bluuebunny/crossref_metadata_2025_split huggingface dataset:
Data Driven Taxonomy for Antipsychotic Medication: A New Classification System
Authors: McCutcheon Robert A. , Harrison Paul J. , Howes Oliver D. , McGuire Philip K. , Taylor David , Pillinger Toby 
Published: January 2023

AbstractBackgroundThere are over 25 licensed antipsychotic medications with diverse pharmacological and clinical profiles. Antipsychotics are commonly described as either ‘typical’ or ‘atypical’, but this does not accurately reflect pharmacological profiles. There is thus a need for a data driven antipsychotic classification scheme suitable for clinicians and researchers which maps onto both pharmacological and clinical effects.MethodWe analysed affinities of 27 antipsychotics for 42 receptors from 3,325 receptor binding studies. We used a clustering algorithm to group antipsychotics based on their pattern of receptor affinity. Using a machine learning model, we examined the ability of this grouping to predict antipsychotic-induced side effects quantified according to an umbrella review of clinical trial and treatment guideline data.ResultsClustering resulted in four groups of antipsychotics. The predominant receptor affinity and effect/side effect ‘fingerprints’ of these four groups were defined, as follows:Group 1 - Muscarinic (M3-M5) receptor antagonism; Cholinergic and metabolic side effects.Group 2 - Dopamine (D2) partial agonism and adrenergic antagonism; Globally low side effect burden.Group 3 - Serotonergic and dopaminergic antagonism; Globally moderate side effect burden.Group 4 - Dopaminergic antagonism; Extrapyramidal and motor side effects.Groups 1 and 4 were more efficacious than clusters 2 and 3. The novel classification was superior to existing approaches when predicting side effects.ConclusionsA receptor affinity-based grouping not only reflects compound pharmacology but also detects meaningful clinical differences to a greater extent than existing approaches. The approach has the potential to benefit both patients and researchers by guiding treatment and informing drug development.
Low frequency optogenetic deep brain stimulation of nucleus accumbens dopamine D1 or D2 receptor-containing neurons attenuates cocaine seeking selectively in male rats in part by reversing synaptic plasticity deficits
Authors: Swinford-Jackson Sarah E. , Rich Matthew T. , Huffman Phillip J. , Knouse Melissa C. , Thomas Arthur S. , Mankame Sharvari , Worobey Samantha J. , Pierce R. Christopher 
Published: January 2023

AbstractBackgroundClinically, deep brain stimulation (DBS) utilizes relatively high frequencies (>100 Hz). In preclinical models, 160 Hz stimulation of the nucleus accumbens in rodents prevents relapse of drug seeking. However, the ability of varied frequencies of accumbens DBS to attenuate drug seeking, and the neuronal subtype specificity of this effect, is unclear.MethodsThe present study examined the effect of DBS in the nucleus accumbens on neuronal plasticity and cocaine-primed reinstatement of cocaine seeking behavior in rats.ResultsElectrical DBS of the accumbens shell attenuated cocaine primed reinstatement across a range of frequencies in male rats, including as low as 12 Hz. The majority of nucleus accumbens neurons are medium spiny neurons (MSNs), which can be differentiated in terms of projections and effects on cocaine-related behaviors by expression of dopamine D1 receptors (D1DRs) or D2DRs. In slice electrophysiology experiments, 12 Hz electrical stimulation evoked long term potentiation (LTP) in eYFP labeled D1DR-MSNs and D2DR-MSNs from cocaine naive male and female rats. However, in rats that self-administered cocaine and underwent extinction training, a paradigm identical to our reinstatement experiments, electrical DBS only elicited LTP in D2DR-MSNs from male rats; this effect was replicated by optical stimulation in rats expressing Cre-dependent ChR2 in D2DR-MSNs. Low-frequency optogenetic-DBS in D1DR-containing or D2DR-containing neurons attenuated cocaine-primed reinstatement of cocaine seeking in male but not female rats.ConclusionsThese results suggest that administering DBS in the nucleus accumbens shell at lower frequencies effectively, but sex-specifically, suppresses cocaine craving, perhaps in part by reversing synaptic plasticity deficits selectively in D2DR-MSNs.
Structural insights into the mechanism of the human SGLT2–MAP17 glucose transporter
Authors: Hiraizumi Masahiro , Akashi Tomoya , Murasaki Kouta , Kishida Hiroyuki , Kumanomidou Taichi , Torimoto Nao , Nureki Osamu , Miyaguchi Ikuko 
Published: January 2023

