Kofodkincaid0183

So far serology has been mostly used for testing for C. burnetii infection. The detection of C. burnetii DNA by PCR in various clinical samples have also been widely used. The disease has remained largely under-reported, underdiagnosed and as a masked zoonosis; and therefore, needs to be explored through well-planned scientific studies for knowing its true status and likely it impact in humans and animals by employing state-of-the-art diagnostics, identifying its diverse and new host range, as well as risk factors involved in different geo-climatic, behavioural and social settings as well as risk groups. Here, we reviewed the current approaches used for the detection of C. burnetii infection in humans and animals at the population and individual level.The main objective of the present investigation was to mechanistically evaluate the potency of the root extract (EEC), its bioactive chloroform fraction (CEC) and eriosematin E (ECM) isolated from Eriosema chinense against Shigella flexneri-induced sub-chronic model of infectious diarrhoea using in vitro, in vivo, and in silico methods. The in vitro antibacterial activity against pathogenic strain of S. flexneri demonstrated maximum effect of ECM followed by CEC and EEC in inhibiting growth of bacteria. Further, for in vivo evaluation, was carried out by inducing diarrhoea to the rats by administering oral suspension of S. flexneri to the animals, which was followed by treatment for a period of 6 days. EEC at 200, CEC at 100 and ECM at 10 mg/kg, p.o. showed promising effect, where EEC and ECM were found to be more effective showing maximum % protection on 6th day. Results also demonstrated a significant restoration of altered antioxidants, pro-inflammatory cytokines (IL-1β and TNF-α) expression, electrolyte balance, Na+/K+-ATPase activity and was also supported by histopathological examinations. Molecular docking study revealed that, eriosematin E inactivated the protease activity of SepA, a protein secreted by Shigella, which is responsible for disruption of epithelial barrier integrity. Thus, the overall observation confirmed the role of eriosematin E from E. chinense in treatment of Shigella flexneri-induced infectious diarrhoea.

The aim of this study is to address the role of HPV in prostate cancer (PCa) development through the inducement of resistance to anoikis.

In this case-control study, prostate tissues and blood samples were collected from 116 individuals, including 72 cases with PCa and 44 non-malignant prostate tissue samples as a control group. The expression level of HPV genes (E2, E6, and E7) and cellular genes including anti-apoptotic mediators (Bcl-2 and survivin), tumor suppressor proteins (Rb and p53), and some mediators involved in anoikis resistance and invasiveness (E-cadherin, N-cadherin, Twist, PTPN13 and SLUG) were evaluated.

HPV genome was identified in 36.1% cases and 15.9% control samples, additionally there was found to be a statistic significant association between the presence of HPV and PCa (OR=1.64, 95% C.I=0.8-1.8, P-value=0.023). HPV genotype 16 and 18 were the most prevalent genotype in both in the PCa group and the control group. The expression level of the tumor suppressor proteins (Rb and p53) and anti-apoptotic mediators (Bcl-2 and Survivin) were significantly decreased and increased, respectively, in the HPV-positive specimens compared to the HPV-negative specimens. Furthermore, the mean expression level of N-cadherin, SLUG, and TWIST in the HPV-positive specimens was higher than HPV-negative specimens while the mean expression level of PTPN-13 and E-cadherin genes in the HPV-positive specimens was lower than HPV-negative specimens.

Our study suggests that HPV infection may be involved in the development of PCa metastases by modulating anoikis resistance related genes.

Our study suggests that HPV infection may be involved in the development of PCa metastases by modulating anoikis resistance related genes.Immunomodulatory therapies are limited by unavoidable side effects as well as poor solubility, stability, and pharmacokinetic properties. Nanomaterial-based drug delivery may overcome these limitations by increasing drug solubility, site-targeting, and duration of action. Here, we prepared innovative drug-integrating amphiphilic nanomaterial assemblies (DIANA) with tunable hydrophobicity, size, and morphology, and we evaluated their ability to deliver cyclosporine A (CsA) for immunomodulatory applications. We synthesized amphiphilic block copolymers made of poly(ethylene glycol)-poly(propylene sulfide) (PEG-PPS) and poly(ethylene glycol)-oligo(ethylene sulfide) (PEG-OES) that can self-assemble into solid core nanomicelles (nMIC, with ≈20 nm diameter) and nanofibrils (nFIB, with ≈5 nm diameter and > 500 nm length), respectively. nMIC and nFIB displayed good CsA encapsulation efficiency (up to 4.5 and 2 mg/mL, respectively in aqueous solution), superior to many other solubilization methods, and provided sustained release (>14 and > 7 days for the nMIC and nFIB) without compromising CsA's pharmacological activity. Treatment of insulin-secreting cells with unloaded DIANAs did not impair cell viability and functionality. Both CsA-loaded DIANAs inhibited the proliferation and activation of insulin-reactive cytotoxic T cells in vitro. Subcutaneous injections of CsA-loaded DIANAs in mice provided CsA sustained release, decreasing alloantigen-induced immune responses in the draining lymph node at lower doses and reduced administration frequency than unformulated CsA. While nMIC solubilized higher amounts and provided more sustained release of CsA in vitro, nFIB enhanced cellular uptake and promoted local retention due to slower trafficking in vivo. DIANAs provide a versatile platform for a local immune suppression regimen that can be applied to allogeneic cell transplantation.Delivering macromolecular drugs, e.g. peptides, to the systemic circulation by oral administration is challenging due to their degradation in the gastrointestinal tract and low transmucosal permeation. In this study, the concept of an oral delivery device utilizing an elastomeric material is presented with the potential of increasing the absorption of peptides, e.g. insulin. Absorption enhancement in the intestine is proposed as a result of self-unfolding of a polydimethylsiloxane foil upon