Aberrant induction of p19Arf-mediated cellular senescence contributes to neurodevelopmental defects

Valproic acid (VPA) is a widely prescribed drug to treat epilepsy, bipolar disorder, and migraine. If taken during pregnancy, however, exposure to the developing embryo can cause birth defects, cognitive impairment, and autism spectrum disorder. How VPA causes these developmental defects remains unknown. We used embryonic mice and human organoids to model key features of VPA drug exposure, including exencephaly, microcephaly, and spinal defects. In the malformed tissues, in which neurogenesis is defective, we find pronounced induction of cellular senescence in the neuroepithelial (NE) cells. Critically, through genetic and functional studies, we identified p19^Arf as the instrumental mediator of senescence and microcephaly, but, surprisingly, not exencephaly and spinal defects. Together, these findings demonstrate that misregulated senescence in NE cells can contribute to developmental defects.

Does cellular senescence contribute to developmental birth defects? This study shows that valproic acid induces cellular senescence in neuroepithelial cells, the precursors of all adult brain cells, and blocks their differentiation, suggesting that aberrant senescence in the embryo may contribute to postnatal cognitive defects.     

Ulcerative Colitis Seems to Imply Oral Microbiome Dysbiosis

Ulcerative colitis (UC) is a recurrent pathology of complex etiology that has been occasionally associated with oral lesions, but the overall composition of the oral microbiome in UC patients and its role in the pathogenesis of the disease are still poorly understood. In this study, the oral microbiome of UC patients and healthy individuals was compared to ascertain the possible changes in the oral microbial communities associated with UC. For this, the salivary microbiota of 10 patients diagnosed with an active phase of UC and 11 healthy controls was analyzed by 16S rRNA gene sequencing (trial ref. ISRCTN39987). Metataxonomic analysis revealed a decrease in the alpha diversity and an imbalance in the relative proportions of some key members of the oral core microbiome in UC patients. Additionally, Staphylococcus members and four differential species or phylotypes were only present in UC patients, not being detected in healthy subjects. This study provides a global snapshot of the existence of oral dysbiosis associated with UC, and the possible presence of potential oral biomarkers.     

Identifying potential drivers of distribution patterns of invasive Corbicula fluminea relative to native freshwater mussels (Unionidae) across spatial scales

This study aimed to identify the importance of ecological factors to distribution patterns of the invasive Clam (Corbicula fluminea) relative to native mussels (family: Unionidae) across seven rivers within the Mobile and Tennessee basins, Southeast United States. We quantitatively surveyed dense, diverse native mussel aggregations across 20 river reaches and estimated mussel density, biomass, and species richness along with density of invasive C. fluminea (hereafter Corbicula). We measured substrate particle size, velocity, and depth in quadrats where animals were collected. Additionally, we characterized reach scale environmental parameters including seston quantity and quality (% Carbon, % Nitrogen, % Phosphorous), water chemistry (ammonium [NH4+], soluble reactive phosphorous [SRP]), and watershed area and land cover. Using model selection, logistic regression, and multivariate analysis, we characterized habitat features and their association to invasive Corbicula within mussel beds. We found that Corbicula were more likely to occur and more abundant in quadrats with greater mussel biomass, larger substrate size, faster water velocity, and shallower water depth. At the reach scale, Corbicula densities increased where particle sizes were larger. Mussel richness, density, and biomass increased with watershed area. Water column NH4+ increased at reaches with more urban land cover. No land cover variables influenced Corbicula populations or mussel communities. The strong overlapping distribution of Corbicula and mussels support the hypothesis that Corbicula are not necessarily limited by habitat factors and may be passengers of change in rivers where mussels have declined due to habitat degradation. Whether Corbicula is facilitated by mussels or negatively interacts with mussels in these systems remains to be seen. Focused experiments that manipulate patch scale variables would improve our understanding of the role of species interactions (e.g., competition, predation, facilitation) or physical habitat factors in influencing spatial overlap between Corbicula and native mussels.     

