bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sleep health education and a personalized smartphone application improve sleep and productivity and reduce healthcare utilization among employees: Results of a randomized clinical trial
Authors: Robbins Rebecca , Weaver Matthew D. , Quan Stuart F. , Sullivan Jason P. , Qadri Salim , Czeisler Charles A. , Barger Laura 
Published: October 2021

AbstractSleep deficiency and undiagnosed or untreated sleep disorders are pervasive among employed adults, yet often ignored in the context of workplace health promotion programs among employers. Smartphone applications (app) are a promising, scalable approach to improving sleep among employees. In this randomized clinical trial, we evaluate the dayzz app, a personalized sleep training program that promotes healthy sleep and sleep disorders awareness through personalized, comprehensive sleep improvement solutions. In a sample of daytime employees affiliated with a large healthcare organization, we evaluated the dayzz app in a parallel-group, randomized, waitlist control trial. Participants were randomly assigned to either use the dayzz app throughout the study or the waitlist control condition where they would receive the dayzz app at the end of the study period. We collected data on employee sleep (e.g., sleep duration, sleep health behavioral changes); workplace outcomes (e.g., employee presenteeism, absenteeism, and performance); and healthcare utilization (e.g., mental health, ambulatory visits, and emergency room visits), throughout the study. Results show that those assigned to the experimental condition exhibited an increase in healthy sleep behaviors; an increase in sleep duration; a trend toward a more regular sleep schedule; and a significant increase in overall sleep quality. Regarding workplace outcomes, results showed that those in the experimental condition also demonstrated a trend toward less absenteeism and significantly lower presenteeism; and those in the experimental condition reported lower healthcare utilization. Results from this randomized clinical trial demonstrate that a workplace sleep wellness program can be beneficial to both the employee and employer.
Functional and structural features of L2/3 pyramidal cells continuously covary with pial depth in mouse visual cortex
Authors: Weiler Simon , Nilo Drago Guggiana , Bonhoeffer Tobias , Hübener Mark , Rose Tobias , Scheuss Volker 
Published: October 2021

AbstractPyramidal cells of neocortical layer 2/3 (L2/3 PyrCs) integrate signals from numerous brain areas and project throughout the neocortex. Within L2/3, PyrCs show functional and structural specializations depending on their pial depth, indicating participation in different functional microcircuits. However, it is unknown whether these depth-dependent differences result from separable L2/3 PyrC subtypes or whether functional and structural features represent a continuum while correlating with pial depth. Here, we assessed the stimulus selectivity, electrophysiological properties, dendritic morphology, and excitatory and inhibitory synaptic connectivity across the depth of L2/3 in the binocular visual cortex (bV1) of female mice. We find that the structure of the apical but not the basal dendritic tree varies with pial depth, which is accompanied by differences in passive but not active electrophysiological properties. PyrCs in lower L2/3 receive increased excitatory and inhibitory input from L4, while upper L2/3 PyrCs receive a larger proportion of intralaminar input. Complementary in vivo calcium imaging revealed a systematic change in visual responsiveness, with deeper L2/3 PyrCs showing more robust responses than superficial PyrCs. Furthermore, deeper L2/3 PyrCs are more strongly driven by contralateral than ipsilateral eye stimulation. In contrast, orientation- and direction-selectivity of L2/3 PyrCs are not dependent on pial depth. Importantly, the transitions of the various properties are gradual, and cluster analysis does not support the classification of L2/3 PyrCs into discrete subtypes. These results show that L2/3 PyrCs’ multiple functional and structural properties systematically correlate with their depth within L2/3, forming a continuum rather than representing discrete subtypes.SIGNIFICANCE STATEMENTNeocortical pyramidal cells in layer 2/3 (L2/3 PyrCs) are crucial for cortical computation and display heterogenous properties. We investigated whether and how these properties vary across the depth of L2/3 and whether L2/3 PyrCs can be subdivided into distinct subtypes. This is important for a better understanding of the coding strategy and information integration processes within L2/3. We find that multiple properties such as morphology, physiology, connectivity, and functional in vivo responses of L2/3 PyrCs correlate with cortical depth in mouse visual cortex. These variations are continuous and do not support classification of L2/3 PyrCs into discrete subtypes. In contrast to L5 and L6, PyrCs in L2/3 therefore process information based on a continuous property space.
Effects of Glucagon-like Peptide-1 Receptor Agonists on Cardiovascular and Renal Outcomes: A Meta-Analysis and Meta-Regression Analysis
Authors: Yoshiji Satoshi , Minamino Hiroto , Tanaka Daisuke , Yamane Shunsuke , Harada Norio , Inagaki Nobuya 
Published: October 2021

