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The maternal gut microbiome plays a critical role in fetal and early postnatal development, shaping fundamental processes including immune maturation and brain development, among others. Consequently, it also contributes to fetal programming of health and disease. Over the last decade, epidemiological studies and work in preclinical animal models have begun to uncover a link between dysbiosis of the maternal gut microbiome and neurodevelopmental disorders in offspring. Neurodevelopmental disorders are caused by both genetic and environmental factors, and their interactions; however, clinical heterogeneity, phenotypic variability, and comorbidities make identification of underlying mechanisms difficult. Among environmental factors, exposure to maternal obesity in utero confers a significant increase in risk for neurodevelopmental disorders. Obesogenic diets in humans, non-human primates, and rodents induce functional modifications in maternal gut microbiome composition, which animal studies suggest are causally related to adverse mental health outcomes in offspring. Here, we review evidence linking maternal diet-induced gut dysbiosis to neurodevelopmental disorders and discuss how it could affect pre- and early postnatal brain development. We are hopeful that this burgeoning field of research will revolutionize antenatal care by leading to accessible prophylactic strategies, such as prenatal probiotics, to improve mental health outcomes in children affected by maternal diet-induced obesity.

Dysbiosis of the maternal gut microbiome during pregnancy is associated with adverse neurodevelopmental outcomes. We previously showed that maternal high-fat diet (MHFD) in mice induces gut dysbiosis, social dysfunction, and underlying synaptic plasticity deficits in male offspring (F(1)). Here, we reason that, if HFD-mediated changes in maternal gut microbiota drive offspring social deficits, then MHFD-induced dysbiosis in F(1) female MHFD offspring would likewise impair F(2) social behavior. Metataxonomic sequencing reveals reduced microbial richness among female F(1) MHFD offspring. Despite recovery of microbial richness among MHFD-descendant F(2) mice, they display social dysfunction. Post-weaning Limosilactobacillus reuteri treatment increases the abundance of short-chain fatty acid-producing taxa and rescues MHFD-descendant F(2) social deficits. L. reuteri exerts a sexually dimorphic impact on gut microbiota configuration, increasing discriminant taxa between female cohorts. Collectively, these results show multigenerational impacts of HFD-induced dysbiosis in the maternal lineage and highlight the potential of maternal microbiome-targeted interventions for neurodevelopmental disorders.

In many Gram-negative and some Gram-positive bacteria, small regulatory RNAs (sRNAs) that bind the RNA chaperone Hfq have a pivotal role in modulating virulence, stress responses, metabolism and biofilm formation. These sRNAs recognize transcripts through base-pairing, and sRNA–mRNA annealing consequently alters the translation and/or stability of transcripts leading to changes in gene expression. We have previously found that the highly conserved 3′-to-5′ exoribonuclease polynucleotide phosphorylase (PNPase) has an indispensable role in paradoxically stabilizing Hfq-bound sRNAs and promoting their function in gene regulation in Escherichia coli. Here, we report that PNPase contributes to the degradation of specific short mRNA fragments, the majority of which bind Hfq and are derived from targets of sRNAs. Specifically, we found that these mRNA-derived fragments accumulate in the absence of PNPase or its exoribonuclease activity and interact with PNPase. Additionally, we show that mutations in hfq or in the seed pairing region of some sRNAs eliminated the requirement of PNPase for their stability. Altogether, our results are consistent with a model that PNPase degrades mRNA-derived fragments that could otherwise deplete cells of Hfq-binding sRNAs through pairing-mediated decay.

