bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep kinematic inference affords efficient and scalable control of bodily movements
Authors: Priorelli Matteo , Pezzulo Giovanni , Stoianov Ivilin Peev
Published: May 2023

Performing goal-directed movements requires mapping goals from extrinsic (workspace-relative) to intrinsic (body-relative) coordinates and then to motor signals. Mainstream approaches based on Optimal Control realize the mappings by minimizing cost functions, which is computationally demanding. Instead, Active Inference uses generative models to produce sensory predictions, which allows a cheaper inversion to the motor signals. However, devising generative models to control complex kinematic chains like the human body is challenging. We introduce a novel Active Inference architecture that affords a simple but effective mapping from extrinsic to intrinsic coordinates via inference and easily scales up to drive complex kinematic chains. Rich goals can be specified in both intrinsic and extrinsic coordinates using attractive or repulsive forces. The proposed model reproduces sophisticated bodily movements and paves the way for computationally efficient and biologically plausible control of actuated systems.
Amyloid pathology impairs experience-dependent inhibitory synaptic plasticity
Authors: Niraula Suraj , Yan Shirley ShiDu , Subramanian Jaichandar
Published: May 2023

Alzheimer’s disease patients and mouse models exhibit aberrant neuronal activity and altered excitatory-to-inhibitory synaptic ratio. Using multicolor two-photon microscopy, we test how amyloid pathology alters the structural dynamics of excitatory and inhibitory synapses and their adaptation to altered visual experiencein vivoin the visual cortex. We show that the baseline dynamics of mature excitatory synapses and their adaptation to visual deprivation are not altered in amyloidosis. Likewise, the baseline dynamics of inhibitory synapses are not affected. In contrast, visual deprivation fails to induce inhibitory synapse loss in amyloidosis, a phenomenon observed in nonpathological conditions. Intriguingly, inhibitory synapse loss associated with visual deprivation in nonpathological mice is accompanied by the broadening of spontaneous but not visually evoked calcium transients. However, such broadening does not manifest in the context of amyloidosis. We also show that excitatory and inhibitory synapse loss is locally clustered under the nonpathological state. In contrast, a fraction of synapse loss is not locally clustered in amyloidosis, indicating an impairment in inhibitory synapse adaptation to changes in excitatory synaptic activity.
Neuro-Environmental Interactions: a time sensitive matter
Authors: Invernizzi Azzurra , Renzetti Stefano , Rechtman Elza , Ambrosi Claudia , Mascaro Lorella , Corbo Daniele , Gasparotti Roberto , Tang Cheuk Y. , Smith Donald R. , Lucchini Roberto G. , Wright Robert O. , Placidi Donatella , Horton Megan K. , Curtin Paul
Published: May 2023

The assessment of resting state (rs) neurophysiological dynamics relies on the control of sensory, perceptual, and behavioral environments to minimize variability and rule-out confounding sources of activation during testing conditions. Here, we investigated how temporally-distal environmental inputs, specifically metal exposures experienced up to several months prior to scanning, affect functional dynamics measured using rs functional magnetic resonance imaging (rs-fMRI). We implemented an interpretable XGBoost-Shapley Additive Explanation (SHAP) model that integrated information from multiple exposure biomarkers to predict rs dynamics in typically developing adolescents. In 124 participants (53% females, ages: 13-25 years) enrolled in the Public Health Impact of Metals Exposure (PHIME) study, we measured concentrations of six metals (manganese, lead, chromium, cupper, nickel and zinc) in biological matrices (saliva, hair, fingernails, toenails, blood and urine) and acquired rs-fMRI scans. Using graph theory metrics, we computed global efficiency (GE) in 111 brain areas (Harvard Oxford Atlas). We used a predictive model based on ensemble gradient boosting to predict GE from metal biomarkers, adjusting for age and biological sex. Model performance was evaluated by comparing predicted versus measured GE. SHAP scores were used to evaluate feature importance. Measured versus predicted rs dynamics from our model utilizing chemical exposures as inputs were significantly correlated (p< 0.001,r= 0.36). Lead, chromium, and copper contributed most to the prediction of GE metrics. Our results indicate that a significant component of rs dynamics, comprising approximately 13% of observed variability in GE, is driven by recent metal exposures. These findings emphasize the need to estimate and control for the influence of past and current chemical exposures in the assessment and analysis of rs functional connectivity.
Paired associated SARS-CoV-2 spike variable positions: a network analysis approach to emerging variants
Authors: Manoussopoulos Yiannis , Anastassopoulou Cleo , Ioannidis John P. A. , Tsakris Athanasios
Published: May 2023

Amino acids in variable positions of proteins may be correlated, with potential structural and functional implications. Here, we apply exact tests of independence in R × C contingency tables to examine noise-free associations between variable positions of the SARS-CoV-2 spike protein, using as a paradigm sequences from Greece deposited in GISAID (N=6,683/1,078 full-length) for the period February 29, 2020 to April 26, 2021 that essentially covers the first three pandemic waves. We examine the fate and complexity of these associations by network analysis, using associated positions (exact p≤0.001 and Average Product Correction ≥2) as links and the corresponding positions as nodes . We found a temporal linear increase of positional differences and a gradual expansion of the number of position associations over time, represented by a temporally evolving intricate web, resulting in a non-random complex network of 69 nodes and 252 links. Overconnected nodes corresponded to the most adapted variant positions in the population, suggesting a direct relation between network degree and position functional importance. Modular analysis revealed 25k-cliques comprising three to 11 nodes. At differentk- clique resolutions, one to four communities were formed, capturing epistatic associations of circulating variants (Alpha, Beta, B.1.1.318), but also Delta, which dominated the evolutionary landscape later in the pandemic. Cliques of aminoacidic positional associations tended to occur in single sequences, enabling the recognition of epistatic positions in real-world virus populations. Our findings provide a novel way of understanding epistatic relationships in viral proteins with potential applications in the design of virus control procedures.

