Miracle-dz/UniFAR-FTUs huggingface dataset:
The DNA damage response is required for oocyte cyst breakdown and follicle formation in mice

Mammalian oogonia proliferate without completing cytokinesis, forming cysts. Within these, oocytes differentiate and initiate meiosis, promoting double-strand break (DSBs) formation, which are repaired by homologous recombination (HR) causing the pairing and synapsis of the homologs. Errors in these processes activate checkpoint mechanisms, leading to apoptosis. At the end of prophase I, in contrast with what is observed in spermatocytes, oocytes accumulate unrepaired DSBs. Simultaneously to the cyst breakdown, there is a massive oocyte death, which has been proposed to be necessary to enable the individualization of the oocytes to form follicles. Based upon all the above-mentioned information, we hypothesize that the apparently inefficient HR occurring in the oocytes may be a requirement to first eliminate most of the oocytes and enable cyst breakdown and follicle formation. To test this idea, we compared perinatal ovaries from control and mutant mice for the effector kinase of the DNA Damage Response (DDR), CHK2. We found that CHK2 is required to eliminate ~50% of the fetal oocyte population. Nevertheless, the number of oocytes and follicles found in Chk2-mutant ovaries three days after birth was equivalent to that of the controls. These data revealed the existence of another mechanism capable of eliminating oocytes. In vitro inhibition of CHK1 rescued the oocyte number in Chk2-/- mice, implying that CHK1 regulates postnatal oocyte death. Moreover, we found that CHK1 and CHK2 functions are required for the timely breakdown of the cyst and to form follicles. Thus, we uncovered a novel CHK1 function in regulating the oocyte population in mice. Based upon these data, we propose that the CHK1- and CHK2-dependent DDR controls the number of oocytes and is required to properly break down oocyte cysts and form follicles in mammals.
A Matter of Size and Placement: Varying the Patch Size of Anisotropic Patchy Colloids

Non-spherical colloids provided with well-defined bonding sites—often referred to as patches—are increasingly attracting the attention of materials scientists due to their ability to spontaneously assemble into tunable surface structures. The emergence of two-dimensional patterns with well-defined architectures is often controlled by the properties of the self-assembling building blocks, which can be either colloidal particles at the nano- and micro-scale or even molecules and macromolecules. In particular, the interplay between the particle shape and the patch topology gives rise to a plethora of tilings, from close-packed to porous monolayers with pores of tunable shapes and sizes. The control over the resulting surface structures is provided by the directionality of the bonding mechanism, which mostly relies on the selective nature of the patches. In the present contribution, we investigate the effect of the patch size on the assembly of a class of anisotropic patchy colloids—namely, rhombic platelets with four identical patches placed in different arrangements along the particle edges. Larger patches are expected to enhance the bond flexibility, while simultaneously reducing the bond selectivity as the single bond per patch condition—which would guarantee a straightforward mapping between local bonding arrangements and long-range pattern formation—is not always enforced. We find that the non-trivial interplay between the patch size and the patch position can either promote a parallel particle arrangement with respect to a non-parallel bonding scenario or give rise to a variety a bonded patterns, which destroy the order of the tilings. We rationalize the occurrence of these two different regimes in terms of single versus multiple bonds between pairs of particles and/or patches.
Influence of Health Related Fitness on the Morphofunctional Condition of Second Mature Aged Women

To analyze the influence of health-related fitness on the condition of second mature aged women. Participants: 65 women divided into two groups. Group 1–40 women, (43.33 ± 0.93) years old and group 2–25 women (44.40 ± 0.93) years old. The participants trained for 8 months, three times a week for 1 h. Group 1 trained dance aerobics (Monday), strength fitness (Wednesday) and stretching (Friday). Group 2 trained only stretching. The body length and mass, handgrip strength test, vital capacity, blood pressure, heart rate, Stange and Genchi tests, and motion amplitude in joints were evaluated before and after the program. The significance of the differences between the groups was evaluated by Student’s criterion (t) and Rosenbaum (Q). The different intensity of the health-related effect was confirmed at the end of the program. Physiometric indicators significantly increased in group 1. The complex physical activity led to a decrease in heart rate. The results of the Stange and Genchi tests significantly increased. Goniometric indicators of group 2 increased. The comparative analysis of the participants indicators confirms the generalized and higher health-related effect of the complex fitness program. The effect of such a program showed an increase of the adaptive potential, a significant increase in the functional capabilities of women, and the optimization of the studied indicators. With the same time expenditure for health-related fitness, the complex program has a more multifaceted effect in comparison with stretching.
Streptococcal phosphotransferase system imports unsaturated hyaluronan disaccharide derived from host extracellular matrices

