Miracle-dz/UniFAR-FTUs huggingface dataset:
Plasmodium falciparum Kelch13 and its artemisinin-resistant mutants assemble as hexamers in solution: a SAXS data driven shape restoration study

Artemisinin-resistant mutations in PfKelch13 identified worldwide are mostly confined to its BTB/POZ and KRP domains. To date, only two crystal structures of the BTB/POZ-KRP domains as tight dimers are available, which limits structure-based interpretations of its functionality. Our solution Small-Angle X-ray Scattering (SAXS) data driven shape restoration of larger length of protein brought forth that: i) PfKelch13 forms a stable hexamer in P6 symmetry, ii) interactions of the N-termini drive the hexameric assembly, and iii) the six KRP domains project independently in space, forming a cauldron-like architecture. While artemisinin-sensitive mutant A578S packed like the wild-type, hexameric assemblies of dominant artemisinin-resistant mutant proteins R539T and C580Y displayed detectable differences in spatial positioning of their BTB/POZ-KRP domains. Lastly, mapping of mutations known to enable artemisinin resistance explained that most mutations exist mainly in these domains because they are non-detrimental to assembly of mutant PfKelch13 and yet can alter the flux of downstream events essential for susceptibility to artemisinin.
Age-related deficits in rapid visuomotor decision-making

Many goal-directed actions that require rapid visuomotor planning and perceptual decision-making are affected in older adults, causing difficulties in execution of many functional activities of daily living. Visuomotor planning and perceptual decision-making are mediated by the dorsal and ventral visual streams, respectively, but it is unclear how age-induced changes in sensory processing in these streams contribute to declines in goal-directed actions. Previously, we have shown that in healthy adults task demands affect the integration of sensory information between the two streams and more motorically demanding tasks induce earlier decisions and more decision errors. Here, we asked the question if older adults would exhibit larger declines in interactions between the two streams during demanding motor tasks. Older adults (n=15) and young controls (n=26) performed a simple reaching task and a more demanding interception task towards virtual objects. In some blocks of trials, participants also had to select an appropriate movement based on the shape of the object. Our results showed that older adults made a similar number of initial decision errors during both the reaching and interception tasks but corrected fewer of those errors during movement. During the more demanding interception decision task, older adults made more decision- and execution-related errors than young adults, which were related to early initiation of their movements. Together, these results suggest that older adults have a reduced ability to integrate new perceptual information to guide online action, which may reflect impaired ventral-dorsal stream interactions. Highlights Older adults showed reduced performance in a visuomotor decision-making task Initial decision errors were similar between young and older adults Older adults were less likely to correct initial decision errors More demanding movements were associated with earlier and less accurate decisions
Cell type classi�cation and discovery across diseases, technologies and tissues reveals conserved gene signatures and enables standardized single-cell readouts

Autoimmune diseases are a major cause of mortality1,2. Current treatments often yield severe insult to host tissue. It is hypothesized that improved therapies will target pathogenic cells selectively and thus reduce or eliminate severe side effects, and potentially induce robust immune tolerance3. However, it remains challenging to systematically identify which cellular phenotypes are present in cellular ensembles. Here, we present a novel machine learning approach, Signac, which uses neural networks trained with ow-sorted gene expression data to classify cellular phenotypes in single cell RNA-sequencing data. We demonstrate that Signac accurately classi�ed single cell RNA-sequencing data across diseases, technologies, species and tissues. Then we applied Signac to identify known and novel immune-relevant candidate drug targets (n = 12) in rheumatoid arthritis. A full release of this work�ow can be found at our GitHub repository (https://github.com/mathewchamberlain/Signac).
Population genomic analysis of Cryptococcus Brazilian isolates reveals an African type subclade distribution

