In addition, molecules associated with apoptosis and autophagy were also abnormally expressed, such as increased Bak mRNA, an increased activated caspase-3 to caspase-3 ratio, and increased Atg12 protein expression. All of these changes are associated with the mitochondria and lead to lipid deposition and inflammation in the liver.

Long-term androgen excess contributes to insulin resistance and hepatic steatosis by affecting mitochondrial function and causing an imbalance in apoptosis and autophagy, thus suggesting the pathogenesis of NAFLD in women with PCOS.

Long-term androgen excess contributes to insulin resistance and hepatic steatosis by affecting mitochondrial function and causing an imbalance in apoptosis and autophagy, thus suggesting the pathogenesis of NAFLD in women with PCOS.Although much has been discovered regarding the characteristics of SARS-CoV-2, its presence in aerosols and their implications in the context of the pandemic is still controversial. More research on this topic is needed to contribute to these discussions. Presented herein are the results of ongoing research to detect SARS-CoV-2 RNA in aerosol in different hospital facilities (indoor environments) and public spaces (outdoor environments) of a metropolitan center in Brazil. From May to August 2020, 62 samples were collected using active sampling method (air samplers with filters) and passive method (petri dishes) in two hospitals, with different occupancies and infrastructure for contamination control. Outdoor public spaces such as sidewalks and a bus station were also investigated. Five air samples from four facilities in a hospital tested positive for SARS-CoV-2 in suspended and sedimentable particles. SARS-CoV-2 was found in aerosols inside the Intensive Care Unit (ICU), in the protective apparel removal room, in the room containing patient mobile toilets and used clothes (room with natural ventilation) and in an external corridor adjacent to the ICU, probably coming from infected patients and/or from aerosolization of virus-laden particles on material/equipment. Our findings reinforce the hypothesis of airborne transmission of the new coronavirus, contributing to the planning of effective practices for pandemic control.Studies have shown that ambient air pollution is associated with obesity in adults, but epidemiological evidence is scarce for children and adolescents. This study sought to examine the association between long-term exposure to ambient air pollution and obesity in a large population of children and adolescents in China. A cross-sectional analysis was performed from a school-based health lifestyles intervention project between September 1, 2019 and November 31, 2019, including 36,456 participants aged 9-17 years in Jiangsu province of China. Exposure to air pollutants (nitrogen dioxide (NO2), ozone (O3), particulate matter with aerodynamic diameters ≤10 μm (PM10), and ≤2.5 μm (PM2.5)) were measured based on the nearest air monitoring station for each selected school. Data on each participant’s weight and height was also recorded. Demographic and obesity-related behavioral information was collected using a self-reported questionnaire. We used the multivariate regression model to estimate the effects of three-yeous efforts to reduce air pollution level could help ease the increasing prevalence of obesity within a region.The use of monoclonal neutralizing antibodies (mNAbs) is being actively pursued as a viable intervention for the treatment of Severe Acute Respiratory Syndrome CoV-2 (SARS-CoV-2) infection and associated coronavirus disease 2019 (COVID-19). While highly potent mNAbs have great therapeutic potential, the ability of the virus to mutate and escape recognition and neutralization of mNAbs represents a potential problem in their use for the therapeutic management of SARS-CoV-2. Studies investigating natural or mNAb-induced antigenic variability in the receptor binding domain (RBD) of SARS-CoV-2 Spike (S) glycoprotein, and their effects on viral fitness are still rudimentary. In this manuscript we described experimental approaches for the selection, identification, and characterization of SARS-CoV-2 monoclonal antibody resistant mutants (MARMs) in cultured cells. The ability to study SARS-CoV-2 antigenic drift under selective immune pressure by mNAbs is important for the optimal implementation of mNAbs for the therapeutic management of COVID-19. This will help to identify essential amino acid residues in the viral S glycoprotein required for mNAb-mediated inhibition of viral infection, to predict potential natural drift variants that could emerge upon implementation of therapeutic mNAbs, as well as vaccine prophylactic treatments for SARS-CoV-2 infection. Additionally, it will also enable the assessment of MARM viral fitness and its potential to induce severe infection and associated COVID-19 disease.As survival rates in teenagers and young adults diagnosed with haematological malignancies now exceed 70%, it is important that long-term quality of life, including measures to protect future fertility, are considered and discussed with patients and their families. Although discussion on the effect of planned cancer treatment on fertility is standard of care, knowledge of potential fertility treatment options and when they should be offered in haematological malignancies is not always so clear. In each case, the advice on the appropriate preservation of fertility depends upon a complex interplay of factors, weighing out the risk of future infertility against the risk of fertility preservation treatment, and recommendations must be made on a case-by-case basis. The aim of this Review is to evaluate the gonadotoxicity of treatments of prevalent haematological malignancies in teenagers and young adults, and provide an evidence-based framework to help with fertility discussion and management at the time of diagnosis, relapse or resistant disease, and in long-term follow-up settings.

Approval of hypomethylating agents in patients with chronic myelomonocytic leukaemia is based on trials done in patients with myelodysplastic syndromes. We aimed to investigate whether hypomethylating agents provide a benefit in subgroups of patients with chronic myelomonocytic leukaemia compared with other treatments.