AbstractSelective sodium-glucose cotransporter 2 (SGLT2) plays an important role in glucose reabsorption. SGLT2 inhibitors suppress glucose reabsorption from the kidneys, thus reducing blood glucose levels in type 2 diabetes patients. We and other groups have developed several SGLT2 inhibitors starting from a natural product, phlorizin, but their action mechanisms remain unknown. Here, we elucidated the physiological hSGLT2–MAP17 complex structures bound to five SGLT2 inhibitors using single-particle cryo-electron microscopy. Canagliflozin, dapagliflozin, TA-1887, and sotagliflozin were bound in the outward-facing structure, whereas phlorizin was bound in the inward-open structure. The phlorizin–hSGLT2 interaction biochemically exhibited biphasic binding. Phlorizin weakly binds, via the phloretin motif, from its intracellular side near the Na+-binding site, while strongly interacts from its extracellular side. Unexpectedly, bound Na+stabilizes the outward-open conformation, while its release allows the transporter to adopt inward-open state. Our results first visualized the Na+-binding and inward-open conformation of hSGLT2–MAP17, clarifying the unprecedented Na+-dependent sugar transport mechanism with MAP17 acting as a scaffold, and may pave the way for development of next-generation SGLT inhibitors.
The stability of NPM1 oligomers regulated by acidic disordered regions controls the quality of liquid droplets
Authors: Okuwaki Mitsuru , Ozawa Shin-Ichiro , Ebine Shuhei , Juichi Motoki , Umeki Tadanobu , Niioka Kazuki , Kikuchi Taiyo , Tanaka Nobutada 
Published: January 2023

AbstractA nucleolus is a typical membrane-less nuclear body that is formed by liquid–liquid phase separation (LLPS) of its components. A major component that drives LLPS in the nucleolus is nucleophosmin (NPM1). The oligomer formation and inter-oligomer interactions of NPM1 are suggested to cooperatively contribute to the induction of LLPS. However, the molecular mechanism of how the quality of the liquid droplets formed by NPM1 is regulated is currently not well understood. In this manuscript, we revealed the regulatory mechanism of NPM1 oligomer formation and its relationship with the ability to form liquid droplets. Molecular dynamics simulations and mutant protein analyses suggest that the acidic amino acids in the N-terminal and central disordered regions of NPM1 disturb the key interactions between monomers. We also demonstrate that mutants with attenuated oligomer stability form liquid droplets as do the wild-type; the fluidity of the formed liquid droplets was greater than that of the wild-type. These results suggest that the stability of NPM1 oligomers is a critical determinant of liquid droplet quality. Furthermore, we observed that when the net negative charges in the acidic disordered regions were increased by phosphomimetic mutations at Ser125, the NPM1 oligomer stability decreased, which increased the fluidity of the liquid droplets. Our results provide a novel mechanistic insight into how nucleolar dynamics are regulated during the cell cycle.
Aspartyl protease in the secretome of honey bee trypanosomatid parasite is essential for the efficient infection of host
Authors: Yuan Xuye , Sun Jianying , Kadowaki Tatsuhiko 
Published: January 2023

