Sequences of events are ubiquitous in sensory, motor, and cognitive function. Key computational operations, including pattern recognition, event prediction, and plasticity, involve neural ...discrimination of spatio-temporal sequences. Here, we show that synaptically-driven reaction-diffusion pathways on dendrites can perform sequence discrimination on behaviorally relevant time-scales. We used abstract signaling models to show that selectivity arises when inputs at successive locations are aligned with, and amplified by, propagating chemical waves triggered by previous inputs. We incorporated biological detail using sequential synaptic input onto spines in morphologically, electrically, and chemically detailed pyramidal neuronal models based on rat data. Again, sequences were recognized, and local channel modulation downstream of putative sequence-triggered signaling could elicit changes in neuronal firing. We predict that dendritic sequence-recognition zones occupy 5 to 30 microns and recognize time-intervals of 0.2 to 5 s. We suggest that this mechanism provides highly parallel and selective neural computation in a functionally important time range.
Excitation-inhibition (EI) balance controls excitability, dynamic range, and input gating in many brain circuits. Subsets of synaptic input can be selected or 'gated' by precise modulation of finely ...tuned EI balance, but assessing the granularity of EI balance requires combinatorial analysis of excitatory and inhibitory inputs. Using patterned optogenetic stimulation of mouse hippocampal CA3 neurons, we show that hundreds of unique CA3 input combinations recruit excitation and inhibition with a nearly identical ratio, demonstrating precise EI balance at the hippocampus. Crucially, the delay between excitation and inhibition decreases as excitatory input increases from a few synapses to tens of synapses. This creates a dynamic millisecond-range window for postsynaptic excitation, controlling membrane depolarization amplitude and timing via subthreshold divisive normalization. We suggest that this combination of precise EI balance and dynamic EI delays forms a general mechanism for millisecond-range input gating and subthreshold gain control in feedforward networks.
tRNA-derived fragments have been reported in many different organisms and have diverse cellular roles, such as regulating gene expression, inhibiting protein translation, silencing transposable ...elements, and modulating cell proliferation. In particular, tRNA halves, a class of tRNA fragments produced by the cleavage of tRNAs in the anti-codon loop, have been widely reported to accumulate under stress and regulate translation in cells. Here, we report the presence of tRNA-derived fragments in
, with tRNA halves being the most abundant. We further established that tRNA halves accumulate in the parasites upon different stress stimuli such as oxidative stress, heat shock, and serum starvation. We also observed differential expression of tRNA halves during developmental changes of trophozoite-to-cyst conversion, with various tRNA halves accumulating during early encystation. In contrast to other systems, the stress response does not appear to be mediated by a few specific tRNA halves, as multiple tRNAs appear to be processed during the various stresses. Furthermore, we identified some tRNA-derived fragments associated with
Argonaute proteins,
Ago2-2 and
Ago2-3, which have a preference for different tRNA-derived fragment species. Finally, we show that tRNA halves are packaged inside extracellular vesicles secreted by amoebas. The ubiquitous presence of tRNA-derived fragments, their association with the Argonaute proteins, and the accumulation of tRNA halves during multiple different stresses, including encystation, suggest a nuanced level of gene expression regulation mediated by different tRNA-derived fragments in
.
In the present study, we report for the first time the presence of tRNA-derived fragments in
. tRNA-derived fragments were identified by bioinformatics analyses of small-RNA sequencing data sets from the parasites and also confirmed experimentally. We found that tRNA halves accumulated in parasites exposed to environmental stress or during the developmental process of encystation. We also found that shorter tRNA-derived fragments are bound to
Argonaute proteins, indicating that they may have a potential role in the Argonaute-mediated RNA-interference pathway, which mediates robust gene silencing in
. We noticed that in response to heat shock, the protein translation levels were elevated in the parasites. This effect was reversed in the presence of an analog of leucine, which also reduced the levels of the tRNA halves in the stressed cells. Our results suggest that tRNA-derived fragments in
have a possible role in regulating gene expression during environmental stress.
COVID-19 manifests with respiratory, systemic, and gastrointestinal (GI) symptoms.
SARS-CoV-2 RNA is detected in respiratory and fecal samples, and recent reports demonstrate viral replication in ...both the lung and intestinal tissue.2, 3, 4 Although much is known about early fecal RNA shedding, little is known about long-term shedding, especially in those with mild COVID-19. Furthermore, most reports of fecal RNA shedding do not correlate these findings with GI symptoms.
.
We analyzed the dynamics of fecal RNA shedding up to 10 months after COVID-19 diagnosis in 113 individuals with mild to moderate disease. We also correlated shedding with disease symptoms.
Fecal SARS-CoV-2 RNA is detected in 49.2% 95% confidence interval, 38.2%-60.3% of participants within the first week after diagnosis. Whereas there was no ongoing oropharyngeal SARS-CoV-2 RNA shedding in subjects at 4 months, 12.7% 8.5%-18.4% of participants continued to shed SARS-CoV-2 RNA in the feces at 4 months after diagnosis and 3.8% 2.0%-7.3% shed at 7 months. Finally, we found that GI symptoms (abdominal pain, nausea, vomiting) are associated with fecal shedding of SARS-CoV-2 RNA.
The extended presence of viral RNA in feces, but not in respiratory samples, along with the association of fecal viral RNA shedding with GI symptoms suggest that SARS-CoV-2 infects the GI tract and that this infection can be prolonged in a subset of individuals with COVID-19.
This research was supported by a Stanford ChemH-IMA grant; fellowships from the AACR and NSF; and NIH R01-AI148623, R01-AI143757, and UL1TR003142.
