bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Poor Sleep With Depressive and Anxiety Symptoms by HIV Disease Status: Women's Interagency HIV Study
Authors: Daubert Elizabeth , French Audrey L. , Burgess Helen J. , Sharma Anjali , Gustafson Deborah , Cribbs Sushma K. , Weiss Deborah Jones , Ramirez Catalina , Konkle-Parker Deborah , Kassaye Seble , Weber Kathleen M.
Published: November 2021

Background:

Sleep disturbances are prevalent in women living with HIV (WLWH) and can affect mental health and overall quality of life. We examined the prevalence and predictors of poor sleep quality in a US cohort of WLWH and HIV-uninfected controls and the relationship between sleep quality and mental health symptom burden stratified by HIV disease status (viremic WLWH, aviremic WLWH, and HIV-uninfected women).

Methods:

Sleep quality was assessed using the Pittsburgh Sleep Quality Index in 1583 (400 viremic WLWH, 723 aviremic WLWH, and 460 HIV-uninfected women) Women's Interagency HIV Study participants. Depressive and anxiety symptoms were concurrently assessed using the Center for Epidemiological Studies-Depression (CES-D) scale and General Anxiety Disorder (GAD-7) scale. Associations between poor sleep quality (global Pittsburgh Sleep Quality Index >5) and both high depressive (CES-D ≥16) and anxiety (GAD-7 ≥10) symptoms were each assessed by HIV disease status using multivariable logistic regression models.

Results:

Prevalence of poor sleep quality in the overall sample was 52%, differed by HIV disease status (P = 0.045), and was significantly associated with high depressive and anxiety symptoms in (1) viremic WLWH, (2) aviremic WLWH, and (3) HIV-uninfected women [CES-D: (1) adjusted odds ratio (aOR) = 7.50, 95% confidence interval (CI): 4.10 to 13.7; (2) aOR = 4.54, 95% CI: 3.07 to 6.73; and (3) aOR = 6.03, 95% CI: 3.50 to 10.4; GAD-7: (1) aOR = 5.20; 95% CI: 2.60 to 10.4, (2) aOR = 6.03; 95% CI: 3.67 to 9.91, and (3) aOR = 6.24; 95% CI: 3.11 to 12.6].

Conclusions:

Poor sleep quality is highly prevalent, as is mental health symptom burden, among WLWH and HIV-uninfected controls. Future longitudinal studies are necessary to clarify the directionality of the relationship.
Administration of Intravenous Dexmedetomidine and Acetaminophen for Improved Postoperative Pain Management in Primary Palatoplasty
Authors: Ichiuji Brynne , Mantilla-Rivas Esperanza , Rana Md Sohel , Mamidi Ishwarya , Manrique Monica , Stein Jason , Aivaz Marudeen , McGrath Jennifer , Rogers Gary F. , Oh Albert K.
Published: November 2021

Objective:

Suboptimal pain management after primary palatoplasty (PP) may lead to complications such as hypoxemia, and increased hospital length of stay. Opioids are the first option for postoperative acute pain control after PP; however, adverse effects include excessive sedation, respiratory depression, and death, among others. Thus, optimizing postoperative pain control using opioid-sparing techniques is critically important. This paper aims to analyze efficacy and safety of combined intravenous (IV), dexmedetomidine, and IV acetaminophen during PP.

Methods:

Review of a cohort of patients who underwent PP from April 2009 to July 2018 at a large free-standing children's hospital was performed, comparing patients who received combined IV dexmedetomidine and acetaminophen with those who did not receive either of the 2 medications. Efficacy was measured through opioid and nonopioid analgesic dose and timing, pain scores, duration to oral intake, and length of stay. Safety was measured by 30-day complication rates including readmission for bleeding and need for supplementary oxygen.

Results:

Total postoperative acetaminophen (P = 0.01) and recovery room fentanyl (P < 0.001) requirements were significantly lower in the study group compared with the control group. Length of stay, oral intake duration, pain scores, total postoperative opioid requirements, and complications rates trended favorably in the study group, though differences did not reach statistical significance.

Conclusions:

Intraoperative IV dexmedetomidine and acetaminophen during PP provides safe and effective perioperative pain control, resulting in statistically significant decreased need for postoperative acetaminophen and fentanyl. Larger studies are necessary to determine if other trends identified in this study may be significant.
Synthetic Biology Tool Development Advances Predictable Gene Expression in the Metabolically Versatile Soil Bacterium Rhodopseudomonas palustris
Authors: Immethun Cheryl , Kathol Mark , Changa Taity , Saha Rajib
Published: November 2021