AbstractExoproteome represents the proteome consisting of all secreted proteins and proteins derived from the cell surface and lysed cell. The exoproteome of the trypanosomatid parasite should interact with the host cells and the associated microbiota; however, the roles of infecting insect hosts are not yet understood. To uncover the functions of exoproteome, we identified the exoproteome of honey bee trypanosomatid parasite,Lotmaria passim, and found that approximately 28 % are shared with that common betweenLeishmaniaspp. It demonstrates a core exoproteome with conserved functions exists in the Leishmaniinae lineage. The bioinformatic characterization suggests thatL. passimexoproteome may interact with the host and its microbiota as well as their metabolites. Deletion of genes encoding two secretome proteins revealed that an aspartyl protease but not chitinase affects the development ofL. passimunder the culture condition and is necessary for the efficient infection in the honey bee gut. Our results demonstrate that the exoproteome represents a resource to uncover the mechanisms of trypanosomatid parasites to infect the insect host by interacting with the gut environment.
Evidence for subjective values guiding cognitive integration of gravity in a free speed manifold pointing task
Authors: Devemy Arthur , Papaxanthis Charalambos , da Silva Pontes Lucieny , Pozzo Thierry , Hilt Pauline M. 
Published: January 2023

AbstractStudies of regularities in human movement control have led to the idea that our brains incorporate generic motor laws that guide our behaviors and thus these regularities. Among these, it has been argued that a generic internal model of gravity minimizes the body’s energy expenditure during actions performed in the vertical plane. According to this hypothesis, the energy criterion would represent the factor dominating motor planning. However, a growing body of experimental evidence indicates the presence of significant individual sensorimotor differences that suggest the use of various motor decision criteria.We asked 41 voluntary participants to perform a free speed manifold pointing task (i.e., at three free different speeds and toward non-salient targets), in the vertical plane designed to avoid situation-specific responses and favor the expression of singularities. We found that temporal parameters (duration of motion and vigor) were idiosyncratic and not affected by mechanical effects induced by changes in velocity and gravitational force (i.e., assistive or resistive forces). Upward motions had a shorter time to reach maximum velocity than downward motions confirming the presence of asymmetric movement timing. Finally, synchronization of up-down movements was not correlated with energy minimization, indicating that movements performed in the vertical plane do not rely exclusively on a standard representation of gravity reducing effort. Rather, we concluded that individual values and the subjective rewards associated with each of these values could influence the planning of movements executed along the vertical plane as well as the cognitive integration of the gravitational force field.
Charting the Heterogeneity of Colorectal Cancer Consensus Molecular Subtypes using Spatial Transcriptomics
Authors: Valdeolivas Alberto , Amberg Bettina , Giroud Nicolas , Richardson Marion , Gálvez Eric J.C. , Badillo Solveig , Julien-Laferrière Alice , Turos Demeter , von Voithenberg Lena Voith , Wells Isabelle , Lo Amy A. , Yángüez Emilio , Das Thakur Meghna , Bscheider Michael , Sultan Marc , Kumpesa Nadine , Jacobsen Björn , Bergauer Tobias , Saez-Rodriguez Julio , Rottenberg Sven , Schwalie Petra C. , Hahn Kerstin 
Published: January 2023

AbstractThe heterogeneity of colorectal cancer (CRC) contributes to substantial differences in patient response to standard therapies. The consensus molecular subtypes (CMS) of CRC is the most widely-used gene expression-based classification and has contributed to a better understanding of disease heterogeneity and prognosis. Nevertheless, CMS intratumoral heterogeneity restricts its clinical application, stressing the necessity of further characterizing the composition and architecture of CRC. Here, we used Spatial Transcriptomics (ST) in combination with single-cell RNA sequencing (scRNA-seq) to decipher the spatially resolved cellular and molecular composition of CRC. In addition to mapping the intratumoral heterogeneity of CMS and their microenvironment, we identified cell communication events in the tumor-stroma interface of CMS2 carcinomas. This includes tumor growth-inhibiting as well as -activating signatures, such as the potential regulation of the ETV4 transcriptional activity by DCN or the PLAU-PLAUR ligand-receptor interaction. Our data show the power of ST to bring the CMS-based classification of CRC to another level and thereby gain useful molecular insights for personalized therapy.
Visual short-term memory related EEG components in a virtual reality setup
Authors: Klotzsche Felix , Gaebler Michael , Villringer Arno , Sommer Werner , Nikulin Vadim , Ohl Sven 
Published: January 2023