For this retrospective cohort study, data were retrieved between Nov 30, 2017, and Jan 5, 2019, from 38 centres in the USA and Europe. We included non-selected, consecutive patients diagnosed with chronic myelomonocytic leukaemia, who received chronic myelomonocytic leukaemia-directed therapy. Patients with acute myeloid leukaemia according to 2016 WHO criteria at initial diagnosis (ie, ≥20% blasts in the bone marrow or peripheral blood) or with unavailability of treatment data were excluded. Outcomes assessed included overall survival, time to next treatment, and time to transformation to acute myeloid leukaemia. Analyses were adjusted by age, sex, platelet count, and Chronic myelomonocytihypomethylating agents. Further evidence from prospective cohorts would be desirable.

The Austrian Group for Medical Tumor Therapy.

The Austrian Group for Medical Tumor Therapy.

Secondary CNS lymphoma is a rare but potentially lethal event in patients with diffuse large B-cell lymphoma. We aimed to assess the activity and safety of an intensive, CNS-directed chemoimmunotherapy consolidated by autologous haematopoietic stem-cell transplantation (HSCT) in patients with secondary CNS lymphoma.

This international, single-arm, phase 2 trial was done in 24 hospitals in Italy, the UK, the Netherlands, and Switzerland. Adults (aged 18-70 years) with histologically diagnosed diffuse large B-cell lymphoma and CNS involvement at the time of primary diagnosis or at relapse and Eastern Cooperative Oncology Group Performance Status of 3 or less were enrolled and received three courses of MATRix (rituximab 375 mg/m

, intravenous infusion, day 0; methotrexate 3·5 g/m

, the first 0·5 g/m

in 15 min followed by 3 g/m

in a 3 h intravenous infusion, day 1; cytarabine 2 g/m

every 12 h, in 1 h intravenous infusions, days 2 and 3; thiotepa 30 mg/m

, 30 min intravenous infusion, day 4) followed ).

MATRix-RICE plus autologous HSCT was active in this population of patients with very poor prognosis, and had an acceptable toxicity profile.

Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.