Importance

Paired positional associations of adapted amino acids in virus proteins may provide new insights for understanding virus evolution and variant formation. We investigated potential intramolecular relationships between variable SARS-CoV-2 spike positions by exact tests of independence in R × C contingency tables, having applied Average Product Correction (APC) to eliminate background noise. Associated positions (exact p≤0.001 and APC≥2) formed a non- random, epistatic network of 25 cliques and 1-4 communities at different clique resolutions, revealing evolutionary ties between variable positions of circulating variants, and a predictive potential of previously unknown network positions. Cliques of different sizes represented theoretical combinations of changing residues in sequence space, allowing the identification of significant aminoacidic combinations in single sequences of real-world populations. Our analytic approach that links network structural aspects to mutational aminoacidic combinations in the spike sequence population offers a novel way to understand virus epidemiology and evolution.
Computational principles of adaptive multisensory combination in theDrosophilalarva
Authors: Wong Philip H. , Braun Andreas , Malagarriga Daniel , Moehlis Jeff , Moreno-Bote Rubén , Pouget Alexandre , Louis Matthieu
Published: May 2023

Many sensory systems have evolved to optimally combine signals from multiple sensory modalities to improve perception. While theories have been proposed to explain how this process is accomplished through probabilistic inference using large neural populations in vertebrates, how animals with dramatically smaller nervous systems such as theDrosophila melanogasterlarva achieve multisensory combination remains elusive. Here, we systematically characterize larval navigation in different configurations of odor and temperature gradients with optogenetically-controlled noise. Using a data-driven agent-based model, we find that larvae adapt to the reliability of individual sensory signals, and in some cases minimize the variance of the combined signal. Besides firmly establishing that probabilistic inference directs natural orientation behaviors in theDrosophilalarva, our results indicate that the exact mechanism underlying the combination of sensory information may be modality-dependent. By underscoring that probabilistic inference is inherent to insect nervous systems, our work opens the way for studying its neural implementation.
Protein Engineering for Thermostability through Deep Evolution
Authors: Chu Huanyu , Tian Zhenyang , Hu Lingling , Zhang Hejian , Chang Hong , Bai Jie , Liu Dingyu , Cheng Jian , Jiang Huifeng
Published: May 2023

Protein engineering for increased thermostability through iterative mutagenesis and high throughput screening is labor-intensive, expensive and inefficient. Here, we developed a deep evolution (DeepEvo) strategy to engineer protein thermostability through global sequence generation and selection using deep learning models. We firstly constructed a thermostability selector based on a protein language model to extract thermostability-related features in high-dimensional latent spaces of protein sequences with high temperature tolerance. Subsequently, we constructed a variant generator based on a generative adversarial network to create protein sequences containing the desirable function with more than 50% accuracy. Finally, the generator and selector were utilized to iteratively improve the performance of DeepEvo on the model protein glyceraldehyde-3-phosphate dehydrogenase (G3PDH), whereby 8 highly thermostable variants were obtained from only 30 generated sequences, demonstrating the high efficiency of DeepEvo for the engineering of protein thermostability.
Nanomolar range of FAM237B can activate receptor GPR83
Authors: Li Hao-Zheng , Wang Ya-Fen , Hu Wen-Feng , Liu Ya-Li , Xu Zeng-Guang , Guo Zhan-Yun
Published: May 2023

The orphan G protein-coupled receptor 83 (GPR83) is implicated in the regulation of energy metabolism and certain anxiety-related behaviors. Our recent study confirmed that family with sequence similarity 237 member A (FAM237A), also known as neurosecretory protein GL (NPGL), is an efficient agonist for GPR83, but did not support the proprotein convertase subtilisin/kexin type 1 inhibitor (PCSK1N, also known as proSAAS)-derived peptide PEN and the procholecystokinin-derived peptide proCCK56-63 as ligands of this receptor. FAM237B (also known as NPGM) is a paralog of FAM237A that was previously reported as a weak agonist for GPR83 with approximately 100-fold lower activity in an inositol 1-phosphate accumulation assay. In the present study, we prepared mature human FAM237B via an intein-fusion approach and measured its activity towards human GPR83 via a NanoLuc Binary Technology (NanoBiT)-based ligand□receptor binding assay and a NanoBiT-based β-arrestin recruitment assay. Mature FAM237B displayed moderately lower activity than its paralog FAM237A in these binding and activation assays, but could cause a significant activation effect at the nanomolar range (1□10 nM). Thus, FAM237B appears to be another endogenous agonist for receptor GPR83.
Resilient functioning is associated with altered structural brain network topology in adolescents exposed to childhood adversity
Authors: González-García Nadia , Buimer Elizabeth E.L. , Moreno-López Laura , Sallie Samantha N. , Váša František , Lim Sol , Romero-Garcia Rafael , Scheuplein Maximilian , Whitaker Kirstie , Jones Peter B. , Dolan Ray ,   NSPN consortium, Fonagy Peter , Goodyer Ian , Bullmore Ed , van Harmelen Anne-Laura
Published: May 2023

