tbuckley/cabot-search huggingface dataset:
Meta-analysis of the implied distribution of callous-unemotional traits across sampling methods and informant
Authors: Arthur Kary, Caroline Moul
Journal: Clinical Psychology Review (2024)

Callous-unemotional (CU) traits have been measured in a variety of sample-types (e.g., community or forensic) and from the perspective of different informants (e.g., self-report or parent-report) using the inventory of callous-unemotional traits total score (ICU-T). Although the positive association between CU traits and antisocial behavior is uncontroversial, the degree to which sample-types are different from each other has received little attention despite such knowledge being important for generalization and interpretation of research findings. To address this gap in the literature, we estimated the implied distribution of the ICU-T across sample-types, informants, and their interaction using meta-analytic models of sample means and variances. In unconditional models, we found that sample-type significantly moderated mean ICU-T scores but not variance, while informant significantly moderated the variance of ICU-T scores but not means. There was also a significant interaction between sample-type and informant. Mean parent-reported ICU-T scores were significantly lower than self-reported scores in community samples, but not significantly different in samples with elevated levels of antisocial behavior. Implications of our findings include improved research efficiency, the need for different ICU-T norms across informants, and greater understanding of informant biases.
Disrupting circadian control of autophagy induces podocyte injury and proteinuria
Authors: Lulu Wang, Han Tian, Haiyan Wang, Xiaoming Mao, Jing Luo, Qingyun He, Ping Wen, Hongdi Cao, Li Fang, Yang Zhou, Junwei Yang, Lei Jiang
Journal: Kidney International (2024)

The circadian clock influences a wide range of biological process and controls numerous aspects of physiology to adapt to the daily environmental changes caused by Earth's rotation. The kidney clock plays an important role in maintaining tubular function, but its effect on podocytes remains unclear. Here, we found that podocytes expressed CLOCK proteins, and that 2666 glomerular gene transcripts (13.4%), including autophagy related genes, had 24-hour circadian rhythms. Deletion of Clock in podocytes resulted in 1666 gene transcripts with the loss of circadian rhythm including autophagy genes. Podocyte-specific Clock knockout mice at age three and eight months showed deficient autophagy, loss of podocytes and increased albuminuria. Chromatin immunoprecipitation (ChIP) sequence analysis indicated autophagy related genes were targets of CLOCK in podocytes. ChIP-PCR further confirmed Clock binding to the promoter regions of Becn1 and Atg12, two autophagy related genes. Furthermore, the association of CLOCK regulated autophagy with chronic sleep fragmentation and diabetic kidney disease was analyzed. Chronic sleep fragmentation resulted in the loss of glomerular Clock rhythm, inhibition of podocyte autophagy, and proteinuria. Rhythmic oscillations of Clock also disappeared in high glucose treated podocytes and in glomeruli from diabetic mice. Finally, circadian differences in podocyte autophagy were also abolished in diabetic mice. Deletion Clock in podocytes aggravated podocyte injury and proteinuria in diabetic mice. Thus, our findings demonstrate that clock-dependent regulation of autophagy may be essential for podocyte survival. Hence. loss of circadian controlled autophagy may play an important role in podocyte injury and proteinuria.
Identification of highly repetitive barley enhancers with long-range regulation potential via STARR-seq
Authors: Wanlin Zhou, Haoran Shi, Zhiqiang Wang, Yuxin Huang, Lin Ni, Xudong Chen, Yan Liu, Haojie Li, Caixia Li, Yaxi Liu
Journal: Genomics Proteomics & Bioinformatics (2024)