Certain bacterial species target the polysaccharide glycosaminoglycans (GAGs) of animal extracellular matrices for colonization and/or infection. GAGs such as hyaluronan and chondroitin sulfate consist of repeating disaccharide units of uronate and amino sugar residues, and are depolymerized to unsaturated disaccharides by bacterial extracellular or cell-surface polysaccharide lyase. The disaccharides are degraded and metabolized by cytoplasmic enzymes such as unsaturated glucuronyl hydrolase, isomerase, and reductase. The genes encoding these enzymes are assembled to form a GAG genetic cluster. Here, we demonstrate the Streptococcus agalactiae phosphotransferase system (PTS) for import of unsaturated hyaluronan disaccharide. S. agalactiae NEM316 was found to depolymerize and assimilate hyaluronan, whereas its mutant with a disruption in PTS genes included in the GAG cluster was unable to grow on hyaluronan, while retaining the ability to depolymerize hyaluronan. Using toluene-treated wild-type cells, the PTS import activity of unsaturated hyaluronan disaccharide was significantly higher than that observed in the absence of the substrate. In contrast, the PTS mutant was unable to import unsaturated hyaluronan disaccharide, indicating that the corresponding PTS is the only importer of fragmented hyaluronan, which is suitable for PTS to phosphorylate the substrate at the C-6 position. The three-dimensional structure of streptococcal EIIA, one of the PTS components, was found to contain a Rossman-fold motif by X-ray crystallization. Docking of EIIA with another component EIIB by modeling provided structural insights into the phosphate transfer mechanism. This study is the first to identify the substrate (unsaturated hyaluronan disaccharide) recognized and imported by the streptococcal PTS. IMPORTANCE (118/120 words) The PTS identified in this work imports sulfate group-free unsaturated hyaluronan disaccharide as a result of the phosphorylation of the substrate at the C-6 position. S. agalactiae can be indigenous to animal hyaluronan-rich tissues owing to the bacterial molecular system for fragmentation, import, degradation, and metabolism of hyaluronan. Distinct from hyaluronan, most GAGs, which are sulfated at the C-6 position, are unsuitable for PTS due to its inability to phosphorylate the substrate. More recently, we have identified a solute-binding protein-dependent ABC transporter in a pathogenic Streptobacillus moniliformis as an importer of sulfated and non-sulfated fragmented GAGs without any substrate modification. Our findings regarding PTS and ABC transporter shed light on bacterial clever colonization/infection system targeting various animal GAGs.
Synergistic interactions of plant essential oils with antimicrobial agents: a new antimicrobial therapy

Abstract The problem of drug resistance of food borne pathogens is becoming more and more serious. Although traditional antimicrobial agents have good therapeutic effects on a variety of food borne pathogens, more effective antimicrobial agents are still needed to combat the development of drug-resistant food borne pathogens. Plant-based natural essential oils (EOs) are widely used because of their remarkable antimicrobial activity. A potential strategy to address food borne pathogens drug resistance is to use a combination of EOs and antimicrobial agents. Because EOs have multi-target inhibitory effects on microorganisms, combining them with drugs can enhance the activity of the drugs and avoid the emergence of food borne pathogens drug resistance. This paper introduces the main factors affecting the antibacterial activity of EOs and describes methods for evaluating their synergistic antibacterial effects. The possible mechanisms of action of EOs and the synergistic inhibitory effects on pathogens of EOs in combination with antimicrobial agents is described. In summary, the combined use of EOs and existing antimicrobial agents is a promising potential new antibacterial therapy.
Dysregulated thyroid hormones correlate with anxiety and depression risk in patients with autoimmune disease

