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Introduction. Risk factors for thrombotic events in patients receiving treatment for Hodgkin lymphoma are not well known. Administration of some cytostatic medication, especially via central venous catheter, corticosteroids, and hyperlipidemia can present some of them. Case outline. A case of a 15-year-old boy that had been newly diagnosed with Hodgkin lymphoma is presented here. Chemotherapy according to vincristine, etoposide, prednisone, and doxorubicin (OEPA) protocol was introduced a month before headache and vomiting occurred, so subsequently, brain computer tomography was performed, and reviled laminar subdural pseudo-hemorrhage in the right occipital region. After performing magnetic resonance imaging (MRI) venous thrombosis of the posterior part of superior sagittal sinus, right transverses, and sigmoid sinus were presented. Low-molecular-weight heparin (LMWH) and anti-edematous therapy was immediately initiated. Two weeks later, the patient resumed the second cycle of chemotherapy combined with LMWH, as the previous symptoms of intracranial hypertension resolved. Two years later, MRI showed an almost complete resolution of the finding. The boy was in good clinical condition. Conclusion. Although administration of oral corticosteroids, could be rarely a risk factor per se for cerebral sinus venous thrombosis in Hodgkin lymphoma patients, it remains an important treatment option. Adequate and prompt diagnostics and therapy are mandatory in cases of wide intracranial venous thrombosis as the prevention of possible intracranial hypertension and even fatal outcome.

Introduction. In about one-third of the patients with aneurysmal subarachnoid bleeding, multiple intracranial aneurysms are confirmed. Risk factors such as female sex, smoking, hypertension, and age over 60 tend to be associated with multiple aneurysms. In this paper, we also discuss family predisposition and the treatment approach for multiple cerebral aneurysms. Case outline. Here, we present a case of a 64-year-old female patient, with spontaneous subarachnoid hemorrhage that had nine intracranial aneurysms. The patient was treated for hypertension for a long time, excessive smoker, and two of her nearest members of the family died from intracranial bleeding. The patient was fully conscious, without any neurological impairment. Subarachnoid bleeding was diffuse and neither brain-computer tomography finding or digital subtraction angiography could not suggest the source or location of bleeding among nine presented aneurisms. Magnetic resonance imaging had to be done, and the T1W fast spin-echo sequence showed a 9 mm large ruptured an aneurysm at the basilar tip, after contrast application, beside others. Three days after the insult, endovascular embolization was done and two basilar aneurysms were excluded from the circulation, including the one that bled. Conclusion. The patient had the majority of risk factors for multiple intracranial aneurysms. Knowledge of the family predisposition of multiple intracranial aneurysms allowed us to make a proper diagnostics of a patient?s descendant and reveal a new patient.

Gut microbial composition is associated with metabolic risk and differs markedly between industrialized (IND) and non-industrialized (non-IND) populations. Objective: To characterize the gut microbiome of American Indian (AI) children with overweight/obesity relative to IND and non-IND individuals (including ancient AI gut microbiomes) . Methods: Stool samples were from 7-10-year-old AI children with overweight/obesity enrolled in a lifestyle intervention trial on diabetes risk factors (2019-21) . Metagenomic analysis was performed on 39 samples from 25 individuals and compared to samples from age-matched (5-12-year-old) non-AI children in IND (N=380) or non-IND (N=90) populations. Results: Mean age was 8.4 years (SD 1.11) , 44% were male. Mean age-sex-adjusted BMI z-score was 2.12 (SD 0.45) . By principal coordinates analysis, AI samples clustered in an intermediate position between the IND and non-IND samples (Figure 1) . AI children shared microbes with non-IND children that are rare in IND populations but common in ancient AI individuals (Prevotella copri, Coprococcus catus) . Conclusions: The gut microbiome in a subset of AI children is distinct from the non-AI American gut microbiome. Further, AI children may have "inherited" gut microbes from their AI ancestors, which may contribute to differences in their metabolism relative to non-AI children. Disclosure A.Kostic: None. R.L.Hanson: None. M.Sinha: None. Funding American Diabetes Association (1-17-INI-13) ; National Institutes of Health (P30DK036836)

In the past 30 years the efforts to protect river beds and banks have increased significantly. The selection and design of proper structural solution means finding a solution in accordance with construction principles, river geomorphology, avoiding channel aggradation, bed scour, bank erosion, resulting structure failure and significant harm to the stream and nearby property. On the other hand, the structure should be environmentally-friendly. Hydraulic structures generally have a strong impact on the environment, so providing ?the right solution? presents a real challenge to engineers.