Harnessing the unique biochemical capabilities of non-model microorganisms would expand the array of biomanufacturing substrates, process conditions, and products. There are non-model microorganisms that fix nitrogen and carbon dioxide, derive energy from light, catabolize methane and lignin-derived aromatics, are tolerant to physiochemical stresses and harsh environmental conditions, store lipids in large quantities, and produce hydrogen. Model microorganisms often only break down simple sugars and require low stress conditions, but they have been engineered for the sustainable manufacture of numerous products, such as fragrances, pharmaceuticals, cosmetics, surfactants, and specialty chemicals, often by using tools from synthetic biology. Transferring complex pathways with all of the needed cofactors, energy sources, and cellular conditions from a non-model microorganism to a common chassis has proven to be exceedingly difficult. Utilization of unique biochemical capabilities could also be achieved by engineering the host; although, synthetic biology tools developed for model microbes often do not perform as designed in other microorganisms. The metabolically versatile Rhodopseudomonas palustris CGA009, a purple non-sulfur bacterium, catabolizes aromatic compounds derived from lignin in both aerobic and anaerobic conditions and can use light, inorganic, and organic compounds for its source of energy. R. palustris utilizes three nitrogenase isozymes to fulfill its nitrogen requirements while also generating hydrogen. Furthermore, the bacterium produces two forms of RuBisCo in response to carbon dioxide/bicarbonate availability. While this potential chassis harbors many beneficial traits, stable heterologous gene expression has been problematic due to its intrinsic resistance to many antibiotics and the lack of synthetic biology parts investigated in this microbe. To address these problems, we have characterized gene expression and plasmid maintenance for different selection markers, started a synthetic biology toolbox specifically for the photosynthetic R. palustris, including origins of replication, fluorescent reporters, terminators, and 5’ untranslated regions, and employed the microbe’s endogenous plasmid for exogenous protein production. This work provides essential synthetic biology tools for engineering R. palustris’ many unique biochemical processes and has helped define the principles for expressing heterologous genes in this promising microbe through a methodology that could be applied to other non-model microorganisms.
Prioritising Autoimmunity Risk Variants for Functional Analyses by Fine-Mapping Mutations Under Natural Selection
Authors: Pankratov Vasili , Yunusbaeva Milyausha , Ryakhovsky Sergei , Zarodniuk Maksym ,   Estonian Biobank Research Team, Yunusbayev Bayazit
Published: November 2021

Pathogens imposed selective pressure on humans and shaped genetic variation in immunity genes. This can also be true for a fraction of causal variants implicated in chronic inflammatory disorders. Hence, locating adaptive mutations among candidate variants for these disorders can be a promising way to prioritize and decipher their functional response to microbial stimuli and contribution to pathogenesis. This idea has been discussed for decades, but challenges in locating adaptive SNPs hindered its application in practice. Our study addresses this issue and shows that a fraction of candidate variants for inflammatory conditions evolved under moderate and weak selection regimes (sweeps), and such variants are mappable. Using a novel powerful local-tree-based methodology, we show that 204 out of 593 risk loci for 21 autoimmune disorders contain at least one candidate SNP with strong evidence of selection. More importantly, in 28% of cases, these candidates for causal variants colocalize with SNPs under natural selection that we fine-mapped in this study. Causal SNPs under selection represent promising targets for functional experiments. Such experiments will help decipher molecular events triggered by infectious agents, a likely early event in autoimmunity. Finally, we show that a large fraction (60%) of candidate variants are either hitchhikers or linked with the selected mutation. Our findings, thus, support both hitchhiking and natural selection models, with the latter having important practical implications in medicine.
Surprise: a unified theory and experimental predictions
Authors: Modirshanechi Alireza , Brea Johanni , Gerstner Wulfram
Published: November 2021

Surprising events trigger measurable brain activity and influence human behavior by affecting learning, memory, and decision-making. Currently there is, however, no consensus on the definition of surprise. Here we identify 16 mathematical definitions of surprise in a unifying framework, show how these definitions relate to each other, and prove under what conditions they are indistinguishable. We classify these surprise measures into four main categories: (i) change-point detection surprise, (ii) information gain surprise, (iii) prediction surprise, and (iv) confidence-correction surprise. We design experimental paradigms where different categories make different predictions: we show that surprise-modulation of the speed of learning leads to sensible adaptive behavior only for change-point detection surprise whereas surprise-seeking leads to sensible exploration strategies only for information gain surprise. However, since neither change-point detection surprise nor information gain surprise perfectly reflect the definition of ‘surprise’ in natural language, a combination of prediction surprise and confidence-correction surprise is needed to capture intuitive aspects of surprise perception. We formalize this combination in a new definition of surprise with testable experimental predictions. We conclude that there cannot be a single surprise measure with all functions and properties previously attributed to surprise. Consequently, we postulate that multiple neural mechanisms exist to detect and signal different aspects of surprise.

Author note

AM is grateful to Vasiliki Liakoni, Martin Barry, and Valentin Schmutz for many useful discussions in the course of the last few years, and to Andrew Barto for insightful discussions through and after EPFL Neuro Symposium 2021 on “Surprise, Curiosity and Reward: from Neuroscience to AI”. We thank K. Robbins and collaborators for their publicly available experimental data (Robbins et al., 2018). All code needed to reproduce the results reported here will be made publicly available after publication acceptance. This research was supported by Swiss National Science Foundation (no. 200020_184615). Correspondence concerning this article should be addressed to Alireza Modirshanechi, School of Computer and Communication Sciences and School of Life Sciences, EPFL, Lausanne, Switzerland. E-mail: alireza.modirshanechi@epfl.ch.
Base-resolution prediction of transcription factor binding signals by a deep learning framework
Authors: Zhang Qinhu , He Ying , Wang Siguo , Chen Zhanheng , Guo Zhenhao , Cui Zhen , Huang De-Shuang
Published: November 2021