Autoimmune disease (AID) patients always present with increased risk of psychiatric disorders, and thyroid function or thyroid hormone may play a critical role in the development of anxiety and depression. Thus, this study aimed to assess the free triiodothyronine (FT3), free tetraiodothyronine (FT4), thyroid‐stimulating hormone (TSH) levels, and their correlations with anxiety/depression in patients with AID.
Heterodimerization With 5-HT2BR Is Indispensable for β2AR-Mediated Cardioprotection

Supplemental Digital Content is available in the text. Rationale: The β2-adrenoceptor (β2-AR), a prototypical GPCR (G protein-coupled receptor), couples to both Gs and Gi proteins. Stimulation of the β2-AR is beneficial to humans and animals with heart failure presumably because it activates the downstream Gi-PI3K-Akt cell survival pathway. Cardiac β2-AR signaling can be regulated by crosstalk or heterodimerization with other GPCRs, but the physiological and pathophysiological significance of this type of regulation has not been sufficiently demonstrated. Objective: Here, we aim to investigate the potential cardioprotective effect of β2-adrenergic stimulation with a subtype-selective agonist, (R,R’)-4-methoxy-1-naphthylfenoterol (MNF), and to decipher the underlying mechanism with a particular emphasis on the role of heterodimerization of β2-ARs with another GPCR, 5-hydroxytryptamine receptors 2B (5-HT2BRs). Methods and Results: Using pharmacological, genetic and biophysical protein-protein interaction approaches, we studied the cardioprotective effect of the β2-agonist, MNF, and explored the underlying mechanism in both in vivo in mice and cultured rodent cardiomyocytes insulted with doxorubicin, hydrogen peroxide (H2O2) or ischemia/reperfusion. In doxorubicin (Dox)-treated mice, MNF reduced mortality and body weight loss, while improving cardiac function and cardiomyocyte viability. MNF also alleviated myocardial ischemia/reperfusion injury. In cultured rodent cardiomyocytes, MNF inhibited DNA damage and cell death caused by Dox, H2O2 or hypoxia/reoxygenation. Mechanistically, we found that MNF or another β2-agonist zinterol markedly promoted heterodimerization of β2-ARs with 5-HT2BRs. Upregulation of the heterodimerized 5-HT2BRs and β2-ARs enhanced β2-AR-stimulated Gi-Akt signaling and cardioprotection while knockdown or pharmacological inhibition of the 5-HT2BR attenuated β2-AR-stimulated Gi signaling and cardioprotection. Conclusions: These data demonstrate that the β2-AR-stimulated cardioprotective Gi signaling depends on the heterodimerization of β2-ARs and 5-HT2BRs.
Effects of Antibiotic Use on Outcomes in Cancer Patients Treated Using Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis.

Antibiotic (ATB) use seems to negatively affect the outcomes of immune checkpoint inhibitors (ICIs). The aim of this review is to clarify whether ATB use influences the efficacy of ICI treatment in cancer patients. Databases of MEDLINE, Embase, and Cochrane Library were searched for reports published in English between January 2007 and December 2019. We included studies that compared the outcomes of ATB use and no-ATB use in cancer patients using ICIs. Two reviewers independently selected eligible studies and extracted the data. Meta-analysis was performed with pooling of unadjusted hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS), and with pooling of odds ratios (ORs) for objective response rate (ORR). Thirty-eight studies involving 8409 patients were finally included for qualitative or quantitative analyses. Cancer types included renal cell carcinoma, non-small cell lung cancer, urothelial carcinoma, melanoma, gastrointestinal cancer, and others. Meta-analyses revealed that ATB use was associated with poor OS [HR: 1.80, 95% confidence interval (CI): 1.44-2.26, P<0.001], PFS (HR: 1.55, 95% CI: 1.26-1.91, P<0.001) and ORR (OR: 0.63, 95% CI: 0.42-0.95, P=0.03). Subgroup analysis found that these relationships were not influenced by cancer type or ICI regimens, but were dependent on the timing of ATB use. Narrative results of multivariable analyses further confirmed the negative effects of ATB use on OS and PFS. In cancer patients using ICIs, pre-ATB use close to the start of ICI treatment (within 60 d) was detrimental to outcomes in terms of OS, PFS, and ORR.
Stem Cell Metabolism: Powering Cell-Based Therapeutics