The authors examine the problems the European Monetary Union in the circumstances of the global economic crisis. They especially elaborated the battle for the financial stability of the European Monetary Union. The authors problematize the interaction of the European Central Bank and national central banks, emphasizing the deficiencies in the coordination of fiscal and monetary policy. They investigated the reasons that require a cautious strategy when it comes to the admission of new member states into the European Monetary Union and in that sense the conditions for nominal and real convergence. The authors consider the management of the economic crisis and the introduction of new institutions with the task to stabilize the situation in the monetary field. They explored the problems of helping countries like Greece from the point of view of the developed countries relationship. The authors especially paid attention to the level of transparency in relation to their citizens when making decisions on certain aid giving issues. They have proposed solutions for getting out of the vicious circle and the need to redesign the European Monetary Union and in this context the problem of the stabilization of the euro in order for it to be competitive with the dollar.

Introduction. Parkes-Weber syndrome (PWS) is a complex and rare genetic disease of combined vascular malformations that primarily occur in the extremities and can involve the pelvic blood vessels. In extremely rare cases, the disease is manifested by endocranial and spinal involvement, while the treatment of such patients represents a challenge for neurosurgical centers and requires multidisciplinary approach. Case report. We present the case of a 46-year-old male patient who was admitted to the emergency department due to spontaneous subarachnoid hemorrhage (SAH), moderate flaccid paraparesis and urinary incontinence. Furthermore, the patient was previously diagnosed with PWS, while the genetic evaluation proved the RASA1 gene mutation. He experienced a spontaneous SAH and was hospitalized 26 years ago, while 6 years ago he underwent a right nephrectomy due to multiple hilar aneurysms of the right renal artery and its branches. Digital subtraction angiography of the endocranium was performed, which detected no aneurysmal dilatations or arteriovenous malformations (AVM). The magnetic resonance imaging recorded spinal intradural AVM in the vertebral levels between T12 and L3, which completely filled the dural sac. After the conservative treatment, there was a significant improvement in the patient's neurological and clinical condition. Conclusion. To the best of our knowledge, this is the only case report of a patient with PWS who had a spinal intradural AVM and spontaneous SAH without high-output heart failure, with a history of a previous nephrectomy.

Background/Aim. There are several serious complications that can accompany both spontaneous and posttraumatic subarachnoid hemorrhage (SAH) such as the development of intracranial hypertension, hydrocephalus, rebleeding, cerebral hypoxia, cerebral vasospasm, impaired pituitary function, electrolyte imbalance and electrocardiographic (ECG) abnormalities. Although there is a declining trend in mortality, the treatment of SAH and its complications represents a challenge even in imposing neurosurgical centers. Therefore, the aim of the study was to compare some clinical characteristics and complications between spontaneous and posttraumatic SAH. Methods. This retrospective study included 138 patients treated at the Clinic for Neurosurgery in the period from January of 2018 to the January of 2023. There were 71 patients with spontaneous and 67 patients with posttraumatic SAH. Results. A predominance of spontaneous SAH in female and posttraumatic SAH in male patients (p < 0.00001) was found. There was a statistically significant difference in the frequency of hydrocephalus between groups of spontaneous and posttraumatic SAH patients (p = 0.012663). Cerebral vasospasm was significantly more prevalent in patients with spontaneous SAH (p = 0.000091). A statistically significant association was also obtained between the thickness of the coagulum in these two groups (p = 0.000187). Patients with spontaneous SAH were significantly more likely to have a negative T wave (p = 0.000315). Furthermore, there was no statistically significant difference regarding electrolyte imbalance in these two groups of patients with SAH. Conclusion. There were statistically significant differences between gender distribution, the frequency of abnormal ECG findings in the form of a negative T wave, greater coagulum thickness, vasospasm occurrence and a higher rate of hydrocephalus in patients with spontaneous SAH compared to patients with posttraumatic SAH.

The technological leap of DNA sequencing generated a tension between modern metagenomics and historical microbiology. We are forcibly harmonizing the output of a modern tool with centuries of experimental knowledge derived from culture-based microbiology. As a thought experiment, we borrow the notion of Cartesian doubt from philosopher Rene Descartes, who used doubt to build a philosophical framework from his incorrigible statement that “I think therefore I am.” We aim to cast away preconceived notions and conceptualize microorganisms through the lens of metagenomic sequencing alone. Specifically, we propose funding and building analysis and engineering methods that neither search for nor rely on the assumption of independent genomes bound by lipid barriers containing discrete functional roles and taxonomies. We propose that a view of microbial communities based in sequencing will engender novel insights into metagenomic structure and may capture functional biology not reflected within the current paradigm.

The genetic makeup of Indigenous populations inhabiting Mexico has been strongly influenced by geography and demographic history. Here, we perform a genome-wide analysis of 716 newly genotyped individuals from 60 of the 68 recognized ethnic groups in Mexico. We show that the genetic structure of these populations is strongly influenced by geography, and our demographic reconstructions suggest a decline in the population size of all tested populations in the last 15–30 generations. We find evidence that Aridoamerican and Mesoamerican populations diverged roughly 4–9.9 ka, around the time when sedentary farming started in Mesoamerica. Comparisons with ancient genomes indicate that the Upward Sun River 1 (USR1) individual is an outgroup to Mexican/South American Indigenous populations, whereas Anzick-1 was more closely related to Mesoamerican/South American populations than to those from Aridoamerica, showing an even more complex history of divergence than recognized so far., Indigenous populations, including in those in Mexico are underrepresented in genetic studies. Here, the authors perform a population genetics study of indigenous peoples in Mexico to explore demographic histories of the region in the context of geography and cultural influences.

