Miracle-dz/UniFAR-FTUs huggingface dataset:
Brain-Immune Alterations and Mitochondrial Dysfunctions in a Mouse Model of Paediatric Autoimmune Disorder Associated with Streptococcus: Exacerbation by Chronic Psychosocial Stress

Adverse psychosocial experiences have been shown to modulate individual responses to immune challenges and affect mitochondrial functions. The aim of this study was to investigate inflammation and immune responses as well as mitochondrial bioenergetics in an experimental model of Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS). Starting in adolescence (postnatal day 28), male SJL/J mice were exposed to five injections (interspaced by two weeks) with Group-A beta-haemolytic streptococcus (GAS) homogenate. Mice were exposed to chronic psychosocial stress, in the form of protracted visual exposure to an aggressive conspecific, for four weeks. Our results indicate that psychosocial stress exacerbated individual response to GAS administrations whereby mice exposed to both treatments exhibited altered cytokine and immune-related enzyme expression in the hippocampus and hypothalamus. Additionally, they showed impaired mitochondrial respiratory chain complexes IV and V, and reduced adenosine triphosphate (ATP) production by mitochondria and ATP content. These brain abnormalities, observed in GAS-Stress mice, were associated with blunted titers of plasma corticosterone. Present data support the hypothesis that challenging environmental conditions, in terms of chronic psychosocial stress, may exacerbate the long-term consequences of exposure to GAS processes through the promotion of central immunomodulatory and oxidative stress.
Cox regression with survival‐time‐dependent missing covariate values

Analysis with time‐to‐event data in clinical and epidemiological studies often encounters missing covariate values, and the missing at random assumption is commonly adopted, which assumes that missingness depends on the observed data, including the observed outcome which is the minimum of survival and censoring time. However, it is conceivable that in certain settings, missingness of covariate values is related to the survival time but not to the censoring time. This is especially so when covariate missingness is related to an unmeasured variable affected by the patient's illness and prognosis factors at baseline. If this is the case, then the covariate missingness is not at random as the survival time is censored, and it creates a challenge in data analysis. In this article, we propose an approach to deal with such survival‐time‐dependent covariate missingness based on the well known Cox proportional hazard model. Our method is based on inverse propensity weighting with the propensity estimated by nonparametric kernel regression. Our estimators are consistent and asymptotically normal, and their finite‐sample performance is examined through simulation. An application to a real‐data example is included for illustration.
Antipyretic, Antinociceptive, and Anti-Inflammatory Activities from Pogostemon benghalensis Leaf Extract in Experimental Wister Rats

Background:Pogostemon benghalensis leaves have traditionally been utilized for relieving body aches, headaches and fever. Based on its uses, the present study was designed to investigate the antinociceptive, antipyretic and anti-edematogenic activities from P. benghalensis leaves’ methanol extract (PBME) in Wister rats. Methods: The thermal (hot plate) and chemical (acetic acid-induced writhing and formalin test) models for antinociceptive effects, and the Brewer’s yeast induced hyperthermia test for antipyretic action and rat paw edema by carrageenan for anti-edematogenic activity, were applied for PBME at different dose levels. The acute toxicity of PBME through the oral route was performed to determine the lethal dose. Results: PBME significantly and dose-dependently reduced pyrexia and diminished edema volume, which depicted its antipyretic and anti-edematogenic effects respectively. The inhibition of writhing reflex, increased reaction latency and reduced frequency of licking indicated that PBME has significant dose-dependent antinociceptive activity. P. benghalensis methanol extract at 4000 mg/kg shows no sign of toxicity, which is a considerable, good margin of safety. Conclusions: The study illustrated the antipyretic, antinociceptive and anti-inflammatory potential of P. benghalensis leaf extract with a safety margin, and validated its traditional use to alleviate fever, pain, and inflammation.
Effects of three major protein sources on performance, gut morphology and fermentation characteristics in broilers