The genomes of a large number of Cryptococcus neoformans isolates have been sequenced and analyzed in recent years. These genomes have been used to understand the global population structure of this opportunistic pathogen. However, only a small number of South American isolates have been considered in these studies, and the population structure of C. neoformans in this part of the world remains elusive. Here, we analyzed the genomic sequences of 53 Brazilian Cryptococcus isolates and deciphered the C. neoformans population structure in this country. Our data reveal an African-like structure that suggested repeated intercontinental transports from Africa to South America. We also identified a mutator phenotype in one VNBII Brazilian isolate, exemplifying how fast-evolving isolates can shape the Cryptococcus population structure. Finally, phenotypic analyses revealed wide diversity but not lineage specificity in the expression of classical virulence traits within the set of isolates.
Enhanced habit formation in Tourette syndrome: dopamine release and striatal disinhibition modulate shortcut connections in a hierarchical model of cortico-basal ganglia loops

In the Gilles de la Tourette syndrome, tics are often considered as habitual responses towards unwanted premonitory urges. Support for the relationship between tics and habits comes from devaluation protocols, which reveal that unmedicated Tourette patients show an increased tendency towards responses to devalued outcomes. We use a neuro-computational model of hierarchically organized cortico-basal ganglia-thalamo-cortical loops to shed more light on enhanced habit formation of Tourette patients. In our model, habitual behavior emerges from cortico-thalamic shortcut connections, where enhanced habit formation can be linked to faster plasticity in the shortcut or to a stronger feedback from the shortcut to the basal ganglia. Irregular activity in such shortcut connections may have different pathophysiological origins. Based on our model, we explore decreased local striatal inhibition, which may correspond to a loss of inhibitory interneurons, and increased dopaminergic modulation of striatal medium spiny neurons as causes for irregular shortcut plasticity or activation. Both lead to higher rates of response towards devalued outcomes in our model, similar to what is observed in Tourette patients. Our results support the view of tics in Tourette syndrome as maladaptive habits. We suggest to reveal more shortcuts between cortico-basal ganglia-thalamo-cortical loops in the human brain and study their potential role in the development of the Tourette syndrome.
Emergence of probabilistic representation in the neural network of primary visual cortex

During the early development of mammalian visual system, the distribution of neuronal preferred orientations in the primary visual cortex (V1) gradually shifts to match the major orientation features of an environment, achieving optimal representation of the environment. By combining the computational modeling and experimental electrophysiological recording, we provide a circuitry plasticity mechanism that underlies the developmental emergence of such matched representation in the visual cortical network. Specifically, in a canonical circuit of densely interconnected pyramidal cells and inhibitory parvalbumin-expressing (PV+) fast-spiking interneurons in the V1 layer 2/3, our model successfully simulates the experimental observations and further reveals that the non-uniform inhibition, mediated by local interneurons, exerts a key role in shaping the network representation through spike timing-dependent synaptic modifications. The experimental results confirm that PV+ interneurons in the V1 are capable of providing such non-uniform inhibition during a short period after the vision onset. Thus, our study elucidates a circuitry mechanism for acquisition of the prior knowledge of environment for optimal inference in sensory neural system.
Molecular mechanism of capsid disassembly in hepatitis B virus