Enhancers are DNA sequences that can strengthen transcription initiation. However, the global identification of plant enhancers is complicated due to uncertainty in the distance and orientation of enhancers, especially in species with large genomes. In this study, we performed self-transcribing active regulatory region sequencing (STARR-seq) for the first time to identify enhancers across the barley genome. A total of 7323 enhancers were successfully identified, and among 45 randomly selected enhancers, over 75% were effective as validated by a dual-luciferase reporter assay system in the lower epidermis of tobacco leaves. Interestingly, up to 53.5% of the barley enhancers were repetitive sequences, especially transposable elements (TEs), thus reinforcing the vital role of repetitive enhancers in gene expression. Both the common active mark H3K4me3 and repressive mark H3K27me3 were abundant among the barley STARR-seq enhancers. In addition, the functional range of barley STARR-seq enhancers seemed much broader than that of rice or maize and extended to ±100 kb of the gene body, and this finding was consistent with the high expression levels of genes in the genome. This study specifically depicts the unique features of barley enhancers and provides available barley enhancers for further utilization.
Update on the management of relapsed/refractory chronic lymphocytic leukemia
Authors: Rory Bennett, John F. Seymour
Journal: Blood Cancer Journal (2024)

Chronic lymphocytic leukemia (CLL) predominantly affects older adults, characterized by a relapsing and remitting pattern with sequential treatments available for many patients. Identification of progressive/relapsed CLL should prompt close monitoring and early discussion about the next therapies when treatment indications are present. The intervening period represents an opportunity to optimize patient health, including establishing adequate vaccination and surveillance for second primary malignancies, and treating non-CLL-related comorbidities which may impact well-being and CLL therapy. We now see patients with relapsed/refractory (RR) CLL in the clinic who have been previously treated with chemoimmunotherapy (CIT) and/or one or more novel therapies. Continuous covalent inhibitors of Bruton's tyrosine kinase (cBTKi) and fixed-duration venetoclax (Ven)-anti-CD20 monoclonal antibody (mAb) are preferred over CIT given the survival advantages associated with these therapies, although have never been evaluated head-to-head. While both classes are effective for RR CLL, potential side effects and the logistics of administration differ. Few randomized data demonstrate the sequential use of cBTKi and fixed-duration Ven-anti-CD20 mAb; however, they may be used in either sequence. Newer non-covalent BTKi, active against BTK C481 resistance mutations emerging with continuous cBTKi exposure, and novel approaches such as BTK degraders, bispecific antibodies, and chimeric antigen receptor T-cell therapies demonstrate impressive efficacy. In this review of RR CLL we explore relevant investigations, consideration of broader CLL- and non-CLL-related health needs, and evidence for efficacy and safety of B-cell receptor inhibitors and Ven, including available data to support drug sequencing or switching. We describe novel approaches to RR CLL, including rechallenging with fixed-duration therapies, allogeneic stem cell transplant indications in the novel therapy era, and highlight early data supporting the use of T-cell directing therapies and novel drug targets.
α-Synuclein oligomers potentiate neuroinflammatory NF-κB activity and induce Cav3.2 calcium signaling in astrocytes
Authors: Emmanouela Leandrou, Ioanna Chalatsa, Dimitrios Anagnostou, Christina Machalia, Maria Semitekolou, Vicky Filippa, Manousos Makridakis, Antonia Vlahou, Ema Anastasiadou, Kostas Vekrellis, Evangelia Emmanouilidou
Journal: Translational Neurodegeneration (2024)