Managing postprandial glycemic response, or the increase in blood sugar following a meal, is a crucial component to maintaining healthy blood sugar in patients with diabetes. To test whether oral probiotics can impact postprandial glycemic response, E. coli Nissle 1917 (EcN) was evaluated in an oral glucose tolerance test. Oral gavage of EcN concurrent with a glucose bolus reduced the post-gavage glycemic response in mice. However, there was no difference in glycemic response when comparing EcN to a mutant deficient in glucose metabolism. This suggests that while EcN can alter glycemic response to a glucose bolus, this effect is not mediated by direct uptake of glucose. Of the possible indirect effects EcN could have, gastric emptying rate was highlighted as a likely cause, but EcN had no effect on gastric emptying rate in mice. This leaves many more possible indirect explanations for the interaction between EcN and host glucose metabolism to be explored in future work.

Previous studies have shown that there is a strong interaction between the diet and the gut microbiome. This is often linked to circulating metabolites, however, in most studies these metabolites are measured in peripheral circulation, after hepatic clearance of intestinal venous drainage. In the present study, we have determined the effects of high fat diet (HFD) and the microbiome on changes in portal and peripheral metabolites and their link to physiology by performing global metabolomics using LC-MS/MS on portal versus systemic (cardiac) blood in C57BL/6 mice on chow diet, HFD or HFD supplemented with either vancomycin or metronidazole in the drinking water to change gut flora. Among the 644 known metabolites that were identified, 77 were more abundant in cardiac blood whereas 160 were enriched in the portal blood (FC=1.5). In portal blood there was enrichment of secondary bile acids, short-chain fatty acids (butyrate), cinnamoylglycine, indoxylsulfate and hydrocinnamate that are strongly decreased by antibiotics, indicating a direct gut microbial origin. More surprisingly, we also identified several metabolites involved in the TCA cycle, including aconitate, mesaconate and the 2-hydroxyglutarate enriched in portal blood that were not affected by diet but significantly altered by both antibiotics, indicating origin in the gut microbiome. By contrast, some metabolites were enriched in cardiac blood, such as 6, 8 dihydroxypurine, 20-hydroxydocosahexaenoic acid and C46:0 triacylglyercide, were also significantly changed by antibiotics, suggesting they are peripherally produced but depend on precursors coming from gut bacteria. Thus, the interaction between gut microbiota and circulating metabolites is complex and may affect their production from the small intestine but also from extra intestinal tissues. In addition, the gut microbiome is the source of important circulating metabolites which can enter and modify cellular metabolism at the level of the TCA cycle. Disclosure F. Moreau: None. B. B. Brandao: None. J. Avila: None. H. Pan: None. J. Dreyfuss: None. A. Kostic: Other Relationship; Self; DeepBiome Therapeutics, Inc., FitBiomics, Inc. C. B. Clish: None. C. Kahn: Advisory Panel; Self; ERX Pharmaceuticals, Kaleido Biosciences, Inc., Consultant; Self; Flagship Pioneering, Sana/Cobalt.

Studies have demonstrated differences in gut microbial characteristics in diseases compared to healthy states. Knowledge of how diet alters the gut microbiome is limited by the lack of dietary interventional studies reporting on gut microbial characterization. We explored whether dairy foods differing in fat content alter the gut microbiota of patients with type 2 diabetes (T2D). We randomized 111 subjects with T2D into 3 groups: high-fat (HF) and low-fat (LF) dairy groups (≥ 3 servings/d of HF and LF dairy, respectively), and a control group (CON) maintained baseline dairy intake. Subjects were evaluated at baseline, 12 wk, and 24 wk. Next generation sequencing was performed using an Illumina NextSeq (2x150 bp, high output mode) in 32 subjects (16 in HF, 5 in LF, and 11 in CON). At 24 wk, featurewise testing revealed a higher Faecalibacterium prausnitzii abundance (MaAsLin2 coefficient = 0.0746, FDR-adjusted p = 0.0034; MaAsLin2 coefficient = 0.0691, FDR-adjusted p = 0.0195; respectively) and a higher Bifidobacterium pseudocatenulatum abundance (MaAsLin2 coefficient = 0.0022, FDR-adjusted p = 0.0673; MaAsLin2 coefficient = 0.0022, FDR-adjusted p = 0.1135; respectively) in LF compared to HF and CON in univariable models. Functional analyses revealed 11 significant associations including a lower abundance of UDP-glucose-derived O-antigen building blocks biosynthesis pathway (MaAsLin2 coefficient = –0.0006, FDR-adjusted p = 0.1584) related to lipopolysaccharides (LPS) production in HF compared to CON in a multivariable model and a lower L-methionine biosynthesis III pathway abundance (MaAsLin2 coefficient = –0.0015, FDR-adjusted p = 0.1975) in LF compared to HF in a univariable model. In conclusion, consumption of ≥ 3 servings/d of LF and HF dairy changed the gut microbiota of patients with T2D compared to CON. Further analysis will reveal whether a decrease in LPS biosynthesis-related pathway in HF influences inflammation. Disclosure S. Tomah: Stock/Shareholder; Self; Amarin Corporation plc. O. Hamdy: Advisory Panel; Self; Nestlé, Consultant; Self; Abbott, AstraZeneca, Sanofi, Research Support; Self; Eli Lilly and Company, Gilead Sciences, Inc., National Dairy Council, Novo Nordisk, Stock/Shareholder; Self; Healthimation, LLC. A. Kostic: Other Relationship; Self; DeepBiome Therapeutics, Inc., FitBiomics, Inc. J. Mitri: Consultant; Self; L-Nutra. J. E. Wilkinson: None. C. Li: None. M. Tasabehji: None. A. H. Eldib: None. M. Al-badri: None. H. Gardner: None. Funding National Dairy Council; National Institute of Diabetes and Digestive and Kidney Diseases