AbstractVirtual reality (VR) offers a powerful tool for investigating cognitive processes, as it allows researchers to gauge behaviors and mental states in complex, yet highly controlled, scenarios. The use of VR head-mounted displays in combination with physiological measures such as EEG presents new challenges and raises the question whether established findings also generalize to a VR setup. Here, we used a VR headset to assess the spatial constraints underlying two well-established EEG correlates of visual short-term memory: the amplitude of the contralateral delay activity (CDA) and the lateralization of induced alpha power during memory retention. We tested observers’ visual memory in a delayed match-to-sample task with bilateral stimulus arrays of either two or four items while varying the horizontal eccentricity of the memory arrays (4, 9, or 14 degrees of visual angle). The CDA amplitude differed between high and low memory load at the two smaller eccentricities, but not at the largest eccentricity. Neither memory load nor eccentricity significantly influenced the observed alpha lateralization. We further fitted time-resolved spatial filters to decode memory load from the event-related potential as well as from its time-frequency decomposition. Classification performance during the retention interval was above chance level for both approaches and did not vary significantly across eccentricities. We conclude that commercial VR hardware can be utilized to study the CDA and lateralized alpha power, and we provide caveats for future studies targeting these EEG markers of visual memory in a VR setup.Impact statementCombining EEG with virtual reality, we studied how the eccentricity of a memory array during encoding affects well-known neural markers of visual short-term memory. We reveal that the previously reported occurrence of these EEG components during visual memory retention can be replicated in such a setup. These EEG markers were differently affected by eccentricity, hence providing valuable constraints for future experimental designs.
Mis-spliced transcripts generatede novoproteins in TDP-43-related ALS/FTD
Authors: Seddighi Sahba , Qi Yue A. , Brown Anna-Leigh , Wilkins Oscar G. , Bereda Colleen , Belair Cedric , Zhang Yongjie , Prudencio Mercedes , Keuss Matthew J , Khandeshi Aditya , Pickles Sarah , Hill Sarah E. , Hawrot James , Ramos Daniel M. , Yuan Hebao , Roberts Jessica , Sacramento Erika Kelmer , Shah Syed I. , Nalls Mike A. , Colon-Mercado Jenn , Reyes Joel F. , Ryan Veronica H. , Nelson Matthew P. , Cook Casey , Li Ziyi , Screven Laurel , Kwan Justin Y , Shantaraman Anantharaman , Ping Lingyan , Koike Yuka , Oskarsson Björn , Staff Nathan , Duong Duc M. , Ahmed Aisha , Secrier Maria , Ule Jerneg , Jacobson Steven , Rohrer Jonathan , Malaspina Andrea , Glass Jonathan D. , Ori Alessandro , Seyfried Nicholas T. , Maragkakis Manolis , Petrucelli Leonard , Fratta Pietro , Ward Michael E. 
Published: January 2023

AbstractFunctional loss of TDP-43, an RNA-binding protein genetically and pathologically linked to ALS and FTD, leads to inclusion of cryptic exons in hundreds of transcripts during disease. Cryptic exons can promote degradation of affected transcripts, deleteriously altering cellular function through loss-of-function mechanisms. However, the possibility ofde novoprotein synthesis from cryptic exon transcripts has not been explored. Here, we show that mRNA transcripts harboring cryptic exons generatede novoproteins both in TDP-43 deficient cellular models and in disease. Using coordinated transcriptomic and proteomic studies of TDP-43 depleted iPSC-derived neurons, we identified numerous peptides that mapped to cryptic exons. Cryptic exons identified in iPSC models were highly predictive of cryptic exons expressed in brains of patients with TDP-43 proteinopathy, including cryptic transcripts that generatedde novoproteins. We discovered that inclusion of cryptic peptide sequences in proteins altered their interactions with other proteins, thereby likely altering their function. Finally, we showed that thesede novopeptides were present in CSF from patients with ALS. The demonstration of cryptic exon translation suggests new mechanisms for ALS pathophysiology downstream of TDP-43 dysfunction and may provide a strategy for novel biomarker development.One Sentence SummaryLoss of TDP-43 function results in the expression ofde novoproteins from mis-spliced mRNA transcripts.
Anatomo-functional changes in neural substrates of cognitive memory in developmental amnesia: Insights from automated and manual MRI examinations
Authors: Chareyron Loïc J. , Chong W.K. Kling , Banks Tina , Burgess Neil , Saunders Richard C. , Vargha-Khadem Faraneh 
Published: January 2023