Significance Hepatitis B virus (HBV) is a DNA virus that is 100 times more infectious than HIV. Despite the availability of a vaccine, the chronic infection rate of this virus is still over 250 million people globally. HBV chronic infection, for which no cure is currently available, can lead to liver cancer. Therefore, there is an unmet need to investigate the infection cycle of the virus. One of the most crucial steps in the virus-replication cycle is the release of its genetic material to the nucleus. During this step, the viral capsid enclosing the genetic material disassembles. However, its mechanism is unknown. Here, we utilize molecular simulations to shed light on the events leading to the capsid disassembly with atomistic detail. The disassembly of a viral capsid leading to the release of its genetic material into the host cell is a fundamental step in viral infection. In hepatitis B virus (HBV), the capsid consists of identical protein monomers that dimerize and then arrange themselves into pentamers or hexamers on the capsid surface. By applying atomistic molecular dynamics simulation to an entire solvated HBV capsid subjected to a uniform mechanical stress protocol, we monitor the capsid-disassembly process and analyze the process down to the level of individual amino acids in 20 independent simulation replicas. The strain of an isotropic external force, combined with structural fluctuations, causes structurally heterogeneous cracks to appear in the HBV capsid. Analysis of the monomer–monomer interfaces reveals that, in contrast to the expectation from purely mechanical considerations, the cracks mainly occur within hexameric sites, whereas pentameric sites remain largely intact. Only a small subset of the capsid protein monomers, different in each simulation, are engaged in each instance of disassembly. We identify specific residues whose interactions are most readily lost during disassembly; R127, I139, Y132, N136, A137, and V149 are among the hot spots at the interfaces between dimers that lie within hexamers, leading to disassembly. The majority of these hot-spot residues are conserved by evolution, hinting to their importance for disassembly by avoiding overstabilization of capsids.
Consistent population activity on the scale of minutes in the mouse hippocampus

Neurons in the hippocampus fire in consistent sequence over the timescale of seconds during the delay period of some memory experiments. For longer timescales, firing of hippocampal neurons also changes slowly over minutes within experimental sessions. It was thought that these slow dynamics are caused by stochastic drift or a continuous change in the representation of the episode, rather than consistent sequences unfolding over minutes. This paper studies the consistency of contextual drift in three chronic calcium imaging recordings from the hippocampus CA1 region in mice. Computational measures of consistency show reliable sequences within experimental trials at the scale of seconds as one would expect from time cells or place cells during the trial, as well as across experimental trials on the scale of minutes within a recording session. Consistent sequences in the hippocampus are observed over a wide range of time scales, from seconds to minutes. Hippocampal activity could reflect a scale-invariant spatiotemporal context as suggested by theories of memory from cognitive psychology.
Long-term conservation effects of protected areas in stochastic population dynamics

Terrestrial and marine protected areas are essential tools in mitigating anthropogenic impacts and promoting population persistence and resource sustainability. Adequately implemented protected areas (PAs) promote long-term conservation effects. Stochasticity causes fluctuations in the conservation effects of PAs, and so it is important to investigate the variabilities of these conservation effects to inform their long-term conservation effects. To investigate long-term conservation effects, I develop and analyze new models of stochastic processes that encompass the fluctuations generated by demographic or environmental stochasticity in PAs management. The stochastic model is built upon individual processes. In the model, density-independent mortality, migration between PAs and non-PAs, and site preferences characterize the features of the PA. The effect of PAs size is also examined. The long-term conservation effects are quantified using the coefficient of variation (CV) of population size in PAs, where a lower CV indicates higher robustness in stochastic variations. Typically, the results from this study demonstrate that sufficiently reduced density-independent mortality in PAs and high site preference and immigration rate of PA are likely to decrease the CV. However, different types of stochasticity induce rather different consequences: under demographic stochasticity, the CV is always reduced when PAs increase the population size therein, but an increased population size by PAs does not always decrease the CV under environmental stochasticity. The deterministic dynamics of the model are investigated, facilitating effective management decisions.
Alpha-arrestins Aly1 and Aly2 regulate trafficking of the glycerophosphoinositol transporter Git1 and impact phospholipid homeostasis