Stand Up To Cancer Campaign for Cancer Research UK, the Swiss Cancer Research foundation, and the Swiss Cancer League.Skeletal and glycemic traits have shared etiology, but the underlying genetic factors remain largely unknown. To identify genetic loci that may have pleiotropic effects, we studied Genome-wide association studies (GWASs) for bone mineral density and glycemic traits and identified a bivariate risk locus at 3q21. Using sequence and epigenetic modeling, we prioritized an adenylate cyclase 5 (ADCY5) intronic causal variant, rs56371916. This SNP changes the binding affinity of SREBP1 and leads to differential ADCY5 gene expression, altering the chromatin landscape from poised to repressed. These alterations result in bone- and type 2 diabetes-relevant cell-autonomous changes in lipid metabolism in osteoblasts and adipocytes. We validated our findings by directly manipulating the regulator SREBP1, the target gene ADCY5, and the variant rs56371916, which together imply a novel link between fatty acid oxidation and osteoblast differentiation. Our work, by systematic functional dissection of pleiotropic GWAS loci, represents a framework to uncover biological mechanisms affecting pleiotropic traits.Complex I functions as a primary redox-driven proton pump in aerobic respiratory chains, establishing a proton motive force that powers ATP synthesis and active transport. Recent cryo-electron microscopy (cryo-EM) experiments have resolved the mammalian complex I in the biomedically relevant active (A) and deactive (D) states (Zhu et al., 2016; Fiedorczuk et al., 2016; Agip et al., 2018 [1-3]) that could regulate enzyme turnover, but it still remains unclear how the conformational state and activity are linked. We show here how global motion along the A/D transition accumulates molecular strain at specific coupling regions important for both redox chemistry and proton pumping. Our data suggest that the A/D motion modulates force propagation pathways between the substrate-binding site and the proton pumping machinery that could alter electrostatic and conformational coupling across large distances. Our findings provide a molecular basis to understand how global protein dynamics can modulate the biological activity of large molecular complexes.Drought is an abiotic scourge, one of the major environmental stress factors that adversely affect plant growth and photosynthesis machinery through a disruption of cell organelles, arrangement thylakoid membranes and the electron transport chain. Herein, we probed the effect of drought stress on photosynthetic performance of Chenopodium quinoa Willd. Beforehand, plants were subjected to water deficit (as 15% Field Capacity, FC) for one (D-1W) or two weeks (D-2W), and were then re-watered at 95% FC for 2 weeks. Light and electron microscopy analysis of leaves showed no apparent changes in mesophyll cell organization and chloroplast ultrastructure after one week of drought stress, while a swelling of thylakoids and starch accumulation were observed after the prolonged drought (D-2W). The latter induced a decrease in both PSI and PSII quantum yields which was accompanied by an increase in F0 (minimum fluorescence) and a decline in Fm (maximum fluorescence). Drought stress influenced the fluorescence transients,ssage of this investigation is the elevated recovery capacities of PSII and PSI photochemical activities after re-watering.Recent studies have investigated the composition and functional effects of extracellular vesicles (EVs) secreted by a variety of cell types. However, the mechanisms underlying the impact of these vesicles on neurotransmission remain unclear. Here, we isolated EVs secreted by rat and mouse hippocampal neurons and found that they contain synaptic-vesicle-associated proteins, in particular the vesicular SNARE (soluble N-ethylmaleimide-sensitive factor [NSF]-attachment protein receptor) synaptobrevin (also called VAMP). Using a combination of electrophysiology and live-fluorescence imaging, we demonstrate that this extracellular pool of synaptobrevins can rapidly integrate into the synaptic vesicle cycle of host neurons via a CD81-dependent process and selectively augment inhibitory neurotransmission as well as specifically rescue neurotransmission in synapses deficient in synaptobrevin. These findings uncover a novel means of interneuronal communication and functional coupling via exchange of vesicular SNAREs.Immunoglobulins (Ig) A and M are the only human antibodies that form oligomers and undergo transcytosis to mucosal secretions via the polymeric Ig receptor (pIgR). When complexed with the J-chain (JC) and the secretory component (SC) of pIgR, secretory IgA and IgM (sIgA and sIgM) play critical roles in host-pathogen defense. Recently, we determined the structure of sIgA-Fc which elucidated the mechanism of polymeric IgA assembly and revealed an extensive binding interface between IgA-Fc, JC, and SC. Despite low sequence identity shared with IgA-Fc, IgM-Fc also undergoes JC-mediated assembly and binds pIgR. Here, we report the structure of sIgM-Fc and carryout a systematic comparison to sIgA-Fc. Our structural analysis reveals a remarkably conserved mechanism of JC-templated oligomerization and SC recognition of both IgM and IgA through a highly conserved network of interactions. These studies reveal the structurally conserved features of sIgM and sIgA required for function in mucosal immunity.We aimed to establish an in vitro differentiation procedure to generate matured small intestinal cells mimicking human small intestine from human-induced pluripotent stem cells (iPSCs). We previously reported the efficient generation of CDX2-expressing intestinal progenitor cells from embryonic stem cells (ESCs) using 6-bromoindirubin-3′-oxime (BIO) and (3,5-difluorophenylacetyl)-L-alanyl-L-2-phenylglycine tert-butyl ester (DAPT) to treat definitive endodermal cells. Here, we demonstrate the generation of enterocyte-like cells by culturing human iPSC-derived intestinal progenitor cells on a collagen vitrigel membrane (CVM) and treating cells with a simple maturation medium containing BIO, DMSO, dexamethasone, and activated vitamin D3. Functional tests further confirmed that these iPSC-derived enterocyte-like cells exhibit P-gp- and BCRP-mediated efflux and cytochrome P450 3A4 (CYP3A4)-mediated metabolism. We concluded that hiPS cell-derived enterocyte-like cells can be used as a model for the evaluation of drug transport and metabolism studies in the human small intestine.Organoids (ORGs) are increasingly used as models of cerebral cortical development. Here, we compared transcriptome and cellular phenotypes between telencephalic ORGs and monolayers (MONs) generated in parallel from three biologically distinct induced pluripotent stem cell (iPSC) lines. Multiple readouts revealed increased proliferation in MONs, which was caused by increased integrin signaling. MONs also exhibited altered radial glia (RG) polarity and suppression of Notch signaling, as well as impaired generation of intermediate progenitors, outer RG, and cortical neurons, which were all partially reversed by reaggregation of dissociated cells. Network analyses