Miracle-dz/UniFAR-FTUs huggingface dataset:
Prefrontal network engagement by deep brain stimulation in limbic hubs

Background Prefrontal circuits in the human brain play an important role in cognitive and affective processing. Neuromodulation therapies delivered to certain key hubs within these circuits are being used with increasing frequency to treat a host of neuropsychiatric disorders. However, the detailed neurophysiological effects of stimulation to these hubs are largely unknown. Methods Here, we performed intracranial recordings across prefrontal networks while delivering electrical stimulation to two well-established white matter hubs involved in cognitive regulation and depression: the subcallosal cingulate (SCC) and ventral capsule/ventral striatum (VC/VS). Results We demonstrate a shared frontotemporal circuit consisting of the ventromedial PFC, amygdala, and lateral orbitofrontal cortex where gamma oscillations are differentially modulated by stimulation target. Additionally, we found subject-specific responses to stimulation in the dorsal anterior cingulate cortex and demonstrate the capacity for further tuning of neural activity using current-steered stimulation. Conclusions Our findings indicate a potential neurophysiological mechanism for the dissociable therapeutic effects seen across the SCC and VC/VS DBS targets for psychiatric neuromodulation and our results lay the groundwork for personalized, network-guided neurostimulation therapy.
Conserved intramolecular networks in GDAP1 are closely connected to CMT-linked mutations and protein stability

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its subtypes are linked to mutations in dozens of different genes, including the gene coding for ganglioside-induced differentiation-associated protein 1 (GDAP1). The main GDAP1-linked CMT subtypes are the demyelinating CMT4A and the axonal CMT2K. Over a hundred different missense CMT mutations in the GDAP1 gene have been reported. However, despite implications for mitochondrial fission and fusion, cytoskeletal interactions, and response to reactive oxygen species, the etiology of GDAP1-linked CMT is poorly understood at the protein level. Based on earlier structural data, CMT-linked mutations could affect intramolecular interaction networks within the GDAP1 protein. We carried out structural and biophysical analyses on several CMT-linked GDAP1 protein variants and describe new crystal structures of the autosomal recessive R120Q and the autosomal dominant A247V and R282H GDAP1 variants. These mutations reside in the structurally central helices α3, α7, and α8. In addition, solution properties of the CMT mutants R161H, H256R, R310Q, and R310W were analysed. All disease variant proteins retain close to normal structure and solution behaviour. All mutations, apart from those affecting Arg310 outside the folded GDAP1 core domain, decreased thermal stability. In addition, a bioinformatics analysis was carried out to shed light on the conservation and evolution of GDAP1, which is an outlier member of the GST superfamily. Many CMT mutation sites are highlighted in the bioinformatics analyses focusing on sequence conservation and entropy, and the analyses support the outlier nature of GDAP1 in the GST superfamily. A central role for the α6-α7 loop, within a conserved interaction network, is identified for GDAP1 protein stability. To conclude, we have expanded the structural analysis on GDAP1, strengthening the hypothesis that alterations in conserved intramolecular interactions may alter GDAP1 stability and function, eventually leading to mitochondrial dysfunction, impaired protein-protein interactions, and neuronal degeneration.
The potent broadly neutralizing antibody VIR-3434 controls Hepatitis B and D Virus infection and reduces HBsAg in humanized mice

Background & Aims Chronic hepatitis B is a major global public health problem, and coinfection with hepatitis delta virus (HDV) worsens disease outcome. Here, we describe a hepatitis B virus (HBV) surface antigen (HBsAg)-targeting monoclonal antibody (mAb) with the potential to promote functional cure of chronic hepatitis B and D to address this unmet medical need. Methods HBsAg-specific mAbs were isolated from memory B cells of HBV vaccinated individuals. In vitro neutralization was determined against HBV and HDV enveloped with HBsAg representing eight HBV genotypes. Human liver-chimeric mice were treated twice weekly with a candidate mAb starting three weeks post HBV inoculation (spreading phase) or during stable HBV or HBV/HDV coinfection (chronic phase). Results From a panel of human anti-HBs mAbs, VIR-3434 was selected and engineered for pre-clinical development. VIR-3434 targets a putative conserved, conformational epitope within the antigenic loop of HBsAg and neutralized HBV and HDV infection with >12,000-fold higher potency than Hepatitis B Immunoglobulins in vitro. Neutralization was pan-genotypic against strains representative of HBV genotypes A-H. In the spreading phase of HBV infection in human liver-chimeric mice, a parental mAb of VIR-3434 (HBC34) prevented HBV dissemination and intrahepatic HBV RNA and cccDNA increase. In the chronic phase of HBV infection or co-infection with HDV, HBC34 treatment decreased circulating HBsAg by >1 log and HDV RNA by >2 logs. Conclusions This in vitro and in vivo characterization identified the potent anti-HBs mAb VIR-3434, which reduces circulating HBsAg and HBV/HDV viremia in human liver-chimeric mice. VIR-3434 is currently in clinical development for treatment of patients with chronic hepatitis B or D. Lay summary Chronic infection with hepatitis B virus places approximately 290 million individuals worldwide at risk for severe liver disease and cancer. Currently available treatments result in low rates of functional cure or require lifelong therapy that does not eliminate the risk of liver disease. We isolated and characterized a potent, human antibody that neutralizes hepatitis B and D viruses and reduces infection in a mouse model. This antibody could provide a new treatment for patients with chronic hepatitis B and D. Highlights Identification of a human mAb VIR-3434 that potently neutralizes HBV and HDV VIR-3434 targets a conserved, conformational epitope of the HBsAg antigenic loop VIR-3434 treatment blocks intrahepatic HBV spread in human liver-chimeric mice VIR-3434 treatment reduces circulating HBsAg and HDV RNA in co-infected mice Data have enabled clinical development of VIR-3434 against chronic hepatitis B/D
Development of a new cold hardiness prediction model for grapevine using phased integration of acclimation and deacclimation responses