release from enteric coated capsules. A pH-sensitive polymer coating prevents capsule disintegration until arrival in the small intestine where complete unfolding of the elastomeric foil ensures close contact with the intestinal mucosa. Foils with close-packed hexagonal compartments for optimal drug loading are produced by casting against a deep-etched silicon master. Complete unfolding of the foil upon capsule disintegration is verified in vitro and the insulin release profile of the final delivery device confirms insulin protection at gastric pH. In vivo performance is evaluated with the outcome of quantifiable plasma insulin concentrations in all rats receiving duodenal administration of the novel delivery device. By taking advantage of elastomeric material properties for drug delivery, this approach might serve as inspiration for further development of commercially viable biocompatible devices for oral delivery of macromolecules.Social inhibition may be associated with individual differences in emotion regulation. Mechanisms relating emotion regulation to social inhibition are largely unknown. We therefore examined how social inhibition is associated with emotional, sympathetic, and parasympathetic responses during sadness induction, and while employing emotion regulation strategies during social interaction after sadness induction. Undergraduate students (N = 216; 72% female) completed the Social Inhibition Questionnaire and participated in a sadness induction and emotion regulation (i.e., suppression and reappraisal) social interaction task, while emotional states, and sympathetic and parasympathetic reactivity were assessed. Repeated measures ANCOVAs showed that during sadness induction, social inhibition was unrelated to the emotional response, but social inhibition was associated with a blunted parasympathetic withdrawal response, due to an already withdrawn parasympathetic tone at rest. This may be suggestive of increased allostatic load with higher social inhibition, and may contribute to stress-related health risks. Both suppression and reappraisal tasks successfully diminished sadness, and this reduction was smaller with increasing levels of social inhibition. Physiological responses to emotion regulation efforts were independent of social inhibition. Elevated sadness in response to instructed emotion regulation in socially inhibited individuals may indicate more emotional distress during social interaction due to heightened threat sensitivity they experience.Strategies of malingering detection have brought about a wealth of neuropsychological studies in the last decades. However, the investigation of physiological measures to reliably differentiate between authentic and manipulated symptom presentations is still in its infancy. The present study examined event-related potentials (ERP) to identify feigned memory impairment. We tested instructed malingerers (n = 25) and control participants (n = 22) with a recognition task similar to the Test of Memory Malingering. No differences between groups were found for P1 (70-110 ms) but for N1 (120-170 ms) and P300 components, with lower amplitudes for instructed malingerers. Behavioral data showed a typical pattern of unrealistically high errors in a forced-choice recognition task and less overall recalled stimuli in instructed malingerers. We also found study-phase repetition and old/new effects in the P300, but no interactions with groups (control vs. malingering). Post-hoc analyses revealed that the P300 effect is greater when participants reported an attention-based faking strategy, as opposed to response-based malingerers and controls. The employment of physiological measures can yield additional information on the validity of test data without the need to perform additional tests.Here we report the unusual presence of thalamic reticular neurons immunoreactive for tyrosine hydroxylase in equids. The diencephalons of one adult male of four equid species, domestic donkey (Equus africanus asinus), domestic horse (Equus caballus), Cape mountain zebra (Equus zebra zebra) and plains zebra (Equus quagga), were sectioned in a coronal plane with series of sections stained for Nissl substance, myelin, or immunostained for tyrosine hydroxylase, and the calcium-binding proteins parvalbumin, calbindin and calretinin. In all equid species studied the thalamic reticular nucleus was observed as a sheet of neurons surrounding the rostral, lateral and ventral portions of the nuclear mass of the dorsal thalamus. In addition, these thalamic reticular neurons were immunopositive for parvalbumin, but immunonegative for calbindin and calretinin. Moreover, the thalamic reticular neurons in the equids studied were also immunopositive for tyrosine hydroxylase. Throughout the grey matter of the dorsal thalamus a terminal network also immunoreactive for tyrosine hydroxylase was present. Thus, the equid thalamic reticular neurons appear to provide a direct and novel potentially catecholaminergic innervation of the thalamic relay neurons. This finding is discussed in relation to the function of the thalamic reticular nucleus and the possible effect of a potentially novel catecholaminergic pathway on the neural activity of the thalamocortical loop.Quantitative real-time polymerase chain reaction (qRT-PCR) is a powerful tool for evaluating gene expression, but its accuracy is affected by the stability of the reference genes used for normalization. The Minimum Information for Publication of Quantitative Real-time PCR Experiments (MIQE) guidelines indicated that it was important to use multiple stable reference genes as compound reference genes for acquiring optimal experimental results. In this study, the expression levels of eight candidate reference genes (SDHA, TBP, GAPDH, etc.) were detected by qRT-PCR in rat long bones at different developmental stages [gestation day (GD) 20, postnatal week (PW) 6 and PW12] under physiological conditions. Software geNorm, NormFinder, and BestKeeper were used to comprehensively evaluate the stability of the eight reference genes for screening out the most stable compound reference genes in each period. Additionally, the pathological model of prenatal dexamethasone exposure (PDE) was used to verify the stability and reliability of the selected compound reference genes. The result showed that two reference