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The resilience of the microbiota can protect us from disease, but a resilient dysbiotic microbiota may also cause disease. This Opinion article discusses the concepts and mechanisms of microbial resilience against dietary, antibiotic or bacteriotherapy-induced perturbations and the implications these have for human health. The composition of the intestinal microbiota varies among individuals and throughout development, and is dependent on host and environmental factors. However, although the microbiota is constantly exposed to environmental challenges, its composition and function in an individual are stable against perturbations, as microbial communities are resilient and resistant to change. The maintenance of a beneficial microbiota requires a homeostatic equilibrium within microbial communities, and also between the microorganisms and the intestinal interface of the host. The resilience of the healthy microbiota protects us from dysbiosis-related diseases, such as inflammatory bowel disease (IBD) or metabolic disorder. By contrast, a resilient dysbiotic microbiota may cause disease. In this Opinion article, we propose that microbial resilience has a key role in health and disease. We will discuss the concepts and mechanisms of microbial resilience against dietary, antibiotic or bacteriotherapy-induced perturbations and the implications for human health.

Background Assessment of seed germination is an essential task for seed researchers to measure the quality and performance of seeds. Usually, seed assessments are done manually, which is a cumbersome, time consuming and error-prone process. Classical image analyses methods are not well suited for large-scale germination experiments, because they often rely on manual adjustments of color-based thresholds. We here propose a machine learning approach using modern artificial neural networks with region proposals for accurate seed germination detection and high-throughput seed germination experiments. Results We generated labeled imaging data of the germination process of more than 2400 seeds for three different crops, Zea mays (maize), Secale cereale (rye) and Pennisetum glaucum (pearl millet) , with a total of more than 23,000 images. Different state-of-the-art convolutional neural network (CNN) architectures with region proposals have been trained using transfer learning to automatically identify seeds within petri dishes and to predict whether the seeds germinated or not. Our proposed models achieved a high mean average precision (mAP) on a hold-out test data set of approximately 97.9%, 94.2% and 94.3% for Zea mays , Secale cereale and Pennisetum glaucum respectively. Further, various single-value germination indices, such as Mean Germination Time and Germination Uncertainty, can be computed more accurately with the predictions of our proposed model compared to manual countings. Conclusion Our proposed machine learning-based method can help to speed up the assessment of seed germination experiments for different seed cultivars. It has lower error rates and a higher performance compared to conventional and manual methods, leading to more accurate germination indices and quality assessments of seeds.

Pyrrolone-fused benzosuberene (PBS) compounds were semi-synthesized from  α,β,γ -Himachalenes extracted from the essential oil of Cedrus deodara following amino-vinyl-bromide substituted benzosuberenes as intermediates. These PBSs compounds classified as an attractive source of therapeutics. The α-isoform of PI3K which is a pivotal modulator of PI3K/AKT/mTOR signaling pathway, responsible for neurological disorders like epilepsy, found as a potential target molecule against these 17 semi-synthesized PBS compounds using in silico ligand-based pharmacophore mapping and target screening. The compounds screened using binding affinities, ADMET properties, and toxicity that were accessed by in silico docking simulations and pharmacokinetics profiling. Ultimately two compounds viz ., PBS-8 and PBS-9 were selected for further in vivo evaluation using a zebrafish ( Danio rerio ) model of pentylenetetrazol (PTZ)-induced clonic convulsions. Additionally, gene expression studies performed for the genes of the PI3K/AKT/mTOR pathway which further validated our results. In conclusion, these findings suggested that PBS-8 is a promising candidate that could bedeveloped as a potential antiepileptic.