revealed co-clustering of cell adhesion, Notch-related transcripts and their transcriptional regulators in a module strongly downregulated in MONs. The data suggest that ORGs, with respect to MONs, initiate more efficient Notch signaling in ventricular RG owing to preserved cell adhesion, resulting in subsequent generation of intermediate progenitors and outer RG, in a sequence that recapitulates the cortical ontogenetic process.Mutations in the photoreceptor transcription factor gene cone-rod homeobox (CRX) lead to distinct retinopathy phenotypes, including early-onset vision impairment in dominant Leber congenital amaurosis (LCA). Using induced pluripotent stem cells (iPSCs) from a patient with CRX-I138fs48 mutation, we established an in vitro model of CRX-LCA in retinal organoids that showed defective photoreceptor maturation by histology and gene profiling, with diminished expression of visual opsins. Adeno-associated virus (AAV)-mediated CRX gene augmentation therapy partially restored photoreceptor phenotype and expression of phototransduction-related genes as determined by single-cell RNA-sequencing. Retinal organoids derived from iPSCs of a second dominant CRX-LCA patient carrying K88N mutation revealed the loss of opsin expression as a common phenotype, which was alleviated by AAV-mediated augmentation of CRX. Our studies provide a proof-of-concept for developing gene therapy of dominant CRX-LCA and other CRX retinopathies.Severe congenital neutropenia (SCN) is a life-threatening disorder most often caused by dominant mutations of ELANE that interfere with neutrophil maturation. We conducted a pooled CRISPR screen in human hematopoietic stem and progenitor cells (HSPCs) that correlated ELANE mutations with neutrophil maturation potential. Highly efficient gene editing of early exons elicited nonsense-mediated decay (NMD), overcame neutrophil maturation arrest in HSPCs from ELANE-mutant SCN patients, and produced normal hematopoietic engraftment function. Conversely, terminal exon frameshift alleles that mimic SCN-associated mutations escaped NMD, recapitulated neutrophil maturation arrest, and established an animal model of ELANE-mutant SCN. Surprisingly, only -1 frame insertions or deletions (indels) impeded neutrophil maturation, whereas -2 frame late exon indels repressed translation and supported neutrophil maturation. Gene editing of primary HSPCs allowed faithful identification of variant pathogenicity to clarify molecular mechanisms of disease and encourage a universal therapeutic approach to ELANE-mutant neutropenia, returning normal neutrophil production and preserving HSPC function.Despite of its high morbidity and mortality, there is still a lack of effective treatment for ischemic stroke in part due to our incomplete understanding of molecular mechanisms of its pathogenesis. In this study, we demonstrate that SHH-PTCH1-GLI1-mediated axonal guidance signaling and its related neurogenesis, a central pathway for neuronal development, also plays a critical role in early stage of an acute stroke model. Specifically, in vivo, we evaluated the effect of GXNI on ischemic stroke mice via using the middle cerebral artery embolization model, and found that GXNI significantly alleviated cerebral ischemic reperfusion (I/R) injury by reducing the volume of cerebral infarction, neurological deficit score and cerebral edema, reversing the BBB permeability and histopathological changes. A combined approach of RNA-seq and network pharmacology analysis was used to reveal the underlying mechanisms of GXNI followed by RT-PCR, immunohistochemistry and western blotting validation. It was pointed out that axon guidance signaling pathway played the most prominent role in GXNI action with Shh, Ptch1, and Gli1 genes as the critical contributors in brain protection. In addition, GXNI markedly prevented primary cortical neuron cells from oxygen-glucose deprivation/reoxygenation damage in vitro, and promoted axon growth and synaptogenesis of damaged neurons, which further confirmed the results of in vivo experiments. Moreover, due to the inhibition of the SHH-PTCH1-GLI1 signaling pathway by cyclopropylamine, the effect of GXNI was significantly weakened. Hence, our study provides a novel option for the clinical treatment of acute ischemic stroke by GXNI via SHH-PTCH1-GLI1-mediated axonal guidance signaling, a neuronal development pathway previously considered for after-stroke recovery.Owing to the dysregulation of protein kinase activity in many diseases including cancer, the protein kinase enzyme family has become one of the most important drug targets in the 21st century. There are 62 FDA-approved therapeutic agents that target about two dozen different protein kinases and eight of these were approved in 2020. All of the FDA-approved drugs are orally effective with the exception of netarsudil (a ROCK1/2 non-receptor protein-serine/threonine kinase antagonist given as an eye drop for the treatment of glaucoma) and temsirolimus (an indirect mTOR inhibitor given intravenously for the treatment of renal cell carcinoma). Of the approved drugs, ten target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), thirteen block non-receptor protein-tyrosine kinases, and 35 target receptor protein-tyrosine kinases. The data indicate that 55 of these drugs are prescribed for the treatment of neoplasms (52 against solid tumors including breast, langiocarcinoma), pralsetinib and selpercatinib (non-small cell lung cancer, medullary thyroid cancer, differentiated thyroid cancer), selumetinib (neurofibromatosis type I), and tucatinib (HER2-positive breast cancer). All of the eight drugs approved in 2020 fulfill Lipinski’s rule of five criteria for an orally effective medicine (MW of 500 Da or less, five or fewer hydrogen bond donors, 10 or fewer hydrogen bond acceptors, calculated log10 of the partition coefficient of five or less) with the exception of three drugs with a molecular weight greater that 500 Da pralsetinib (534), selpercatinib (526) and ripretinib (510). This review summarizes the physicochemical properties of all 62 FDA-approved small molecule protein kinase inhibitors.Offspring born from complicated pregnancies are at greater risk of cardiovascular disease in adulthood. Prenatal hypoxia is a common pregnancy complication that results in placental oxidative stress and impairs fetal development. Adult offspring exposed to hypoxia during fetal life are more susceptible to develop cardiac dysfunction, and show decreased cardiac tolerance to an ischemia/reperfusion (I/R) insult. To improve offspring cardiac outcomes, we have assessed the use of a placenta-targeted intervention during hypoxic pregnancies, by encapsulating the mitochondrial antioxidant MitoQ into nanoparticles (nMitoQ). We hypothesized that maternal nMitoQ treatment during hypoxic pregnancies improves cardiac tolerance to I/R insult in adult male and female offspring. Pregnant Sprague-Dawley rats were exposed to normoxia (21 % O2) or hypoxia (11 % O2) from gestational day 15-20, after injection with 100 μL saline or nMitoQ (125 μM) on GD15 (n=6-8/group). Male and female offspring were aged to 4 months. Both male l hypoxia.