genes as compound reference genes for normalization were optimal. In the intrauterine period, SDHA and TBP could be selected as the compound reference genes, while YWHAZ and GAPDH could be selected at PW6 and PW12, and there was no significant gender difference in the selection of reference genes. The above compound reference genes remained stable in the PDE model and could make the statistical significance of the experimental results more remarkable. In conclusion, this study screened out the optimal compound reference genes in rat long bones before and after birth.A cross-sectional serological survey was carried out in two long-term care facilities that experienced COVID-19 outbreaks in order to evaluate current clinical COVID-19 case definitions. Among individuals with a negative or no previous COVID-19 diagnostic test, myalgias, headache, and loss of appetite were associated with serological reactivity. The US CDC probable case definition was also associated with seropositivity. Public health and infection control practitioners should consider these findings for case exclusion in outbreak settings.Aptamers are single-stranded DNA or RNA oligonucleotides generated by SELEX that exhibit binding affinity and specificity against a wide variety of target molecules. Compared to RNA aptamers, DNA aptamers are much more stable and therefore are widely adopted in a number of applications especially in diagnostics. The tediousness and rigor associated with certain steps of the SELEX intensify the efforts to adopt in silico molecular docking approaches together with in vitro SELEX procedures in developing DNA aptamers. Inspired by these endeavors, we carry out an overview of the in silico molecular docking approaches in DNA aptamer generation, by detailing the stepwise procedures as well as shedding some light on the various softwares used. The in silico maturation strategy and the limitations of the in silico approaches are also underscored.Toluene intoxication produces deleterious effects on cognitive function, which has been associated with the inhibition of N-methyl-d-aspartate receptor (NMDAR). The present study determined whether N,N-dimethylglycine (DMG), a nutrient supplement and a partial agonist for NMDAR glycine binding site, could counteract recognition memory deficits and hippocampal synaptic dysfunction after acute toluene exposure. Male ICR mice were treated with toluene (250-750 mg/kg) for monitoring the sociability and social novelty in three-chamber test and long-term potentiation (LTP) of hippocampal synaptic transmission. Moreover, the combined effects of DMG (30-100 mg/kg) pretreatment with toluene (750 mg/kg) on three-chamber test, novel location and object recognition test and synaptic function were determined. Toluene decreased the sociability, preference for social novelty, hippocampal synaptic transmission and LTP in a dose-dependent manner. DMG pretreatment significantly reduced the toluene-induced memory impairment in social recognition, object location and object recognition and synaptic dysfunction. Furthermore, NMDAR glycine binding site antagonist, 7-chlorokynurenic acid, abolished the protective effects of DMG. These results indicate that DMG could prevent toluene-induced recognition memory deficits and synaptic dysfunction and its beneficial effects might be associated with modulation of NMDAR. These findings suggest that DMG supplementation might be an effective approach to prevent memory problems for the workers at risk of high-level toluene exposure or toluene abusers.Motor behavior alterations are a shared hallmark of neurodegenerative diseases affecting motor circuits, such as amyotrophic lateral sclerosis (ALS), Parkinson's, and Huntington's diseases. In patients and transgenic animal models of amyotrophic lateral sclerosis fine movements controlled by distal muscles are the first to be affected, but its study and knowledge remain poorly understood, mainly because most of the tests used for describing the motor alterations are focused on the function of proximal muscles and gross movements. In this study we demonstrate that alterations of phalangeal fine movements can be quantitatively evaluated using a novel procedure designed by us, phalangeal tension recording test, which showed high sensitivity to detect such alterations. The evaluation was carried out during the motor neuron (MN) degenerative process induced by the acute and chronic overactivation of AMPA receptors in the lumbar rat spinal cord, using previously described models. The new method allowed the quantification of significant alterations of the fine movements of the hindpaws phalanges when AMPA was infused in the lumbar segment controlling the distal muscles, but not when a more rostral spinal segment was infused, and these alterations were not detected by the rotarod or the stride tests. These changes occurred before the paralysis of the hindlimbs. Studying the early distal motor alterations before the total paralysis at late stages is essential for understanding the initial consequences of MN degeneration and therefore for designing new strategies for the control, treatment and prevention of MN diseases.Human social activities are realized by a synergy of neuronal activity over various regions of the brain, which is supported by their connectivity. In the present study, we examined associations between social activities, represented by work hours, and brain connectivity as quantified using diffusion tensor imaging (DTI). In 483 healthy participants, DTI analysis was performed using 3 T magnetic resonance imaging, and work hours were calculated, considering hours of paid employment (the "Work for Pay" category), hours of housework (the "Work at Home" category), and hours of school-related study (the "Student" category). The correlations between each class of work time and DTI indices were analyzed. The mean diffusivity (MD) values of the anterior limb of the internal capsule (ALIC) and the superior fronto-occipital fasciculus (SFO) were negatively correlated with total work hours (ALIC r = -0.192, p =  2.3 × 10-5; SFO r = -0.161, p =  3.8 × 10-4). We also found that the MD values of the ALIC and the SFO were correlated with work hours in the Work for Pay category (ALIC r = -0.211, p =  3.2 × 10-6; SFO r = -0.163, p =  3.4 × 10-4) but not with those in the Work at