ABSTRACT 1. This study determined the effects of three protein sources (PS), each at two digestibility crude protein (DCP) levels, on performance, gut morphology and fermentation characteristics in the hindgut of broilers. 2. It was hypothesised that broilers fed ingredients high in indigestible CP, i.e. rapeseed meal (RSM) or maize gluten (MG), could potentially cause reduced growth, impaired gut health, and more protein fermentation products in caecal digesta. Increasing the DCP level in each of the indigestible CP diets may compensate for these detrimental effects. 3. In total, 288 one-d-old male Ross 308 broilers were used in a completely randomised 3 × 2 factorial design, with six replicate pens per treatment. Three PS: soybean meal (SBM), rapeseed meal (RSM) or maize gluten (MG), and two DCP levels: 15.8 and 17.2% were used. 4. Broilers fed SBM had increased feed intake and BWG and improved FCR compared with those fed RSM and MG diets. Broilers fed high DCP had better performance compared with those on low DCP. No significant effects of PS or DCP level were found on gastrointestinal tract development, caecal ammonia or volatile fatty acid concentrations. 5. Broilers fed SBM had longer villi, smaller crypts and increased villus height to crypt depth ratio compared with those fed RSM and MG diets. Broilers fed RSM diet had a lower caecal pH, and had 16.5% and 14.9% more branched chain fatty acid contents in caecal digesta compared with those fed SBM and MG diets, respectively, indicating more proteolytic fermentation. 6. Replacing SBM by RSM and MG negatively affected growth performance and gut morphology. Hindgut protein fermentation was substantially increased in RSM fed birds. 7. To a certain extent, retarded growth performance in RSM and MG fed birds could be counterbalanced by increasing the dietary level of digestible CP.
Special Collection: Twenty Years of West Nile Virus in the United States Epidemiology of West Nile Virus in the United States: Implications for Arbovirology and Public Health

Since West Nile virus (WNV) emerged in the United States in 1999, 22,999 neuroinvasive disease cases in humans were reported through 2017. These cases have arisen from an estimated seven million human infections. Population incidence is geographically heterogeneous and is highest in the West and Midwest. Upwards of 2% of the population in some jurisdictions may become infected during outbreaks. Before universal screening of the United States blood supply, this high infection incidence and that approximately 75% of those infected remain asymptomatic translated into a considerable risk of WNV transfusion transmission despite the short duration of viremia following infection. Universal blood donor screening has nearly eliminated the risk of WNV transfusion transmission, but at enormous cost. WNV transmission via transplanted organs carries extremely high morbidity and mortality. Improved vector surveillance and timely and effective response to surveillance data can reduce the impact of WNV and should remain public health priorities.
Early detection and monitoring of cerebral ischemia using calcium-responsive MRI probes

Significance The duration of cerebral ischemia is a key factor in determining the severity of brain damage and the course of action. Thus, an accurate and timely observation of the ischemic process is highly critical. Here we present a molecular neuroimaging approach that enables direct detection and real-time visualization of transient cerebral ischemia. The method relies on high-resolution observation of extracellular calcium alterations associated with the spatiotemporal dynamics of cerebral ischemia, using a selective molecular MRI probe. The rapid detection of calcium fluctuations in healthy and disease states will not only lead to essential insights for successful treatment and recovery of ischemic brain tissue but will also improve our understanding of the underlying neurobiology of neurological and psychiatric disorders. Cerebral ischemia is one of the leading causes of mortality and disability in infants and adults and its timely diagnosis is essential for an efficient treatment. We present a methodology for fast detection and real-time monitoring of fluctuations of calcium ions associated with focal ischemia using a molecular functional MRI approach. We used a dinuclear paramagnetic gadolinium(III) complex chelate that changes MR image contrast through its reversible interaction with extracellular calcium ions, while applying a remote transient middle cerebral artery occlusion as a model for ischemic stroke. Our method sensitively recognizes the onset and follows the dynamics of the ischemic core and penumbra with submillimeter spatial and second-scale temporal resolution, thus paving the way for noninvasive monitoring and development of targeted treatment strategies for cerebral ischemia.
Impact of FDG PET Imaging for Expanding Patient Eligibility and Measuring Treatment Response in a Genome-Driven Basket Trial of the Pan-HER Kinase Inhibitor, Neratinib