Childhood adversity is one of the strongest predictors of adolescent mental illness. Therefore, it is critical that the mechanisms that aid resilient functioning in individuals exposed to childhood adversity are better understood. Here, we examined whether resilient functioning was related to structural brain network topology. We quantified resilient functioning at the individual level as psychosocial functioning adjusted for the severity of childhood adversity in a large sample of adolescents (N=2406, aged 14-24). Next, we examined nodal degree (the number of connections that brain regions have in a network) using brain-wide cortical thickness measures in a representative subset (N=275) using a sliding window approach. We found that higher resilient functioning was associated with lower nodal degree of multiple regions including the dorsolateral prefrontal cortex, the medial prefrontal cortex, and the posterior superior temporal sulcus (z> 1.645). During adolescence, decreases in nodal degree are thought to reflect a normative developmental process that is part of the extensive remodelling of structural brain network topology. Prior findings in this sample showed that decreased nodal degree was associated with age, as such our findings of negative associations between nodal degree and resilient functioning may therefore potentially resemble a more mature structural network configuration in individuals with higher resilient functioning.
Cross-modal feature based attention facilitates spatial transfer of perceptual learning in motion-domain figure-ground segregation
Authors: Fromm Catherine A. , Huxlin Krystel R. , Diaz Gabriel J.
Published: May 2023

This study tested the role of a cross-modal feature based attention (FBA) cue on perceptual learning and spatial transfer. The trained task was figure-ground segregation in the motion domain. The experiment involved a pre-test, ten days of training, and a post-test. Twelve visually intact participants were immersed in a virtual environment and tasked with identifying the location and motion direction of a peripheral 10◦aperture of semi-coherently moving dots embedded at randomized locations within whole-field random dot motion. The aperture contained both randomly moving dots and signal dots which had global leftward or rightward motion. To manipulate motion coherence, a 3-up-1-down staircase adjusted the direction range of the signal dots in response to segregation judgments. The dot stimulus was preceded by a 1s white-noise spatialized auditory cue emitted from the fixation point (neutral group), or from an emitter moving in the direction of signal dots at 80◦/s in a horizontal arc centered on the fixation point (FBA cue group). Visual feedback indicated the selected and true aperture locations, and correctness of the motion direction judgment. Analysis measured MD discrimination within the aperture as well as segregation ability, both measured in terms of direction range threshold (DRT). At trained locations, MD DRT improved similarly in FBA and neutral groups, and learning was retained when the pre-cue was removed (ΔDRT from pretest to posttest: 61±10◦(SD) FBA, 74±10◦neutral), and transferred to untrained locations (41±10◦FBA, 45±10◦neutral). DRT for localization also improved in both groups when pre-cues were removed (49±10◦FBA, 44±10◦neutral), but only the FBA group showed full transfer of learning to untrained locations in the segregation task (32±10◦FBA, 23±10◦neutral). In summary, transfer occurred for both motion direction and segregation tasks, but the segregation transfer required the presence of the cross-modal FBA cue during training.
Up-regulation of cholesterol synthesis pathways and limited neurodegeneration in a knock-inSod1mutant mouse model of ALS
Authors: Dominov Janice A. , Madigan Laura A. , Whitt Joshua P. , Rademacher Katerina L. , Webster Kristin M. , Zhang Hesheng , Banno Haruhiko , Tang Siqi , Zhang Yifan , Wightman Nicholas , Shychuck Emma M. , Page John , Weiss Alexandra , Kelly Karen , Kucukural Alper , Brodsky Michael H. , Jaworski Alexander , Fallon Justin R. , Lipscombe Diane , Brown Robert H.
Published: May 2023

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disorder affecting brain and spinal cord motor neurons. Mutations in the copper/zinc superoxide dismutase gene (SOD1) are associated with ∼20% of inherited and 1-2% of sporadic ALS cases. Much has been learned from mice expressing transgenic copies of mutant SOD1, which typically involve high-level transgene expression, thereby differing from ALS patients expressing one mutant gene copy. To generate a model that more closely represents patient gene expression, we created a knock-in point mutation (G85R, a human ALS-causing mutation) in the endogenous mouseSod1gene, leading to mutant SOD1G85Rprotein expression. HeterozygousSod1G85Rmutant mice resemble wild type, whereas homozygous mutants have reduced body weight and lifespan, a mild neurodegenerative phenotype, and express very low mutant SOD1 protein levels with no detectable SOD1 activity. Homozygous mutants exhibit partial neuromuscular junction denervation at 3-4 months of age. Spinal cord motor neuron transcriptome analyses of homozygousSod1G85Rmice revealed up-regulation of cholesterol synthesis pathway genes compared to wild type. Transcriptome and phenotypic features of these mice are similar toSod1knock-out mice, suggesting theSod1G85Rphenotype is largely driven by loss of SOD1 function. By contrast, cholesterol synthesis genes are down-regulated in severely affected humanTgSOD1G93Atransgenic mice at 4 months. Our analyses implicate dysregulation of cholesterol or related lipid pathway genes in ALS pathogenesis. TheSod1G85Rknock-in mouse is a useful ALS model to examine the importance of SOD1 activity in control of cholesterol homeostasis and motor neuron survival.