Home category or the Student category. These results suggest that social activity is associated with the white matter microstructure of the ALIC and the SFO. The main difference between "Work for Pay" and the other two social activities appears to be the type of motivation-for example, external versus internal. Therefore, the white matter microstructure of the ALIC and SFO may be related to externally motivated social activities.An exploration of the physiological correlates of subjective emotional states has theoretical and practical significance. Previous studies have reported that subjective valence and arousal correspond to facial electromyography (EMG) and electrodermal activity (EDA), respectively, across stimuli. However, the reported results were inconsistent, no study investigated subjective-physiological concordance across time, and measures of arousal remain controversial. To investigate these issues, while healthy adults (n = 20) viewed emotional films, we assessed overall and continuous ratings of valence and arousal and recorded EMG from the corrugator supercilii and zygomatic major, EDA from the palms and forehead, and nose-tip temperature. The corrugator and zygomatic EMG were negatively and positively associated with valence ratings, respectively, across stimuli and time. EDA (both sites) and nose-tip temperature were positively and negatively associated with arousal ratings, respectively, across stimuli and time. It is concluded that subjective emotional valence and arousal dynamics have specific physiological correlates.P-glycoprotein (P-gp) associated multidrug resistance (MDR) represents a major failure in cancer treatment. The overexpression of P-gp is responsible for ATP-dependent efflux of drugs that decrease their intracellular accumulation. An effective downregulation of MDR1 gene using small interfering RNA (siRNA) is one of the safe and effective tools to overcome the P-gp triggered MDR. Therefore, the development of an efficient and non-toxic carrier system for siRNA delivery is a fundamental challenge for effective cancer treatment. Polyamidoamine (PAMAM) dendrimer has been used for efficient delivery of siRNA (dendriplexes) to the tumor cells but the associated toxicity problems render its use in biological applications. A non-covalent lipid modification (lipodendriplexes) is supposed to offer a promising strategy to overcome the demerits linked to the naked dendriplexes system. In the current study, we deliver siRNA, designed against MDR1 gene (si-MDR1), in colorectal carcinoma cells (Caco-2), having overexpression of P-gp, to check the role of MDR1 gene in tumor progression and multidrug resistance using two dimensional (2D) and three dimensional (3D) environment. Imatinib mesylate (IM), a P-gp substrate, was used as model drug. Our results revealed that the effective knockdown by lipodendriplexes system can significantly reduce the tumor cell migration in 2D (p less then 0.001) and 3D (p less then 0.001) cell cultures as compared to unmodified dendriplexes and si-Control groups. It was also observed that lipodendriplexes aided downregulation of MDR1 gene effectively, re-sensitized the Caco-2 cells for IM uptake and showed a significantly (p less then 0.001) higher apoptosis. Our findings imply that our lipodendriplexes system has a great potential for siRNA delivery, however, further in vivo application using a suitable targeted system can play a major role for better cancer therapeutics.Advanced stage of prostate cancer cells preferentially metastasizes to varying bones of prostate cancer patients, resulting in incurable disease with poor prognosis and limited therapeutical treatment options. Calcitonin gene-related peptide (CGRP), a neuropeptide produced by prostate gland, is known to play a pivotal role in facilitating tumor growth and metastasis of numerous human cancers. In this study, we aim to investigate the clinical relevance of CGRP in prostate cancer patients and the effects of CGRP and CGRP antagonists on prostate tumor growth in the mouse model. The prostate tumor-bearing mice were received either CGRP or CGRP antagonist treatment, and the tumor growth was monitored by quantification of luminescence intensities. We found that the CGRP+ nerve fiber density and serum CGRP levels were substantially upregulated in the bone or serum specimens from advanced prostate cancer patients as well as in prostate tumor-bearing mice. Administration of CGRP promoted, whereas treatment of CGRP antagonists inhibited prostate tumor growth in the femurs of mice. In addition, CGRP treatment activated extracellular signal-regulated kinases (ERKs)/ Signal transducer and activator of transcription 3 (STAT3) signaling in prostate cancer cells. Targeting CGRP may serve as a potential therapeutic strategy for advanced prostate cancer patients.Cannabis is the most frequently used illicit drug among pregnant women, yet the potential consequences of prenatal cannabis exposure on development are not well understood. Electronic cigarettes have become an increasingly popular route of administration among pregnant women, in part to user's perception that e-cigarettes are a safer route for consuming cannabis products. Importantly, half of pregnant women who consume cannabis also report consuming alcohol, but research investigating co-consumption of these drugs is limited, particularly with current routes of administration. The purpose of this study was to establish a co-exposure vapor inhalation model of alcohol and THC in pregnant rats, to ultimately determine the effects on fetal development. Pregnant Sprague-Dawley rats were exposed to moderate doses of THC via e-cigarettes, alcohol, the combination, or vehicle daily from gestational days 5-20. Importantly, pharmacokinetic interactions of alcohol and THC were observed during pregnancy. Combined exposurt.

The aim of this study is to analyse the causes of cardiac arrests (CA) in the emergency departments (ED) in the United States and their clinical outcomes according to whether they had a primary or a secondary diagnosis of CA.

Data from the Nationwide Emergency Department Sample was assessed for episodes of CA in the emergency department (ED) for adults from 2006 to 2014. Primary and secondary diagnoses of CA and mortality outcomes were evaluated in ED, inpatient and the combined in-hospital setting.