Purpose: To determine whether FDG PET can expand eligibility in biomarker-selected clinical trials by providing a means to quantitate response in patients with non-assessable disease by RECIST. Experimental Design: SUMMIT (NCT01953926) is a multicenter phase II “basket” trial of the Pan-HER kinase inhibitor, neratinib. Patients had advanced ERBB2 (HER2)-mutant solid tumors, ≥1 measurable lesion, preferably defined unidimensionally by RECIST v1.1, or alternatively metabolically by PET Response Criteria (PRC). The primary aim was to determine the proportion of additional breast cancer patients accrued using PRC who would have otherwise been ineligible based on RECIST criteria alone. The secondary aim was to determine the concordance of response versus non-response between RECIST and PRC. Results: Eighty-one patients with HER2-mutant metastatic breast cancer were accrued; 77 were evaluable for response by RECIST and/or PRC. 63 (82%) were RECIST-evaluable and 14 (18%) were accrued using PRC alone. Bone-only disease (n = 11; 79%) was the most common reason for classification as non-measurable by RECIST. Twenty-nine patients were accrued and followed using both criteria, of which 25 (86%; 95% confidence interval, 68%–96%) were concordant for response versus non-response as defined by RECIST and PRC. Conclusions: PRC allowed patients with non-RECIST measurable disease access to therapy and facilitated more rapid accrual of patients to this trial of a rare biomarker. PRC and RECIST both provided methods of response assessment and were generally concordant. Thus, PRC was useful as a supplement to RECIST criteria. This provides a rationale for including FDG PET measurements in future clinical trials involving rare tumors or rare genomically defined subpopulations of more common cancers.
Computational identification of key genes that may regulate gene expression reprogramming in Alzheimer’s patients

The dementia epidemic is likely to expand worldwide as the aging population continues to grow. A better understanding of the molecular mechanisms that lead to dementia is expected to reveal potentially modifiable risk factors that could contribute to the development of prevention strategies. Alzheimer’s disease is the most prevalent form of dementia. Currently we only partially understand some of the pathophysiological mechanisms that lead to development of the disease in aging individuals. In this study, Switch Miner software was used to identify key switch genes in the brain whose expression may lead to the development of Alzheimer’s disease. The results indicate that switch genes are enriched in pathways involved in the proteasome, oxidative phosphorylation, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and metabolism in the hippocampus and posterior cingulate cortex. Network analysis identified the krupel like factor 9 (KLF9), potassium channel tetramerization domain 2 (KCTD2), Sp1 transcription factor (SP1) and chromodomain helicase DNA binding protein 1 (CHD1) as key transcriptional regulators of switch genes in the brain of AD patients. These transcriptions factors have been implicated in conditions associated with Alzheimer’s disease, including diabetes, glucocorticoid signaling, stroke, and sleep disorders. The specific pathways affected reveal potential modifiable risk factors by lifestyle changes.
Investigating the Role of Prolactin as a Potential Biomarker of Stress in Castrated Male Domestic Dogs