SIGNIFICANCE STATEMENT

Amyotrophic lateral sclerosis is a devastating disease involving the progressive loss of motor neurons and motor function for which there is currently no cure. Understanding biological mechanisms leading to motor neuron death is critical for developing new treatments. Using a new knock-in mutant mouse model carrying aSod1mutation that causes ALS in patients, and in the mouse, causes a limited neurodegenerative phenotype similar toSod1loss-of-function, we show that cholesterol synthesis pathway genes are up-regulated in mutant motor neurons, whereas the same genes are down-regulated in transgenicSOD1mice with a severe phenotype. Our data implicate dysregulation of cholesterol or other related lipid genes in ALS pathogenesis and provide new insights that could contribute to strategies for disease intervention.
Distinct mechanisms for sebaceous gland self-renewal and regeneration provide durability in response to injury
Authors: Veniaminova Natalia A. , Jia Yunlong , Hartigan Adrien M. , Huyge Thomas J. , Tsai Shih-Ying , Grachtchouk Marina , Nakagawa Seitaro , Dlugosz Andrzej A. , Atwood Scott X. , Wong Sunny Y.
Published: May 2023

Sebaceous glands (SGs) release oils that protect our skin, but how these glands respond to injury has not been previously examined. Here, we report that SGs are largely self-renewed by dedicated stem cell pools during homeostasis. Using targeted single cell RNA-sequencing, we uncovered both direct and indirect paths by which these resident SG progenitors ordinarily differentiate into sebocytes, including transit through a PPARγ+Krt5+ transitional cell state. Upon skin injury, however, SG progenitors depart their niche, reepithelialize the wound, and are replaced by hair follicle-derived stem cells. Furthermore, following targeted genetic ablation of >99% of SGs from dorsal skin, these glands unexpectedly regenerate within weeks. This regenerative process is mediated by alternative stem cells originating from the hair follicle bulge, is dependent upon FGFR signaling, and can be accelerated by inducing hair growth. Altogether, our studies demonstrate that stem cell plasticity promotes SG durability following injury.
The infralimbic and prelimbic cortical areas bidirectionally regulate safety learning during normal and stress conditions
Authors: Felix-Ortiz Ada C. , Terrell Jaelyn M. , Gonzalez Carolina , Msengi Hope D. , Ramos Angelica R. , Boggan Miranda B. , Lopez-Pesina Savannah M. , Magalhães Gabrielle , Burgos-Robles Anthony
Published: May 2023

Safety learning is a critical function for behavioral adaptation, environmental fitness, and mental health. Animal models have implicated the prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) in safety learning. However, whether these regions differentially contribute to safety learning and how their contributions become affected by stress still remain poorly understood. In this study, we evaluated these issues using a novel semi-naturalistic mouse model for threat and safety learning. As mice navigated within a test arena, they learned that specific zones were associated with either noxious cold temperatures (“threat”) or pleasant warm temperatures (“safety”). Optogenetic-mediated inhibition revealed critical roles for the IL and PL regions for selectively controlling safety learning during these naturalistic conditions. This form of safety learning was also highly susceptible to stress pre-exposure, and while IL inhibition mimicked the deficits produced by stress, PL inhibition fully rescued safety learning in stress-exposed mice. Collectively, these findings indicate that IL and PL bidirectionally regulate safety learning during naturalistic situations, with the IL region promoting this function and the PL region suppressing it, especially after stress. A model of balanced IL and PL activity is proposed as a fundamental mechanism for controlling safety learning.

Visual Abstract
Impairments in hippocampal oscillations accompany the loss of LTP induced by GIRK activity blockade
Authors: Contreras Ana , Djebari Souhail , Temprano-Carazo Sara , Múnera Alejandro , Gruart Agnès , Delgado-Garcia José M. , Jiménez-Díaz Lydia , Navarro-López Juan D.
Published: May 2023

Learning and memory occurrence requires of hippocampal long-term synaptic plasticity and a precise neural activity orchestrated by brain network oscillations, both processes reciprocally influencing each other. As G-protein-gated inwardly rectifying potassium (GIRK) channels rule synaptic plasticity that supports hippocampal-dependent memory, here we assessed their unknown role in hippocampal oscillatory activity in relation to synaptic plasticity induction.

In alert male mice, pharmacological GIRK modulation did not alter neural oscillations before long-term potentiation (LTP) induction. However, after an LTP generating protocol, bothgain- andloss-ofbasal GIRK activity transformed LTP into long-term depression, but only specific suppression of constitutive GIRK activity caused a disruption of network synchronization (δ, α, γbands), even leading to long-lasting ripples and fast ripples pathological oscillations.