AbstractDespite bilateral hippocampal damage dating to perinatal or early-childhood period, and severely-impaired episodic memory that unfolds in later childhood, patients with developmental amnesia continue to exhibit well-developed semantic memory across the developmental trajectory. Detailed information on the extent and focality of brain damage in these patients is needed to hypothesize about the neural substrate that supports their remarkable capacity for encoding and retrieval of semantic memory. In particular, we need to assess whether the residual hippocampal tissue is involved in this preservation, or whether the surrounding cortical areas reorganise to rescue aspects of these critical cognitive memory processes after early injury.We used voxel-based morphometry (VBM) analysis, automatic (FreeSurfer) and manual segmentation to characterize structural changes in the brain of an exceptionally large cohort of 23 patients with developmental amnesia in comparison with 32 control subjects.Both the VBM and the FreeSurfer analyses revealed severe structural alterations in the hippocampus and thalamus of patients with developmental amnesia. Milder damage was found in the amygdala, caudate and parahippocampal gyrus. Manual segmentation demonstrated differences in the degree of atrophy of the hippocampal subregions in patients. The level of atrophy in CA-DG subregions and subicular complex was more than 40% while the atrophy of the uncus was moderate (−23%). Anatomo-functional correlations were observed between the volumes of residual hippocampal subregions in patients and selective aspects of their cognitive performance viz, intelligence, working memory, and verbal and visuospatial recall.Our findings suggest that in patients with developmental amnesia, cognitive processing is compromised as a function of the extent of atrophy in hippocampal subregions, such that the greater the damage, the more likely it is that surrounding cortical areas will be recruited to rescue the putative functions of the damaged subregions. Our findings document for the first time not only the extent, but also the limits of circuit reorganization occurring in the young brain after early bilateral hippocampal damage.
Cont-ID: Detection of samples cross-contamination in viral metagenomic data
Authors: Rollin Johan , Rong Wei , Massart Sébastien 
Published: January 2023

BackgroundHigh Throughput sequencing (HTS) technologies completed by the bioinformatic analysis of the generated data are becoming an important detection technique for virus diagnostics. They have the potential to replace or complement the current PCR-based methods thanks to their improved inclusivity and analytical sensitivity, as well as their overall good repeatability and reproducibility. Cross-contamination is a well-known phenomenon in molecular diagnostics and corresponds to the exchange of genetic material between samples. Cross-contamination management was a key drawback during the development of PCR-based detection and is now adequately monitored in routine diagnostics. HTS technologies are facing similar difficulties due to their very high analytical sensitivity. As a single viral read could be detected in millions of sequencing reads, it is mandatory to fix a detection threshold that will be influenced by cross-contamination. Cross-contamination monitoring should therefore be a priority when detecting viruses by HTS technologies.ResultsWe present Cont-ID, a bioinformatic tool designed to check for cross-contamination by analysing the relative abundance of virus sequencing reads identified in sequence metagenomic datasets and their duplication between samples. It can be applied when the samples in a sequencing batch have been processed in parallel in the laboratory and with at least one external alien control. Using 273 real datasets, including 68 virus species from different hosts (fruit tree, plant, human) and several library preparation protocols (Ribodepleted total RNA, small RNA and double stranded RNA), we demonstrated that Cont-ID classifies with high accuracy (91%) viral species detection into (true) infection or (cross) contamination. This classification raises confidence in the detection and facilitates the downstream interpretation and confirmation of the results by prioritising the virus detections that should be confirmed.ConclusionsCross-contamination between samples when detecting viruses using HTS can be monitored and highlighted by Cont-ID (provided an alien control is present). Cont-ID is based on a flexible methodology relying on the output of bioinformatics analyses of the sequencing reads and considering the contamination pattern specific to each batch of samples. The Cont-ID method is adaptable so that each laboratory can optimise it before its validation and routine use.