Simple Summary Although cortisol is usually considered the main reference for the assessment of stress, in some animal species it has been shown that prolactin can be used as a biomarker of both acute and chronic stress. Behavioural parameters can also be used to assess the state of welfare and stress. This study was aimed at evaluating the possible relationship between serum prolactin, serum cortisol and behavioural signs of stress in domestic dogs. To reduce the possible influence of some factors, the study was performed on a homogeneous sample formed by 40 castrated male Spanish Greyhound dogs housed in a dog shelter. The weak negative correlation found between serum cortisol and prolactin values agrees with results obtained in other studies, indicating that prolactin response might be an alternative to cortisol response. Abstract Prolactin has been recently regarded as a potential biomarker of both acute and chronic stress in several species. Since only few studies until now have focussed on domestic dogs, this study was aimed at evaluating whether prolactin, cortisol and stress behaviour correlated with each other in sheltered dogs. Both cortisol and prolactin analysis were performed in serum samples through a hormone-specific ELISA kit. For each dog, a stress score was calculated by summing the number of occurrences of stress-related behaviours. The presence/absence of fear during the time spent in the collection room was also scored for each individual. Results revealed a weak negative correlation between cortisol and prolactin levels. Neither of the hormones was correlated with the stress score, nor did their values seem to be influenced by showing fear in the collection room. The weak negative correlation found between cortisol and prolactin values agrees with results obtained in other studies, indicating that prolactin response might be an alternative to cortisol response. This, together with the high serum prolactin levels compared to those reported by other authors for healthy domestic dogs, may indicate that prolactin might be a good biomarker of chronic stress, and although further studies are needed to better understand the potential role of prolactin in the evaluation of canine welfare.
Regulation of Membrane Calcium Transport Proteins by the Surrounding Lipid Environment

Calcium ions (Ca2+) are major messengers in cell signaling, impacting nearly every aspect of cellular life. Those signals are generated within a wide spatial and temporal range through a large variety of Ca2+ channels, pumps, and exchangers. More and more evidences suggest that Ca2+ exchanges are regulated by their surrounding lipid environment. In this review, we point out the technical challenges that are currently being overcome and those that still need to be defeated to analyze the Ca2+ transport protein–lipid interactions. We then provide evidences for the modulation of Ca2+ transport proteins by lipids, including cholesterol, acidic phospholipids, sphingolipids, and their metabolites. We also integrate documented mechanisms involved in the regulation of Ca2+ transport proteins by the lipid environment. Those include: (i) Direct interaction inside the protein with non-annular lipids; (ii) close interaction with the first shell of annular lipids; (iii) regulation of membrane biophysical properties (e.g., membrane lipid packing, thickness, and curvature) directly around the protein through annular lipids; and (iv) gathering and downstream signaling of several proteins inside lipid domains. We finally discuss recent reports supporting the related alteration of Ca2+ and lipids in different pathophysiological events and the possibility to target lipids in Ca2+-related diseases.
Common Host Responses in Murine Aerosol Models of Infection Caused by Highly Virulent Gram-Negative Bacteria from the Genera Burkholderia, Francisella and Yersinia

Highly virulent bacterial pathogens cause acute infections which are exceptionally difficult to treat with conventional antibiotic therapies alone. Understanding the chain of events that are triggered during an infection of a host has the potential to lead to new therapeutic strategies. For the first time, the transcriptomic responses within the lungs of Balb/C mice have been compared during an acute infection with the intracellular pathogens Burkholderia pseudomallei, Francisella tularensis and Yersinia pestis. Temporal changes were determined using RNAseq and a bioinformatics pipeline; expression of protein was also studied from the same sample. Collectively it was found that early transcriptomic responses within the infected host were associated with the (a) slowing down of critical cellular functions, (b) production of circulatory system components, (c) lung tissue integrity, and (d) intracellular regulatory processes. One common molecule was identified, Errfi1 (ErbB receptor feedback inhibitor 1); upregulated in response to all three pathogens and a potential novel marker of acute infection. Based upon the pro-inflammatory responses observed, we sought to synchronise each infection and report that 24 h p.i. of B. pseudomallei infection closely aligned with 48 h p.i. of infection with F. tularensis and Y. pestis. Post-transcriptional modulation of RANTES expression occurred across all pathogens, suggesting that these infections directly or indirectly modulate cell trafficking through chemokine expression/detection. Collectively, this unbiased NGS approach has provided an in-depth characterisation of the host transcriptome following infection with these highly virulent pathogens ultimately aiding in the development of host-directed therapies as adjuncts or alternatives to antibiotic treatment.
Will the Real Dahl S Rat Please Stand Up?