Transcription factors (TFs) play an important role in regulating gene expression, thus the identification of the sites bound by them has become a fundamental step for molecular and cellular biology. In this paper, we developed a deep learning framework leveraging existing fully convolutional neural networks (FCN) to predict TF-DNA binding signals at the base-resolution level, called FCNsignal. The proposed FCNsignal can simultaneously achieve the following tasks: (i) modeling the base-resolution signals of binding regions; (ii) discriminating binding or non-binding regions; (iii) locating TF-DNA binding regions; (iv) predicting binding motifs. The experimental results on 53 TF ChIP-seq datasets and 6 chromatin accessibility ATAC-seq datasets show that our proposed framework outperforms some existing state-of-the-art methods. In addition, we explored to use the trained FCNsignal to locate all potential TF-DNA binding regions on a whole chromosome and predict DNA sequences of arbitrary length, and the results show that our framework can find most of the known binding regions and accept sequences of arbitrary length. Furthermore, we demonstrated the potential ability of our framework in discovering causal disease-associated single-nucleotide polymorphisms (SNPs) through a series of experiments.

Author summary

Identification of transcription factor binding sites (TFBSs) is fundamental to study gene regulatory networks in biological systems, as TFs activate or suppress the transcription of genes by binding to specific TFBSs. With the development of high-throughput sequencing technologies and deep learning (DL), several DL-based approaches have been developed for systematically studying TFBSs, achieving impressive performance. Nevertheless, these methods either excessively focus on discriminating binding or non-binding sequences or individually accomplish multiple TFBSs-associated tasks. In this work, we provide an integrated framework, which utilizes the FCN architecture to predict TF-DNA binding signals at the base-resolution level, to simultaneously study multiple TFBSs-associated tasks. More importantly, we also demonstrate that our proposed framework has the ability to locate all potential TF-DNA binding regions from DNA sequences of arbitrary length. We hope that our framework can provide a new perspective on studying the mechanism of TF-DNA binding and its related tasks.
Distinct neurostructural signatures of anxiety-, fear-related and depressive disorders: a comparative voxel-based meta-analysis
Authors: Liu Xiqin , Klugah-Brown Benjamin , Zhang Ran , Zhang Jie , Becker Benjamin
Published: November 2021

Internalizing disorders encompass anxiety, fear and depressive disorders. While the DSM-5 nosology conceptualizes anxiety and fear-related disorders as an entity, dimensional psychopathology models suggest that generalized anxiety disorders (GAD) and major depression originate from an overarching “anxious-misery” factor whereas fear-related disorders originate from the “fear” factor. Given that a neurobiological evaluation is lacking, we conducted a comparative neuroimaging meta-analysis of gray matter volume alterations to determine common and disorder-specific brain structural signatures in these disorders. The PubMed, Web of Knowledge, and Scopus databases were searched for case-control voxel-based morphometric studies through December, 2020 in GAD, fear-related anxiety disorders (FAD, i.e., social anxiety disorders, SAD; specific phobias, SP; panic disorders, PD; and agoraphobia, AG) and major depressive disorder (MDD). Neurostructural abnormalities were assessed within each disorder group followed by quantitative comparison and conjunction analyses using Seed-based d-Mapping (SDM-PSI). GAD (9 studies, 226 patients) showed disorder-specific decreased volumes in left insula (z=-2.98, pFWE-corrected<0.05) and lateral/medial prefrontal cortex (z=-2.10, pFWE-corrected<0.05,) as well as increased right putamen volume (z=1.86, pFWE-corrected<0.05) relative to FAD (10 SAD, 11 PD, 2 SP studies, 918 patients). Both GAD and MDD (46 studies, 2,575 patients) exhibited decreased prefrontal volumes compared to controls and FAD. While FAD showed less robust alterations in lingual gyrus (p < 0.0025, uncorrected), this group presented intact frontal integrity. No shared structural abnormalities were found. Unique clinical features characterizing anxiety-, fear-related and depressive disorders are reflected by disorder-specific neuroanatomical abnormalities. Targeting the disorder-specific neurostructural signatures could improve therapeutic efficacy.
Violet light modulates the central nervous system to regulate memory and mood
Authors: Sasaki Nobunari , Gusain Pooja , Hayano Motoshi , Sugaya Tetsuro , Tonegawa Naoya , Hatanaka Yusuke , Tamura Risako , Okuyama Kei , Osada Hideto , Ban Norimitsu , Mitsukura Yasue , Lang Richard A. , Mimura Masaru , Tsubota Kazuo
Published: November 2021

Light stimuli from the external environment serves as a signal. Photoreceptors receive photons at the outer nuclear layer of the retina. Non-visual photoreceptors, such as opsin5 (also known as OPN5 or neuropsin), are expressed in the retinal ganglion cells (RGCs) and hypothalamus to regulate the circadian cycle and body temperature. Here, we show that violet light (VL) stimuli received by OPN5-positive RGCs are transmitted to the habenula brain region. VL improves memory in aged mice and simultaneously increases neural architecture-related genes such as oligodendrocyte-related genes in the hippocampus. In addition, VL improves depressive-like behaviors in the social defeat stress model in an OPN5 dependent manner. Following VL exposure, cFos activation is observed at the nucleus accumbens (NAc) and the paraventricular thalamic nucleus (PVT). Taken together, the results indicate that violet light modulates brain function such as memory and mood by transmitting the signal from RGCs to the habenula region in the brain.
Conjugation of palbociclib with MHI-148 has an increased cytotoxic effect for breast cancer cells and an altered mechanism of action
Authors: Leung Euphemia , Tomek Petr , Tercel Moana , Reynisson Jóhannes , Park Thomas , Cooper Elizabeth , Denny William , Choi Peter , Jose Jiney
Published: November 2021