There were 2,852,347 ED episodes with a diagnosis of CA (50.5% primary diagnosis, 49.5% secondary diagnosis). Among patients with a secondary diagnosis of CA, ∼33% patients had a primary cardiac diagnosis, followed by infectious and respiratory diagnoses. The survival to ED discharge was 53.2%; lower for primary versus secondary CA diagnosis (20.4% vs 86.7%). The in-hospital survival rate for all CA was 28.7%, and was lower for primary versus secondary CA diagnosis (15.7% vs 41.9%). Survival to hospital discharge was highest in the age group of 41-60 years (33.0%) and was least among >80 years (20.9%). Survival was also noted to be lower among female patients (27.9% vs 29.2%) and in the winter months.

Survival with CA in ED is <30% of patients and is greater among patients with a secondary diagnosis of CA. CAs are associated with significant mortality in ED and hospital settings and measures should be taken to better manage cardiac, infection and respiratory causes particularly in the winter months.

Survival with CA in ED is less then 30% of patients and is greater among patients with a secondary diagnosis of CA. CAs are associated with significant mortality in ED and hospital settings and measures should be taken to better manage cardiac, infection and respiratory causes particularly in the winter months.It is a difficult task to describe what constitutes a 'healthy' shellfish (e.g., crustacean, bivalve). Visible defects such as discolouration, missing limbs or spines, fouling, lesions, and exoskeletal fractures can be indicative of underlying issues, senescence, or a 'stressed' animal. The absence of such symptoms is not evidence of a disease-free or a stress-free state. Now, more than ever, aquatic invertebrates must cope with acute and chronic environmental perturbations, such as, heatwaves and cold shocks, xenobiotic contaminants, intoxication events, and promiscuous pathogens expanding their host and geographic ranges. With that in mind, how does one determine the extent to which shellfish become stressed in situ (natural) or in cultured (artificial) settings to enhance disease susceptibility? Many biomarkers - predominantly biochemical and cellular measures of shellfish blood (haemolymph) - are considered to gauge immunosuppression and immunocompetence. Such measures range from immune cell (haemocyte) counts to enzymic activities and metabolite quantitation. Stressed invertebrates often reflect degraded conditions of their ecosystems, referred to as environmental indicators. We audit briefly the broad immune functions of shellfish, how they are modulated by known and emerging stressors, and discuss these concepts with respect to neuroendocrinology and immunotoxicology. We assert that chronic stress, alone or in combination with microbial, chemical and abiotic factors, increases the risk of infectious disease in shellfish, exacerbates idiopathic morbidity, and reduces the likelihood of recovery. Acute stress events can lead to immunomodulation, but these effects are largely transient. Enhancing our understanding of shellfish health and immunity is imperative for tackling losses at each stage of the aquatic food cycle and disease outbreaks in the wild.Cancer is one of the leading causes of premature death and constitutes a challenge for both low- and high-income societies. Previous evidence supports a close association between modifiable risk factors, including dietary habits, and cancer risk. Investigation of molecular mechanisms that mediate the pro-oncogenic and anti-oncogenic effects of diet is therefore fundamental. MicroRNAs (miRNAs) have received much attention in the past few decades as crucial molecular elements of human physiology and disease. Aberrant expression patterns of these small noncoding transcripts have been observed in a wide array of cancers. Interestingly, human miRNAs not only can be modulated by bioactive dietary components, but it has also been proposed that diet-derived miRNAs may contribute to the pool of human miRNAs. Results from independent groups have suggested that these exogenous miRNAs may be functional in organisms. These findings open the door to novel and innovative approaches to cancer therapy. Here, we provide an overview of the biology of miRNAs, with a special focus on plant-derived dietary miRNAs, summarize recent findings in the field of cancer, address the possible applications to clinical practice and discuss obstacles and challenges in the field.Neuronal cells possess a certain degree of plasticity to recover from cell damage. When the stress levels are higher than their plasticity capabilities, neuronal degeneration is triggered. However, the factors correlated to the plasticity capabilities need to be investigated. In this study, we generated a novel mouse model that able to express in an inducible manner a dominant-negative form of MFN2, a mitochondrial fusion factor. We then compared the phenotype of the mice continuously expressing the mutated MFN2 with that of the mice only transiently expressing it. Remarkably, the phenotypes of the group transiently expressing mutant MFN2 could be divided into 3 types equivalent to what was observed in the continuous expression group, intermediate between the continuous expression group and the control group, and equivalent to the control group. In particular, in the continuous expression group, we observed remarkable hyperactivity and marked cognitive impairments, which were not seen, or were very mild in the transient expression group. These results indicate that abnormal mitochondrial dynamics lead to stress, triggering neuron degeneration; therefore, the neurodegeneration progression can be prevented via the normalization of the mitochondrial dynamics. Since the availability of mouse models suitable for the reproduction of both neurodegeneration and recovery at least partially is very limited, our mouse model can be a useful tool to investigate neuronal plasticity mechanisms and neurodegeneration.Phase 2 and phase 3 clinical studies showed that hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) efficiently increased hemoglobin levels in both dialysis-dependent and non-dialysis-dependent chronic kidney disease (CKD) patients. However, the effects of HIF-PHIs