Type 1 diabetes (T1D) is an autoimmune disorder that results from T cell-mediated destruction of the insulin-producing β cells of the pancreatic islets. Accumulating evidence from both human and animal studies points to the gut microbiome, the 100 trillion microbes inhabiting our intestinal tract, as a key component driving the inflammatory processes leading to T1D. However, the mechanisms therein are poorly understood. We propose that this inflammatory milieu occurs in the pancreas, where microbes or microbial fragments that translocate from their usual luminal, mucosal sites persist and induce the cytokine and chemokine signals needed for destructive, autoimmune cellular and humoral responses that destroy the insulin producing β cells. By controlling this inflammation via vaccination against a highly conserved microbial surface antigen, poly-N-acetyl glucosamine (PNAG), we can decrease the inflammatory response such that vaccination prevents diabetes. In analyses of human and murine pancreatic islets, we have found that PNAG is readily detectable within diabetic, but not healthy, pancreases and associated with both T cells and polymorphonuclear cells (PMNs). This finding suggests that inducing an effective immune response that can clear PNAG-containing microbes or microbial fragments may be critical in counteracting the microbiota-driven inflammation leading to autoimmunity. We report that NOD female mice vaccinated against PNAG exhibited a drastic reduction in diabetes incidence from in 70% of 21 controls to 17% of 18 PNAG-immune mice. Immunophenotyping on these mice indicates that PNAG vaccination dramatically increases Foxp3+ Tregs as well as CD4+ and CD4- IL-10-producing cells. Taken together, our work provides evidence that the translocation of microbial antigens to the pancreas may drive inflammation leading to T1D, and that vaccination against one particular microbial antigen, PNAG, may lead to protection against this disease. Disclosure A. Kostic: Other Relationship; Self; DeepBiome Therapeutics, Inc., FitBiomics, Inc. Funding American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-13 to A.K.)

Microbial community metabolomics, particularly in the human gut, are beginning to provide a new route to identify functions and ecology disrupted in disease. However, these data can be costly and difficult to obtain at scale, while amplicon or shotgun metagenomic sequencing data are readily available for populations of many thousands. Here, we describe a computational approach to predict potentially unobserved metabolites in new microbial communities, given a model trained on paired metabolomes and metagenomes from the environment of interest. Focusing on two independent human gut microbiome datasets, we demonstrate that our framework successfully recovers community metabolic trends for more than 50% of associated metabolites. Similar accuracy is maintained using amplicon profiles of coral-associated, murine gut, and human vaginal microbiomes. We also provide an expected performance score to guide application of the model in new samples. Our results thus demonstrate that this ‘predictive metabolomic’ approach can aid in experimental design and provide useful insights into the thousands of community profiles for which only metagenomes are currently available., Obtaining metabolomic data from microbial communities can be costly and difficult, whereas many microbial community sequence datasets are already available. Here Mallick et al. describe a computational approach to predict metabolic features from microbial DNA sequencing information.

The human gut microbiome is linked to many states of human health and disease1. The metabolic repertoire of the gut microbiome is vast, but the health implications of these bacterial pathways are poorly understood. In this study, we identify a link between members of the genus Veillonella and exercise performance. We observed an increase in Veillonella relative abundance in marathon runners postmarathon and isolated a strain of Veillonella atypica from stool samples. Inoculation of this strain into mice significantly increased exhaustive treadmill run time. Veillonella utilize lactate as their sole carbon source, which prompted us to perform a shotgun metagenomic analysis in a cohort of elite athletes, finding that every gene in a major pathway metabolizing lactate to propionate is at higher relative abundance postexercise. Using 13C3-labeled lactate in mice, we demonstrate that serum lactate crosses the epithelial barrier into the lumen of the gut. We also show that intrarectal instillation of propionate is sufficient to reproduce the increased treadmill run time performance observed with V. atypica gavage. Taken together, these studies reveal that V. atypica improves run time via its metabolic conversion of exercise-induced lactate into propionate, thereby identifying a natural, microbiome-encoded enzymatic process that enhances athletic performance.