Together, our data showed that constitutive GIRK activity plays a key role in the tuning mechanism of hippocampal oscillatory activity during long-term synaptic plasticity processes that underlies hippocampal-dependent cognitive functions.
Structure-function analysis of the cyclic β-1,2-glucan synthase
Authors: Sedzicki Jaroslaw , Ni Dongchun , Lehmann Frank , Stahlberg Henning , Dehio Christoph
Published: May 2023

The synthesis of complex sugars is a key aspect of microbial biology. Cyclic β-1,2-glucan (CβG) is a circular polysaccharide critical for host interactions of many bacteria, including major pathogens of humans (Brucella) and plants (Agrobacterium). CβG is produced by the cyclic glucan synthase (Cgs), a massive multi-domain membrane protein. So far, its structure as well as the mechanisms underlining the synthesis have not been clarified. Here we use cryo-electron microscopy (cryo-EM) and functional approaches to study Cgs fromA. tumefaciens. We were able to determine the structure of this complex protein machinery and clarify key aspects of CβG synthesis. Our research opens new possibilities for combating pathogens that rely on polysaccharide virulence factors and can lead to new synthetic biology approaches for producing complex cyclic sugars.
Opposing roles for TGFβ- and BMP-signaling during nascent alveolar differentiation in the developing human lung
Authors: Frum Tristan , Hsu Peggy P. , Hein Renee F.C. , Conchola Ansley S. , Zhang Charles J. , Utter Olivia R. , Anand Abhinav , Zhang Yi , Clark Sydney G. , Glass Ian , Sexton Jonathan Z. , Spence Jason R.
Published: May 2023

Alveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in repair after injury. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development. Using lung explant and organoid models, we identified opposing effects of TGFβ- and BMP-signaling, where inhibition of TGFβ- and activation of BMP-signaling in the context of high WNT- and FGF-signaling efficiently differentiated early lung progenitors into AT2-like cellsin vitro. AT2-like cells differentiated in this manner exhibit surfactant processing and secretion capabilities, and long-term commitment to a mature AT2 phenotype when expanded in media optimized for primary AT2 culture. Comparing AT2-like cells differentiated with TGFβ-inhibition and BMP-activation to alternative differentiation approaches revealed improved specificity to the AT2 lineage and reduced off-target cell types. These findings reveal opposing roles for TGFβ- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell typein vitro.
Sex similarities and dopaminergic differences in interval timing
Authors: Stutt Hannah R. , Weber Matthew A. , Cole Rachael C. , Bova Alexandra S. , Ding Xin , McMurrin Madison S. , Narayanan Nandakumar S.
Published: May 2023

Rodent behavioral studies have largely focused on male animals, which has limited the generalizability and conclusions of neuroscience research. Working with humans and rodents, we studied sex effects during interval timing that requires participants to estimate an interval of several seconds by making motor responses. Interval timing requires attention to the passage of time and working memory for temporal rules. We found no differences between human females and males in interval timing response times (timing accuracy) or the coefficient of variance of response times (timing precision). Consistent with prior work, we also found no differences between female and male rodents in timing accuracy or precision. In female rodents, there was no difference in interval timing between estrus and diestrus cycle stages. Because dopamine powerfully affects interval timing, we also examined sex differences with drugs targeting dopaminergic receptors. In both female and male rodents, interval timing was delayed after administration of sulpiride (D2-receptor antagonist), quinpirole (D2-receptor agonist), and SCH-23390 (D1-receptor antagonist). By contrast, after administration of SKF-81297 (D1-receptor agonist), interval timing shifted earlier only in male rodents. These data illuminate sex similarities and differences in interval timing. Our results have relevance for rodent models of both cognitive function and brain disease by increasing represenation in behavioral neuroscience.
Predicting Parkinson’s disease progression using MRI-based white matter radiomic biomarker and machine learning: a reproducibility and replicability study
Authors: Arafe Mohanad , Bhagwat Nikhil , Chatelain Yohan , Dugré Mathieu , Sokołowski Andrzej , Wang Michelle , Xiao Yiming , Sharp Madeleine , Poline Jean-Baptiste , Glatard Tristan
Published: May 2023

Background

The availability of reliable biomarkers of Parkinson’s disease (PD) progression is critical to the understanding of the disease and development of treatment options. Magnetic Resonance Imaging (MRI) provides a promising source of PD biomarkers, however, neuroimaging results have been shown to be markedly sensitive to analytical conditions and population sampling, which motivates investigations of their robustness. This study is part of a project to investigate the replicability of 11 structural MRI measures of PD identified in a recent review.

Objective

This paper attempts to reproduce (similar data, similar analysis) and replicate (variations in data and analysis) the design of the machine learning (ML) model described in [1] to predict PD progression from T1-weighted MRIs.

Methods

We used the Parkinson’s Progression Markers Initiative dataset (PPMI,ppmi-info.org) used in [1] and we followed as closely as possible the original methods. We also investigated slight methodological variations in cohort selection, feature extraction, ML model design, and evaluation techniques.