Abstract Background It is now realized that Parkinson’s disease (PD) pathology extends beyond the substantia nigra, affecting both central and peripheral nervous systems, and exhibits a variety of non-motor symptoms often preceding motor features. Neuroinflammation induced by activated microglia and astrocytes is thought to underlie these manifestations. α-Synuclein aggregation has been linked with sustained neuroinflammation in PD, aggravating neuronal degeneration; however, there is still a lack of critical information about the structural identity of the α-synuclein conformers that activate microglia and/or astrocytes and the molecular pathways involved. Methods To investigate the role of α-synuclein conformers in the development and maintenance of neuroinflammation, we used primary quiescent microglia and astrocytes, post-mortem brain tissues from PD patients and A53T α-synuclein transgenic mice that recapitulate key features of PD-related inflammatory responses in the absence of cell death, i.e., increased levels of pro-inflammatory cytokines and complement proteins. Biochemical and -omics techniques including RNAseq and secretomic analyses, combined with 3D reconstruction of individual astrocytes and live calcium imaging, were used to uncover the molecular mechanisms underlying glial responses in the presence of α-synuclein oligomers in vivo and in vitro. Results We found that the presence of SDS-resistant hyper-phosphorylated α-synuclein oligomers, but not monomers, was correlated with sustained inflammatory responses, such as elevated levels of endogenous antibodies and cytokines and microglial activation. Similar oligomeric α-synuclein species were found in post-mortem human brain samples of PD patients but not control individuals. Detailed analysis revealed a decrease in Iba1 Low /CD68 Low microglia and robust alterations in astrocyte number and morphology including process retraction. Our data indicated an activation of the p38/ATF2 signaling pathway mostly in microglia and a sustained induction of the NF-κB pathway in astrocytes of A53T mice. The sustained NF-κB activity triggered the upregulation of astrocytic T-type Ca v 3.2 Ca 2+ channels, altering the astrocytic secretome and promoting the secretion of IGFBPL1, an IGF-1 binding protein with anti-inflammatory and neuroprotective potential. Conclusions Our work supports a causative link between the neuron-produced α-synuclein oligomers and sustained neuroinflammation in vivo and maps the signaling pathways that are stimulated in microglia and astrocytes. It also highlights the recruitment of astrocytic Ca v 3.2 channels as a potential neuroprotective mediator against the α-synuclein-induced neuroinflammation. Graphical Abstract
Resistance of HNSCC cell models to pan-FGFR inhibition depends on the EMT phenotype associating with clinical outcome
Authors: Felix Broghammer, Irina Korovina, Mahesh Gouda, Martina Celotti, Johan van Es, Inga Lange, Cornelia Brunner, Jovan Mircetic, Robert P. Coppes, Olivier Gires, Andreas Dahl, Michael Seifert, Nils Cordes
Journal: Molecular Cancer (2024)

Abstract Background Focal adhesion signaling involving receptor tyrosine kinases (RTK) and integrins co-controls cancer cell survival and therapy resistance. However, co-dependencies between these receptors and therapeutically exploitable vulnerabilities remain largely elusive in HPV-negative head and neck squamous cell carcinoma (HNSCC). Methods The cytotoxic and radiochemosensitizing potential of targeting 10 RTK and β1 integrin was determined in up to 20 3D matrix-grown HNSCC cell models followed by drug screening and patient-derived organoid validation. RNA sequencing and protein-based biochemical assays were performed for molecular characterization. Bioinformatically identified transcriptomic signatures were applied to patient cohorts. Results Fibroblast growth factor receptor (FGFR 1–4) targeting exhibited the strongest cytotoxic and radiosensitizing effects as monotherapy and combined with β1 integrin inhibition, exceeding the efficacy of the other RTK studied. Pharmacological pan-FGFR inhibition elicited responses ranging from cytotoxicity/radiochemosensitization to resistance/radiation protection. RNA sequence analysis revealed a mesenchymal-to-epithelial transition (MET) in sensitive cell models, whereas resistant cell models exhibited a partial epithelial-to-mesenchymal transition (EMT). Accordingly, inhibition of EMT-associated kinases such as EGFR caused reduced adaptive resistance and enhanced (radio)sensitization to FGFR inhibition cell model- and organoid-dependently. Transferring the EMT-associated transcriptomic profiles to HNSCC patient cohorts not only demonstrated their prognostic value but also provided a conclusive validation of the presence of EGFR-related vulnerabilities that can be strategically exploited for therapeutic interventions. Conclusions This study demonstrates that pan-FGFR inhibition elicits a beneficial radiochemosensitizing and a detrimental radioprotective potential in HNSCC cell models. Adaptive EMT-associated resistance appears to be of clinical importance, and we provide effective molecular approaches to exploit this therapeutically.
Leveraging electronic health records and knowledge networks for Alzheimer’s disease prediction and sex-specific biological insights
Authors: Alice S. Tang, Katherine P. Rankin, Gabriel Cerono, Silvia Miramontes, Hunter Mills, Jacquelyn Roger, Billy Zeng, Charlotte Nelson, Karthik Soman, Sarah Woldemariam, Yaqiao Li, Albert Lee, Riley Bove, Maria Glymour, Nima Aghaeepour, Tomiko T. Oskotsky, Zachary Miller, Isabel E. Allen, Stephan J. Sanders, Sergio Baranzini, Marina Sirota
Journal: Nature Aging (2024)