Tularemia is a zoonotic disease of global proportions. Francisella tularensis subspecies tularensis (type A) and holarctica (type B) cause disease in healthy humans, with type A infections resulting in higher mortality. Repeated passage of a type B strain in the mid‐20th century generated the Live Vaccine Strain (LVS). LVS remains unlicensed, does not protect against high inhalational doses of type A, and its exact mechanisms of attenuation are poorly understood. Recent data suggest that live attenuated vaccines derived from type B may cross‐protect against type A. However, there is a dearth of knowledge regarding virulent type B pathogenesis and its capacity to stimulate the host's innate immune response. We therefore sought to increase our understanding of virulent type B in vitro characteristics using strain OR96‐0246 as a model. Adding to our knowledge of innate immune kinetics in macrophages following infection with virulent type B, we observed robust replication of strain OR96‐0246 in murine and human macrophages, reduced expression of pro‐inflammatory cytokine genes from “wild type” type B‐infected macrophages compared to LVS, and delayed macrophage cell death suggesting that virulent type B may suppress macrophage activation. One disruption in LVS is in the gene encoding the chloride transporter ClcA. We investigated the role of ClcA in macrophage infection and observed a replication delay in a clcA mutant. Here, we propose its role in acid tolerance. A greater understanding of LVS attenuation may reveal new mechanisms of pathogenesis and inform strategies toward the development of an improved vaccine against tularemia., A better understanding of how Francisella tularensis type B strains behave in macrophages is required to further elucidate the attenuating mechanisms of the Live Vaccine Strain, which is not FDA approved. Here we evaluate innate immune kinetics in human and murine macrophages following infection with a virulent type B strain compared with its attenuated counterpart, LVS, and a clcA mutant. Our results suggest that the disruption of the chloride transporter ClcA is one contributor to LVS attenuation and may be a target for a live attenuated vaccine against tularemia.

Small regulatory RNAs (sRNAs) are an important class of bacterial post-transcriptional regulators that control numerous physiological processes, including stress responses. In Gram-negative bacteria including Escherichia coli, the RNA chaperone Hfq binds many sRNAs and facilitates pairing to target transcripts, resulting in changes in mRNA transcription, translation, or stability. Here, we report that poly(A) polymerase (PAP I), which promotes RNA degradation by exoribonucleases through the addition of poly(A) tails, has a crucial role in the regulation of gene expression by Hfq-dependent sRNAs. Specifically, we show that deletion of pcnB, encoding PAP I, paradoxically resulted in an increased turnover of certain Hfq-dependent sRNAs, including RyhB. RyhB instability in the pcnB deletion strain was suppressed by mutations in hfq or ryhB that disrupt pairing of RyhB with target RNAs, by mutations in the 3′ external transcribed spacer of the glyW-cysT-leuZ transcript (3′ETSLeuZ) involved in pairing with RyhB, or an internal deletion in rne, which encodes the endoribonuclease RNase E. Finally, the reduced stability of RyhB in the pcnB deletion strain resulted in impaired regulation of some of its target mRNAs, specifically sodB and sdhCDAB. Altogether our data support a model where PAP I plays a critical role in ensuring the efficient decay of the 3′ETSLeuZ. In the absence of PAP I, the 3′ETSLeuZ transcripts accumulate, bind Hfq, and pair with RyhB, resulting in its depletion via RNase E-mediated decay. This ultimately leads to a defect in RyhB function in a PAP I deficient strain.

Objectives This study examines the relationship between alcohol consumption and incident stroke among older adults and tests whether alcohol consumption contributes to observed race and sex differences in stroke. Method Data are from a U.S. national cohort of black and white adults aged 45 and older, the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Current and past drinking levels were reported at baseline (2003-2007). Participants who had never had a stroke were followed for adjudicated stroke events through September 2015 (n = 27,265). We calculated Cox proportional hazard models for stroke, adjusting for demographic, socioeconomic, behavioral, and health characteristics. Results Participants, mean age 64.7 years, consumed on average 2.2 drinks/week and experienced 1,140 first-time stroke events over median 9.1 years follow-up. Nondrinkers had a 12% higher risk of stroke than current drinkers; the risk of stroke among nondrinkers largely reflected high risks among past drinkers; these differences were explained by socioeconomic characteristics. Among current drinkers, light drinkers had significantly lower stroke risks than moderate drinkers after accounting for demographic, socioeconomic, behavioral, and health characteristics. Implications of alcohol did not differ between blacks and whites but did differ by sex: Especially among women, nondrinkers, and specifically past drinkers, had higher risks; these differences were largely explained by health characteristics and behaviors. Alcohol did not explain race and sex differences in stroke incidence. Discussion Among older adults, those who used to, but no longer, drink had higher risks of stroke, especially among women; current light drinkers had the lowest risk of stroke.