Duration of intracranial pressure (ICP) monitoring depends on the clinician`s necessity for the data that influence type and length of the management of intracranial hypertension (ICHT). On the other hand, it is also affected by the possibility of the development of the infection, which is very often fatal when it occurs in the central nervous system. A prospective study of the 32 patients with severe brain trauma (SBT) that had intracranial pressure (ICP) monitoring is presented in here. There were 22 patients with intracranial hypertension (ICHT) and 10 without it. In the ICHT group, the monitoring lasted 5.81 ± 2.70 and 4.45 ± 1.81 in the control group. We have not found a significant difference in the duration of the ICP monitoring between two groups (t = 1.71, p > 0.05). Patients with ICHT had significantly shorter survival than the control group (p = 0.04). It seems that need for prolonged monitoring of the patients with ICHT is suppressed by their shorter survival, comparing to brain-injured patients with normal intracranial pressure.

In this paper, using the concept of w-distance on a metric space, we prove some new best proximity point results for the mappings of Meir-Keeler type. As an application, we derive some recent best proximity point results of the aforementioned type.

Current treatment options for diffuse glioma patients include maximum safe resection followed by a combination of radiation therapy and chemotherapy with alkylating agents. The DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) counteracts the cytotoxic effect of alkylating agents and mediates chemoresistance. Disruption of the DNA methylation mechanism in diffuse glioma cells results in epigenetic silencing of MGMT through methylation of cytidine-phosphate-guanosine dinucleotides (CpG) in the promoter region. The methylation status of MGMT is widely accepted to be a strong prognostic factor in diffuse glioma patients. This study was designed to screen Serbian diffuse glioma patients for hypermethylation of the MGMT promoter and to estimate its impact on overall survival. The results obtained in our study on 33 samples of diffuse glioma detected a positive methylation status in 17 patients (51.5%) by methylation-specific polymerase chain reaction. The positive methylation status of the MGMT promoter did not correlate with overall survival. In this study group, the patients older than 50 years had significantly lower overall survival in comparison with younger patients (7 months–19 months median survival). Extent of tumour resection also had influence on overall survival of patients. The relevance of the MGMT promoter methylation status should be further evaluated in a larger study and in association with other markers.

We study best proximity points in the framework of metric spaces with $w$ -distances. The results extend, generalise and unify several well-known fixed point results in the literature.

We propose microbiome disease “architectures”: linking >1 million microbial features (species, pathways, and genes) to 7 host phenotypes from 13 cohorts using a pipeline designed to identify associations that are robust to analytical model choice. Here, we quantify conservation and heterogeneity in microbiome-disease associations, using gene-level analysis to identify strain-specific, cross-disease, positive and negative associations. We find coronary artery disease, inflammatory bowel diseases, and liver cirrhosis to share gene-level signatures ascribed to the Streptococcus genus. Type 2 diabetes, by comparison, has a distinct metagenomic signature not linked to any one specific species or genus. We additionally find that at the species-level, the prior-reported connection between Solobacterium moorei and colorectal cancer is not consistently identified across models—however, our gene-level analysis unveils a group of robust, strain-specific gene associations. Finally, we validate our findings regarding colorectal cancer and inflammatory bowel diseases in independent cohorts and identify that features inversely associated with disease tend to be less reproducible than features enriched in disease. Overall, our work is not only a step towards gene-based, cross-disease microbiome diagnostic indicators, but it also illuminates the nuances of the genetic architecture of the human microbiome, including tension between gene- and species-level associations., Here, combing the massive gene-universe of the gut microbiome to identify strain-specific, cross-disease, associations across seven human diseases, the authors introduce the concept of microbiome architecture, defined as the complete set of positive and negative associations between microbial genes and human host disease, highlighting microbiome architectures as potential diagnostic indicators.

The gut microbiota is critical to immune homeostasis, but our understanding of the underlying molecular mechanisms is very limited. Here, we demonstrate a division of labor among members of the eight-membered “model microbiome” altered Schaedler flora in promoting distinct immunophenotypes. We report that Parabacteroides goldsteinii ASF519 induces immune tolerance by promoting interleukin (IL)-10 production in a variety of myeloid-derived immune cells. The IL-10 induction is dependent on the activation of adenosine receptor A2a by microbial enzymes of the methionine cycle. ASF519 colonization in mice increased the level of adenosine in ceca and induced IL-10 secreting dendritic cells in colonic lamina propria. These immunophenotypes were pharmacologically reversed by A2a blockage. In mouse models of human autoimmune diseases, ASF519 supplementation significantly ameliorated insulitis in type 1 diabetes and collagen-induced arthritis. This study unveils a novel paradigm of gut microbiota-adenosine receptor interactions in immune tolerance and potentially provides a new therapeutic strategy for immune disorders.