Results

The Area under the ROC Curve (AUC) achieved by our model closely reproducing the original study remained lower than 0.5. Across all tested models, we obtained a peak AUC of 0.685, which is better than chance performance but remained lower than the AUC value of 0.795 reported in [1].

Conclusion

We managed to train a model that predicts disease progression with a performance better than chance on a cohort extracted from the PPMI dataset, using methods adapted from [1]. However, the performance of this model remains substantially lower than the one reported in [1]. Our difficulties to reproduce or replicate the original work are likely explained by the relatively low sample size in the original study. We provide recommendations on how to improve the reproducibility of MRI-based ML models of PD in the future.
Physiological acetic acid concentrations from ethanol metabolism stimulate accumbens shell neurons via NMDAR activation in a sex-dependent manner
Authors: Chapp Andrew D. , Nwakama Chinonso A. , Mermelstein Paul G. , Thomas Mark J.
Published: May 2023

Recent studies have implicated the ethanol metabolite, acetic acid, as neuroactive, perhaps even more so than ethanol itself. In this study, we investigated sex-specific metabolism of ethanol (1, 2, and 4g/kg) to acetic acidin vivoto guide electrophysiology experiments in the accumbens shell (NAcSh), a key node in the mammalian reward circuit. There was a sex-dependent difference in serum acetate production, quantified via ion chromatography only at the lowest dose of ethanol (males>females).Ex vivoelectrophysiology recordings of NAcSh neurons in brain slices demonstrated that physiological concentrations of acetic acid (2 mM and 4 mM) increased NAcSh neuronal excitability in both sexes.N-methyl-D-aspartate receptor (NMDAR) antagonists, AP5, and memantine robustly attenuated the acetic acid-induced increase in excitability. Acetic acid-induced NMDAR-dependent inward currents were greater in females compared to males. These findings suggest a novel NMDAR-dependent mechanism by which the ethanol metabolite, acetic acid, may influence neurophysiological effects in a key reward circuit in the brain.
Non-invasive neuromodulation of sub-regions of the human insula differentially affect pain processing and heart-rate variability
Authors: Legon Wynn , Strohman Andrew , In Alexander , Stebbins Katelyn , Payne Brighton
Published: May 2023

The insula is a portion of the cerebral cortex folded deep within the lateral sulcus covered by the overlying opercula of the inferior frontal lobe and superior portion of the temporal lobe. The insula has been parsed into sub-regions based upon cytoarchitectonics and structural and functional connectivity with multiple lines of evidence supporting specific roles for each of these sub-regions in pain processing and interoception. In the past, causal interrogation of the insula was only possible in patients with surgically implanted electrodes. Here, we leverage the high spatial resolution combined with the deep penetration depth of low-intensity focused ultrasound (LIFU) to non-surgically modulate either the anterior insula (AI) or posterior insula (PI) in humans for effect on subjective pain ratings, electroencephalographic (EEG) contact head evoked potentials (CHEPs) and time-frequency power as well as autonomic measures including heart-rate variability (HRV) and electrodermal response (EDR). N = 23 healthy volunteers received brief noxious heat pain stimuli to the dorsum of their right hand during continuous heart-rate, EDR and EEG recording. LIFU was delivered to either the AI (anterior short gyrus), PI (posterior longus gyrus) or under an inert sham condition time-locked to the heat stimulus. Results demonstrate that single-element 500 kHz LIFU is capable of individually targeting specific gyri of the insula. LIFU to both AI and PI similarly reduced perceived pain ratings but had differential effects on EEG activity. LIFU to PI affected earlier EEG amplitudes around 300 milliseconds whereas LIFU to AI affected EEG amplitudes around 500 milliseconds. In addition, only LIFU to the AI affected HRV as indexed by an increase in standard deviation of N-N intervals (SDNN) and mean HRV low frequency power. There was no effect of LIFU to either AI or PI on EDR or blood pressure. Taken together, LIFU looks to be an effective method to individually target sub-regions of the insula in humans for site-specific effects on brain biomarkers of pain processing and autonomic reactivity that translates to reduced perceived pain to a transient heat stimulus. These data have implications for the treatment of chronic pain and several neuropsychological diseases like anxiety, depression and addiction that all demonstrate abnormal activity in the insula concomitant with dysregulated autonomic function.
Inhibition of the serine/threonine kinase BUB1 reverses taxane resistance in prostate cancer
Authors: Maria Julia Martinez , Rolando DZ Lyles , Nahuel Peinetti , Alex Michael Grunfeld , Kerry L Burnstein
Published: May 2023

Background:Men with incurable castration resistant prostate cancer (CRPC) are typically treated with taxanes; however, drug resistance rapidly develops. Thus, overcoming taxane resistant PC is a major clinical need. We previously identified a seven gene network in aggressive CRPC, which includes the mitotic serine threonine kinaseBUB1, a major regulator of the spindle assembly checkpoint (SAC). Alterations in mitotic kinases (and SAC malfunction) are associated with advanced PC and taxane resistance development and thereby represent potential vulnerabilities.