SCAI promotes error‐free repair of DNA interstrand crosslinks via the Fanconi anemia pathway

DNA interstrand crosslinks (ICLs) are cytotoxic lesions that threaten genome integrity. The Fanconi anemia (FA) pathway orchestrates ICL repair during DNA replication, with ubiquitylated FANCI‐FANCD2 (ID2) marking the activation step that triggers incisions on DNA to unhook the ICL. Restoration of intact DNA requires the coordinated actions of polymerase ζ (Polζ)‐mediated translesion synthesis (TLS) and homologous recombination (HR). While the proteins mediating FA pathway activation have been well characterized, the effectors regulating repair pathway choice to promote error‐free ICL resolution remain poorly defined. Here, we uncover an indispensable role of SCAI in ensuring error‐free ICL repair upon activation of the FA pathway. We show that SCAI forms a complex with Polζ and localizes to ICLs during DNA replication. SCAI‐deficient cells are exquisitely sensitive to ICL‐inducing drugs and display major hallmarks of FA gene inactivation. In the absence of SCAI, HR‐mediated ICL repair is defective, and breaks are instead re‐ligated by polymerase θ‐dependent microhomology‐mediated end‐joining, generating deletions spanning the ICL site and radial chromosomes. Our work establishes SCAI as an integral FA pathway component, acting at the interface between TLS and HR to promote error‐free ICL repair.     

Determination of tissue contributions to the circulating lipid pool in cold exposure via systematic assessment of lipid profiles

Plasma lipid levels are altered in chronic conditions such as type 2 diabetes and cardiovascular disease as well as during acute stresses such as fasting and cold exposure. Advances in MS-based lipidomics have uncovered a complex plasma lipidome of more than 500 lipids that serve functional roles, including as energy substrates and signaling molecules. This plasma lipid pool is maintained through regulation of tissue production, secretion, and uptake. A major challenge in understanding the lipidome complexity is establishing the tissues of origin and uptake for various plasma lipids, which is valuable for determining lipid functions. Using cold exposure as an acute stress, we performed global lipidomics on plasma and in nine tissues that may contribute to the circulating lipid pool. We found that numerous species of plasma acylcarnitines (ACars) and ceramides (Cers) were significantly altered upon cold exposure. Through computational assessment, we identified the liver and brown adipose tissue as major contributors and consumers of circulating ACars, in agreement with our previous work. We further identified the kidney and intestine as novel contributors to the circulating ACar pool and validated these findings with gene expression analysis. Regression analysis also identified that the brown adipose tissue and kidney are interactors with the plasma Cer pool. Taken together, these studies provide an adaptable computational tool to assess tissue contribution to the plasma lipid pool. Our findings have further implications in understanding the function of plasma ACars and Cers, which are elevated in metabolic diseases.     

The burden of T. solium cysticercosis and selected neuropsychiatric disorders in Mocuba district,Zambézia province,Mozambique

BackgroundTaenia solium (neuro-)cysticercosis, a neglected tropical disease, can be associated with epileptic seizures and other neuropsychiatric (= neurological and psychiatric) disorders. This study aimed to evaluate the association of T. solium cysticercosis with selected neuropsychiatric disorders and/or symptoms (chronic headache, epileptic seizures/epilepsy and psychosis) in Mocuba district, Mozambique.MethodologyBetween March and May 2018, a cross-sectional study was conducted among 1,086 participants aged 2 years or above in Mocuba district, Zambézia province, central Mozambique, to assess the seroprevalence of human cysticercosis and risk factors for infection, as well as to explore its relation to selected neuropsychiatric disorders. Socio-demographic and clinical data were collected from each participant using a modified questionnaire designed by the Cysticercosis Working Group for Eastern and Southern Africa. Additionally, neuropsychiatric disorders, such as chronic headache, epileptic seizures/epilepsy and psychosis were assessed using four vignettes. T. solium antigen and cysticercosis IgG in serum were detected using both T. solium antigen B158/B60 enzyme linked immunosorbent assay (ELISA) and LDBIO Cysticercosis Western Blot, respectively.Principal findingsOverall, 112/1,086 participants (10.3%) were sero-positive for T. solium antigen or antibodies. Prevalence of antibodies (6.6%; n = 72) was higher than of antigens (4.9%; n = 54). In the questionnaires, 530 (49.5%) of participants reported chronic headache, 293 (27%) had generalized epileptic seizures, 188 (18%) focal seizures and 183 (18.3%) psychosis. We found a statistically significant association between seropositivity for T. solium and chronic headache (p = 0.013). Additionally, increasing age (p = 0.03) was associated with Ag-ELISA seropositivity.ConclusionsOur study revealed that in Mocuba, T. solium cysticercosis is prevalent and associated with self-reported chronic headache. Additionally, in the study setting, the seroprevalence of cysticercosis increased with age. However, it is not associated with other neuropsychiatric disorders such epileptic seizures/epilepsy and psychosis. Future studies are needed to confirm the high burden of neuropsychiatric disorders and their possible etiology, including neurocysticercosis, using additional serological, molecular biological and radiological diagnostic tools, as well as in-depth clinical examinations.     