Cold injury limits distribution of perennial agricultural crops, though replacement of plants and other management practices may allow for some damage tolerance. However, winter damage to crops such as grapevines (Vitis spp.) can result in losses in yield the following year if buds are damaged, but over many years when vines must be replaced and reach maturity before fruiting. Despite risks, grapevines are cultivated at the edge of permissible climate and rely on cold hardiness monitoring programs to determine when cold damage mitigation and management practices are required. These monitoring programs represent a critical, but laborious process for tracking cold hardiness. To reduce the need for continuous monitoring, a model (WAUS.2) using cold hardiness data collected over many years from Washington state, USA, growers was published in 2014. Although the WAUS.2 model works well regionally, it underperforms in other regions. Therefore, the objective of this work was to develop a new model (NYUS.1) that incorporates recent knowledge of cold hardiness dynamics for better prediction outcomes. Cold hardiness data from V. labruscana ‘Concord’, and V. vinifera ‘Cabernet Sauvignon’ and ‘Riesling’ from Geneva, NY, USA were used. Data were separated in calibration (~2/3) and validation (~1/3) datasets. The proposed model uses three functions to describe acclimation, and two functions to describe deacclimation, with a total of nine optimized parameters. A shared chill response between acclimation and deacclimation provides a phased integration where acclimation responses decrease over the course of winter and are overcome by deacclimation. The NYUS.1 model outperforms the WAUS.2 model, reducing RMSE by up to 37% depending on cultivar. The NYUS.1 model also tends to be more conservative in its prediction, slightly underpredicting cold hardiness, as opposed to the overprediction from the WAUS.2 model. Some optimized parameters were shared between cultivars, suggesting conserved physiology was captured by the new model. Highlights - Multi-year cold hardiness data from three grapevine cultivars were used for modeling - Cold hardiness was modeled based on daily temperature and accumulated chill - Phased acclimation and deacclimation processes result in cold hardiness predictions - The new model was compared to the currently available model for grapevines - The model proposed here outperforms the currently available model
Phylogeny-aware linear B-cell epitope predictor detects candidate targets for specific immune responses to Monkeypox virus

Monkeypox is a disease caused by the Monkeypox virus (MPXV), a double-stranded DNA virus from genus Orthopoxvirus under family Poxviridae, that has recently emerged as a global health threat after decades of local outbreaks in Central and Western Africa. Effective epidemiological control against this disease requires the development of cheaper, faster diagnostic tools to monitor its spread, including antigen and serological testing. There is, however, little available information about MPXV epitopes, particularly those that would be effective in discriminating between MPXV infections and those by other virus from the same family. We used the available data from the Immune Epitope Database (IEDB) to generate and validate a predictive model optimised for detecting linear B-cell epitopes (LBCEs) from Orthopoxvirus, based on a phylogeny-aware data selection strategy. By coupling this predictive approach with conservation and similarity analyses, we identified nine specific peptides from MPXV that are likely to represent distinctive LBCEs for the diagnostic of Monkeypox infections, including the independent detection of a known epitope experimentally characterised as a potential specific diagnostic target for MPXV. The results obtained indicate ability of the proposed pipeline to uncover promising targets for the development of cheaper, more specific diagnostic tests for this emerging viral disease. A full reproducibility package (including code, data, and outputs) is available at https://doi.org/10.5281/zenodo.7838331.
Two Synaptic Convergence Motifs