Methods:We evaluated BUB1 expression in publicly available data sets and in existing and newly generated taxane resistant PC cells. The effects of BUB1 depletion on the growth of a panel of PC and non-tumorigenic prostate epithelial cells was determined. We examined the capacity of pharmacologic inhibition of BUB1 kinase to reverse taxane-resistant PC growth. We evaluated the role of the prevalent androgen receptor variant AR-V7, in regulating BUB1 expression and taxane resistance.

Results:BUB1 mRNA was over-expressed in PC, metastatic castration resistant prostate cancer (mCRPC) and in tumors of patients treated with taxane-based chemotherapeutics compared to benign prostate tissue. Furthermore, BUB1 levels were elevated in taxane resistant PC cell lines compared to their sensitive counterparts. BUB1 depletion decreased growth of CRPC cells through delayed mitosis but did not affect proliferation of androgen dependent (ADPC) or non-tumorigenic prostate epithelial cells. Furthermore, BUB1 inhibition with the specific kinase inhibitor, BAY1816032, re-sensitized taxane resistant CRPC cells to the clinically used drugs, docetaxel and cabazitaxel. Consistent with AR-V7 regulation of BUB1, we also found that AR-V7 was elevated in taxane resistant CRPC cells. Moreover, ectopic expression of AR-V7 in CRPC cells that lack this protein resulted in increased BUB1 and conferred docetaxel resistance. BUB1 pharmacologic inhibition in combination with taxanes sensitized AR-V7 expressing CRPC cells to docetaxel treatment.

Conclusion:These data support BUB1 as an exploitable and therapeutically tractable vulnerability in taxane resistant CRPC including in AR variant driven CRPC.
Refinement of Multiconformer Ensemble Models from Multi-temperature X-ray Diffraction Data
Authors: Du Siyuan , Wankowicz Stephanie A. , Yabukarski Filip , Doukov Tzanko , Herschlag Daniel , Fraser James S.
Published: May 2023

Conformational ensembles underlie all protein functions. Thus, acquiring atomic-level ensemble models that accurately represent conformational heterogeneity is vital to deepen our understanding of how proteins work. Modeling ensemble information from X-ray diffraction data has been challenging, as traditional cryo-crystallography restricts conformational variability while minimizing radiation damage. Recent advances have enabled the collection of high quality diffraction data at ambient temperatures, revealing innate conformational heterogeneity and temperature-driven changes. Here, we used diffraction datasets for Proteinase K collected at temperatures ranging from 313 to 363K to provide a tutorial for the refinement of multiconformer ensemble models. Integrating automated sampling and refinement tools with manual adjustments, we obtained multiconformer models that describe alternative backbone and sidechain conformations, their relative occupancies, and interconnections between conformers. Our models revealed extensive and diverse conformational changes across temperature, including increased bound peptide ligand occupancies, different Ca2+binding site configurations and altered rotameric distributions. These insights emphasize the value and need for multiconformer model refinement to extract ensemble information from diffraction data and to understand ensemble-function relationships.
Mitotic spindle positioning protein (MISP) is an actin bundler that senses ADP-actin and binds near the pointed ends of filaments
Authors: Morales E. Angelo , Tyska Matthew J.
Published: May 2023

Actin bundling proteins crosslink filaments into polarized structures that shape and support membrane protrusions including filopodia, microvilli, and stereocilia. In the case of epithelial microvilli, mitotic spindle positioning protein (MISP) is an actin bundler that localizes specifically to the basal rootlets, where the pointed ends of core bundle filaments converge. Previous studies established that MISP is prevented from binding more distal segments of the core bundle by competition with other actin binding proteins. Yet whether MISP holds a preference for binding directly to rootlet actin remains an open question. Usingin vitroTIRF microscopy assays, we found that MISP exhibits a clear binding preference for filaments enriched in ADP-actin monomers. Consistent with this, assays with actively growing actin filaments revealed that MISP binds at or near their pointed ends. Moreover, although substrate attached MISP assembles filament bundles in parallel and antiparallel configurations, in solution MISP assembles parallel bundles consisting of multiple filaments exhibiting uniform polarity. These discoveries highlight nucleotide state sensing as a mechanism for sorting actin bundlers along filaments and driving their accumulation near filament ends. Such localized binding might drive parallel bundle formation and/or locally modulate bundle mechanical properties in microvilli and related protrusions.
Direct androgen receptor regulation of sexually dimorphic gene expression in the mammalian kidney
Authors: Xiong Lingyun , Liu Jing , Han Seung Yub , Koppitch Kari , Guo Jin-Jin , Rommelfanger Megan , Gao Fan , Hallgrimsdottir Ingileif B. , Pachter Lior , Kim Junhyong , MacLean Adam L. , McMahon Andrew P.
Published: May 2023

Mammalian organs exhibit distinct physiology, disease susceptibility and injury responses between the sexes. In the mouse kidney, sexually dimorphic gene activity maps predominantly to proximal tubule (PT) segments. Bulk RNA-seq data demonstrated sex differences were established from 4 and 8 weeks after birth under gonadal control. Hormone injection studies and genetic removal of androgen and estrogen receptors demonstrated androgen receptor (AR) mediated regulation of gene activity in PT cells as the regulatory mechanism. Interestingly, caloric restriction feminizes the male kidney. Single-nuclear multiomic analysis identified putative cis-regulatory regions and cooperating factors mediating PT responses to AR activity in the mouse kidney. In the human kidney, a limited set of genes showed conserved sex-linked regulation while analysis of the mouse liver underscored organ-specific differences in the regulation of sexually dimorphic gene expression. These findings raise interesting questions on the evolution, physiological significance, and disease and metabolic linkage, of sexually dimorphic gene activity.
Review of learning materials of an ecology course at Universitas Terbuka
Authors: Hewindati Yuni Tri , Kurniati Handayani Sri , Zuhairi Aminudin , Gerungan Raflen Aril
Published: May 2023