Loss of gut microbial diversity1–6 in industrial populations is associated with chronic diseases7, underscoring the importance of studying our ancestral gut microbiome. However, relatively little is known about the composition of pre-industrial gut microbiomes. Here we performed a large-scale de novo assembly of microbial genomes from palaeofaeces. From eight authenticated human palaeofaeces samples (1,000–2,000 years old) with well-preserved DNA from southwestern USA and Mexico, we reconstructed 498 medium- and high-quality microbial genomes. Among the 181 genomes with the strongest evidence of being ancient and of human gut origin, 39% represent previously undescribed species-level genome bins. Tip dating suggests an approximate diversification timeline for the key human symbiont Methanobrevibacter smithii. In comparison to 789 present-day human gut microbiome samples from eight countries, the palaeofaeces samples are more similar to non-industrialized than industrialized human gut microbiomes. Functional profiling of the palaeofaeces samples reveals a markedly lower abundance of antibiotic-resistance and mucin-degrading genes, as well as enrichment of mobile genetic elements relative to industrial gut microbiomes. This study facilitates the discovery and characterization of previously undescribed gut microorganisms from ancient microbiomes and the investigation of the evolutionary history of the human gut microbiota through genome reconstruction from palaeofaeces., Ancient microbiomes from palaeofaeces are more similar to non-industrialized than industrialized human gut microbiomes regardless of geography, but 39% of their de novo reconstructed genomes represent previously undescribed microbial species.

A substantial number of subjects with Type 1 Diabetes (T1D) of long duration never develop albuminuria or renal function impairment, yet the underlying protective mechanisms remain unknown. Therefore, our study included 308 Joslin Kidney Study subjects who had T1D of long duration (median: 24 years), maintained normal renal function and had either normoalbuminuria or a broad range of albuminuria within the 2 years preceding the metabolomic determinations. Serum samples were subjected to global metabolomic profiling. 352 metabolites were detected in at least 80% of the study population. In the logistic analyses adjusted for multiple testing (Bonferroni corrected α = 0.000028), we identified 38 metabolites associated with persistent normoalbuminuria independently from clinical covariates. Protective metabolites were enriched in Medium Chain Fatty Acids (MCFAs) and in Short Chain Fatty Acids (SCFAs) and particularly involved odd-numbered and dicarboxylate Fatty Acids. One quartile change of nonanoate, the top protective MCFA, was associated with high odds of having persistent normoalbuminuria (OR (95% CI) 0.14 (0.09, 0.23); p –12). Multivariable Random Forest analysis concordantly indicated to MCFAs as effective classifiers. Associations of the relevant Fatty Acids with albuminuria seemed to parallel associations with tubular biomarkers. Our findings suggest that MCFAs and SCFAs contribute to the metabolic processes underlying protection against albuminuria development in T1D that are independent from mechanisms associated with changes in renal function.

The human gut microbiota has been associated with diverse autoimmune diseases; however, the underlying mechanisms are largely unknown. To identify gut microbes and derived bioactive molecules that can promote immune tolerance, we systematically investigated the immunoregulatory potential of each member in the Altered Schaedler Flora (ASF) that has demonstrated diverse immune functions in mice. We observed that the eight ASF members presented a division of labor in promoting distinct immunophenotypes of bone marrow-derived dendritic cells, such as the production of IL-10, TNF-a, and TGF-b, and the induction of regulatory T cells. Interestingly, Parabacteroides goldsteinii ASF519 induced strong immune tolerance via novel mechanisms as evidenced by non-pan T cells-mediated promotion of Foxp3+ Treg proliferation and reduction of cytotoxic CD8 T cells, as well as TNF-a signaling-independent IL-10 production. Via bioactivity-guided fractionation, ASF519-derived molecules responsible for inducing immune tolerance were identified to be heat-labile secretory proteins with yet-uncharacterized functions. Genome-wide screening additionally identified a complex regulatory network that controls the immunoregulatory potency of ASF519. ASF519 colonization in germ-free mice significantly reduced IL-4 and IL-5 in sera and increased the transcript abundance of ll-10 and ll-17A in colon, suggesting potential roles of ASF519 in modulating both intestinal and systemic immune functions. In mouse immune disease models, oral administration of ASF519 demonstrated a protective role in the development of dextran sodium sulfate-induced colitis and collagen-induced arthritis. Relevant mechanisms are now under investigation. This study has the potential to provide novel therapeutic avenues for the prevention and treatment of autoimmune diseases. Disclosure A. Kostic: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-17-INI-13)