erosion of vulnerable atherosclerotic plaques may cause life-threatening thromboembolic complications. There is indeed an urgent need to recognize a clear-cut biomarker able to identify vulnerable plaques. Here, we focused on circulating proteins belonging to the lectin pathway (LP) of complement activation.

we analyzed mannose-binding lectin (MBL), ficolin-1, -2 and -3 (LP initiators) levels by ELISA in sera from n = 240 of an already published cohort of patients undergoing endarterectomy for severe carotid stenosis and followed-up until 18 months after surgery. Immunofluorescence followed by confocal and polarized light microscopy was used to detect LP initiator intraplaque localization. Spearman’s rank test was drawn to investigate correlation between serum LP levels and circulating inflammatory proteins or intraplaque components. Survival analyses were then performed to test the predictive role of LP on long-term adverse outcome.

ficolins, but not MBL, correlated positively with 1) high circulating ficolin-2 a strong predictive value toward adverse cardiovascular events was demonstrated. This evidence offers potentially new pharmacological target to dampen the inflammatory mechanisms leading to plaque vulnerability.By promising more accurate diagnostics and individual treatment recommendations, deep neural networks and in particular convolutional neural networks have advanced to a powerful tool in medical imaging. Here, we first give an introduction into methodological key concepts and resulting methodological promises including representation and transfer learning, as well as modelling domain-specific priors. After reviewing recent applications within neuroimaging-based psychiatric research, such as the diagnosis of psychiatric diseases, delineation of disease subtypes, normative modeling, and the development of neuroimaging biomarkers, we discuss current challenges. This includes for example the difficulty of training models on small, heterogeneous and biased data sets, the lack of validity of clinical labels, algorithmic bias, and the influence of confounding variables.Biologists since Darwin have been fascinated by the evolution of sexually selected ornaments, particularly those that reduce viability. Uncovering the genetic architecture of these traits is key to understanding how they evolve and are maintained. Here, we investigate the genetic architecture and evolutionary loss of a sexually selected ornament, the „sword” fin extension that characterizes many species of swordtail fish (Xiphophorus). Using sworded and swordless sister species of Xiphophorus, we generated a mapping population and show that the sword ornament is polygenic-with ancestry across the genome explaining substantial variation in the trait. After accounting for the impacts of genome-wide ancestry, we identify one major-effect quantitative trait locus (QTL) that explains ~5% of the overall variation in the trait. Using a series of approaches, we narrow this large QTL interval to several likely candidate genes, including genes involved in fin regeneration and growth. Furthermore, we find evidence of selection on ancestry at one of these candidates in four natural hybrid populations, consistent with selection against the sword in these populations.Systematic tool production and use is one of humanity’s defining characteristics, possibly originating as early as >3 million years ago.1-3 Although heightened manual dexterity is considered to be intrinsically intertwined with tool use and manufacture, and critical for human evolution, its role in the emergence of early culture remains unclear. Most previous research on this question exclusively relied on direct morphological comparisons between early hominin and modern human skeletal elements, assuming that the degree of a species’ dexterity depends on its similarity with the modern human form. Here, we develop a new approach to investigate the efficiency of thumb opposition, a fundamental component of manual dexterity, in several species of fossil hominins. Our work for the first time takes into account soft tissue as well as bone anatomy, integrating virtual modeling of musculus opponens pollicis and its interaction with three-dimensional bone shape form. Results indicate that a fundamental aspect of efficient thumb opposition appeared approximately 2 million years ago, possibly associated with our own genus Homo, and did not characterize Australopithecus, the earliest proposed stone tool maker. This was true also of the late Australopithecus species, Australopithecus sediba, previously found to exhibit human-like thumb proportions. In contrast, later Homo species, including the small-brained Homo naledi, show high levels of thumb opposition dexterity, highlighting the increasing importance of cultural processes and manual dexterity in later human evolution.The translation of functionally active natural products into fully synthetic small-molecule mimetics has remained an important process in medicinal chemistry. We recently discovered that the terpene natural product nimbolide can be utilized as a covalent recruiter of the E3 ubiquitin ligase RNF114 for use in targeted protein degradation-a powerful therapeutic modality within modern-day drug discovery. Using activity-based protein profiling-enabled covalent ligand-screening approaches, here we report the discovery of fully synthetic RNF114-based recruiter molecules that can also be exploited for PROTAC applications, and demonstrate their utility in degrading therapeutically relevant targets, such as BRD4 and BCR-ABL, in cells. The identification of simple and easily manipulated drug-like scaffolds that can mimic the function of a complex natural product is beneficial in further expanding the toolbox of E3 ligase recruiters, an area of great importance in drug discovery and chemical biology.Pathologists use histological features to classify tumors and assign site of origin for metastasis. How and why tumors organize the way they do and recreate their histological organization during metastasis is unknown. Here, I discuss the concept of „histostasis” conferring tumors a histological memory and hypothesize its implications for metastasis.Neutrophils can facilitate the metastatic spread of cancer; however, how neutrophils are activated at metastatic sites remains poorly understood. In this issue, Xiao et al. demonstrate that the protease cathepsin C, secreted by breast cancer cells, triggers neutrophils to form neutrophil extracellular traps in the metastatic niche, thereby promoting lung metastasis.In this issue, Lin et al. report that, in malignant cells, stanniocalcin-1 (STC1) prevents the cell surface exposure of the „eat me” signal calreticulin, thereby avoiding phagocytosis by antigen-presenting cells. STC1 overexpression joins an arsenal of mechanisms through which tumor cells suppress