Purpose

This article presented the results of studies that examined the appropriateness of the content, readability of printed learning materials and the effectiveness of external resources in ecology course offered at Universitas Terbuka. To integrate external resources, links to their websites were provided in the printed materials.

Design/methodology/approach

An in-depth interview with a content expert was employed to review the course content, while digital and printed learning materials were reviewed for readability and to determine the usefulness of the external resources. A total of 47 students completed surveys and a focus group discussion that included in-depth interviews were conducted with 21 selected students.

Findings

The results revealed that the content of ecology course was conceptually valid. However, two key aspects needed to be emphasized, including the application of ecology phenomena for further development of the science and its applications in real-life situations. Regarding readability, students stated that the course materials were easily comprehended. In terms of the benefit, 79% of the students found the external resources interesting and helpful in understanding the learning materials.

Practical implications

Printed learning materials were crucial for students, specifically those residing in remote areas. Therefore, the institution should ensure that the materials were high-quality, easy to comprehend and enriched with up-to-date content/materials through scannable links to external resources.

Originality/value

The value added to the findings of this study was that the provision of links to external resources within printed learning materials improves students' understanding of the course content.
Viewing humanitarian project closure through the lens of an ethics of the temporary
Authors: Eckenwiler Lisa , Hunt Matthew R. , Crismo Jan Joy Louise G. , Conde Elyse , Hyppolite Shelley-Rose , Luneta Mayfourth , Munoz-Beaulieu Isabel , Mohammed Saeed Handreen , Schwartz Lisa
Published: May 2023

Purpose

In this paper, the authors propose a new lens to examine international humanitarian organizations' responsibilities in the context of project closure, what authors call “an ethics of the temporary”. The authors offer this as an orienting ethical ideal to facilitate the moral imagination of humanitarian planners, practitioners and stakeholders.

Design/methodology/approach

The authors drew on recent philosophical work on responsibilities for global justice to analyze an ethical concern inherent to humanitarian practice, the proper scope of responsibility in the context of closure of humanitarian projects.

Findings

The ethics of the temporary includes four elements: situating humanitarian action temporally with attention to the past and how it shapes a current crisis and crisis response, focusing attention on anticipating and seeking to mitigate potential harm, promoting sustainability and greater equity going forward and emphasizing inclusive, collaborative approaches. The authors propose a set of questions that can foster discussion and reflection about the scope of humanitarian responsibilities at project closure.

Practical implications

Although the authors' work is primarily conceptual, it has many practical implications for humanitarian policy and practice. It can support critical reflection and offers a process for considering the scope of responsibility at project closure and decisions around how to close a given intervention in a manner that avoids causing harm and advances equity.

Originality/value

Very little work has been done on ethical closure of humanitarian projects. Most literature offers critiques. This essay contributes a new approach to closure, the ethical ideal and practice of an ethics of the temporary.
Research on forestry labor input measurement and forestry industry development in China
Authors: Zhang Bei , Jiang Xuemei
Published: May 2023

Purpose

At present, China’s forestry development is mainly driven by the traditional production factors such as forestry labor force, land resources and capital and thus the top priority of forestry development is to optimize forestry production factors. Scientific and effective forestry labor input has a significant role in promoting the development of forestry industry. Given that the actual input to forestry labor is not clear, the accuracy of the forestry industry development may be slightly affected. Based on the monitoring project of collective forest tenure reform (RCFT), this paper uses the survey data of 3,500 rural households in seven provinces of China from 2010 to 2014 and 2016 to 2017 to measure the actual labor force in China, and empirically analyzes and studies the factors influencing the development of forestry industry based on the provincial data of forestry in China, and further discusses the heterogeneous impact of forestry production factors on the development of forestry industry.

Design/methodology/approach

In this paper, the generalized least squares estimation model is used to calculate the actual number of forestry labor in China, and then the Cobb–Douglas production function is selected to explore the influencing factors of forestry industry development.

Findings

The results show that the actual number of forestry labor force in China continues to decline and the degree of reduction varies from different regions. The forestry labor is a major factor that promotes the development of the forestry industry, but this promotion is affected by the low matching degree between the forestry production factors and thus further inhibits the development of the forestry industry. Due to the time lag of the reform, the implementation of RCFT first weakens and then promotes the development of forestry production. Further on, the forestry labor input is heterogeneous in land resource endowment, forestry investment source and the proportion of management personnel.

Originality/value

Therefore, researches show that the feasible way to promote the development of forestry industry is to expand the scale of forestry labor force, optimize the mutual allocation of forestry production factors, enhance the input of human capital in forestry and deepen the RCFT.