information in the morphology optimization of VGs for high performance energy storage applications.
Concordance between patient‐identified concerns and skin cancer diagnosis – an observational cross‐sectional study

patient teledermatology (e.g. through mobile phones or tablets). Other studies found a reduction in face-to-face evaluations by 69%–81% using a teledermatology system. However, it was used for all kinds of diseases and not only for tumours. In our case, the teledermatology referral is used as a register for the patient appointment and treatment by the Dermatology Department when needed, and not only for a diagnosis confirmation. New teledermatological options could be used to follow-up on chronic diseases, such as acne or psoriasis. It can also be used for presurgical planning and is a costeffective procedure when compared with face-to-face evaluations. The use of images obtained using dermoscopy by the primary care physician in teleconsultation can improve dermatological care provided through the system. Quality teledermatology systems could help to palliate the lack of specialists and remoteness to hospitals in rural areas.
Feasibility of fetal left modified myocardial performance index in twin anemia polycythemia sequence and perinatal outcomes after antenatal intervention

Abstract Objective To evaluate the feasibility and clinical value of fetal left modified myocardial performance index (Mod-MPI) in assessment and management of prenatal twin anemia polycythemia sequence (TAPS). Methods We retrospectively reviewed fetuses with TAPS diagnosed prenatally between 2015 and 2019 at Asan Medical Center. Doppler ultrasound evaluation including the peak systolic velocity (PSV) of the middle cerebral artery (MCA) and fetal echocardiography including left Mod-MPI were evaluated and followed up after antenatal management. Results Among 10 cases of fetal twin pregnancies with prenatal TAPS, six were spontaneous and four were post-laser TAPS. Left Mod-MPI was abnormal in one or both twins of nine cases (90%) including all post-laser TAPS (n = 4) and 83.3% of spontaneous TAPS (n = 5). Three recipients, one donor and three former recipients/new donors had elevated left Mod-MPI values, and one donor, one recipient, two former donors/new recipients had decreased values. Antenatal intervention was performed in eight cases with intrauterine transfusion (n = 4), fetoscopic laser surgery (n = 2), radiofrequency ablation (n = 1), and intrauterine transfusion followed by radiofrequency ablation (n = 1). The remaining two cases were either delivered or managed expectantly. MCA-PSV and left Mod-MPI became normal on the follow-up scans in all cases except the delivered case. There were four fetal deaths: two occurred spontaneously and two were selectively terminated by radiofrequency ablation. Overall perinatal survival per fetus was 80% (16/20) and the median gestational age at delivery was 34.4 (range, 29.2–37.4) weeks. Neither postnatal death nor neurodevelopmental delay occurred during a median follow-up of 13 months (range, 0.25–60 months). Conclusion Fetal left Mod-MPI was useful for assessment of compromised fetal cardiac function in cases with prenatal TAPS. Application of fetal left Mod-MPI in prenatal staging of TAPS might help evaluate the severity of TAPS and decide timely antenatal intervention.
Clinical outcomes, quality of life, and costs evaluation of peritoneal dialysis management models in Shanghai Songjiang District: a multi-center and prospective cohort study

Abstract Background: The new Family-Community-Hospital (FCH) three-level comprehensive management aimed to improve the efficiency and scale of peritoneal dialysis (PD) to meet the increased population of end-stage renal disease (ESRD). Our study focused on the clinical outcomes, quality of life, and costs evaluation of this model in a multi-center and prospective cohort study. Methods: A total of 190 ESRD patients who commenced PD at Shanghai Songjiang District were enrolled. According to different PD management models, patients were divided into the Family-Community-Hospital three-level management model (n = 90) and the conventional all-course central hospital management model (n = 100). The primary outcome was clinical outcomes of PD. The secondary outcomes were health-related quality of life (HRQOL) and medical costs evaluation. Results: Compared to conventional management, community-based FCH management achieved a similar dialysis therapeutic effect, including dropout rate (p = 0.366), peritonitis rate (p = 0.965), patient survival (p = 0.441), and technique survival (p = 0.589). Follow-up data showed that similar levels of the renal and peritoneal functions, serum albumin, cholesterol and triglyceride, PTH, serum calcium, and phosphorus between the two groups (all p > 0.05). HRQOL survey showed that the FCH management model helped to improve the psychological status of PD patients, including social functioning (p = 0.006), role-emotional (p = 0.032), and mental health (p = 0.036). FCH management also reduced the hospitalization (p = 0.009) and outpatient visits (p = 0.001) and saved annual hospitalization costs (p = 0.005), outpatient costs (p = 0.026), and transport costs (p = 0.006). Conclusions: Compared with conventional management, community-based FCH management achieved similar outcomes, improved psychological health, reduced medical budgets, and thus had a good social prospect.
Biosynthesis and characterization of MgO nanoparticles from plant extracts via induced molecular nucleation

Plant based green synthesis approaches are gaining prominence due to their simplicity, cost-effectiveness, ecological friendliness, commercial scalability, efficiency in large scale synthesis, and versatility in harnessing a wide range of value added products. Leaf extract based synthesis of metal oxide nanoparticles facilitates the production of non-toxic nanoparticles due to the presence of various phytochemicals and biochemical compounds that are beneficial for biological and pharmaceutical applications. In the current study, leaf extracts from three different plants: Amaranthus tricolor, Andrographis paniculata and Amaranthus blitum were used for the synthesis of magnesium oxide (MgO) nanoparticles. The biophysical characteristics of the synthesized MgO nanoparticles were investigated using ultraviolet-visible spectra and dynamic light scattering techniques. Fourier Transform Infrared (FTIR) spectroscopy and Transmission Electron Microscopy (TEM) were also used to identify and analyze the functional groups accompanying the extracts and the morphology of the nanoparticles respectively. The absorbance at 320 nm from UV-visible spectroscopy indicates the formation of metal oxide in the sample. Key parameters affecting the synthesis process, including temperature, heating time and precursor concentration, were investigated to probe their effects on the stability and particle size distribution of the nanoparticles. The FTIR results showed that the modifications in the functional groups are responsible for the formation of nanoparticles and the peak between 660 and 540 cm−1 confirms the presence of magnesium oxide. The TEM results showed that all the samples demonstrated stability with a particulate size range of 18–80 nm. The process of smaller MgO nanoparticle formation due to utilization of different precursors and leaf extracts was also explained. Overall, the green synthesis approach demonstrated potential for developing highly stable MgO nanoparticles with tight particle size distribution from different plant materials for applications in biosensing and therapeutic development.