Increased white rice (WR) with parallel decreased brown rice (BR) consumption has been associated with increased prevalence of type 2 diabetes (T2DM). To test whether WR and BR have differential effects on energy and glucose metabolism, C57BL/6 mice were fed 6 different diets: control diet (CD, 10% Fat), high-fat diet (HFD, 46% Fat) with either no rice, WR or BR. BR and, surprisingly, WR activated PGC1α and UCP-1 expressions in brown adipose tissue (BAT) and increased energy expenditure as measured by oxygen consumption, CO2 release and heat production, resulting in reduced body weight (36%, 23%) and improvements of glucose tolerance and insulin sensitivity while on HFD after 18 weeks. To investigate the underlying mechanism, gut microbial analysis was performed. Gut microbiota composition showed clear differences between HFD vs. CD or vs. the addition of BR or WR. Ratio of Firmicutes to Bacteroidetes was 3.7-fold increased in HFD vs.CD, but decreased by the WR (46%) or BR (59%). Increased alpha diversity was observed by WR and BR on HFD. Heat map binary showed that several genera are different in HFD+BR vs. HFD or HFD+WR vs. HFD. Analysis of family abundance revealed that Lachnospiraceae, Ruminococcaceae and Streptococcaceae are 2.5, 1.2 and 2.6-fold increased in HFD, which were reduced by WR or BR. Analysis of genus abundance showed that Lactococcus, Dorea, Peptococcus, Clostridium XIVb, Johnsonella, Anaerovorax are 2.6, 3.7, 2.9, 2.7, 4.7 and 1.7-fold respectively, increased in HFD, which were reduced by WR or BR on HFD. In addition, mice on BR+HFD showed greater reductions than mice on WR+HFD in family and genus levels. Our results demonstrated that supplementation with BR or WR, to a lesser degree, changed HFD-induced gut microbial composition at family and genus levels, in parallel with improved systemic energy and glucose metabolism via activation of BAT and increased energy expenditure, resulting in reduced body weight and improved insulin sensitivity. Disclosure H. Yokomizo: None. A. Ishikado: Employee; Self; Sunstar Group. Employee; Spouse/Partner; Sunstar Group. T. Shinjo: None. K. Park: None. Y. Maeda: None. Q. Li: None. I. Wu: None. M. Matsumoto: Employee; Self; Sunstar Group. S. Devkota: None. A. Kostic: None. G.L. King: Research Support; Self; Janssen Pharmaceuticals, Inc.

The microbiome is a new frontier for building predictors of human phenotypes. However, machine learning in the microbiome is fraught with issues of reproducibility, driven in large part by the wide range of analytic models and metagenomic data types available. We aimed to build robust metagenomic predictors of host phenotype by comparing prediction performances and biological interpretation across 8 machine learning methods and 4 different types of metagenomic data. Using 1,570 samples from 300 infants, we fit 7,865 models for 6 host phenotypes. We demonstrate the dependence of accuracy on algorithm choice and feature definition in microbiome data and propose a framework for building microbiome-derived indicators of host phenotype. We additionally identify biological features predictive of age, sex, breastfeeding status, historical antibiotic usage, country of origin, and delivery type. Our complete results can be viewed at http://apps.chiragjpgroup.org/ubiome_predictions/., Author summary The human microbiome is hypothesized to influence human phenotype. However, many published host-microbe associations may not be reproducible. A number of reasons could be behind irreproducible results, including a wide array of methods for measuring the microbiome through genetic sequence, annotation pipelines, and analytical models/prediction approaches. Therefore, there is a need to compare different modeling strategies and microbiome data types (i.e. species abundance versus metabolic pathway abundance) to determine how to build robust and reproducible host-microbiome predictions. In this work, we executed a broad comparison of different predictive methods as a function of microbiome data types to effectively predict host characteristics. Our pipeline was able uncover robust microbial associations with phenotype. We additionally recommended considerations for reproducible microbiome-host association pipeline development. We claim our work is a necessary stepping stone in increasing the utility of emerging cohort data and enabling the next generation of efficient microbiome association studies in human health.