Phosphatidylinositol (PI) is an essential phospholipid and critical component of membrane bilayers. The complete deacylation of PI by phospholipases of the B-type leads to the production of intracellular and extracellular glycerophosphoinositol (GPI), a water-soluble glycerophosphodiester. Extracellular GPI is transported into the cell via Git1, a member of the Major Facilitator Superfamily of transporters that resides at the plasma membrane in yeast. Once internalized, GPI can be degraded to produce inositol, phosphate and glycerol, thereby contributing to reserves of these building blocks. Not surprisingly, GIT1 gene expression is controlled by nutrient balance, with limitation for phosphate or inositol each increasing GIT1 expression to facilitate GPI uptake. Less is known about how Git1 protein levels or localization are controlled. Here we show that the α-arrestins, an important class of protein trafficking adaptor, regulate the localization of Git1 in a manner dependent upon their association with the ubiquitin ligase Rsp5. Specifically, α-arrestin Aly2 is needed for effective Git1 internalization from the plasma membrane under basal conditions. However, in response to GPI-treatment of cells, either Aly1 or Aly2 can promote Git1 trafficking to the vacuole. Retention of Git1 at the cell surface, as occurs in aly1Δ aly2Δ cells, results in impaired growth in the presences of excess exogenous GPI and results in increased uptake of radiolabeled GPI, suggesting that accumulation of this metabolite or its downstream products leads to cellular toxicity. We further show that regulation of α-arrestin Aly1 by the protein phosphatase calcineurin improves both steady-state and ligand-induced trafficking of Git1 when a mutant allele of Aly1 that mimics the dephosphorylated state at calcineurin-regulated residues is employed. Thus, calcineurin regulation of Aly1 is important for the GPI-ligand induced trafficking of Git1 by this α-arrestin, however, the role of calcineurin in regulating Git1 trafficking is much broader than can simply be explained by regulation of the α-arrestins. Finally, we find that loss of Aly1 and Aly2 leads to an increase in phosphatidylinositol-3-phosphate on the limiting membrane of the vacuole and this alteration is further exacerbated by addition of GPI, suggesting that the effect is at least partially linked to Git1 function. Indeed, loss of Aly1 and Aly2 leads to increased incorporation of inositol label from 3H-inositol-labelled GPI into PI, confirming that internalized GPI influences PI synthesis and indicating a role for the α-arrestins in regulating the process.
Expanded Asgard archaea shed new light on the origin of eukaryotes and support a 2-domain tree of life

The hypothesis that eukaryotes originated from within the domain Archaea has been strongly supported by recent phylogenomic analyses placing Heimdallarchaeota from the Asgard superphylum as the closest known archaeal sister-group to eukaryotes. At present, only seven phyla are described in the Asgard superphylum, which limits our understanding of the relationship between eukaryotes and archaea, as well as the evolution and ecological functions of Asgard archaea. Here, we describe five novel phylum-level Asgard archaeal lineages, tentatively named Tyr-, Sigyn-, Freyr-, Hoder- and Balderarchaeota. Comprehensive phylogenomic analyses supported a new Asgard lineage Tyrarchaeota was identified as a deeper branching lineage cluster with the eukaryotic nuclear host lineage than Heimdallarchaeota that were previously considered as the closest archaeal relatives of eukaryotes. Metabolic reconstruction of Tyrarchaeota suggests a mixotrophic lifestyle of this archaea, capable of peptides and amino acids utilization while having the potential using the Wood-Ljungdahl pathway for carbon fixation and acetogenesis. This study largely expands the Asgard superphylum, provides additional evidences to support the 2-domain life tree thus sheds new light on the evolution and geochemical functions of the Asgard archaea.
Large-scale tandem mass spectrum clustering using fast nearest neighbor searching

Rationale Advanced algorithmic solutions are necessary to process the ever increasing amounts of mass spectrometry data that is being generated. Here we describe the falcon spectrum clustering tool for efficient clustering of millions of MS/MS spectra. Methods falcon succeeds in efficiently clustering large amounts of mass spectral data using advanced techniques for fast spectrum similarity searching. First, high-resolution spectra are binned and converted to low-dimensional vectors using feature hashing. Next, the spectrum vectors are used to construct nearest neighbor indexes for fast similarity searching. The nearest neighbor indexes are used to efficiently compute a sparse pairwise distance matrix without having to exhaustively perform all pairwise spectrum comparisons within the relevant precursor mass tolerance. Finally, density-based clustering is performed to group similar spectra into clusters. Results Several state-of-the-art spectrum clustering tools were evaluated using a large draft human proteome dataset consisting of 25 million spectra, indicating that alternative tools produce clustering results with different characteristics. Notably, falcon generates larger highly pure clusters than alternative tools, leading to a larger reduction in data volume without the loss of relevant information for more efficient downstream processing. Conclusions falcon is a highly efficient spectrum clustering tool. It is publicly available as open source under the permissive BSD license at https://github.com/bittremieux/falcon.
Physiological underpinning of default-mode network emergence in the human infant brain