The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative as well as estrogen receptor positive breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells suggesting the mechanism of action differed from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.
A life cycle alteration can correct molting defects in Caenorhabditis elegans
Authors: Binti Shaonil , Melinda Rosa V. , Joseph Braveen B. , Edeen Phil , Miller Sam D. , Fay David S.
Published: November 2021

Molting is a widespread feature in the development of many invertebrates, including nematodes and arthropods. In Caenorhabditis elegans, the highly conserved protein kinases NEKL-2/NEK8/9 and NEKL-3/NEK6/7 (NEKLs) promote molting through their involvement in the uptake and intracellular trafficking of epidermal cargos. We found that the relative requirements for NEKL-2 and NEKL-3 differed at different life-cycle stages and under different environmental conditions. Most notably, the transition from the second to the third larval stage (L2→L3 molt) required a higher level of NEKL function than during several other life stages or when animals had experienced starvation at the L1 stage. Specifically, larvae that entered the pre-dauer L2d stage could escape molting defects when transiting to the (non-dauer) L3 stage. Consistent with this, mutations that promote entry into L2d suppressed nekl-associated molting defects, whereas mutations that inhibit L2d entry reduced starvation-mediated suppression. We further showed that loss or reduction of NEKL functions led to defects in the transcription of cyclically expressed molting genes, many of which are under the control of systemic steroid hormone regulation. Moreover, the timing and severity of these transcriptional defects correlated closely with the strength of nekl alleles and with their stage of arrest. Interestingly, transit through L2d rescued nekl-associated expression defects in suppressed worms, providing an example of how life-cycle decisions can impact subsequent developmental events. Given that NEKLs are implicated in the uptake of sterols by the epidermis, we propose that loss of NEKLs leads to a physiological reduction in steroid-hormone signaling and consequent defects in the transcription of genes required for molting.
Fendrr synergizes with Wnt signalling to regulate fibrosis related genes during lung development via its RNA:dsDNA Triplex Element
Authors: Ali Tamer , Rogala Sandra , Krause Nina M , Bains Jasleen K , Melissari Maria-Theodora , Waehrisch Sandra , Herrmann Bernhard G , Schwalbe Harald , Grote Phillip
Published: November 2021

Long non-coding RNAs are a very versatile class of molecules that can have important roles in regulating a cells function, including regulating other genes on the transcriptional level. One of these mechanisms is that RNA can directly interact with DNA thereby recruiting additional components such as proteins to these sites via a RNA:dsDNA triplex formation. We genetically deleted the triplex forming sequence (FendrrBox) from the lncRNA Fendrr in mice and find that this FendrrBox is partially required for Fendrr function in vivo. We find that the loss of the triplex forming site in developing lungs causes a dysregulation of gene programs, associated with lung fibrosis. A set of these genes contain a triplex site directly at their promoter and are expressed in fibroblasts. We confirm the formation of RNA:dsDNA formation with target promoters. We find that Fendrr with the Wnt signalling pathway regulates these genes, implicating that Fendrr synergizes with Wnt signalling in lung fibrosis.
An interolog-based barley interactome as an integration framework for immune signaling
Authors: Velásquez-Zapata Valeria , Elmore J. Mitch , Fuerst Greg , Wise Roger P.
Published: November 2021

The barley MLA nucleotide-binding, leucine-rich-repeat (NLR) receptor and its orthologs confer recognition specificity to many cereal diseases, including powdery mildew, stem and stripe rust, Victoria blight, and rice blast. We used interolog inference to construct a barley protein interactome (HvInt) comprising 66133 edges and 7181 nodes, as a foundation to explore signaling networks associated with MLA. HvInt was compared to the experimentally validated Arabidopsis interactome of 11253 proteins and 73960 interactions, verifying that the two networks share scale-free properties, including a power-law distribution and small-world network. Then, by successive layering of defense-specific ‘omics’ datasets, HvInt was customized to model cellular response to powdery mildew infection. Integration of HvInt with expression quantitative trait loci (eQTL) enabled us to infer disease modules and responses associated with fungal penetration and haustorial development. Next, using HvInt and an infection-time-course transcriptome, we assembled resistant (R) and susceptible (S) subnetworks. The resulting differentially co-expressed (R-S) interactome is essential to barley immunity, facilitates the flow of signaling pathways and is linked toMlathrough trans eQTL associations. Lastly, next-generation, yeast-two-hybrid screens identified fifteen novel MLA interactors, which were incorporated into HvInt, to predict receptor localization, and signaling response. These results link genomic, transcriptomic, and physical interactions during MLA-specified immunity.