calreticulin exposure and escape from immunosurveillance.Immunotherapy induces durable clinical responses in a fraction of patients with cancer. However, therapeutic resistance poses a major challenge to current immunotherapies. Here, we identify that expression of tumor stanniocalcin 1 (STC1) correlates with immunotherapy efficacy and is negatively associated with patient survival across diverse cancer types. Gain- and loss-of-function experiments demonstrate that tumor STC1 supports tumor progression and enables tumor resistance to checkpoint blockade in murine tumor models. Mechanistically, tumor STC1 interacts with calreticulin (CRT), an „eat-me” signal, and minimizes CRT membrane exposure, thereby abrogating membrane CRT-directed phagocytosis by antigen-presenting cells (APCs), including macrophages and dendritic cells. Consequently, this impairs APC capacity of antigen presentation and T cell activation. Thus, tumor STC1 inhibits APC phagocytosis and contributes to tumor immune evasion and immunotherapy resistance. We suggest that STC1 is a previously unappreciated phagocytosis checkpoint and targeting STC1 and its interaction with CRT may sensitize to cancer immunotherapy.Treg cells are essential for re-establishing self-tolerance in lupus. However, given that direct Treg therapies may be inadequate to control autoimmunity and inflammation, a strategy of inducing or expanding endogenous Treg cells in vivo may be a good option. Macrophages are main tissue-infiltrating cells and play a role in promoting Treg differentiation while paeoniflorin (PF), a monoterpene glycoside, exhibits anti-inflammatory and immunoregulatory effects. Here, we studied the effects of PF on CD4+FoxP3+ Treg frequency and the potential mechanisms involving M2 macrophages. We demonstrated that PF ameliorated lupus nephritis in lupus-prone B6/gld mice by reducing urinary protein, serum creatinine and anti-dsDNA levels, diminishing renal cellular infiltration, improving renal immunopathology and downregulating renal gene and protein expressions of key cytokines, including IFN-γ, IL-6, IL-12 and IL-23. PF also lowered the percentage of CD44highCD62Llow effector T cells while augmenting CD4+FoxP3+ Treg frequency in B6/gld mice. Importantly, PF increased TNFR2 expression on CD4+FoxP3+ Tregs, but not CD4+FoxP3- T cells, in vivo and in vitro. Furthermore, we found that CD206+ subset of F4/80+CD11b+ macrophages expressed a higher level of mTNF-α than their CD206- counterparts while PF increased mTNF-α expression on CD206+ macrophages in vitro and in vivo. In vitro studies showed that mTNF-α+ M2 macrophages were more potent in inducing Treg differentiation and proliferation than their mTNF-α- counterparts, whereas the effects of mTNF-α+ M2 macrophages were largely reversed by separation of M2 macrophages using a transwell or TNFR2-blocking Ab in the culture. Finally, PF also promoted in vitro Treg generation induced by M2 macrophages. Thus, we demonstrated that mTNFα-TNFR2 interaction is a new mechanism responsible for Treg differentiation mediated by M2 macrophages. We provided the first evidence that PF may be used to treat lupus nephritis.Major Depression is a severe psychiatric condition with a still poorly understood etiology. In the last years, evidence supporting the neuroinflammatory hypothesis of depression has increased. In the current clinical scenario, in which the available treatments for depression is far from optimal, there is an urgent need to develop fast-acting drugs with fewer side effects. In this regard, recent pieces of evidence suggest that cannabidiol (CBD), the major non-psychotropic component of Cannabis sativa with anti-inflammatory properties, appears as a drug with antidepressant properties. In this work, CBD 30 mg/kg was administered systemically to mice 30 min before lipopolysaccharide (LPS; 0.83 mg/kg) administration as a neuroinflammatory model, and behavioral tests for depressive-, anhedonic- and anxious-like behavior were performed. NF-ĸB, IκBα and PPARγ levels were analyzed by western blot in nuclear and cytosolic fractions of cortical samples. IL-6 and TNFα levels were determined in plasma and prefrontal corte in depression linked to inflammation.CaV1.2 channels play a fundamental role in the regulation of vascular smooth muscle tone. The aim of the present study was to synthesize morin derivatives bearing the nitrophenyl moiety of dihydropyridine Ca2+ antagonists to increase the flavonoid vasorelaxant activity. The effects of morin and its derivatives were assessed on CaV1.2 and KCa1.1 channels, both in vitro and in silico, as well as on the contractile responses of rat aorta rings. All compounds were effective CaV1.2 channel blockers, positioning in the α1C subunit region where standard blockers bind. Among the four newly synthesized morin derivatives, the penta-acetylated morin-1 was the most efficacious Ca2+ antagonist, presenting a vasorelaxant profile superior to that of the parent compound and, contrary to morin, antagonized also the release of Ca2+ from the sarcoplasmic reticulum; surprisingly, it also stimulated KCa1.1 channel current. Computational analysis demonstrated that morin-1 bound close to the KCa1.1 channel S6 segment. In conclusion, these findings open a new avenue for the synthesis of valuable multi-functional, vasorelaxant morin derivatives capable to target several pathways underpinning the pathogenesis of hypertension.Optineurin (OPTN) is a multifunctional protein that mediates a network of cellular processes regulating membrane trafficking, inflammatory responses and autophagy. The OPTN-rich interactome includes Group I metabotropic glutamate receptors (mGluR1 and 5), members of the Gαq/11 protein receptor family. Recent evidence has shown that mGluR5, in addition to its canonical Gαq/11 protein-coupled signaling, regulates autophagic machinery via mTOR/ULK1 and GSK3β/ZBTB16 pathways in both Alzheimer’s and Huntington’s disease mouse models. Despite its potential involvement, the role of OPTN in mediating mGluR5 downstream signaling cascades remains largely unknown. Here, we employed a CRISPR/Cas9 OPTN-deficient STHdhQ7/Q7 striatal cell line and global OPTN knockout mice to investigate whether Optn gene deletion alters both mGluR5 canonical and noncanonical signaling. We find that OPTN is required for mGluR5-activated Ca2+ flux and ERK1/2 signaling following receptor activation in STHdhQ7/Q7 cells and acute hippocampal slices. Deletion of OPTN impairs both GSK3β/ZBTB16 and mTOR/ULK1 autophagic signaling in STHdhQ7/Q7 cells. Furthermore, mGluR5-dependent regulation of GSK3β/ZBTB16 and mTOR/ULK1 autophagic signaling is impaired in hippocampal slices of OPTN knockout mice. Overall, we show that the crosstalk between OPTN and mGluR5 can have major implication on receptor signaling and therefore potentially contribute to the pathophysiology