Rare neurological and neuropsychiatric syndromes, although individually uncommon, collectively contribute to misdiagnosis, avoidable investigations, and occasional preventable harm. Many of these conditions sit at the interface of neurology and psychiatry and are vulnerable to diagnostic overshadowing, in which clinically unfamiliar presentations are dismissed as functional or psychiatric. This narrative review examines six clinically significant entities that exemplify this problem: Beauty Parlor Stroke Syndrome (BPSS), Alice in Wonderland Syndrome (AIWS), Alien Hand Syndrome (AHS) and Alien Limb Phenomenon (ALP), Exploding Head Syndrome (EHS), Cotard’s Delusion (CD), and the syndrome of transient Headache and Neurological Deficits with cerebrospinal fluid Lymphocytosis (HaNDL). These conditions were selected because each is uncommon, each is reproducibly misclassified in routine practice (typically as a psychiatric, functional, or benign positional disorder), and each has a defined neurological substrate with implications for management. We provide a narrative synthesis of published literature, drawing on case series, cohort studies, narrative reviews, and consensus criteria such as the International Classification of Headache Disorders, 3rd edition (ICHD-3) for HaNDL. BPSS is discussed as a mechanical cause of vertebrobasilar ischaemia, classically following cervical hyperextension at a salon basin, in which symptoms are commonly attributed initially to benign positional vertigo or anxiety. AIWS is described as a perceptual disorder characterised by dysmetropsia and altered body schema, most often associated with migraine in adults and with viral infection (particularly Epstein–Barr virus) in children; reported lifetime prevalence in adult migraineurs varies between studies in the approximate range of 16–19%, with higher rates in those with migraine with aura. The distinction between AHS, typically of acute callosal or frontal medial origin, and ALP, more typically associated with parietal dysfunction in corticobasal syndrome, is clarified. EHS is presented as a benign sensory parasomnia that mimics serious intracranial events. Cotard’s delusion is described as a nihilistic delusion most often arising in severe depression with psychotic features and carrying a significant risk of self-neglect and suicide. HaNDL is framed according to ICHD-3 criteria as an important stroke and encephalitis mimic. We discuss cross-cutting diagnostic pitfalls, summarise recommended investigations and management, and outline the limitations of the current evidence base, which is dominated by case reports and small case series. We also briefly consider the limited but emerging role of digital symptom search and artificial-intelligence tools as adjuncts to clinical reasoning, not as substitutes for it.

Background In a subgroup of patients suffering from progressive multiple sclerosis (MS), which is an inflammation-mediated neurodegenerative disease of the central nervous system (CNS), B cell aggregates were discovered within the meninges. Occurrence of these structures was associated with a more severe disease course and cortical histopathology. We have developed the B cell-dependent MP4-induced experimental autoimmune encephalomyelitis (EAE) as a mouse model to mimic this trait of the human disease. The aim of this study was to determine a potential role of lymphoid tissue inducer (LTi) and T H 17 cells in the process of B cell aggregate formation in the MP4 model. Methods We performed flow cytometry of cerebellar and splenic tissue of MP4-immunized mice in the acute and chronic stage of the disease to analyze the presence of CD3 − CD5 − CD4 + RORγt + LTi and CD3 + CD5 + CD4 + RORγt + T H 17 cells. Myelin oligodendrocyte glycoprotein (MOG):35–55-induced EAE was used as B cell-independent control model. We further determined the gene expression profile of B cell aggregates using laser capture microdissection, followed by RNA sequencing. Results While we were able to detect LTi cells in the embryonic spleen and adult intestine, which served as positive controls, there was no evidence for the existence of such a population in acute or chronic EAE in neither of the two models. Yet, we detected CD3 − CD5 − CD4 − RORγt + innate lymphoid cells (ILCs) and T H 17 cells in the CNS, the latter especially in the chronic stage of MP4-induced EAE. Moreover, we observed a unique gene signature in CNS B cell aggregates compared to draining lymph nodes of MP4-immunized mice and to cerebellum as well as draining lymph nodes of mice with MOG:35–55-induced EAE. Conclusion The absence of LTi cells in the cerebellum suggests that other cells might take over the function as an initiator of lymphoid tissue formation in the CNS. Overall, the development of ectopic lymphoid organs is a complex process based on an interplay between several molecules and signals. Here, we propose some potential candidates, which might be involved in the formation of B cell aggregates in the CNS of MP4-immunized mice.