15 Bushy neurons of the cochlear nucleus encode temporal fine structure and modulation of sound 16 with high fidelity. However, the synaptic maps and electrotonic structures that underlie these 17 properties are not specified in meaningful explanatory detail. We employed modern volume 18 electron microscopy techniques to provide exact data on the numbers of synaptic inputs and 19 their weights determined by the number of contained active zones, and the surface areas of all 20 postsynaptic cellular compartments. Leveraging these high-resolution images, we discovered 21 cabling of dendrite branches and new structures within dendrites, and identified non-innervated 22 dendrites. We extend current nanoscale connectomic studies with methods to export cellular 23 reconstructions into morphologically-constrained, biophysically-based predictive computational 24 models. We reveal both coincidence detection and mixed supra/subthreshold modes of input 25 convergence across the bushy cell population and show subthreshold inputs contribute to 26 enhanced temporal encoding even in the presence of suprathreshold inputs. We demonstrate 27 the variation of dendritic load and axon parameters and their importance in controlling 28 excitability as potential homeostatic mechanisms, thereby defining heterogeneity in 29 stimulus-evoked responses across the BC population. 30
Minute-scale Periodicity of Neuronal Firing in the Human Entorhinal Cortex

Grid cells in the entorhinal cortex demonstrate spatially periodic firing patterns, which are thought to provide a map of space on behaviorally relevant length scales. It is unknown, however, whether such periodicity exists for behaviorally relevant time scales in the human brain. Here we investigated neuronal firing during a temporally continuous uninterrupted experience by presenting fourteen neurosurgical patients with an audiovisual video while recording single neuron activity from multiple brain regions. We report on a set of units that modulate their activity in a strikingly periodic manner across different timescales—from seconds to many minutes. These cells were most prevalent in the entorhinal cortex. Time within the video could be decoded from their population activity. Furthermore, these cells remapped their dominant periodicity to shorter timescales during a subsequent recognition memory task. When the audiovisual sequence was presented at two different speeds (regular and faster), a significant percentage of these temporally periodic cells (TPCs) maintained their timescales, suggesting a degree of invariance with respect to the narrative content. The temporal periodicity of TPCs may complement the spatial periodicity of grid cells Whether these cells provide scalable spatiotemporal metrics for encoding and retrieval of human experience warrants future investigations.
CP204L Is a Multifunctional Protein of African Swine Fever Virus That Interacts with The VPS39 Subunit of HOPS Complex and Promotes Lysosome Clustering

Virus replication depends on a complex interplay between viral and host proteins. In the case of African swine fever virus (ASFV), a large DNA virus, only few virus-host protein-protein interactions have been identified to date. In this study, we demonstrate that the ASFV protein CP204L directly interacts with the cellular homotypic fusion and protein sorting (HOPS) protein VPS39, blocking its association with the lysosomal HOPS complex, that modulates endolysosomal trafficking and promotes lysosome clustering. Instead, VPS39 is targeted to the sites of virus replication termed virus factories. Furthermore, we show that loss of VPS39 reduces the levels of virus proteins synthesized in the early phase of infection and delays ASFV replication but does not completely inhibit it. Collectively, these results identify a novel virus-host protein interaction that modulates host membrane rearrangement during infection and provide evidence that CP204L is a multifunctional protein engaged in distinct steps of the ASFV life cycle. Importance African swine fever virus (ASFV) was first identified over a hundred years ago. Since then, much effort has been made to understand the pathogenesis of ASFV. Yet, the specific roles of many individual ASFV proteins during the infection remain enigmatic. This study provides evidence that CP204L, one of the most abundant ASFV proteins, modulates endosomal trafficking during virus infection. Through direct protein-protein interaction, CP204L prevents the recruitment of VPS39 to the endosomal and lysosomal membranes, resulting in their accumulation. Consequently, CP204L and VPS39 become sequestered to the ASFV replication site. These results uncover a novel function of viral protein CP204L and extend our understanding of complex interaction between virus and host.
A membrane-associated light harvesting model is enabled by functionalized assemblies of gene-doubled TMV proteins