“To Tell the Truth” was a classic television game show that ran from 1956 to 1978 with the basic premise that three challengers were introduced, all claiming to be the “central character. ” The announcer would ask the challengers, standing side by side, “What is your name, please? ” Each challenger would answer, “My name is [central character’s]. ” After questioning was completed by a celebrity panel, each member would vote on which of the challengers they believed to be the central character. Once votes were in, the host would ask, “Will the real [person’s name] please stand up? ” The central character would, usually with playful feigning among the challengers, stand. Interestingly, during this same period of time, the Dahl salt-sensitive (S) rat was being developed as a model of salt-sensitive hypertension by Lewis Dahl, and most relevant to this analogy is that there have been several other “Dahl S strain challengers” used and/or commercialized (SS/Jr, SS/Iwai, SS/JrHsd, SS/JrHsdEnv, SS/JrHsdMcwi, and SS/ JrHsdMcwiCrl). Variability and inconsistency in blood pressure (BP) have been noted in commercially available Dahl S rats (62, 85), particularly related to salt sensitivity and susceptibility to kidney injury, with some claiming that the “Dahl S” rat is exhibiting a new and previously unobserved enhanced BP phenotype (SS/JrHsdEnv) (53). To look at this from a different perspective, are all these “Dahl S” models really the same, and, if so, how is it that the “same” model exhibits such significant variability from study to study or investigator to investigator? Aside from the direct impact on researchers that use the Dahl S model, these issues are highly relevant to biomedical research as animal models play a significant role in understanding human health and disease. This article will discuss how the various “Dahl S” strains are similar, why they may be different, and whether these factors can ultimately impact study conclusions.
Food Preservatives Induce Proteobacteria Dysbiosis in Human-Microbiota Associated Nod2-Deficient Mice

The worldwide incidence of many immune-mediated and metabolic diseases, initially affecting only the wealthy Western countries, is increasing rapidly. Many of these diseases are associated with the compositional and functional alterations of gut microbiota, i.e., dysbiosis. The most consistent markers of the dysbiosis are a decrease in microbiota diversity and an expansion of Proteobacteria. The role of food preservatives as potential triggers of gut microbiota dysbiosis has been long overlooked. Using a human microbiota-associated mouse model, we demonstrate that a mixture of common antimicrobial food additives induces dysbiosis characterised by an overgrowth of Proteobacteria phylum and a decrease in the Clostridiales order. Remarkably, human gut microbiota in a Nod2-deficient genetic background is even more susceptible to the induction of Proteobacteria dysbiosis by additives than the microbiota in a wild-type background. To conclude, our data demonstrate that antimicrobial food additives trigger gut microbiota dysbiosis in both wild-type and Nod2-deficient backgrounds and at the exposure levels reached in European populations. Whether this additive-modified gut microbiota plays a significant role in the pathogenesis of immune-mediated and metabolic diseases remains to be elucidated.
Design of a Bioreactor to Assess the Effect of Passive Joint Loading in a Live Chick Embryo In Ovo.

There is increasing interest in understanding how mechanical cues (e.g., physical forces due to kicking and other movements) influence the embryological development of tissues and organs. For example, recent studies from our lab and others have used the chick embryo model to demonstrate that the compositional and mechanical properties of developing tendons are strongly regulated by embryo movement frequency. However, current research tools for manipulating embryological movements and in ovo (or in utero) mechanical forces are generally limited to chemical treatments that either paralyze or overstimulate muscles without allowing for precise control of physical cues. Thus, in this study, we introduce an instrument that enables application of passive, dynamic ankle flexion at prescribed amplitudes and frequencies in live, developing chick embryos. This device meets the design goals of allowing for precise (< 1.5°) control of different waveforms of ankle motion at a physiologically relevant frequency (0.17 Hz) across a range of ankle angles (0° to 90° plantarflexion) with maintenance of embryo viability comparable to other methods.