Shotgun metagenomics applied to archaeological feces (paleofeces) can bring new insights into the composition and functions of human and animal gut microbiota from the past. However, paleofeces often undergo physical distortions in archaeological sediments, making their source species difficult to identify on the basis of fecal morphology or microscopic features alone. Here we present a reproducible and scalable pipeline using both host and microbial DNA to infer the host source of fecal material. We apply this pipeline to newly sequenced archaeological specimens and show that we are able to distinguish morphologically similar human and canine paleofeces, as well as non-fecal sediments, from a range of archaeological contexts. This work was supported by the US National Institutes of Health R01GM089886 (to Christina Warinner and Cecil Lewis), the Deutsche Forschungsgemeinschaft EXC 2051 #390713860 (to Christina Warinner), and the Max Planck Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Highlights • Molecular mechanisms of how microorganisms communicate with sensory afferent neurons. • How pathogenic microorganisms directly communicate with nociceptor neurons to inflict pain on the host. • Symbiotic bacterial communication with gut-extrinsic sensory afferent neurons. • Plausible roles on how gut symbionts directly mediate pain and nociception., Nociceptor sensory neurons innervate barrier tissues that are constantly exposed to microbial stimuli. During infection, pathogenic microorganisms can breach barrier surfaces and produce pain by directly activating nociceptors. Microorganisms that live in symbiotic relationships with their hosts, commensals and mutualists, have also been associated with pain, but the molecular mechanisms of how symbionts act on nociceptor neurons to modulate pain remain largely unknown. In this review, we will discuss the known molecular mechanisms of how microbes directly interact with sensory afferent neurons affecting nociception in the gut, skin and lungs. We will touch on how bacterial, viral and fungal pathogens signal to the host to inflict or suppress pain. We will also discuss recent studies examining how gut symbionts affect pain. Specifically, we will discuss how gut symbionts may interact with sensory afferent neurons either directly, through secretion of metabolites or neurotransmitters, or indirectly,through first signaling to epithelial cells or immune cells, to regulate visceral, neuropathic and inflammatory pain. While this area of research is still in its infancy, more mechanistic studies to examine microbial-sensory neuron crosstalk in nociception may allow us to develop new therapies for the treatment of acute and chronic pain.

Background Connection between the duplication of the middle cerebral artery (DMCA) and the presence of multiple aneurysms has been described in a small number of cases. Case presentation The presence of a rare type of DMCA associated with cerebral aneurysms was diagnosed in 56 year old woman after a rupture of an aneurysm on the dorsal segment of the DMCA. .. The presence of equal diameters of branches of the DMCA and anterior cerebral artery (ACA) could be recorded as trifurcation of the carotid internal artery (ICA). However, due to the anastomosis of the DMCA branches in the area of the M2 segment, the recorded anatomical change represented a segmental duplication of MCA. Three aneurysms that were directly related to the segmental DMCA were diagnosed. Conclusions Anatomical variation by type of segmental DMCA is a rare subtype of DMCA. The presence of multiple aneurysms associated with this type of anatomical variation in MCA indicates their high hemodynamic instability.

Over the past decade, studies of the human genome and microbiome have deepened our understanding of the connections between human genes, environments, microbes, and disease. For example, the sheer number of indicators of the microbiome and human genetic common variants associated with disease has been immense, but clinical utility has been elusive. Here, we compared the predictive capabilities of the human microbiome versus human genomic common variants across 13 common diseases. We concluded that microbiomic indicators outperform human genetics in predicting host phenotype (overall Microbiome-Association-Study [MAS] area under the curve [AUC] = 0.79 [SE = 0.03], overall Genome-Wide-Association-Study [GWAS] AUC = 0.67 [SE = 0.02]). Our results, while preliminary and focused on a subset of the totality of disease, demonstrate the relative predictive ability of the microbiome, indicating that it may outperform human genetics in discriminating human disease cases and controls. They additionally motivate the need for population-level microbiome sequencing resources, akin to the UK Biobank, to further improve and reproduce metagenomic models of disease.

The aim of this paper is to provide a new framework for the study of measures of noncompactness in generalized metric spaces. Firstly, we introduce the notion of w-measure of noncompactness on metric spaces with a w-distance and extend the diameter and Kuratowski functionals to this setting. At the end we give a characterization of metric completeness via our main results, providing a new answer to the open question mentioned by Arandjelović in his PhD thesis [2].

Summary: Diet, genetics, and the gut microbiome are determinants of metabolic status, in part through production of metabolites by the gut microbiota. To understand the mechanisms linking these factors, we performed LC-MS-based metabolomic analysis of cecal contents and plasma from C57BL/6J, 129S1/SvImJ, and 129S6/SvEvTac mice on chow or a high-fat diet (HFD) and HFD-treated with vancomycin or metronidazole. Prediction of the functional metagenome of gut bacteria by PICRUSt analysis of 16S sequences revealed dramatic differences in microbial metabolism. Cecal and plasma metabolites showed multifold differences reflecting the combined and integrated effects of diet, antibiotics, host background, and the gut microbiome. Eighteen plasma metabolites correlated positively or negatively with host insulin resistance across strains and diets. Over 1,000 still-unidentified metabolite peaks were also highly regulated by diet, antibiotics, and genetic background. Thus, diet, host genetics, and the gut microbiota interact to create distinct responses in plasma metabolites, which can contribute to regulation of metabolism and insulin resistance. : Fujisaka et al. show that mice with differing propensities to obesity and diabetes have differing metabolomic responses to diet and antibiotic treatment. Several serum metabolites correlate with changes in the gut microbiota or with insulin resistance across strains. Thus, diet, genetics, and the gut microbiota interact to create distinct plasma metabolomic responses. Keywords: gut microbiome, serum metabolomics, cecal metabolomics, obesity, diabetes, serum lipids, TMAO, bile acids, antibiotics, diet