AbstractAimsCardiovascular and renal effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been inconsistent in cardiovascular outcome trials, and factors associated with the efficacy of GLP-1RAs remain to be clarified. Here, we evaluate the cardiovascular and renal outcomes with GLP-1RAs and associations between these outcomes and HbA1c or weight reduction.Materials and MethodsWe searched PubMed/MEDLINE, EMBASE, and CENTRAL for randomized, placebo-controlled trials of GLP1-RAs reporting major adverse cardiovascular events (MACE; a composite of cardiovascular mortality, stroke, and myocardial infarction) as the primary outcome. We conducted a meta-regression analysis of primary and secondary outcomes with HbA1c or weight reduction following a meta-analysis with a random-effects model for these outcomes.ResultsWe extracted data of 60,800 individuals from eight eligible studies (ELIXA, LEADER, SUSTAIN-6, EXSCEL, HARMONY, PIONEER 6, REWIND, and AMPLITUDE-O). GLP-1RAs reduced MACE (hazard ratio [HR] 0.86; 95% CI: 0.80–0.93; P < 0.001) and secondary outcomes including the composite renal outcome (0.80; 0.73–0.87; P < 0.001). In meta-regression analysis, every 1% reduction in HbA1c was associated with 26% and 35% decreases in the logarithm of HR of MACE (P = 0.044; R2 = 0.65) and the composite renal outcome (P = 0.040; R2 = 0.85), respectively. On the contrary, weight reduction was not associated with any outcome, including MACE (P = 0.390).ConclusionsThe reduction in HbA1c, but not body weight, is associated with cardiovascular and renal outcomes. The magnitude of HbA1c reduction can be a surrogate for cardiovascular and renal benefits of treatment with GLP-1RAs.
Adapting cleft care protocols in low- and middle-income countries during and after COVID-19: a process-driven review with recommendations
Authors: Fell Matthew , Goldwasser Michael , Jayanth B.S , Rodrigues Pereira Rui Manuel , Nawej Christian Tshisuz , Winer Rachel , Daftari Neeti , Brewster Hugh , Goldschmied Karen 
Published: October 2021

ABSTRACTObjectiveA consortium of global cleft professionals, predominantly from low- and middle-income countries, identified adaptions to cleft care protocols during and after COVID as a priority learning area of need.DesignA multidisciplinary international working group met on a videoconferencing platform in a multi-staged process to make consensus recommendations for adaptions to cleft protocols within resource-constrained settings. Feedback was sought from a roundtable discussion forum and global organisations involved in comprehensive cleft care.ResultsFoundational principles were agreed to enable recommendations to be globally relevant and two areas of focus within the specified topic were identified. First the safety aspects of cleft surgery protocols were scrutinised and COVID adaptions, specifically in the pre and peri-operative periods, were highlighted. Second, surgical operations and access to services were prioritized according to their relationship to functional outcomes and time-sensitivity. The operations assigned the highest priority were emergent interventions for breathing and nutritional requirements and primary palatoplasty. The cleft services assigned the highest priority were new-born assessments, paediatric support for children with syndromes, management of acute dental or auditory infections and speech pathology intervention.ConclusionsA collaborative, interdisciplinary and international working group delivered consensus recommendations to assist with the provision of cleft care in low- and middle-income countries. At a time of global cleft care delays due to COVID-19, a united approach amongst global cleft care providers will be advantageous to advocate for children born with cleft lip and palate in resource-constrained settings.
Lin28a rejuvenates muscle stem cells via mitochondrial optimization
Authors: Wang Peng , Liu Xupeng , Elwin Tan Jun-Hao , Jason Chua Min-Wen , Benjamin Chua Yan-Jiang , Luo Lanfang , Ma Shilin , Cao Wenhua , Ma Wenwu , Yao Ziyue , Chen Yu , Miao Hefan , Guo Luyao , Zhang Liping , Guang Lu , Liang Kun , Wang Yuefan , Su Jiali , Liu Shuqing , Liu Ruirui , Wang Ruiqi Rachel , Li Chunwei , Ai Na , Li Yun , Jiang Zongming , Liu Taoyan , Teh Bin Tean , Jiang Lan , Yu Kang , Shyh-Chang Ng 
Published: October 2021