on iron regulation have not been consistent among clinical trials. We performed a systematic review and meta-analysis of randomized controlled trials to evaluate the effects of six HIF-PHIs on iron regulation in non-dialysis CKD patients. Electronic databases were searched from inception to April 20, 2020, for eligible studies. Changes from baseline in transferrin saturation (TSAT), total iron-binding capacity (TIBC), iron, ferritin, and hepcidin levels were pooled using the inverse-variance method and presented as the mean difference (MD) or standardized MD (SMD) with 95 % confidence intervals (CIs). Meta-analysis of the included studies showed that, in non-dialysis-dependent CKD patients, HIF-PHIs decreased TSAT (MD, -4.51; 95 % CI, -5.81 to -3.21), ferritin (MD, -47.29; 95 % CI, -54.59 to -40.00) and hepcidin (SMD, -0.94; 95 % CI, -1.25 to -0.62), increased TIBC (MD, 9.15; 95 % CI, 7.08-11.22), and did not affect serum iron (MD, -0.31; 95 % CI, -2.05 to 1.42) despite enhanced erythropoiesis. This systematic review suggests that HIF-PHIs promote iron utilization in non-dialysis-dependent CKD patients. Importantly, HIF-PHIs are associated with increased transferrin levels (and TIBC), leading to reduced TSAT. Therefore, the reduction of TSAT after HIF-PHIs should not be interpreted as iron deficiency.Chronic stress can lead to depression due to elevated levels of stress hormones such as glucocorticoid. This is accompanied by an increase in reactive oxygen species (ROS) levels in the brain, which can cause dendritic spine loss and atrophy in neurons, followed by memory loss. Dicaffeoylquinic acids (diCQAs) are naturally occurring polyphenolic antioxidant compounds in Arctium lappa extracts (AL). The effects of natural derivatives of cafferoylqunic acid on stress hormone-induced depressive behavior and their underlying mechanisms are uncertain. In the current study, we showed that diCQAs reduced depressive behaviors including memory loss in corticosterone (CORT) treated mice. The mechanism of anti-depressants of diCQAs is likely through reduction of ROS production by inhibiting the activity of monoamine oxidase (MAO) type A and B in neurons and astrocytes. Among diCQAs, 3,4- and 3,5-diCQA significantly inhibited the activity of MAO enzymes followed by the reduction of ROS in neurons and astrocytes and also protected neuronal atrophy and synaptic transmission against stress hormone. These results suggest that 3,4- and 3,5-diCQAs effectively reduced depressive symptoms and inhibited ROS production to alleviate memory loss in stress hormone-induced depressive mice and hence, which provide some potential natural antidepressants.Plasma contains several bioactive molecules (RNA, DNA, proteins, lipids, and metabolites), which are well preserved in extracellular vesicles, that are involved in many types of cell-to-cell interactions, and are capable of modifying biological processes in recipient cells. To obtain information about the source of mRNA molecules present in the plasma, we analyzed the plasma extracellular RNA (exRNA) of healthy individuals using RNA-sequencing and compared it to that of the peripheral blood mononuclear cell (PBMCs) of the same individual. The resultant data indicates that large proportion of the transcripts in plasma are derived from cell types other than PBMCs. To assess aging-associated changes in the plasma exRNA composition, gene ontology enrichment analysis was performed, revealing a functional decline in biological processes as a result of aging. Additionally, plasma RNA levels were analyzed with differential expression analysis, revealing 10 transcripts with significant aging-associated changes. Thus, it seems that the plasma exRNA is not fully derived from the PBMCs. Instead, other cell types supply RNAs to constitute the plasma exRNA compartment. This was true in both the young and elderly individuals that were tested. Furthermore, the RNA content of the plasma showed significant changes due to aging, affecting important biological processes.Impaired mobility often co-occurs with depression. However, there is no systematic review evidence as to whether mobility impairments precede the onset of depression. The objective of this systematic review and meta-analysis was to evaluate whether mobility impairment could predict incident depression. A systematic search of cohort studies were performed in MEDLINE, EMBASE, CINAHL and PsycINFO. The target population was people with no depressive symptoms at baseline and follow-up for depression or depressive symptoms of at least three months. Of 1061 identified abstracts, 13 studies met the review eligibility criteria. The majority of included studies (8 out of 13) were of high methodological quality. Follow-up periods ranged from 12 months to 16 years. Gait speed was the most consistently reported mobility measure. Participants with slow gait speed were at higher risk of developing depressive symptoms (pooled OR = 1.93, 95%CI 1.54 to 2.42, 11 studies). This review shows that slow gait speed is predictive of the onset of depressive symptoms. Systematic review registration number CRD42020153791.Dietary patterns, microbiome dysbiosis, and gut microbial metabolites (GMMs) have a pivotal role in the homeostasis of intestinal epithelial cells and in disease progression, such as that of colorectal cancer (CRC). Although GMMs and microorganisms have crucial roles in many biological activities, models for deciphering diet-microbiome-host relationships are largely limited to animal models. Thus, intestinal organoids (IOs) have provided unprecedented opportunities for the generation of in vitro platforms with the sufficient level of complexity to model physiological and pathological diet-microbiome-host conditions. Overall, IO responses to GMM metabolites and microorganisms can provide new insights into the mechanisms by which those agents may prevent or trigger diseases, significantly extending our knowledge of diet-microbiome-host interactions.Diabetes and cardiovascular disease (CVD) have evolved as the leading cause of mortality and morbidity worldwide. In addition to traditional risk factors, recent studies have established that the human microbiota, particularly gut bacteria, plays a role in the