AUTHOR SUMMARY

Powdery mildew fungi infect more than 9,500 agronomic and horticultural plant species. In order to prevent economic loss due to diseases caused by pathogens, plant breeders incorporate resistance genes into varieties that are grown for food, feed, fuel and fiber. One of these resistance genes encodes the barley MLA immune receptor, an ancestral cereal protein that confers recognition to powdery mildew, stem and stripe rust, rice blast and Victoria blight. However, in order to function properly, these immune receptors must interact with additional proteins and protein complexes during the different stages of fungal infection and plant defense. We used a combination of computational- and laboratory-based methods to predict over 66,000 possible protein-protein interactions in barley. This network of proteins was then integrated with various defense-specific datasets to assemble the molecular building blocks associated with resistance to the powdery mildew pathogen, in addition to those proteins that interact with the MLA immune receptor. Our application of genome-scale, protein-protein interaction data provides a foundation to decipher the complex molecular components that control immune responses in crops.
Laser-driven Wireless Deep Brain Stimulation using Temporal Interference and Organic Electrolytic Photocapacitors
Authors: Missey Florian , Donahue Mary J. , Weber Pascal , Ngom Ibrahima , Acerbo Emma , Botzanowski Boris , Migliaccio Ludovico , Jirsa Viktor , Głowacki Eric Daniel , Williamson Adam
Published: November 2021

Deep brain stimulation (DBS) is a technique commonly used both in clinical and fundamental neurosciences. Classically, brain stimulation requires an implanted and wired electrode system to deliver stimulation directly to the target area. Although techniques such as temporal interference (TI) can provide stimulation at depth without involving any implanted electrodes, these methods still rely on a wired apparatus which limits free movement. Herein we report organic photocapacitors as untethered light-driven electrodes which convert deep-red light into electric current. Pairs of these ultrathin devices can be driven using lasers at two different frequencies to deliver stimulation at depth via temporally interfering fields. We validate this concept of laser TI stimulation using numerical modeling, ex vivo tests with phantom samples, and finally in vivo tests. Wireless organic photocapacitors are placed on the cortex and elicit stimulation in the hippocampus, while not delivering off-target stimulation in the cortex. This laser-driven wireless TI evoked a neuronal response at depth that is comparable to control experiments induced with deep brain stimulation protocols using implanted electrodes. Our work shows that a combination of these two techniques – temporal interference and organic electrolytic photocapacitors – provides a reliable way to target brain structures requiring neither deeply implanted electrodes nor tethered stimulator devices. The laser TI protocol demonstrated here address two of the most important drawbacks in the field of deep brain stimulation and thus holds potential to solve many issues in freely-moving animal experiments or for clinical chronic therapy application.
A deeper cascade of mechanisms involved in cold resistance inHevea brasiliensis
Authors: Silva Carla Cristina Da , Bajay Stephanie Karenina , Aono Alexandre Hild , Francisco Felipe Roberto , Junior Ramir Bavaresco , Mantello Camila Campos , de Souza Anete Pereira , Vicentini dos Santos Renato
Published: November 2021

Background

Hevea brasiliensisis the main global source of natural rubber. Due to fungal disease pressure in hot, humid regions, rubber plantations have been moved to drier “escape areas” with lower temperatures. In order to analyze gene expression regulation during cold exposure, we studied young GT1 and RRIM 600 rubber tree clones with different cold tolerance strategies.

Results

Alongside traditional differential expression approaches, an RNA-seq gene coexpression network (GCN) was developed with 27,220 genes grouped into 205 gene clusters. The GCN related most rubber tree cold stress molecular responses to 31 clusters across three GCN modules: a downregulated group with 16 clusters and two upregulated groups with twelve and three clusters. The hub genes of the cold-responsive modules were also identified and analyzed. We observed that the general response to short-term cold exposure involves complex regulation of the jasmonic acid (JA) stress response and programmed cell death (PCD), upregulation of ethylene-responsive genes, and relaxation of florigen gene inhibition. As a result, we identified single DEGs and gained insights into the mechanisms involved in the response to cold stress in young rubber trees.

Conclusions

Our findings may represent the species’ genetic stress responses developed during the course of evolution, since the examined varieties were genotypes selected during the early years of rubber tree domestication. Understanding the cold response mechanisms inH. brasiliensiscould improve breeding strategies for this crop, which has a narrow genetic base, is being impacted by climate change and is the only source for large-scale rubber production.
Different structures and pathologies of α-synuclein fibrils derived from preclinical and postmortem patients of Parkinson’s disease
Authors: Fan Yun , Sun Yunpeng , Yu Wenbo , Tao Youqi , Xia Wencheng , Liu Yiqi , Tang Yilin , Sun Yimin , Liu Fengtao , Cao Qin , Wu Jianjun , Liu Cong , Wang Jian , Li Dan
Published: November 2021

α-Synuclein (α-syn) fibrillar aggregates are the major component of Lewy bodies and Lewy neurites presenting as the pathology hallmark of Parkinson’s disease (PD). Studies have shown that α-syn is potential to form different conformational fibrils associated with different synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is to be explored. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of preclinical (pre-PD) and late-stage postmortem PD (post-PD) patients. Our results show that compared to the CSF of pre-PD, that of post-PD is markedly stronger in seeding in vitro α-syn aggregation, and the amplified fibrils are more potent in inducing endogenous α-syn aggregation in neurons. Cryo-electron microscopic structures further reveal that the difference between the pre-PD- and post-PD-derived fibrils lies on a minor polymorph which in the pre-PD fibrils is morphologically straight, while in the post-PD fibrils represents a single protofilament assembled by a distinctive conformation of α-syn. Our work demonstrates structural and pathological differences between pre-PD and post-PD α-syn aggregation and suggests potential alteration of α-syn fibrils during the progression of PD clinical phases.