Photosynthetic light harvesting requires efficient energy transfer within dynamic networks of light harvesting complexes embedded within phospholipid membranes. Artificial light harvesting models are valuable tools for understanding the structural features underpinning energy absorption and transfer within chromophore arrays. Most artificial light harvesting complexes are static or in the solution phase, rather than in a two-dimensional fluid environment as in natural photosynthesis. We have developed a method for attaching a protein-based light harvesting model to a supported lipid bilayer (SLB), which provides an extended fluid membrane surface stably associated with a solid substrate. The protein model consisted of the tobacco mosaic viral capsid proteins (TMV) that were gene-doubled to create a tandem dimer (dTMV). Assemblies of dTMV were shown to break the facial symmetry of the double disk to allow for differentiation between the disk faces. Single reactive lysine and cysteine residues were incorporated into opposing surfaces of each monomer of the dTMV assemblies. This allowed for the site-selective attachment of both chromophores for light absorption and a peptide for attachment to the SLB. A cysteine modification strategy using the enzyme tyrosinase was employed for the bioconjugation of a peptide containing a polyhistidine tag for association with SLBs. The dual-modified dTMV complexes showed significant association with SLBs and exhibited mobility on the bilayer. The techniques used herein offer a new method for protein-surface attachment and provide a platform for evaluating excited state energy transfer events in a dynamic, fully synthetic artificial light harvesting system. Significance Statement Here we have constructed a model photosynthetic membrane containing proteins, chromophores, lipids, and aqueous components, all of which can be modified in their composition. This model is based on an asymmetric disk assembly consisting of engineered tandem dimers of the tobacco mosaic viral capsid protein (dTMV). We have developed methods to achieve dye conjugation and attachment of a supported lipid bilayers (SLB) site selectively on distinct protein surfaces. These dye-labeled protein complexes exhibit mobility on the SLB, resulting in a dynamic model of light harvesting membranes using entirely synthetic components. Additionally, this unique asymmetric assembly of TMV and the facile methods for protein functionalization are expected to expand the tunability of model light harvesting systems.
Logarithmic Representability of Integers as k-Sums

A set A=A_{k,n} in [n]\cup{0} is said to be an additive k-basis if each element in {0,1,. ,kn} can be written as a k-sum of elements of A in at least one way. Seeking multiple representations as k-sums, and given any function phi(n), with lim(phi(n))=infinity, we say that A is a truncated phi(n)-representative k-basis for [n] if for each j in [alpha n, (k-alpha)n] the number of ways that j can be represented as a k-sum of elements of A_{k,n} is Theta(phi(n)). In this paper, we follow tradition and focus on the case phi(n)=log n, and show that a randomly selected set in an appropriate probability space is a truncated log-representative basis with probability that tends to one as n tends to infinity. This result is a finite version of a result proved by Erdos (1956) and extended by Erdos and Tetali (1990).
Branch point evolution controls species-specific alternative splicing and regulates long term potentiation

Regulation and functionality of species-specific alternative splicing has remained enigmatic to the present date. Calcium/calmodulin-dependent protein kinase IIβ (CaMKIIβ) is expressed in several splice variants and plays a key role in learning and memory. Here, we identify and characterize several primate-specific CAMK2B splice isoforms, which show altered kinetic properties and changes in substrate specificity. Furthermore, we demonstrate that primate-specific Camk2β alternative splicing is achieved through branch point weakening during evolution. We show that reducing branch point and splice site strengths during evolution globally renders constitutive exons alternative, thus providing a paradigm for cis-directed species-specific alternative splicing regulation. Using CRISPR/Cas9 we introduced a weaker human branch point into the mouse genome, resulting in human-like CAMK2B splicing in the brain of mutant mice. We observe a strong impairment of long-term potentiation in CA3-CA1 synapses of mutant mice, thus connecting branch point-controlled, species-specific alternative splicing with a fundamental function in learning and memory.
Optogenetic induction of chronic glucocorticoid exposure in early-life impairs stress-response in larval zebrafish

Organisms respond to stressors through a coordinated set of physiological and behavioural responses. Zebrafish provides an opportunity to study conserved mechanisms underlying the stress-response that is regulated largely by the neuroendocrine Hypothalamus-Pituitary-Adrenal/Interrenal (HPA) axis, with glucocorticoids (GC) as the final effector. In this study, we evaluated the effect of chronically active GC signalling in early life on the baseline and stress evoked GC(cortisol) levels in larval zebrafish. To this end, we employed an optogenetic actuator, Beggiatoa photoactivated adenylyl cyclase, expressed in the interrenal cells of zebrafish and demonstrate that its chronic activation leads to hypercortisolaemia and dampens the acute-stress evoked cortisol levels, across a variety of stressor modalities during early life. This blunting of stress-response, a phenotype reported by many studies to be observed in human subjects exposed to early-life trauma, was conserved in ontogeny at a later developmental stage. Furthermore, we observe a strong reduction of proopiomelanocortin (POMC)-expressing cells in the pituitary as well as global upregulation of FKBP5 gene expression, impinging on the negative feedback regulation elicited by elevated cortisol levels. Going forward, we propose that this model can be leveraged to tease apart the mechanisms underlying developmental programming of HPA axis by early-life stress and its implications for vulnerability and resilience to stress in adulthood.