Batrachochytrium dendrobatidis is a globally distributed generalist pathogen that has driven many amphibian populations to extinction. The life cycle of B. dendrobatidis has two main cell types, motile zoospores, and sessile reproductive sporangia. When grown in a nutrient-rich liquid medium, B. dendrobatidis forms aggregates of sporangia that transition into monolayers on surfaces and at the air-liquid interface. Pathogenic microorganisms use biofilms as mechanisms of group interactions to survive under harsh conditions in the absence of a suitable host. We used fluorescent and electron microscopy, crystal violet, transcriptomic, and gas chromatographic analyses to understand the characteristics of B. dendrobatidis monolayers. The cell-free monolayer fraction showed the presence of extracellular ribose, mannose, xylose, galactose, and glucose. Transcriptome analysis showed that 27%, 26%, and 4% of the genes were differentially expressed between sporangia/zoospores, monolayer/zoospores, and sporangia/monolayer pairs respectively. In pond water studies, zoospores developed into sporangia and formed floating aggregates at the air-water interface and attached film on the bottom of growth flasks. We propose that B. dendrobatidis can form surface-attached monolayers in nutrient-rich environments and aggregates of sporangia in nutrient-poor aquatic systems. These monolayers and aggregates may facilitate dispersal and survival of the fungus in the absence of a host. We provide evidence for using a combination of plant-based chemicals, allicin, gingerol, and curcumin as potential anti-chytrid drugs to mitigate chytridiomycosis.

The accumulation of sequenced Francisella strains has made it increasingly apparent that the 16S rRNA gene alone is not enough to stratify the Francisella genus into precise and clinically useful classifications. Continued whole-genome sequencing of isolates will provide a larger base of knowledge for targeted approaches with broad applicability. Additionally, examination of genomic information on a case-by-case basis will help resolve outstanding questions regarding strain stratification. We report the complete genome sequence of a clinical isolate, designated here as F. novicida-like strain TCH2015, acquired from the lymph node of a 6-year-old male. Two features were atypical for F. novicida: exhibition of functional oxidase activity and additional gene content, including proposed virulence determinants. These differences, which could potentially impact virulence and clinical diagnosis, emphasize the need for more comprehensive methods to profile Francisella isolates. This study highlights the value of whole-genome sequencing, which will lead to a more robust database of environmental and clinical genomes and inform strategies to improve detection and classification of Francisella strains.

Background: Alcohol consumption may reduce the risk of stroke. While both stroke and alcohol consumption patterns differ by race and sex, it is not known to what extent alcohol consumption contributes to the elevated risk of stroke in some groups, particularly in men and blacks in general. Methods: Risk of stroke was studied in 25,162 black and white adults aged 45+, in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Information on alcohol consumption was obtained by telephone interview at baseline. Participants are contacted every 6 months by telephone for self- or proxy-reported stroke; medical records are retrieved and adjudicated by physicians Proportional hazard models, adjusted for demographic, socioeconomic, and stroke risk factors , were used. Results: Participants’ mean age was 64.7 years; 40% were black and 56% were women with 867 stroke events and a median follow-up time of 7.6 years. Compared to current drinkers, non-drinkers had 36% higher hazards of incident stroke which was significantly higher consistent across all race-sex groups except black men. Risks were particularly high among past drinkers (50% higher than among current drinkers), as would be expected since many may have stopped drinking due to health problems. However, risks were also elevated among lifetime abstainers. Differences in stroke risks were explained by demographic and socioeconomic differences between drinkers and non-drinkers. Among those who are current drinkers, those who consumed Conclusions: Results suggest that individuals who do not currently consume alcohol may experience higher risks of stroke, which may be due in part due to socio-demographic and other characteristics associated with consuming alcohol.