AbstractThe well-conserved correlation between juvenility and tissue regeneration was first discussed by Charles Darwin. Ectopic Lin28 is known to play an important role in somatic reprogramming and tissue regeneration, but endogenous Lin28’s role in tissue homeostasis and juvenility had remained unclear. Through lineage tracing, we found that a rare subset of muscle stem cells (MuSCs) expressing Lin28a can respond to acute injury by proliferating as Pax3+ or Pax7+ MuSCs, and contribute to all types of myofibers during muscle regeneration. Compared with conventional Pax7+ MuSCs, Lin28a+ MuSCs express more Pax3 and show enhanced myogenicity in vitro. In terms of the epigenetic clock, adult Lin28a+ MuSCs lie between adult Pax7+ MuSCs and embryonic Pax7+ myoblasts according to their DNA methylation profiles. We found that Lin28a+ MuSCs upregulate several embryonic limb bud mesoderm transcription factors and could maintain a juvenile state with enhanced stem cell self-renewal and stress-responsiveness in vitro and in vivo. When combined with telomerase and TP53 inhibition to biomimic mouse Lin28a+ MuSCs, we found that Lin28a can rejuvenate and dedifferentiate aged human primary myoblasts into engraftable, self-renewing MuSCs. Mechanistic studies revealed that Lin28a activated the HIF1A pathway by optimizing mitochondrial ROS (mtROS), thereby rejuvenating MuSC self-renewal and muscle regeneration. Our findings connect the stem cell factor Lin28, mtROS metabolism and stress response pathways to the process of stem cell rejuvenation and tissue regeneration.
γδ T cells are effectors of immune checkpoint blockade in mismatch repair-deficient colon cancers with antigen presentation defects
Authors: de Vries Natasja L. , van de Haar Joris , Veninga Vivien , Chalabi Myriam , Ijsselsteijn Marieke E. , van der Ploeg Manon , van den Bulk Jitske , Ruano Dina , Haanen John B. , Schumacher Ton N. , Wessels Lodewyk F.A. , Koning Frits , de Miranda Noel F.C.C. , Voest Emile E. 
Published: October 2021

AbstractDNA mismatch repair deficient (MMR-d) cancers present an abundance of neoantigens that likely underlies their exceptional responsiveness to immune checkpoint blockade (ICB)1,2. However, MMR-d colon cancers that evade CD8+ T cells through loss of Human Leukocyte Antigen (HLA) class I-mediated antigen presentation3–6, frequently remain responsive to ICB7 suggesting the involvement of other immune effector cells. Here, we demonstrate that HLA class I-negative MMR-d cancers are highly infiltrated by γδ T cells. These γδ T cells are mainly composed of Vδ1 and Vδ3 subsets, and express high levels of PD-1, activation markers including cytotoxic molecules, and a broad repertoire of killer-cell immunoglobulin-like receptors (KIRs). In vitro, PD-1+ γδ T cells, isolated from MMR-d colon cancers, exhibited a cytolytic response towards HLA class I-negative MMR-d colon cancer cell lines and β2-microglobulin (B2M)-knockout patient-derived tumor organoids (PDTOs), which was enhanced as compared to antigen presentation-proficient cells. This response was diminished after blocking the interaction between NKG2D and its ligands. By comparing paired tumor samples of MMR-d colorectal cancer patients obtained before and after dual PD-1 and CTLA-4 blockade, we found that ICB profoundly increased the intratumoral frequency of γδ T cells in HLA class I-negative cancers. Taken together, these data indicate that γδ T cells contribute to the response to ICB therapy in patients with HLA class I-negative, MMR-d colon cancers, and illustrate the potential of γδ T cells in cancer immunotherapy.
Dysregulated Protein Translation Control in Hidradenitis Suppurativa: Implication for Lesion-associated Squamous Cell Carcinoma Development
Authors: Jin Lin , Kashyap Mahendra P. , Chen Yunjia , Guo Yuanyuan , Khan Jasim , Chen Jari Q. , Lee Madison B , Weng Zhiping , Oak Allen , Sinha Rajesh , Mukhtar M. Shahid , Deshane Jessy S. , Raman Chander , Elmets Craig A. , Athar Mohammad 
Published: October 2021

