More than twelve morphologically and physiologically distinct subtypes of primary somatosensory neuron report salient features of our internal and external environments
. It is unclear how ...specialized gene expression programs emerge during development to endow these subtypes with their unique properties. To assess the developmental progression of transcriptional maturation of each subtype of principal somatosensory neuron, we generated a transcriptomic atlas of cells traversing the primary somatosensory neuron lineage in mice. Here we show that somatosensory neurogenesis gives rise to neurons in a transcriptionally unspecialized state, characterized by co-expression of transcription factors that become restricted to select subtypes as development proceeds. Single-cell transcriptomic analyses of sensory neurons from mutant mice lacking transcription factors suggest that these broad-to-restricted transcription factors coordinate subtype-specific gene expression programs in subtypes in which their expression is maintained. We also show that neuronal targets are involved in this process; disruption of the prototypic target-derived neurotrophic factor NGF leads to aberrant subtype-restricted patterns of transcription factor expression. Our findings support a model in which cues that emanate from intermediate and final target fields promote neuronal diversification in part by transitioning cells from a transcriptionally unspecialized state to transcriptionally distinct subtypes by modulating the selection of subtype-restricted transcription factors.
Evolutionary dynamics in spatially structured populations has been studied for a long time. More recently, the focus has been to construct structures that amplify selection by fixing beneficial ...mutations with higher probability than the well-mixed population and lower probability of fixation for deleterious mutations. It has been shown that for a structure to substantially amplify selection, self-loops are necessary when mutants appear predominately in nodes that change often. As a result, for low mutation rates, self-looped amplifiers attain higher steady-state average fitness in the mutation-selection balance than well-mixed populations. But what happens when the mutation rate increases such that fixation probabilities alone no longer describe the dynamics? We show that self-loops effects are detrimental outside the low mutation rate regime. In the intermediate and high mutation rate regime, amplifiers of selection attain lower steady-state average fitness than the complete graph and suppressors of selection. We also provide an estimate of the mutation rate beyond which the mutation-selection dynamics on a graph deviates from the weak mutation rate approximation. It involves computing average fixation time scaling with respect to the population sizes for several graphs.
A heterogeneous population of inhibitory neurons controls the flow of information through a neural circuit. Inhibitory synapses that form on pyramidal neuron dendrites modulate the summation of ...excitatory synaptic potentials and prevent the generation of dendritic calcium spikes. Precisely timed somatic inhibition limits both the number of action potentials and the time window during which firing can occur. The activity-dependent transcription factor NPAS4 regulates inhibitory synapse number and function in cell culture, but how this transcription factor affects the inhibitory inputs that form on distinct domains of a neuron in vivo was unclear. Here we show that in the mouse hippocampus behaviourally driven expression of NPAS4 coordinates the redistribution of inhibitory synapses made onto a CA1 pyramidal neuron, simultaneously increasing inhibitory synapse number on the cell body while decreasing the number of inhibitory synapses on the apical dendrites. This rearrangement of inhibition is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (Bdnf), which specifically regulates somatic, and not dendritic, inhibition. These findings indicate that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.
Hotspot Mutations in SARS-CoV-2 Saha, Indrajit; Ghosh, Nimisha; Sharma, Nikhil ...
Frontiers in genetics,
11/2021, Letnik:
12
Journal Article
Recenzirano
Odprti dostop
Since its emergence in Wuhan, China, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has spread very rapidly around the world, resulting in a global pandemic. Though the vaccination ...process has started, the number of COVID-affected patients is still quite large. Hence, an analysis of hotspot mutations of the different evolving virus strains needs to be carried out. In this regard, multiple sequence alignment of 71,038 SARS-CoV-2 genomes of 98 countries over the period from January 2020 to June 2021 is performed using MAFFT followed by phylogenetic analysis in order to visualize the virus evolution. These steps resulted in the identification of hotspot mutations as deletions and substitutions in the coding regions based on entropy greater than or equal to 0.3, leading to a total of 45 unique hotspot mutations. Moreover, 10,286 Indian sequences are considered from 71,038 global SARS-CoV-2 sequences as a demonstrative example that gives 52 unique hotspot mutations. Furthermore, the evolution of the hotspot mutations along with the mutations in variants of concern is visualized, and their characteristics are discussed as well. Also, for all the non-synonymous substitutions (missense mutations), the functional consequences of amino acid changes in the respective protein structures are calculated using PolyPhen-2 and I-Mutant 2.0. In addition to this, SSIPe is used to report the binding affinity between the receptor-binding domain of Spike protein and human ACE2 protein by considering L452R, T478K, E484Q, and N501Y hotspot mutations in that region.
STING is a nodal point for cellular innate immune response to microbial infections, autoimmunity and cancer; it triggers the synthesis of the antiviral proteins, type I interferons. Many DNA viruses, ...including Herpes Simplex Virus 1 (HSV1), trigger STING signaling causing inhibition of virus replication. Here, we report that HSV1 evades this antiviral immune response by inducing a cellular microRNA, miR-24, which binds to the 3’ untranslated region of STING mRNA and inhibits its translation. Expression of the gene encoding miR-24 is induced by the transcription factor AP1 and activated by MAP kinases in HSV1-infected cells. Introduction of exogenous miR-24 or prior activation of MAPKs, causes further enhancement of HSV1 replication in STING-expressing cells. Conversely, transfection of antimiR-24 inhibits virus replication in those cells. HSV1 infection of mice causes neuropathy and death; using two routes of infection, we demonstrated that intracranial injection of antimiR-24 alleviates both morbidity and mortality of the infected mice. Our studies reveal a new immune evasion strategy adopted by HSV1 through the regulation of STING and demonstrates that it can be exploited to enhance STING’s antiviral action.