Cell-based therapeutics for cardiac repair have been extensively used during the last decade. Preclinical studies have demonstrated the effectiveness of adoptively transferred stem cells for enhancement of cardiac function. Nevertheless, several cell-based clinical trials have provided largely underwhelming outcomes. A major limitation is the lack of survival in the harsh cardiac milieu as only less than 1% donated cells survive. Recent efforts have focused on enhancing cell-based therapeutics and understanding the biology of stem cells and their response to environmental changes. Stem cell metabolism has recently emerged as a critical determinant of cellular processes and is uniquely adapted to support proliferation, stemness, and commitment. Metabolic signaling pathways are remarkably sensitive to different environmental signals with a profound effect on cell survival after adoptive transfer. Stem cells mainly generate energy through glycolysis while maintaining low oxidative phosphorylation (OxPhos), providing metabolites for biosynthesis of macromolecules. During commitment, there is a shift in cellular metabolism, which alters cell function. Reprogramming stem cell metabolism may represent an attractive strategy to enhance stem cell therapy for cardiac repair. This review summarizes the current literature on how metabolism drives stem cell function and how this knowledge can be applied to improve cell-based therapeutics for cardiac repair.
Evolution of neuroinflammation across the lifespan of individuals with Down syndrome.

Epidemiological and experimental studies suggest that a disease-aggravating neuroinflammatory process is present at preclinical stages of Alzheimer's disease. Given that individuals with Down syndrome are at increased genetic risk of Alzheimer's disease and therefore develop the spectrum of Alzheimer's neuropathology in a uniform manner, they constitute an important population to study the evolution of neuroinflammation across the Alzheimer's continuum. Therefore, in this cross-sectional study, we characterized the brain inflammatory profile across the lifespan of individuals with Down syndrome. Microglial morphology and inflammatory cytokine expression were analysed by immunohistochemistry and electrochemiluminescent-based immunoassays in the frontal cortex from foetuses to adults with Down syndrome and control subjects (16 gestational weeks to 64 years), totalling 127 cases. Cytokine expression in mixed foetal primary cultures and hippocampus of adults with Down syndrome, as well as the effects of sex on cytokine expression were also analysed. A higher microglial soma size-to-process length ratio was observed in the frontal cortex of children and young adults with Down syndrome before the development of full-blown Alzheimer's pathology. Moreover, young adults with Down syndrome also displayed increased numbers of rod-like microglia. Increased levels of interleukin-8 and interleukin-10 were observed in children with Down syndrome (1-10 years; Down syndrome n = 5, controls n = 10) and higher levels of interleukin-1β, interleukin-1α, interleukin-6, interleukin-8, interleukin-10, interleukin-15, eotaxin-3, interferon gamma-induced protein 10, macrophage-derived chemokine, and macrophage inflammatory protein-beta, were found in young adults with Down syndrome compared to euploid cases (13-25 years, Down syndrome n = 6, controls n = 24). Increased cytokine expression was also found in the conditioned media of mixed cortical primary cultures from second trimester foetuses with Down syndrome (Down syndrome n = 7, controls n = 7). Older adults with Down syndrome (39-68 years, Down syndrome n = 22, controls n = 16) displayed reduced levels of interleukin-10, interleukin-12p40, interferon-gamma and tumour necrosis factor-alpha. Microglia displayed larger somas and shorter processes. Moreover, an increase in dystrophic microglia and rod-like microglia aligning to neurons harbouring tau pathology were also observed. Sex stratification analyses revealed that females with Down syndrome had increased interleukin-6 and interleukin-8 levels compared to males with Down syndrome. Finally, multivariate projection methods identified specific cytokine patterns among individuals with Down syndrome. Our findings indicate the presence of an early and evolving neuroinflammatory phenotype across the lifespan in Down syndrome, a knowledge that is relevant for the discovery of stage-specific targets and for the design of possible anti-inflammatory trials against Alzheimer's disease in this population.
The Economics of Guided Pathways: Cost, Funding, and Value