Vanadium Respiration by Geobacter metallireducens: Novel Strategy for In Situ Removal of Vanadium from Groundwater

Vanadium can be an important contaminant in groundwaters impacted by mining activities. In order to determine if microorganisms of the Geobacteraceae, the predominant dissimilatory metal reducers in many subsurface environments, were capable of reducing vanadium(V), Geobacter metallireducens was inoculated into a medium in which acetate was the electron donor and vanadium(V) was the sole electron acceptor. Reduction of vanadium(V) resulted in the production of vanadium(IV), which subsequently precipitated. Reduction of vanadium(V) was associated with cell growth with a generation time of 15 h. No vanadium(V) was reduced and no precipitate was formed in heat-killed or abiotic controls. Acetate was the most effective of all the electron donors evaluated. When acetate was injected into the subsurface to enhance the growth and activity of Geobacteraceae in an aquifer contaminated with uranium and vanadium, vanadium was removed from the groundwater even more effectively than uranium. These studies demonstrate that G. metallireducens can grow via vanadium(V) respiration and that stimulating the activity of Geobacteraceae, and hence vanadium(V) reduction, can be an effective strategy for in situ immobilization of vanadium in contaminated subsurface environments.     

Intermittent Anoxia Reduces Oxygen Free Radicals Formation During Reoxygenation in Rat Hepatocytes

The sensitivity of liver cells to anoxia is a major problem afflicting liver preservation and transplantation. Intermittent ischemia has been proposed to reduce reperfusion injury. The aim of the study was to assess oxygen free radical formation and cell injury during continuous or intermittent anoxia/reoxygenation in rat hepatocytes. Anion superoxide was measured by lucigenin-enhanced chemiluminescence and cell damage by LDH release and trypan blue uptake. During anoxia, superoxide generation dropped to background level in both groups; trypan blue uptake and LDH release, which increased progressively, were significantly greater in hepatocytes exposed to continuous compared to intermittent anoxia. During reoxygenation, a massive generation of superoxide anion formation, followed by a sharp increase in LDH release, was observed in both groups. However, both oxyradical generation and cell injury were significantly greater in cells exposed to continuous compared to intermittent anoxia. The data, showing that intermittent oxygen deprivation reduce liver cell injury and oxygen free radical formation determined by anoxia/reoxygenation, suggest a novel possible approach to the reduction of reperfusion injury.     

Epigenetic alterations are critical for fear memory consolidation and synaptic plasticity in the lateral amygdala

Epigenetic mechanisms, including histone acetylation and DNA methylation, have been widely implicated in hippocampal-dependent learning paradigms. Here, we have examined the role of epigenetic alterations in amygdala-dependent auditory Pavlovian fear conditioning and associated synaptic plasticity in the lateral nucleus of the amygdala (LA) in the rat. Using Western blotting, we first show that auditory fear conditioning is associated with an increase in histone H3 acetylation and DNMT3A expression in the LA, and that training-related alterations in histone acetylation and DNMT3A expression in the LA are downstream of ERK/MAPK signaling. Next, we show that intra-LA infusion of the histone deacetylase (HDAC) inhibitor TSA increases H3 acetylation and enhances fear memory consolidation; that is, long-term memory (LTM) is enhanced, while short-term memory (STM) is unaffected. Conversely, intra-LA infusion of the DNA methyltransferase (DNMT) inhibitor 5-AZA impairs fear memory consolidation. Further, intra-LA infusion of 5-AZA was observed to impair training-related increases in H3 acetylation, and pre-treatment with TSA was observed to rescue the memory consolidation deficit induced by 5-AZA. In our final series of experiments, we show that bath application of either 5-AZA or TSA to amygdala slices results in significant impairment or enhancement, respectively, of long-term potentiation (LTP) at both thalamic and cortical inputs to the LA. Further, the deficit in LTP following treatment with 5-AZA was observed to be rescued at both inputs by co-application of TSA. Collectively, these findings provide strong support that histone acetylation and DNA methylation work in concert to regulate memory consolidation of auditory fear conditioning and associated synaptic plasticity in the LA.