development of diabetes and CVD. Although the presence of microbes in blood has been known for centuries, mounting evidence in this metagenomic era provides new insights into the role of the blood microbiota in the pathogenesis of non-infectious diseases such as diabetes and CVD. We highlight the origin and physiology of the blood microbiota and circulating microbial metabolites in relation to the etiology and progression of diabetes and CVD. We also discuss translational perspectives targeting the blood microbiota in the diagnosis and treatment of diabetes and CVD.Neutralization of tumor necrosis factor (TNF) represents a widely used therapeutic strategy for autoimmune diseases including inflammatory bowel disease (IBD). However, the fact that many patients with IBD are non-responsive to anti-TNF therapies suggests the need for a better understanding of TNF signaling in IBD. Here, we show that co-deletion of TNF receptor 1 (TNFR1, Tnfrsf1a) in the Il10-/- spontaneous colitis model exacerbates disease, resulting in very-early-onset inflammation after weaning. The disease can be interrupted by treatment with antibiotics. The single deletion of TNFR1 induces subclinical colonic epithelial dysfunction and mucosal immune abnormalities, including accumulation of neutrophils and depletion of B cells. During the pre-disease period (before weaning), both Tnfr1-/- and Il10-/-Tnfr1-/- animals exhibit impaired expression of pro-inflammatory cytokines compared with wild-type and Il10-/- controls, respectively. Collectively, these results demonstrate the net anti-inflammatory functions of TNF/TNFR1 signaling through the regulation of colonic immune homeostasis in early life.Diffuse intrinsic pontine glioma (DIPG) is an incurable brain tumor of childhood characterized by histone mutations at lysine 27, which results in epigenomic dysregulation. There has been a failure to develop effective treatment for this tumor. Using a combined RNAi and chemical screen targeting epigenomic regulators, we identify the polycomb repressive complex 1 (PRC1) component BMI1 as a critical factor for DIPG tumor maintenance in vivo. BMI1 chromatin occupancy is enriched at genes associated with differentiation and tumor suppressors in DIPG cells. Inhibition of BMI1 decreases cell self-renewal and attenuates tumor growth due to induction of senescence. Prolonged BMI1 inhibition induces a senescence-associated secretory phenotype, which promotes tumor recurrence. Clearance of senescent cells using BH3 protein mimetics co-operates with BMI1 inhibition to enhance tumor cell killing in vivo.Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment (TME) induces immune dysfunctional tumor-infiltrating DCs (TIDCs), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we report that fatty acid-carrying tumor-derived exosomes (TDEs) induce immune dysfunctional DCs to promote immune evasion. Mechanistically, peroxisome proliferator activated receptor (PPAR) α responds to the fatty acids delivered by TDEs, resulting in excess lipid droplet biogenesis and enhanced fatty acid oxidation (FAO), culminating in a metabolic shift toward mitochondrial oxidative phosphorylation, which drives DC immune dysfunction. Genetic depletion or pharmacologic inhibition of PPARα effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARα lies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target.Animal behavior is motivated by internal drives, such as thirst and hunger, generated in hypothalamic neurons that project widely to many brain areas. We find that water-restricted mice maintain stable, high-level contrast sensitivity and brief reaction time while performing a visual task, but then abruptly stop and become disengaged. Mice consume a significant amount of water when freely provided in their home cage immediately after the task, indicating that disengagement does not reflect cessation of thirst. Neuronal responses of V1 neurons are reduced in the disengaged state, but pupil diameter does not decrease, suggesting that animals' reduced level of arousal does not drive the transition to disengagement. Our findings indicate that satiation level alone does not have an instructive role in visually guided behavior and suggest that animals' behavior is governed by cost-benefit analysis that can override thirst signals.The mammary epithelial cell (MEC) system is a bilayered ductal epithelium of luminal and basal cells, maintained by a lineage of stem and progenitor populations. Here, we used integrated single-cell transcriptomics and chromatin accessibility analysis to reconstruct the cell types of the mouse MEC system and their underlying gene regulatory features in an unbiased manner. We define differentiation states within the secretory type of luminal cells, which forms a continuous spectrum of general luminal progenitor and lactation-committed progenitor cells. By integrating single-cell transcriptomics and chromatin accessibility landscapes, we identify cis- and trans-regulatory elements that are differentially activated in the specific epithelial cell types and our newly defined luminal differentiation states. Our work provides a resource to reveal cis/trans-regulatory elements associated with MEC identity and differentiation that will serve as a reference to determine how the chromatin accessibility landscape changes during breast cancer.The Hippo signaling pathway maintains organ size and tissue homeostasis via orchestration of cell proliferation and apoptosis. How this pathway triggers cell apoptosis remains largely unexplored. Here, we identify NR4A1 as a target of the Hippo pathway that mediates the pro-apoptotic and anti-tumor effects of the Hippo pathway whereby YAP regulates the transcription, phosphorylation, and mitochondrial localization of NR4A1. NR4A1, in turn, functions as a feedback inhibitor of YAP to promote its degradation, thereby inhibiting the function of YAP during liver regeneration and tumorigenesis. Our studies elucidate a regulatory loop between NR4A1 and YAP to coordinate Hippo signaling activity during liver regeneration and tumorigenesis and highlight NR4A1 as a marker of Hippo signaling, as well as a therapeutic target for hepatocellular carcinoma.CellMiner-SCLC (https//discover.nci.nih.gov/SclcCellMinerCDB/) integrates drug sensitivity and genomic data, including high-resolution methylome and transcriptome from 118 patient-derived small cell lung cancer (SCLC) cell lines, providing a resource for research into this "recalcitrant cancer." We demonstrate the reproducibility and stability of data from multiple sources and validate the SCLC consensus nomenclature on the basis of expression of master transcription factors NEUROD1, ASCL1, POU2F3, and YAP1. Our analyses reveal transcription networks linking SCLC subtypes with MYC and its paralogs and the NOTCH and HIPPO pathways. SCLC subsets express specific surface markers, providing potential opportunities for antibody-based targeted therapies. YAP1-driven SCLCs are notable for differential expression of the NOTCH pathway, epithelial-mesenchymal transition (EMT), and antigen-presenting machinery (APM) genes and sensitivity to mTOR and AKT inhibitors. These analyses provide insights into SCLC biology and a framework for future investigations into subtype-specific SCLC vulnerabilities.Store-operated calcium entry (SOCE) through STIM-gated ORAI channels governs vital cellular functions. In this context, SOCE controls cellular redox signaling and is itself regulated by redox modifications. However, the molecular mechanisms underlying this calcium-redox interplay and the functional outcomes are not fully understood. Here, we examine the role of STIM2 in SOCE redox regulation. Redox proteomics identify cysteine 313 as the main redox sensor of STIM2 in vitro and in vivo. Oxidative stress suppresses SOCE and calcium currents in cells overexpressing STIM2 and ORAI1, an effect that is abolished by mutation of cysteine 313. FLIM and FRET microscopy, together with MD simulations, indicate that oxidative modifications of cysteine 313 alter STIM2 activation dynamics and thereby hinder STIM2-mediated gating of ORAI1. In summary, this study establishes STIM2-controlled redox regulation of SOCE as a mechanism that affects several calcium-regulated physiological processes, as well as stress-induced pathologies.Hhex encodes a homeobox transcriptional regulator important for embryonic development and hematopoiesis. Hhex is highly expressed in NK cells, and its germline deletion results in significant defects in lymphoid development, including NK cells. To determine if Hhex is intrinsically required throughout NK cell development or for NK cell function, we generate mice that specifically lack Hhex in NK cells. NK cell frequency is dramatically reduced, while NK cell differentiation, IL-15 responsiveness, and function at the cellular level remain largely normal in the absence of Hhex. Increased IL-15 availability fails to fully reverse NK lymphopenia following conditional Hhex deletion, suggesting that Hhex regulates developmental pathways extrinsic to those dependent on IL-15. Gene expression and functional genetic approaches reveal that Hhex regulates NK cell survival by directly binding Bcl2l11 (Bim) and repressing expression of this key apoptotic mediator. These data implicate Hhex as a transcriptional regulator of NK cell homeostasis and immunity.Homologous recombination is initiated by nucleolytic degradation (resection) of DNA double-strand breaks (DSBs). DSB resection is a two-step process in which an initial short-range step is catalyzed by the Mre11-Rad50-Xrs2 (MRX) complex and limited to the vicinity of the DSB end. Then the two long-range resection Exo1 and Dna2-Sgs1 nucleases extend the resected DNA tracts. How short-range resection is regulated and contributes to checkpoint activation remains to be determined. Here, we show that abrogation of long-range resection induces a checkpoint response that decreases DNA damage resistance. This checkpoint depends on the 9-1-1 complex, which recruits Dpb11 and Rad9 at damaged DNA. Furthermore, the 9-1-1 complex, independently of Dpb11 and Rad9, restricts short-range resection by negatively regulating Mre11 nuclease. We propose that 9-1-1, which is loaded at the leading edge of resection, plays a key function in regulating Mre11 nuclease and checkpoint activation once DSB resection is initiated.TMEM18 is the strongest candidate for childhood obesity identified from GWASs, yet as for most GWAS-derived obesity-susceptibility genes, the functional mechanism remains elusive. We here investigate the relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is downregulated in children with obesity. Functionally, downregulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes, indicating that TMEM18 is important for adipocyte differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG, particularly upregulating PPARG1 promoter activity, and this activation is repressed by inflammatory stimuli. The relationship between TMEM18 and PPARG1 is also evident in adipocytes of children and is clinically associated with obesity and adipocyte hypertrophy, inflammation, and insulin resistance. Our findings indicate a role of TMEM18 as an upstream regulator of PPARG signaling driving healthy adipogenesis, which is dysregulated with adipose tissue dysfunction and obesity.Many gene products exhibit great structural heterogeneity because of an array of modifications. These modifications are not directly encoded in the genomic template but often affect the functionality of proteins. Protein glycosylation plays a vital role in proper protein functions. However, the analysis of glycoproteins has been challenging compared with other protein modifications, such as phosphorylation. Here, we perform an integrated proteomic and glycoproteomic analysis of 83 prospectively collected high-grade serous ovarian carcinoma (HGSC) and 23 non-tumor tissues. Integration of the expression data from global proteomics and glycoproteomics reveals tumor-specific glycosylation, uncovers different glycosylation associated with three tumor clusters, and identifies glycosylation enzymes that were correlated with the altered glycosylation. In addition to providing a valuable resource, these results provide insights into the potential roles of glycosylation in the pathogenesis of HGSC, with the possibility of distinguishing pathological outcomes of ovarian tumors from non-tumors, as well as classifying tumor clusters.