Identification of Alzheimer's disease (AD) onset risk can facilitate interventions before irreversible disease progression. We demonstrate that electronic health records from the University of California, San Francisco, followed by knowledge networks (for example, SPOKE) allow for (1) prediction of AD onset and (2) prioritization of biological hypotheses, and (3) contextualization of sex dimorphism. We trained random forest models and predicted AD onset on a cohort of 749 individuals with AD and 250,545 controls with a mean area under the receiver operating characteristic of 0.72 (7 years prior) to 0.81 (1 day prior). We further harnessed matched cohort models to identify conditions with predictive power before AD onset. Knowledge networks highlight shared genes between multiple top predictors and AD (for example, APOE, ACTB, IL6 and INS). Genetic colocalization analysis supports AD association with hyperlipidemia at the APOE locus, as well as a stronger female AD association with osteoporosis at a locus near MS4A6A. We therefore show how clinical data can be utilized for early AD prediction and identification of personalized biological hypotheses.
Learning Playing Piano with Bionic-Constrained Diffusion Policy for Anthropomorphic Hand
Authors: Yiming Yang, Zechang Wang, Dengpeng Xing, Peng Wang
Journal: Cyborg and Bionic Systems (2024)

Anthropomorphic hand manipulation is a quintessential example of embodied intelligence in robotics, presenting a notable challenge due to its high degrees of freedom and complex inter-joint coupling. Though recent advancements in reinforcement learning (RL) have led to substantial progress in this field, existing methods often overlook the detailed structural properties of anthropomorphic hands. To address this, we propose a novel deep RL approach, Bionic-Constrained Diffusion Policy (Bio-CDP), which integrates knowledge of human hand control with a powerful diffusion policy representation. Our bionic constraint modifies the action space of anthropomorphic hand control, while the diffusion policy enhances the expressibility of the policy in high-dimensional continuous control tasks. Bio-CDP has been evaluated in the simulation environment, where it has shown superior performance and data efficiency compared to state-of-the-art RL approaches. Furthermore, our method is resilient to task complexity and robust in performance, making it a promising tool for advanced control in robotics.
Acupuncture for Combat-Related Posttraumatic Stress Disorder
Authors: Michael Hollifield, An-Fu Hsiao, Tyler Smith, Teresa Calloway, Tanja Jovanovic, Besa Smith, Kala Carrick, Seth D. Norrholm, Andrea Munoz, Ruth Alpert, Brianna Caicedo, Nikki Frousakis, Karen Cocozza
Journal: JAMA Psychiatry (2024)

Current interventions for posttraumatic stress disorder (PTSD) are efficacious, yet effectiveness may be limited by adverse effects and high withdrawal rates. Acupuncture is an emerging intervention with positive preliminary data for PTSD.
Improved Satisfaction While Maintaining Safety and High Time in Range (TIR) With a Medtronic Investigational Enhanced Advanced Hybrid Closed-Loop (e-AHCL) System
Authors: Cheng Yi Yuan, Yee W. Kong, Tess Amoore, Katrin Brown, Benyamin Grosman, Alicia Jenkins, Hannah Jones, Natalie Kurtz, Melissa H. Lee, Richard MacIsaac, Emma Netzer, Barbora Paldus, Lesley Robinson, Anirban Roy, Catriona M. Sims, Steven Trawley, Sara Vogrin, David N. O’Neal
Journal: Diabetes Care (2024)