AbstractHidradenitis Suppurativa (HS) is a proinflammatory painful skin disorder. This chronic disease is often associated with aggressive squamous cell carcinoma (SCC). The molecular pathogenesis of this disease progression remains undefined. The translation initiation factor eIF4E/4G/4A1 complex is overexpressed in a variety of human malignancies. In this study, we found that the expression of eIF4E/4G/4A1 as well as phosphorylated eIF4E were upregulated in HS skin. In the global transcription profiles derived from two public database, we were able to enrich 734 eIF4F-related genes. GSEA pathway enrichment analysis further demonstrated that RAS/MEK/ERK oncogene signaling pathway associated with inflammation signaling were significantly activated in HS lesion. The increase expression of eIF4 protein components was associated with enhanced eIF4E translation targets Cyclin D1 and c-Myc. Confocal fluorescence microscopy analysis further revealed that Cyclin D1 and c-Myc specifically co-localized in nuclei of certain cells in HS epithelium. We also found that many of the PCNA positive hyperproliferative cells were also positive for c-Myc expression. These data demonstrate that 5’-cap□dependent translation is a potential pathway underlying the SCC pathogenesis in chronic HS lesions. Furthermore, being a druggable target, inhibition of eIF4F may block lesion-associated lethal SCCs in HS patients.
Mutual Regulation between Phosphofructokinase 1 platelet isoform and VEGF Promotes Glioblastoma Tumor Growth
Authors: Lim Je Sun , Shi YuJie , Jeon So Mi , Park Su Hwan , Zhang Chuanbao , Park Yun-Yong , Liu Rui , Li Jing , Cho Wan-Seob , Du Linyong , Lee Jong-Ho 
Published: October 2021

AbstractGlioblastoma (GBM) is highly vascular malignant brain tumor that overexpresses vascular endothelial growth factor (VEGF) and phosphofructokinase 1 platelet isoform (PFKP), which catalyzes a rate-limiting reaction in glycolysis. However, it remains unknown whether PFKP and VEGF are reciprocally regulated during GBM tumor growth. Here, we show that PFKP promotes EGFR activation-induced VEGF expression in HIF-1α-dependent and -independent manners in GBM cells. Importantly, we demonstrate that EGFR-phosphorylated PFKP Y64 has critical roles in the AKT/SP1-mediated transcriptional expression ofHIF-1αand in the AKT-mediated β-catenin S552 phosphorylation, to fully enhanceVEGFtranscription and subsequent blood vessel formation and brain tumor growth. The levels of PFKP Y64 phosphorylation in human GBM specimens positively correlate with HIF-1α expression, β-catenin S552 phosphorylation, and VEGF expression. Conversely, VEGF upregulates PFKP expression in a PFKP S386 phosphorylation-dependent manner, leading to increased PFK enzyme activity, aerobic glycolysis, and proliferation in GBM cells. These findings highlight a novel mechanism underlying the mutual regulation that occurs between PFKP and VEGF for promoting GBM tumor growth and provide the therapeutic potential of targeting the PFKP/VEGF regulatory loop for GBM patients.
Interpretable Pairwise Distillations for Generative Protein Sequence Models
Authors: Feinauer Christoph , Meynard-Piganeau Barthelemy , Lucibello Carlo 
Published: October 2021

AbstractMany different types of generative models for protein sequences have been proposed in literature. Their uses include the prediction of mutational effects, protein design and the prediction of structural properties. Neural network (NN) architectures have shown great performances, commonly attributed to the capacity to extract non-trivial higher-order interactions from the data. In this work, we analyze three different NN models and assess how close they are to simple pairwise distributions, which have been used in the past for similar problems. We present an approach for extracting pairwise models from more complex ones using an energy-based modeling framework. We show that for the tested models the extracted pairwise models can replicate the energies of the original models and are also close in performance in tasks like mutational effect prediction.
scSPLAT, a scalable plate-based protocol for single cell WGBS library preparation
Authors: Raine Amanda , Lundmark Anders , Annett Alva , Wiman Ann-Christin , Cavalli Marco , Wadelius Claes , Bergin Claudia , Nordlund Jessica 
Published: October 2021