of neurodegenerative diseases.More than two decades after the natural gene-silencing mechanism of RNA interference was elucidated, small interfering RNA (siRNA)-based therapeutics have finally broken into the pharmaceutical market. With three agents already approved and many others in advanced stages of the drug development pipeline, siRNA drugs are on their way to becoming a standard modality of pharmacotherapy. The majority of late-stage candidates are indicated for rare or orphan diseases, whose patients have an urgent need for novel and effective therapies. Additionally, there are agents that have the potential to meet the need of a broader population. Inclisiran, for instance, is being developed for hypercholesterolemia and has shown benefit in patients who are uncontrolled even after maximal statin therapy. This review provides a brief overview of mechanisms of siRNA action, physiological barriers to its delivery and activity, and the most common chemical modifications and delivery platforms used to overcome these barriers. Furthermore, this review presents comprehensive profiles of the three approved siRNA drugs (patisiran, givosiran, and lumasiran) and the seven other siRNA candidates in Phase 3 clinical trials (vutrisiran, nedosiran, inclisiran, fitusiran, teprasiran, cosdosiran, and tivanisiran), summarizing their modifications and delivery strategies, disease-specific mechanisms of action, updated clinical trial status, and future outlooks.Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.Immunological memory is a mechanism to protect us against reinfection. Antibodies produced by B cells are integral to this defense strategy and underlie virtually all vaccine success. Here, we explain how B cells memory is generated by infection and vaccination, what influences its efficacy and its persistence, and how characterizing these parameters in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will help achieve protective immunity through vaccination.Microfluidics in vitro assays recapitulate a blood vessel microenvironment using surface-immobilized agonists under biofluidic flows. However, these assays do not quantify intrathrombus mass and activities of adhesive platelets at the agonist margin and use fluorescence labeling, therefore limiting clinical translation potential. Here, we describe a label-free multimodal quantitative imaging flow assay that combines rotating optical coherent scattering microscopy and quantitative phase microscopy. The combined imaging platform enables real-time evaluation of membrane fluctuations of adhesive-only platelets and total intrathrombus mass under physiological flow rates in vitro. We call this multimodal quantitative imaging flow assay coherent optical scattering and phase interferometry (COSI). COSI records intrathrombus mass to picogram accuracy and shape changes to a platelet membrane with high spatial-temporal resolution (0.4 μm/s) under physiological and pathophysiological fluid shear stress (1800 and 7500 s-1). With COSI, we generate an axial slice of 4 μm from the coverslip surface, approximately equivalent to the thickness of a single platelet, which permits nanoscale quantification of membrane fluctuation (activity) of adhesive platelets during initial adhesion, spreading, and recruitment into a developing thrombus (mass). Under fluid shear, pretreatment with a broad range metalloproteinase inhibitor (250 μM GM6001) blocked shedding of platelet adhesion receptors that shown elevated adhesive platelet activity at average of 42.1 μm/s and minimal change in intrathrombus mass.Ovarian cancer is frequently detected in advanced stages when the chances of survival are very low. Although chemotherapy is the treatment of choice, it is often rapidly compromised by the development of chemoresistance in patients. There are few pharmacological alternatives for managing chemoresistant ovarian cancer and statins have been suggested as an alternative, but their use is considered controversial. We present an overview of the most relevant epidemiological, in vitro and in vivo studies on the effects of statins in mono- or polytherapy for ovarian cancer. We conclude that the negative or inconclusive results of some epidemiological studies on statin-based cancer treatment are probably due, in large part, to the low doses given to patients, equivalent to those prescribed for hypercholesterolemia. Higher concentrations are well tolerated in animal models and by most patients in clinical trials. Future research is necessary to explore this possibility.The lesions induced by Ibotenic acid (IA) emulate some of the symptoms associated with schizophrenia, such as impaired working memory that is predominantly organized by the medial prefrontal cortex (mPFC), or difficulties in social interactions that aremainly organized by the amygdala (AMG). The plastic capacity of dendritic spines in neurons of the mPFC and AMG is modulated by molecules that participate in the known deterioration of working memory, although the influence of these on the socialization of schizophrenic patients is unknown. Here, the effect of a neonatal IA induced lesion on social behavior and working memory was evaluated in adult rats, along with the changes in cytoarchitecture of dendritic spines and their protein content, specifically the postsynaptic density protein 95 (PSD-95), Synaptophysin (Syn), AMPA receptors, and brain-derived neurotrophic factor (BDNF). Both working memory and social behavior were impaired, and the density of the spines, as well as their PSD-95, Syn, AMPA receptor and BDNF content was lower in IA lesioned animals. The proportional density of thin, mushroom, stubby and wide spines resulted in plastic changes that suggest the activation of compensatory processes in the face of the adverse effects of the lesion. In addition, the reduction in the levels of the modulating factors also suggests that the signaling pathways in which such factors are implicated would be altered in the brains of patients with schizophrenia. Accordingly, the experimental study of such signaling pathways is likely to aid the development of more effective pharmacological strategies for the treatment of schizophrenia.Public health travel restrictions (PHTR) are crucial measures during communicable disease outbreaks to prevent transmission during commercial airline travel and mitigate cross-border importation and spread. We evaluated PHTR implementation for US citizens on the Diamond Princess during its coronavirus disease (COVID-19) outbreak in Japan in February 2020 to explore how PHTR reduced importation of COVID-19 to the United States during the early phase of disease containment. Using PHTR required substantial collaboration among the US Centers for Disease Control and Prevention, other US government agencies, the cruise line, and public health authorities in