Significance Statement

Increasing evidence support different conformational α-syn fibrils in patients with different α-synucleinopathies, but whether the conformation of α-syn fibrils changes in different phases of related diseases is unknown. Here, we show that α-syn fibrils amplified from the cerebrospinal fluid (CSF) of the late-stage postmortem PD (post-PD) patient are more potent in inducing endogenous α-syn aggregation in neurons than that amplified from the preclinical (pre-PD) patient. Cryo-EM structures further reveal that the post-PD fibrils contain a novel conformation that is distinct from either the pre-PD fibrils or those previously reported. Our work suggests conformational evolution of α-syn fibrils along with PD progression.
Cerebello-thalamic activity drives an abnormal motor network into dystonic tremor
Authors: Nieuwhof Freek , Toni Ivan , Dirkx Michiel F. , Gallea Cecile , Vidailhet Marie , Buijink Arthur W.G. , van Rootselaar Anne-Fleur , van de Warrenburg Bart P.C. , Helmich Rick C.
Published: November 2021

Dystonic tremor syndromes are highly burdensome and treatment is often inadequate. This is partly due to poor understanding of the underlying pathophysiology. Several lines of research suggest involvement of the cerebello-thalamo-cortical circuit and the basal ganglia in dystonic tremor syndromes, but their role is unclear. Here we aimed to investigate the contribution of the cerebello-thalamo-cortical circuit and the basal ganglia to the pathophysiology of dystonic tremor syndrome, by directly linking tremor fluctuations to cerebral activity during scanning. In 27 patients with dystonic tremor syndrome (dystonic tremor: n=23; tremor associated with dystonia: n=4), we used concurrent accelerometery and functional MRI during a posture holding task that evoked tremor, alternated with rest. Using multiple regression analyses, we separated tremor-related activity from brain activity related to (voluntary) posture holding. Using dynamic causal modelling, we tested for altered effective connectivity between tremor-related brain regions as a function of tremor amplitude fluctuations. Finally, we compared grey matter volume between patients (n=27) and matched controls (n=27).

We found tremor-related activity in sensorimotor regions of the bilateral cerebellum, contralateral ventral intermediate (VIM) and ventro-oralis posterior nuclei (VOp) of the thalamus, contralateral primary motor cortex (hand area), contralateral pallidum, and the bilateral frontal cortex (laterality with respect to the tremor). Grey matter volume was increased in patients compared to controls in the portion of contralateral thalamus also showing tremor-related activity, as well as in bilateral medial and left lateral primary motor cortex, where no tremor-related activity was present. Effective connectivity analyses showed that inter-regional coupling in the cerebello-thalamic pathway, as well as the thalamic self-connection, were strengthened as a function of increasing tremor power.

These findings indicate that the pathophysiology of dystonic tremor syndromes involves functional and structural changes in the cerebello-thalamo-cortical circuit and pallidum. Deficient input from the cerebellum towards the thalamo-cortical circuit, together with hypertrophy of the thalamus, may play a key role in the generation of dystonic tremor syndrome.
Spatialized Epidemiological Forecasting applied to Covid-19 Pandemic at Departmental Scale in France
Authors: Oliver Matthieu , Georges Didier , Prieur Clémentine
Published: November 2021

In this paper, we present a spatialized extension of a SIR model that accounts for undetected infections and recoveries as well as the load on hospital services. The spatialized compartmental model we introduce is governed by a set of partial differential equations (PDEs) defined on a spatial domain with complex boundary. We propose to solve the set of PDEs defining our model by using a meshless numerical method based on a finite difference scheme in which the spatial operators are approximated by using radial basis functions. Such an approach is reputed as flexible for solving problems on complex domains. Then we calibrate our model on the French department of Isère during the first period of lockdown, using daily reports of hospital occupancy in France. Our methodology allows to simulate the spread of Covid-19 pandemic at a departmental level, and for each compartment. However, the simulation cost prevents from online short-term forecast. Therefore, we propose to rely on reduced order modeling tools to compute short-term forecasts of infection number. The strategy consists in learning a time-dependent reduced order model with few compartments from a collection of evaluations of our spatialized detailed model, varying initial conditions and parameter values. A set of reduced bases is learnt in an offline phase while the projection on each reduced basis and the selection of the best projection is performed online, allowing short-term forecast of the global number of infected individuals in the department.
Comprehensive care programmes in chronic obstructive pulmonary disease: a systematic review and meta-analysis of randomized controlled trials and real-world studies
Authors: Yoo Daniel , Gong Mengqi , Meng Lei , Wong Cheuk Wai , Li Guangping , Sum Lam Michael Huen , Liu Tong , Tse Gary , Roever Leonardo ,   International Health Informatics Study (IHIS) Network
Published: November 2021

Background

Different comprehensive care programmes (CCPs) have been developed for patients with chronic obstructive pulmonary disorder (COPD), but data regarding their effectiveness have been controversial. PubMed and Embase were searched to 1st June 2017 for articles that investigated the effects of the different types of CCPs on hospitalization or mortality rates in COPD.