Background MP4-induced experimental autoimmune encephalomyelitis (EAE) is a mouse model of multiple sclerosis (MS), which enables targeted research on B cells, currently much discussed protagonists in MS pathogenesis. Here, we used this model to study the impact of the S1P 1 receptor modulator FTY720 (fingolimod) on the autoreactive B cell and antibody response both in the periphery and the central nervous system (CNS). Methods MP4-immunized mice were treated orally with FTY720 for 30 days at the peak of disease or 50 days after EAE onset. The subsequent disease course was monitored and the MP4-specific B cell/antibody response was measured by ELISPOT and ELISA. RNA sequencing was performed to determine any effects on B cell-relevant gene expression. S1P 1 receptor expression by peripheral T and B cells, B cell subset distribution in the spleen and B cell infiltration into the CNS were studied by flow cytometry. The formation of B cell aggregates and of tertiary lymphoid organs (TLOs) was evaluated by histology and immunohistochemistry. Potential direct effects of FTY720 on B cell aggregation were studied in vitro. Results FTY720 significantly attenuated clinical EAE when treatment was initiated at the peak of EAE. While there was a significant reduction in the number of T cells in the blood after FTY720 treatment, B cells were only slightly diminished. Yet, there was evidence for the modulation of B cell receptor-mediated signaling upon FTY720 treatment. In addition, we detected a significant increase in the percentage of B220 + B cells in the spleen both in acute and chronic EAE. Whereas acute treatment completely abrogated B cell aggregate formation in the CNS, the numbers of infiltrating B cells and plasma cells were comparable between vehicle- and FTY720-treated mice. In addition, there was no effect on already developed aggregates in chronic EAE. In vitro B cell aggregation assays suggested the absence of a direct effect of FTY720 on B cell aggregation. However, FTY720 impacted the evolution of B cell aggregates into TLOs. Conclusions The data suggest differential effects of FTY720 on the B cell compartment in MP4-induced EAE.

Variation in ATG16L1, a protein involved in autophagy, confers risk for Crohn’s disease, but mice with hypomorphic ATG16L1 activity do not develop spontaneous intestinal inflammation; this study shows that autophagy compensates for endoplasmic reticulum stress — common in inflammatory bowel disease epithelium — specifically in Paneth cells, with Crohn’s-disease-like inflammation of the ileum originating from this cell type when both pathways are compromised. Inflammation in Crohn's disease Variations in ATG16L1 — a protein involved in autophagy — are risk factors for Crohn's disease, but although mice homozygous for a common ATG16L1 risk allele show abnormal Paneth cell function, they do not develop intestinal inflammation as might be expected. Richard Blumberg and colleagues show that impairment of either autophagy or the unfolded protein response within Paneth cells results in each other's compensatory engagement, but that colitis develops only when both pathways are impaired. This work highlights pharmacological augmentation of autophagy as a possible therapeutic approach to controlling intestinal inflammation. The recognition of autophagy related 16-like 1 ( ATG16L1 ) as a genetic risk factor has exposed the critical role of autophagy in Crohn’s disease 1 . Homozygosity for the highly prevalent ATG16L1 risk allele, or murine hypomorphic (HM) activity, causes Paneth cell dysfunction 2 , 3 . As Atg16l1 HM mice do not develop spontaneous intestinal inflammation, the mechanism(s) by which ATG16L1 contributes to disease remains obscure. Deletion of the unfolded protein response (UPR) transcription factor X-box binding protein-1 ( Xbp1 ) in intestinal epithelial cells, the human orthologue of which harbours rare inflammatory bowel disease risk variants, results in endoplasmic reticulum (ER) stress, Paneth cell impairment and spontaneous enteritis 4 . Unresolved ER stress is a common feature of inflammatory bowel disease epithelium 4 , 5 , and several genetic risk factors of Crohn’s disease affect Paneth cells 2 , 4 , 6 , 7 , 8 , 9 . Here we show that impairment in either UPR ( Xbp1 ΔIEC ) or autophagy function ( Atg16l1 ΔIEC or Atg7 ΔIEC ) in intestinal epithelial cells results in each other’s compensatory engagement, and severe spontaneous Crohn’s-disease-like transmural ileitis if both mechanisms are compromised. Xbp1 ΔIEC mice show autophagosome formation in hypomorphic Paneth cells, which is linked to ER stress via protein kinase RNA-like endoplasmic reticulum kinase (PERK), elongation initiation factor 2α (eIF2α) and activating transcription factor 4 (ATF4). Ileitis is dependent on commensal microbiota and derives from increased intestinal epithelial cell death, inositol requiring enzyme 1α (IRE1α)-regulated NF-κB activation and tumour-necrosis factor signalling, which are synergistically increased when autophagy is deficient. ATG16L1 restrains IRE1α activity, and augmentation of autophagy in intestinal epithelial cells ameliorates ER stress-induced intestinal inflammation and eases NF-κB overactivation and intestinal epithelial cell death. ER stress, autophagy induction and spontaneous ileitis emerge from Paneth-cell-specific deletion of Xbp1 . Genetically and environmentally controlled UPR function within Paneth cells may therefore set the threshold for the development of intestinal inflammation upon hypomorphic ATG16L1 function and implicate ileal Crohn’s disease as a specific disorder of Paneth cells.