SummaryDNA methylation is a central epigenetic mark that has diverse roles in gene regulation, development, and maintenance of genome integrity. 5 methyl cytosine (5mC) can be interrogated at base resolution in single cells by using bisulfite sequencing (scWGBS). Several different scWGBS strategies have been described in recent years to study DNA methylation in single cells. However, there remain limitations with respect to cost-efficiency and yield. Herein, we present a new development in the field of scWGBS library preparation; single cell Splinted Ligation Adapter Tagging (scSPLAT). scSPLAT employs a pooling strategy to facilitate sample preparation at a higher scale and throughput than previously possible. We demonstrate the accuracy and robustness of the method by generating data from 225 single K562 cells and from 309 single liver nuclei and compare scSPLAT against other scWGBS methods.MotivationscWGBS library preparation in a one-cell-per-library format presents practical and economical constraints to the number of cells that can be analyzed in a research project. In addition, most of the current scWGBS methods suffer from low read alignment rates. We present a scWGBS protocol which mitigates these issues, empowering single-cell DNA methylation analysis at an increased scale.
Unifying turbulent dynamics framework distinguishes different brain states
Authors: Escrichs Anira , Perl Yonatan Sanz , Uribe Carme , Camara Estela , Türker Basak , Pyatigorskaya Nadya , López-González Ane , Pallavicini Carla , Panda Rajanikant , Annen Jitka , Grosseries Olivia , Laureys Steven , Naccache Lionel , Sitt Jacobo D. , Laufs Helmut , Tagliazucchi Enzo , Kringelbach Morten L. , Deco Gustavo 
Published: October 2021

AbstractRecently, significant advances have been made by identifying the levels of synchronicity of the underlying dynamics of a given brain state. This research has demonstrated that unconscious dynamics tend to be more synchronous than those found in conscious states, which are more asynchronous. Here we go beyond this dichotomy to demonstrate that the different brain states are always underpinned by spatiotemporal chaos but with dissociable turbulent dynamics. We investigated human neuroimaging data from different brain states (resting state, meditation, deep sleep, and disorders of consciousness after coma) and were able to distinguish between them using complementary model-free and model-based measures of turbulent information transmission. Our model-free approach used recent advances describing a measure of information cascade across spatial scales using tools from turbulence theory. Complementarily, our model-based approach used exhaustive in silico perturbations of whole-brain models fitted to the empirical neuroimaging data, which allowed us to study the information encoding capabilities of the brain states. Overall, the current framework demonstrates that different levels of turbulent dynamics are fundamental for describing and differentiating between brain states.
The chromatin regulator HMGA1a undergoes phase separation in the nucleus
Authors: Zhu Hongjia , Narita Masako , Joseph Jerelle A. , Krainer Georg , Arter William E. , Olan Ioana , Saar Kadi L. , Ermann Niklas , Espinosa Jorge R. , Shen Yi , Kuri Masami Ando , Qi Runzhang , Welsh Timothy J. , Xu Yufan , Collepardo-Guevara Rosana , Narita Masashi , Knowles Tuomas P. J. 
Published: October 2021

AbstractThe protein high mobility group A1 (HMGA1) is an important regulator of chromatin organization and function. However, the mechanisms by which it exerts its biological function are not fully understood. Here, we report that the HMGA isoform, HMGA1a, nucleates into foci that display liquid-like properties in the nucleus, and that the protein readily undergoes phase separation to form liquid condensates in vitro. By bringing together machine-leaning modelling, cellular and biophysical experiments and multiscale simulations, we demonstrate that phase separation of HMGA1a is critically promoted by protein–DNA interactions, and has the potential to be modulated by post-transcriptional effects such as phosphorylation. We further show that the intrinsically disordered C-terminal tail of HMGA1a significantly contributes to its phase separation through cation–π and electrostatic interactions. Our work sheds light on HMGA1 phase separation as an emergent biophysical factor in regulating chromatin structure.
Oxalic acid binds to gustatory receptor Gr23a and inhibits feeding in the brown planthopper
Authors: Kang Kui , Zhang Mengyi , Yue Lei , Chen Weiwen , Dai Yangshuo , Lin Kai , Liu Kai , Lv Jun , Guan Zhanwen , Xiao Shi , Zhang Wenqing 
Published: October 2021

AbstractPlants produce diverse secondary compounds as natural protection against microbial and insect attack. Most of these compounds, including bitters and acids, are sensed by insect gustatory receptors (Grs). Acids are potentially toxic to insects, but there are few reports on sour compounds as ligands of insect Grs. Here, using two different heterologous expression systems, the insect Sf9 cell line and the mammalian HEK293T cell line, we started from crude extracts of rice (Oryza sativa) and successfully identified oxalic acid (OA) as a ligand of NlGr23a, a Gr in the brown planthopper Nilaparvata lugens. The antifeedant effect of OA on the brown planthopper was dose dependent, and NlGr23a is essential for OA’s antifeedant activity in both artificial diets and rice plants. NlGr23a is also indispensable for tarsal OA sensing. To our knowledge, OA is the first identified ligand starting from plant crude extracts and the first known strong acid for insect Grs. These findings on rice-planthopper interactions will be of broad interest for pest control in agriculture and also for better understanding of how insects select host plants.Research organismNilaparvata lugens