Objective
Neuroplasticity is essential for recovery after stroke and is the target for new stroke therapies. During recovery from subcortical motor stroke, brain activations associated with movement ...may appear normal despite residual functional impairment. This raises an important question: how far does recovery of motor performance depend on the processes that precede movement execution involving the premotor and prefrontal cortex, rather than recovery of the corticospinal system alone?
Methods
We examined stroke patients with functional magnetic resonance imaging while they either imagined or executed a finger‐thumb opposition sequence. In addition to classical analyses of regional activations, we studied neuroplasticity in terms of differential network connectivity using structural equation modeling. The study included 8 right‐handed patients who had suffered a left‐hemisphere subcortical ischemic stroke with paresis, and 13 age‐matched healthy controls.
Results
With good functional recovery, the regional activations had returned to normal in patients. However, connectivity within the extended motor network remained abnormal. These abnormalities were seen predominantly during motor imagery and correlated with motor performance.
Interpretation
Our results indicate that neuroplasticity can manifest itself as differences in connectivity among cortical areas remote from the infarct, rather than in the degree of regional activation. Connection strengths between nodes of the cortical motor network correlate with motor outcome. The altered organization of connectivity of the prefrontal areas may reflect the role of the prefrontal cortex in higher order planning of movement. Our results are relevant to the assessment and understanding of emerging physical and neurophysiological therapies for stroke rehabilitation. Ann Neurol 2009;66:604–616
Background: Recent research indicated that periodontal infection may worsen systemic diseases, including pulmonary disease. Respiratory infections, such as pneumonia and the exacerbation of chronic ...obstructive pulmonary disease, involve the aspiration of bacteria from the oropharynx into the lower respiratory tract.
Methods: A group of 100 cases (hospitalized patients with respiratory disease) and a group of 100 age‐, sex‐, and race‐matched outpatient controls (systemically healthy patients from the outpatient clinic, Department of Periodontics, Government Dental College and Hospital, Calicut, Kerala, India) were selected for the study. Standardized measures of oral health that were performed and compared included the gingival index (GI), plaque index (PI), and simplified oral hygiene index (OHI). Data regarding probing depths and clinical attachment levels (CALs) were recorded at four sites per tooth and compared statistically. The χ2 and Student t tests were used for statistical analyses.
Results: The comparison of study‐population demographics on the basis of age, sex, education, and income showed no significant differences between groups. Patients with respiratory disease had significantly greater poor periodontal health (OHI and PI), gingival inflammation (GI), deeper pockets, and CALs compared to controls. In the case group, patients with a low income were 4.4 times more prone to periodontal disease compared to high‐income patients. Smokers had significantly higher CALs compared to non‐smokers in the control group.
Conclusion: The findings of the present analysis support an association between respiratory and periodontal disease.
To improve lithium-ion battery technology, it is essential to probe and comprehend the microscopic dynamic processes that occur in a real-world composite electrode under operating conditions. The ...primary and secondary particles are the structural building blocks of battery cathode electrodes. Their dynamic inconsistency has profound but not well-understood impacts. In this research, we combine operando coherent multi-crystal diffraction and optical microscopy to examine the chemical dynamics in local domains of layered oxide cathode. Our results not only pinpoint the asynchronicity of the lithium (de)intercalation at the sub-particle level, but also reveal sophisticated diffusion kinetics and reaction patterns, involving various localized processes, e.g., chemical onset, reaction front propagation, domains equilibration, particle deformation and motion. These observations shed new lights onto the activation and degradation mechanisms of state-of-the-art battery cathode materials.
A diagnosis of MND takes an average 10-16 months from symptom onset. Early diagnosis is important to access supportive measures to maximise quality of life. The COVID-19 pandemic has caused ...significant delays in NHS pathways; the majority of GP appointments now occur online with subsequent delays in secondary care assessment. Given the rapid progression of MND, patients may be disproportionately affected resulting in late stage new presentations. We used Monte Carlo simulation to model the pre-COVID-19 diagnostic pathway and then introduced plausible COVID-19 delays.
The diagnostic pathway was modelled using gamma distributions of time taken: 1) from symptom onset to GP presentation, 2) for specialist referral, and 3) for diagnosis reached after neurology appointment. We incorporated branches to simulate delays: when patients did not attend their GP and when the GP consultation did not result in referral. An emergency presentation was triggered when diagnostic pathway time was within 30 days of projected median survival. Total time-to-diagnosis was calculated over 100,000 iterations. The pre-COVID-19 model was estimated using published data and the Improving MND Care Survey 2019. We estimated COVID-19 delays using published statistics.
The pre-COVID model reproduced known features of the MND diagnostic pathway, with a median time to diagnosis of 399 days and predicting 5.2% of MND patients present as undiagnosed emergencies. COVID-19 resulted in diagnostic delays from 558 days when only primary care was 25% delayed, to 915 days when both primary and secondary care were 75%. The model predicted an increase in emergency presentations ranging from 15.4%-44.5%.
The model suggests the COVID-19 pandemic will result in later-stage diagnoses and more emergency presentations of undiagnosed MND. Late-stage presentations may require rapid escalation to multidisciplinary care. Proactive recognition of acute and late-stage disease with altered service provision will optimise care for people with MND.
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