This paper is the first to investigate the costs of institution-wide reforms at community colleges. Drawing on data from 12 community colleges implementing comprehensive guided pathways reforms, I use the ingredients method to analyze the resources required to implement such reforms and examine their feasibility and affordability, as well as their value for students. For a typical college with 4,000 full-time equivalent students (FTEs) that implements guided pathways over four years, the total implementation cost beyond business-as-usual operations is estimated at $450 per student each year, or $7.1 million in total, which amounts to 12% of the college’s annual budget, or approximately 3% per year. Around one third of this cost is for enhanced student advisement. Extra investments in information technology are also significant. Ongoing operating costs, primarily for student advisement and student success courses, are around $350 per FTE each year. Cost estimates vary depending on how colleges implement guided pathways, but the results are robust to alternative input prices and college characteristics. There is also some evidence of economies of scale. To finance guided pathways, colleges relied mainly on resource reallocation and efficiency gains, extra public funding, and external grants and funds. Increases in tuition/fees were modest, temporary, or delayed until after implementation; increases of just under 1% per year would suffice to support guided pathways reforms. From the student perspective, guided pathways increases the affordability and value for money of community college. With enhanced advising, students take fewer unnecessary courses. Program mapping leads students to take the right courses both at the community college and at any transfer college. Improved advising help students access grants and in-kind services; they also assist with financial plans to pay for college. Overall, the savings these reforms allow for are likely to exceed the modest increase in tuition/fees from guided pathways.
NbN/AlN/NbN Superconducting Tunnel Junctions Fabricated for HSTDM

Terahertz, defined as 0.1-10THz, is an important frequency regime for astronomical observation. THz observations on ground-based telescopes are rather limited due to strong absorption by the Earth’s atmosphere. Space telescopes can overcome this constraint. China is planning to launch a space station around 2020. It will be in full operation hopefully around 2022, with a 2-meter telescope flying with it in a common orbit. Onboard this telescope, there will be a high sensitivity terahertz detection module (HSTDM) based on a niobium nitride (NbN) superconductor-insulator-superconductor (SIS) receiver system operating at 0.41-0.51THz band [1].
Optimizing return‐on‐effort for coral nursery and outplanting practices to aid restoration of the Great Barrier Reef

Coral nursery and outplanting practices have grown in popularity worldwide for targeted restoration of degraded “high value” reef sites, and recovery of threatened taxa. Success of these practices is commonly gauged from coral propagule growth and survival, which fundamentally determines the return‐on‐effort (RRE) critical to the cost‐effectiveness and viability of restoration programs. In many cases, RRE has been optimized from past successes and failures, which therefore presents a major challenge for locations such as the Great Barrier Reef (GBR) where no local history of restoration exists to guide best practice. In establishing the first multi‐taxa coral nursery on the GBR (Opal Reef, February 2018), we constructed a novel scoring criterion from concurrent measurements of growth and survivorship to guide our relative RRE, including nursery propagule numbers (stock density). We initially retrieved RRE scores from a database of global restoration efforts to date (n = 246; 52 studies) to evaluate whether and how success commonly varied among coral taxa. We then retrieved RRE scores for Opal Reef using initial growth and survivorship data for six key coral taxa, to demonstrate that RRE scores were high for all taxa predominantly via high survivorship over winter. Repeated RRE scoring in summer is therefore needed to capture the full dynamic range of success where seasonal factors regulating growth versus survivorship differ. We discuss how RRE scoring can be easily adopted across restoration practices globally to standardize and benchmark success, but also as a tool to aid decision‐making in optimizing future propagation (and outplanting) efforts.