Complete Genome Sequence of Hafnia paralvei Isolate AVS0177, Harboring mcr−9mcr-9 on a Plasmid

Here, we report the complete genome sequence of a Hafnia paralvei strain isolated from a lake in Switzerland in 2020. The genome consists of a 4.7-Mbp chromosome, a large plasmid (213 kb) harboring mcr-9, and a small plasmid (6 kb)

Complete Genome Sequence of Colistin-Resistant, mcr-10-Harboring, Enterobacter cloacae Isolate AVS0889, Recovered from River Water in Switzerland

Here, we report the complete genome sequence of colistin-resistant Enterobacter cloacae sequence type 1 (ST1) isolate AVS0889, which was recovered from a river in Switzerland in 2021. The genome consists of a 4.95-Mbp chromosome and five plasmids, including a large plasmid (90.8 kb) harboring a disrupted mcr-10 gene

Bioluminescence imaging of stroke-induced endogenous neural stem cell response

Brain injury following stroke affects neurogenesis in the adult mammalian brain. However, a complete under¬standing of the origin and fate of the endogenous neural stem cells (eNSCs) in vivo is missing. Tools and technol¬ogy that allow non-invasive imaging and tracking of eNSCs in living animals will help to overcome this hurdle. In this study, we aimed to monitor eNSCs in a photothrombotic (PT) stroke model using in vivo bioluminescence imaging (BLI). In a first strategy, inducible transgenic mice expressing firefly luciferase (Fluc) in the eNSCs were generated. In animals that received stroke, an increased BLI signal originating from the infarct region was ob¬served. However, due to histological limitations, the identity and exact origin of cells contributing to the in¬creased BLI signal could not be revealed. To overcome this limitation, we developed an alternative strategy employing stereotactic injection of conditional lentiviral vectors (Cre-Flex LVs) encoding Fluc and eGFP in the subventricular zone (SVZ) of Nestin-Cre transgenic mice, thereby specifically labeling the eNSCs. Upon induction of stroke, increased eNSC proliferation resulted in a significant increase in BLI signal between 2 days and 2 weeks after stroke, decreasing after 3 months. Additionally, the BLI signal relocalized from the SVZ towards the infarct region during the 2 weeks following stroke. Histological analysis at 90 days post stroke showed that in the peri-infarct area, 36% of labeled eNSC progeny differentiated into astrocytes, while 21% differentiated into mature neu¬rons. In conclusion, we developed and validated a novel imaging technique that unequivocally demonstrates that nestin+ eNSCs originating from the SVZ respond to stroke injury by increased proliferation, migration towards the infarct region and differentiation into both astrocytes and neurons. In addition, this new approach allows non-invasive and specific monitoring of eNSCs overtime, opening perspectives for preclinical evaluation of can¬didate stroke therapeutics

Neurobiological substrates of cognitive rigidity and autonomic inflexibility in generalized anxiety disorder

Generalized anxiety disorder (GAD) is characterized by difficulties in inhibiting both perseverative thoughts (worry and rumination) and autonomic arousal. We investigated the neurobiological substrates of such abnormal inhibitory processes, hypothesizing aberrant functional coupling within ‘default mode’ (DMN) and autonomic brain networks. Functional imaging and heart rate variability (HRV) data were acquired from GAD patients and controls during performance of three tracking tasks interspersed with a perseverative cognition (PC) induction. After detection of infrequent target stimuli, activity within putative DMN hubs was suppressed, consistent with a redirection of attentional resources from internal to external focus. This magnitude of activity change was attenuated in patients and individuals with higher trait PC, but was predicted by individual differences in HRV. Following the induction of PC in controls, this pattern of neural reactivity became closer to that of GAD patients. Results support, at a neural level, the association between cognitive inflexibility and autonomic rigidity

Amygdala functional connectivity as a longitudinal biomarker of symptom changes in generalized anxiety

Generalized anxiety disorder (GAD) is characterized by excessive worry, autonomic dysregulation and functional amygdala dysconnectivity, yet these illness markers have rarely been considered together, nor their interrelationship tested longitudinally. We hypothesized that an individual's capacity for emotion regulation predicts longer-term changes in amygdala functional connectivity, supporting the modification of GAD core symptoms. Sixteen patients with GAD (14 women) and individually matched controls were studied at two time points separated by 1 year. Resting-state fMRI data and concurrent measurement of vagally mediated heart rate variability were obtained before and after the induction of perseverative cognition. A greater rise in levels of worry following the induction predicted a stronger reduction in connectivity between right amygdala and ventromedial prefrontal cortex, and enhanced coupling between left amygdala and ventral tegmental area at follow-up. Similarly, amplified physiological responses to the induction predicted increased connectivity between right amygdala and thalamus. Longitudinal shifts in a distinct set of functional connectivity scores were associated with concomitant changes in GAD symptomatology over the course of the year. Results highlight the prognostic value of indices of emotional dysregulation and emphasize the integral role of the amygdala as a critical hub in functional neural circuitry underlying the progression of GAD symptomatology

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Novel genetic loci underlying human intracranial volume identified through genome-wide association

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five novel loci for intracranial volume and confirmed two known signals. Four of the loci are also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic=0.748), which indicated a similar genetic background and allowed for the identification of four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, Parkinson’s disease, and enriched near genes involved in growth pathways including PI3K–AKT signaling. These findings identify biological underpinnings of intracranial volume and provide genetic support for theories on brain reserve and brain overgrowth