Qinlin Yu , Minhui Ouyang , John A. Detre, Huiying Kang, Di Hu, Bo Hong, Fang Fang, Yun Peng, Hao Huang 2,* 1Department of Radiology, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, United States; 2Department of Radiology, 4Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104,United States; 3Department of Radiology, Beijing Children’s Hospital, Capital Medical University, Beijing, 100045, China; 5Department of Biomedical Engineering, Tsinghua University, Beijing, 100084, China 6School of Psychological and Cognitive Sciences, Peking University, Beijing, 100871,China
Loss of PABPC1 is compensated by elevated PABPC4 and correlates with transcriptome changes

Cytoplasmic poly(A) binding protein (PABP) is an essential translation factor that binds to the 3’ tail of mRNAs to promote translation and regulate mRNA stability. PABPC1 is the most abundant of several PABP isoforms that exist in mammals. Here, we used the CRISPR/Cas genome editing system to shift the isoform composition in HEK293 cells. Disruption of PABPC1 elevated PABPC4 levels. Transcriptome analysis revealed that the shift in the dominant PABP isoform was correlated with changes in key transcriptional regulators. This study provides insight into understanding the role of PABP isoforms in development and differentiation.
Acoustic Context Modulates Natural Sound Discrimination in Auditory Cortex through Frequency-Specific Adaptation

Sound discrimination is essential in many species for communicating and foraging. Bats, for example, use sounds for echolocation and communication. In the bat auditory cortex there are neurons that process both sound categories, but how these neurons respond to acoustic transitions, that is, echolocation streams followed by a communication sound, remains unknown. Here, we show that the acoustic context, a leading sound sequence followed by a target sound, changes neuronal discriminability of echolocation versus communication calls in the cortex of awake bats of both sexes. Nonselective neurons that fire equally well to both echolocation and communication calls in the absence of context become category selective when leading context is present. On the contrary, neurons that prefer communication sounds in the absence of context turn into nonselective ones when context is added. The presence of context leads to an overall response suppression, but the strength of this suppression is stimulus specific. Suppression is strongest when context and target sounds belong to the same category, e.g.,echolocation followed by echolocation. A neuron model of stimulus-specific adaptation replicated our results in silico. The model predicts selectivity to communication and echolocation sounds in the inputs arriving to the auditory cortex, as well as two forms of adaptation, presynaptic frequency-specific adaptation acting in cortical inputs and stimulus-unspecific postsynaptic adaptation. In addition, the model predicted that context effects can last up to 1.5 s after context offset and that synaptic inputs tuned to low-frequency sounds (communication signals) have the shortest decay constant of presynaptic adaptation. SIGNIFICANCE STATEMENT We studied cortical responses to isolated calls and call mixtures in awake bats and show that (1) two neuronal populations coexist in the bat cortex, including neurons that discriminate social from echolocation sounds well and neurons that are equally driven by these two ethologically different sound types; (2) acoustic context (i.e., other natural sounds preceding the target sound) affects natural sound selectivity in a manner that could not be predicted based on responses to isolated sounds; and (3) a computational model similar to those used for explaining stimulus-specific adaptation in rodents can account for the responses observed in the bat cortex to natural sounds. This model depends on segregated feedforward inputs, synaptic depression, and postsynaptic neuronal adaptation.