Myocardial infarction (MI) induces the generation of proinflammatory Ly6Chigh monocytes in the spleen and the recruitment of these cells to the myocardium. CD4+ Foxp3+ CD25+ T-cells (Tregs) promote the healing process after myocardial infarction by engendering a pro-healing differentiation state in myocardial monocyte-derived macrophages. We aimed to study the effects of CD4+ T-cells on splenic myelopoiesis and monocyte differentiation. We instigated MI in mice and found that MI-induced splenic myelopoiesis is abrogated in CD4+ T-cell deficient animals. Conventional CD4+ T-cells promoted myelopoiesis in vitro by cell–cell-contact and paracrine mechanisms, including interferon-gamma (IFN-γ) signalling. Depletion of regulatory T-cells enhanced myelopoiesis in vivo, as evidenced by increases in progenitor cell numbers and proliferative activity in the spleen 5 days after MI. The frequency of CD4+ T-cells-producing factors that promote myelopoiesis increased within the spleen of Treg-depleted mice. Moreover, depletion of Tregs caused a proinflammatory bias in splenic Ly6Chigh monocytes, which showed predominantly upregulated expression of IFN-γ responsive genes after MI. Our results indicate that conventional CD4+ T-cells promote and Tregs attenuate splenic myelopoiesis and proinflammatory differentiation of monocytes.

The interaction between the mammalian host and its resident gut microbiota is known to license adaptive immune responses. Nutritional constituents strongly influence composition and functional properties of the intestinal microbial communities. Here, we report that omission of a single essential amino acid - tryptophan – from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction results in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiota, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation. Food intake shapes intestinal microbiome composition, which in turn shapes adaptive immune responses. Here the authors show that dietary tryptophan restriction (DTR) protects mice from subsequent autoimmune neuropathology challenge by altering intestinal microbiota, highlighting the potential of diet-regulated microbiota to prevent immune pathology.

Home confinement during the COVID-19 pandemic is accompanied by dramatic changes in lifestyle and dietary behaviors that can significantly influence health. We conducted an online cross-sectional survey to assess COVID-19 pandemic-induced dietary and lifestyle changes and their association with perceived health status and self-reported body weight changes among 1000 Indian adults in early 2021. Positive improvements in dietary habits, e.g., eating more nutritious (85% of participants) and home-cooked food (89%) and an increase in overall nutrition intake (79%), were observed. Sixty-five percent of participants self-reported increased oat consumption to support immunity. There were some negative changes, e.g., more binge eating (69%), eating more in between meals (67%), and increasing meal portion size (72%). Two-thirds of participants reported no change in lifestyles, whereas 21 and 23% reported an increase, and 13 and 10% reported a decrease in physical activity and sleep, respectively. Overall, 64 and 65% of participants reported an improvement in perceived health and an increase in body weight during the COVID-19 period compared to pre-COVID-19, respectively. The top motivations for improving dietary habits included improving physical and mental health and building immunity. In conclusion, the overall perceived health was improved and there was an increase in self-reported body weight in most participants during COVID-19. Diet emerged as the most crucial determinant for these changes.