Our current understanding of the composition and stability of the human distal gut microbiota is based largely on studies of infants and adults living in developed countries. In contrast, little is ...known about the gut microbiota and its variation over time in older children and adolescents, especially in developing countries.
We compared the diversity, composition, and temporal stability of the fecal microbiota of healthy children, ages 9 to 14 years, living in an urban slum in Bangladesh with that of children of the same age range in an upper-middle class suburban community in the United States. We analyzed >8,000 near full-length 16S rRNA gene sequences and over 845,000 pyrosequencing reads of the 16S rRNA V1-V3 region. The distal gut of Bangladeshi children harbored significantly greater bacterial diversity than that of U.S. children, including novel lineages from several bacterial phyla. Bangladeshi and U.S. children had distinct fecal bacterial community membership and structure; the microbiota of Bangladeshi children was enriched in Prevotella, Butyrivibrio, and Oscillospira and depleted in Bacteroides relative to U.S. children (although similar to Bangladeshi adults). Furthermore, community membership and structure in Bangladeshi children was significantly less stable month-to-month than U.S. children.
Together, these results suggest that differing environmental or genetic factors may shape the microbiota of healthy children in the two countries. Further investigation is necessary to understand the mechanisms and factors that underlie these differences, and to incorporate these findings into new strategies for the prevention and treatment of childhood and adolescent diseases.
Multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that have mutations associated with increased transmission and antibody escape have arisen over the course of the ...current pandemic. Although the current vaccines have largely been effective against past variants, the number of mutations found on the Omicron (B.1.1.529) spike protein appear to diminish the protection conferred by preexisting immunity. Using vesicular stomatitis virus (VSV) pseudoparticles expressing the spike protein of several SARS-CoV-2 variants, we evaluated the magnitude and breadth of the neutralizing antibody response over time in individuals after infection and in mRNA-vaccinated individuals. We observed that boosting increases the magnitude of the antibody response to wild-type (D614), Beta, Delta, and Omicron variants; however, the Omicron variant was the most resistant to neutralization. We further observed that vaccinated healthy adults had robust and broad antibody responses, whereas responses may have been reduced in vaccinated pregnant women, underscoring the importance of learning how to maximize mRNA vaccine responses in pregnant populations. Findings from this study show substantial heterogeneity in the magnitude and breadth of responses after infection and mRNA vaccination and may support the addition of more conserved viral antigens to existing SARS-CoV-2 vaccines.
The complexity of clinical syndromes of amebiasis, caused by the parasite 'Entamoeba histolytica', stems from the intricate interplay between the host immune system, the virulence of the invading ...parasite, and the surrounding environment. Although there is still a relative paucity of information about the precise relationship between virulence factors and the pathogenesis of 'Entamoeba histolytica', by accumulating data from clinical and basic research, researchers have identified essential pathogenic factors that play a critical role in the pathogenesis of amebiasis, providing important insights into disease development through animal models. Moreover, the parasite's genetic variability has been associated with differences in virulence and disease outcomes, making it important to fully understand the epidemiology and pathogenesis of amebiasis. Deciphering the true mechanism of disease progression in humans caused by this parasite is made more difficult through its ability to demonstrate both genomic and pathological plasticity. The objective of this article is to underscore the heterogeneous nature of disease states and the malleable virulence characteristics in experimental models, while also identifying persistent scientific issues that need to be addressed.
Gandhi and Nehru helped create a myth of nonviolence in ancient India that obscures a troubled, complex heritage: a long struggle to reconcile the ethics of nonviolence with the need to use violence ...to rule. Upinder Singh documents the tension between violence and nonviolence in ancient Indian political thought and practice, 600 BCE to 600 CE.
Mahatma Gandhi and Jawaharlal Nehru helped create the myth of a nonviolent ancient India while building a modern independence movement on the principle of nonviolence (ahimsa). But this myth obscures ...a troubled and complex heritage: a long struggle to reconcile the ethics of nonviolence with the need to use violence to rule. Upinder Singh documents the dynamic tension between violence and nonviolence in ancient Indian political thought and practice over twelve hundred years. Political Violence in Ancient India looks at representations of kingship and political violence in epics, religious texts, political treatises, plays, poems, inscriptions, and art from 600 BCE to 600 CE. As kings controlled their realms, fought battles, and meted out justice, intellectuals debated the boundary between the force required to sustain power and the excess that led to tyranny and oppression. Duty (dharma) and renunciation were important in this discussion, as were punishment, war, forest tribes, and the royal hunt. Singh reveals a range of perspectives that defy rigid religious categorization. Buddhists, Jainas, and even the pacifist Maurya emperor Ashoka recognized that absolute nonviolence was impossible for kings.By 600 CE religious thinkers, political theorists, and poets had justified and aestheticized political violence to a great extent. Nevertheless, questions, doubt, and dissent remained. These debates are as important for understanding political ideas in the ancient world as for thinking about the problem of political violence in our own time.
Molecular bistables are strong candidates for long-term information storage, for example, in synaptic plasticity. Calcium/calmodulin-dependent protein Kinase II (CaMKII) is a highly expressed ...synaptic protein which has been proposed to form a molecular bistable switch capable of maintaining its state for years despite protein turnover and stochastic noise. It has recently been shown that CaMKII holoenzymes exchange subunits among themselves. Here, we used computational methods to analyze the effect of subunit exchange on the CaMKII pathway in the presence of diffusion in two different micro-environments, the post synaptic density (PSD) and spine cytosol. We show that CaMKII exhibits multiple timescales of activity due to subunit exchange. Further, subunit exchange enhances information retention by CaMKII both by improving the stability of its switching in the PSD, and by slowing the decay of its activity in the spine cytosol. The existence of diverse timescales in the synapse has important theoretical implications for memory storage in networks.
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