Japan. Original US PHTR removal criteria were modified to reflect international testing protocols and enable removal of PHTR for persons who recovered from illness. The impact of PHTR on epidemic trajectory depends on the risk for transmission during travel and geographic spread of disease. Lessons learned from the Diamond Princess outbreak provide critical information for future PHTR use.The Faroe Islands was one of the first countries in the Western Hemisphere to eliminate coronavirus disease (COVID-19). During the first epidemic wave in the country, 187 cases were reported between March 3 and April 22, 2020. Large-scale testing and thorough contact tracing were implemented early on, along with lockdown measures. Transmission chains were mapped through patient history and knowledge of contact with prior cases. The most common reported COVID-19 symptoms were fever, headache, and cough, but 11.2% of cases were asymptomatic. Among 187 cases, 8 patients were admitted to hospitals but none were admitted to intensive care units and no deaths occurred. Superspreading was evident during the epidemic because most secondary cases were attributed to just 3 infectors. Even with the high incidence rate in early March, the Faroe Islands successfully eliminated the first wave of COVID-19 through the early use of contact tracing, quarantine, social distancing, and large-scale testing.Human papillomavirus (HPV) infections are found in children, but transmission modes and outcomes are incompletely understood. We evaluated oral samples from 331 children in Finland who participated in the Finnish Family HPV Study from birth during 9 follow-up visits (mean time 51.9 months). We tested samples for 24 HPV genotypes. Oral HPV prevalence for children varied from 8.7% (at a 36-month visit) to 22.8% (at birth), and 18 HPV genotypes were identified. HPV16 was the most prevalent type to persist, followed by HPV18, HPV33, and HPV6. Persistent, oral, high-risk HPV infection for children was associated with oral HPV carriage of the mother at birth and seroconversion of the mother to high-risk HPV during follow-up (odds ratio 1.60-1.92, 95% CI 1.02-2.74). Children acquire their first oral HPV infection at an early age. The HPV status of the mother has a major impact on the outcome of oral HPV persistence for her offspring.Neuronal networks in rodent primary visual cortex (V1) can generate oscillations in different frequency bands depending on the network state and the level of visual stimulation. High-frequency gamma rhythms, for example, dominate the network’s spontaneous activity in adult mice but are attenuated upon visual stimulation, during which the network switches to the beta band instead. The spontaneous local field potential (LFP) of juvenile mouse V1, however, mainly contains beta rhythms and presenting a stimulus does not elicit drastic changes in network oscillations. We study, in a spiking neuron network model, the mechanism in adult mice allowing for flexible switches between multiple frequency bands and contrast this to the network structure in juvenile mice that lack this flexibility. The model comprises excitatory pyramidal cells (PCs) and two types of interneurons the parvalbumin-expressing (PV) and the somatostatinexpressing (SOM) interneuron. In accordance with experimental findings, the pyramidal-PV and pyramidal-SOM cell subnetworks are associated with gamma and beta oscillations, respectively. In our model, they are both generated via a pyramidal-interneuron gamma (PING) mechanism, wherein the PCs drive the oscillations. Furthermore, we demonstrate that large but not small visual stimulation activates SOM cells, which shift the frequency of resting-state gamma oscillations produced by the pyramidal-PV cell subnetwork so that beta rhythms emerge. Finally, we show that this behavior is obtained for only a subset of PV and SOM interneuron projection strengths, indicating that their influence on the PCs should be balanced so that they can compete for oscillatory control of the PCs. In sum, we propose a mechanism by which visual beta rhythms can emerge from spontaneous gamma oscillations in a network model of the mouse V1; for this mechanism to reproduce V1 dynamics in adult mice, balance between the effective strengths of PV and SOM cells is required.This work addresses the problem of network pruning and proposes a novel joint training method based on a multiobjective optimization model. Most of the state-of-the-art pruning methods rely on user experience for selecting the sparsity ratio of the weight matrices or tensors, and thus suffer from severe performance reduction with inappropriate user-defined parameters. Moreover, networks might be inferior due to the inefficient connecting architecture search, especially when it is highly sparse. It is revealed in this work that the network model might maintain sparse characteristic in the early stage of the backpropagation (BP) training process, and evolutionary computation-based algorithms can accurately discover the connecting architecture with satisfying network performance. In particular, we establish a multiobjective sparse model for network pruning and propose an efficient approach that combines BP training and two modified multiobjective evolutionary algorithms (MOEAs). The BP algorithm converges quickly, and the two MOEAs can search for the optimal sparse structure and refine the weights, respectively. Experiments are also included to prove the benefits of the proposed algorithm. We show that the proposed method can obtain a desired Pareto front (PF), leading to a better pruning result comparing to the state-of-the-art methods, especially when the network structure is highly sparse.Brains process information in spiking neural networks. Their intricate connections shape the diverse functions these networks perform. Yet how network connectivity relates to function is poorly understood, and the functional capabilities of models of spiking networks are still rudimentary. The lack of both theoretical insight and practical algorithms to find the necessary connectivity poses a major impediment to both studying information processing in the brain and building efficient neuromorphic hardware systems. The training algorithms that solve this problem for artificial neural networks typically rely on gradient descent. But doing so in spiking networks has remained challenging due to the nondifferentiable nonlinearity of spikes. To avoid this issue, one can employ surrogate gradients to discover the required connectivity. However, the choice of a surrogate is not unique, raising the question of how its implementation influences the effectiveness of the method. Here, we use numerical simulations to systematically study how essential design parameters of surrogate gradients affect learning performance on a range of classification problems.