Results

A total of 67 studies including 3472633 patients (mean age: 76.1±12.7 years old; 41% male) were analyzed. CCPs reduced all-cause hospitalizations (hazard ratio [HR]: 0.70, 95% confidence interval [CI]: 0.63-0.79; P<0.001; I2:96%) and mortality (HR: 0.69, 95% CI: 0.573-0.83; P<0.001; I2:75%). Subgroup analyses for different CCP types were performed. Hospitalizations were reduced by pharmacist-led medication reviews (HR: 0.54; 95% CI: 0.37-0.78; P=0.001; I2:49%), structured care programmes (HR: 0.76; 95% CI: 0.66-0.87; P<0.0001; I2:88%) and self-management programmes (HR: 0.79; 95% CI: 0.64-0.99; P<0.05; I2:78%), but not continuity of care programmes (HR: 0.70; 95% CI: 0.36-1.36; P=0.29; I2:100%), early support discharge or home care packages (HR: 0.97; 95% CI: 0.91-1.04; P=0.37; I2:0%) or telemonitoring (HR: 0.61; 95% CI: 0.32-1.18; P=0.14; I2:94%). Mortality was reduced by early support discharge or home care packages (HR: 0.49; 95% CI: 0.30-0.80; P<0.01; I2:72%), structured care programmes (HR: 0.69; 95% CI: 0.53-0.90; P<0.01; I2:61%) and telemonitoring (HR: 0.52; 95% CI: 0.31-0.89; P<0.05; I2:0%), but not self-management programmes (HR: 0.79; 95% CI: 0.64-0.99; P<0.05; I2:78%).

Conclusions

Comprehensive care programmes reduce hospitalization and mortality in COPD patients.
REACT-1 round 15 interim report: High and rising prevalence of SARS-CoV-2 infection in England from end of September 2021 followed by a fall in late October 2021
Authors: Chadeau-Hyam Marc , Eales Oliver , Bodinier Barbara , Wang Haowei , Haw David , Whitaker Matthew , Walters Caroline E. , Atchison Christina , Diggle Peter J. , Page Andrew J. , Ashby Deborah , Barclay Wendy , Taylor Graham , Cooke Graham , Ward Helen , Darzi Ara , Donnelly Christl A. , Elliott Paul
Published: November 2021

Background

The third wave of COVID-19 in England coincided with the rapid spread of the Delta variant of SARS-CoV-2 from the end of May 2021. Case incidence data from the national testing programme (Pillar 2) in England may be affected by changes in testing behaviour and other biases. Community surveys may provide important contextual information to inform policy and the public health response.

Methods

We estimated patterns of community prevalence of SARS-CoV-2 infection in England using RT-PCR swab-positivity, demographic and other risk factor data from round 15 (interim) of the REal-time Assessment of Community Transmission-1 (REACT-1) study (round 15a, carried out from 19 to 29 October 2021). We compared these findings with those from round 14 (9 to 27 September 2021).

Results

During mid- to late-October 2021 (round 15a) weighted prevalence was 1.72% (1.61%, 1.84%) compared to 0.83% (0.76%, 0.89%) in September 2021 (round 14). The overall reproduction number (R) from round 14 to round 15a was 1.12 (1.11, 1.14) with increases in prevalence over this period (September to October) across age groups and regions except Yorkshire and The Humber. However, within round 15a (mid- to late-October) there was evidence of a fall in prevalence with R of 0.76 (0.65, 0.88). The highest weighted prevalence was observed among children aged 5 to 12 years at 5.85% (5.10%, 6.70%) and 13 to 17 years at 5.75% (5.02%, 6.57%). At regional level, there was an almost four-fold increase in weighted prevalence in South West from round 14 at 0.59% (0.43%,0.80%) to round 15a at 2.18% (1.84%, 2.58%), with highest smoothed prevalence at subregional level also found in South West in round 15a. Age, sex, key worker status, and presence of children in the home jointly contributed to the risk of swab-positivity. Among the 126 sequenced positive swabs obtained up until 23 October, all were Delta variant; 13 (10.3%) were identified as the AY.4.2 sub-lineage.

Discussion

We observed the highest overall prevalence of swab-positivity seen in the REACT-1 study in England to date in round 15a (October 2021), with a two-fold rise in swab-positivity from round 14 (September 2021). Despite evidence of a fall in prevalence from mid- to late-October 2021, prevalence remains high, particularly in school-aged children, with evidence also of higher prevalence in households with one or more children. Thus, vaccination of children aged 12 and over remains a high priority (with possible extension to children aged 5-12) to help reduce within-household transmission and disruptions to education, as well as among adults, to lessen the risk of serious disease among those infected.
An intrinsic temporal order of c-Jun N-terminal phosphorylation regulates its activity by orchestrating co-factor recruitment
Authors: Waudby Christopher A. , Alvarez-Teijeiro Saul , Suppinger Simon , Brown Paul R. , Behrens Axel , Christodoulou John , Mylona Anastasia
Published: November 2021

Protein phosphorylation is a major regulatory mechanism of cellular signalling. The c-Jun proto-oncoprotein is phosphorylated at four residues within its transactivation domain (TAD) by the JNK family kinases, but the functional significance of c-Jun multisite phosphorylation has remained elusive. Here we show that c-Jun phosphorylation by JNK exhibits a defined temporal kinetics, with serine63 and serine73 being phosphorylated more rapidly than threonine91 and threonine93. We identified the positioning of the phosphorylation sites relative to the kinase docking motif, and their primary sequence, as the main factors controlling phosphorylation kinetics. Functional analysis revealed three c-Jun phosphorylation states: unphosphorylated c-Jun recruits the Mbd3 repressor, serine63/73 doubly-phosphorylated c-Jun binds to the Tcf4 co-activator, whereas the fully phosphorylated form disfavours Tcf4 binding attenuating JNK signalling. Thus, c-Jun phosphorylation encodes multiple functional states that drive a complex signalling response from a single JNK input.
Asymmetry of cortical functional hierarchy in humans and macaques suggests phylogenetic conservation and adaptation
Authors: Wan Bin , Bayrak Şeyma , Xu Ting , Schaare H. Lina , Bethlehem Richard A.I. , Bernhardt Boris C. , Valk Sofie L.
Published: November 2021

The human cerebral cortex is symmetrically organized along large-scale axes but also presents inter-hemispheric differences in structure and function. The quantified contralateral homologous difference, i.e., asymmetry, is a key feature of the human brain left-right axis supporting functional processes, such as language. Here, we assessed whether the asymmetry of cortical functional organization is heritable and phylogenetically conserved between humans and macaques. Our findings indicate asymmetric organization along an axis describing a hierarchical functional trajectory from perceptual/action to abstract cognition. Whereas language network showed leftward asymmetric organization, frontoparietal network showed rightward asymmetric organization. These asymmetries were heritable and comparable between humans and macaques, suggesting (phylo)genetic conservation. However, both language and frontoparietal networks showed a qualitatively larger asymmetry in humans relative to macaques and variable heritability in humans. This may reflect an evolutionary adaptation allowing for experience-dependent specialization, linked to higher-order cognitive functions uniquely developed in humans.
PTBP1/HNRNP I controls intestinal epithelial cell regeneration by maintaining stem cell survival and stemness
Authors: Tung Wesley S. , Chembazhi Ullas Valiya , Yang Jing , Nguyen Ka Lam , Lalwani Aryan , Bangru Sushant , Yee Danielle , Chin Kristy , Kalsotra Auinash , Mei Wenyan
Published: November 2021

Properly controlled intestinal epithelial cell regeneration is not only vital for protection against insults from environmental hazards but also crucial for preventing intestinal cancer. Intestinal stem cells located in the crypt region provide the driving force for epithelial regeneration, and thus their survival and death must be precisely regulated. We show here that polypyrimidine tract binding protein 1 (PTBP1, also called heterogeneous nuclear ribonucleoprotein I, or HNRNP I), an RNA-binding protein that post-transcriptionally regulates gene expression, is critical for intestinal stem cell survival and stemness. Mechanistically, we show that PTBP1 inhibits the expression of PHLDA3, an AKT repressor, and thereby maintains AKT activity in the intestinal stem cell compartment to promote stem cell survival and proliferation. Furthermore, we show that PTBP1 inhibits the expression of PTBP2, a paralog of PTBP1 that is known to induce neuron differentiation, through repressing inclusion of alternative exon 10 to Ptbp2 transcript. Loss of PTBP1 results in a significant upregulation of PTBP2, which is accompanied by splicing changes in genes that are important for neuronal cell development. This finding suggests that PTBP1 prevents aberrant differentiation of intestinal stem cells into neuronal cells through inhibiting PTBP2. Our results thus reveal a novel mechanism whereby PTBP1 maintains intestinal stem cell survival and stemness through the control of gene function post-transcriptionally.
The plant-specific DDR factor SOG1 increases chromatin mobility in response to DNA damage
Authors: Meschichi Anis , Reeck Svenja , Sicard Adrien , Pontvianne Frédéric , Rosa Stefanie
Published: November 2021

Homologous recombination (HR) is a conservative DNA repair pathway in which intact homologous sequences are used as a template for repair. How the homology search happens in the crowded space of the cell nucleus is, however, still poorly understood. Here, we measured global chromosome and double-strand break (DSB) site mobility in Arabidopsis thaliana, using lacO/LacI lines and two GFP-tagged HR reporters. We observed an increase in global chromatin mobility upon the induction of DNA damage, specifically at the S/G2 phases of the cell cycle. DSB sites showed remarkably high mobility levels at the early HR stage, with a subsequent drastic decrease in mobility associated with the relocation of DSBs to the nucleus periphery. Importantly, the increase in mobility was lost in sog1-1 mutant, a central transcription factor of the DNA damage response in plants. Our results indicate that repair mechanisms actively regulate chromatin mobility upon DNA damage, implying an important role for this process during the early steps of the DNA damage response.
Anatomically-based skeleton kinetics and pose estimation in freely-moving rodents
Authors: Monsees Arne , Voit Kay-Michael , Wallace Damian J. , Sawinski Juergen , Leks Edyta , Scheffler Klaus , Macke Jakob H. , Kerr Jason N. D.
Published: November 2021

Forming a complete picture of the relationship between neural activity and body kinetics requires quantification of skeletal joint biomechanics during behavior. However, without detailed knowledge of the underlying skeletal motion, inferring joint kinetics from surface tracking approaches is difficult, especially for animals where the relationship between surface anatomy and skeleton changes during motion. Here we developed a videography-based method enabling detailed three-dimensional kinetic quantification of an anatomically defined skeleton in untethered freely-behaving animals. This skeleton-based model has been constrained by anatomical principles and joint motion limits and provided skeletal pose estimates for a range of rodent sizes, even when limbs were occluded. Model-inferred joint kinetics for both gait and gap-crossing behaviors were verified by direct measurement of limb placement, showing that complex decision-making behaviors can be accurately reconstructed at the level of skeletal kinetics using our anatomically constrained model.