To determine feasibility and compare acceptance of an investigational Medtronic enhanced advanced hybrid closed-loop (e-AHCL) system in adults with type 1 diabetes with earlier iterations.
Interventions for Optimization of Guideline-Directed Medical Therapy
Authors: Amber B. Tang, Nicholas K. Brownell, Jacob S. Roberts, Amier Haidar, Antonia Osuna-Garcia, David J. Cho, Pooya Bokhoor, Gregg C. Fonarow
Journal: JAMA Cardiology (2024)

Importance Implementation of guideline-directed medical therapy (GDMT) in real-world practice remains suboptimal. It is unclear which interventions are most effective at addressing current barriers to GDMT in patients with heart failure with reduced ejection fraction (HFrEF). Objective To perform a systematic review to identify which types of system-level initiatives are most effective at improving GDMT use among patients with HFrEF. Evidence Review PubMed, Embase, Cochrane, CINAHL, and Web of Science databases were queried from January 2010 to November 2023 for randomized clinical trials that implemented a quality improvement intervention with GDMT use as a primary or secondary outcome. References from related review articles were also included for screening. Quality of studies and bias assessment were graded based on the Cochrane Risk of Bias tool and Oxford Centre for Evidence-Based Medicine. Findings Twenty-eight randomized clinical trials were included with an aggregate sample size of 19 840 patients. Studies were broadly categorized as interdisciplinary interventions (n = 15), clinician education (n = 5), electronic health record initiatives (n = 6), or patient education (n = 2). Overall, interdisciplinary titration clinics were associated with significant increases in the proportion of patients on target doses of GDMT with a 10% to 60% and 2% to 53% greater proportion of patients on target doses of β-blockers and renin-angiotensin-aldosterone system inhibitors, respectively, in intervention groups compared with usual care. Other interventions, such as audits, clinician and patient education, or electronic health record alerts, were also associated with some improvements in GDMT utilization, though these findings were inconsistent across studies. Conclusions and Relevance This review summarizes interventions aimed at optimization of GDMT in clinical practice. Initiatives that used interdisciplinary teams, largely comprised of nurses and pharmacists, most consistently led to improvements in GDMT. Additional large, randomized studies are necessary to better understand other types of interventions, as well as their long-term efficacy and sustainability.
A tailored series of engineered yeasts for the cell-dependent treatment of inflammatory bowel disease by rational butyrate supplementation
Authors: Jiahao Wu, He Huang, Lina Wang, Mengxue Gao, Shuxian Meng, Shaolan Zou, Yuanhang Feng, Zeling Feng, Zhixin Zhu, Xiaocang Cao, Bingzhi Li, Guangbo Kang
Journal: Gut Microbes (2024)

Intestinal microbiota dysbiosis and metabolic disruption are considered essential characteristics in inflammatory bowel disorders (IBD). Reasonable butyrate supplementation can help patients regulate intestinal flora structure and promote mucosal repair. Here, to restore microbiota homeostasis and butyrate levels in the patient's intestines, we modified the genome of Saccharomyces cerevisiae to produce butyrate. We precisely regulated the relevant metabolic pathways to enable the yeast to produce sufficient butyrate in the intestine with uneven oxygen distribution. A series of engineered strains with different butyrate synthesis abilities was constructed to meet the needs of different patients, and the strongest can reach 1.8 g/L title of butyrate. Next, this series of strains was used to co-cultivate with gut microbiota collected from patients with mild-to-moderate ulcerative colitis. After receiving treatment with engineered strains, the gut microbiota and the butyrate content have been regulated to varying degrees depending on the synthetic ability of the strain. The abundance of probiotics such as Bifidobacterium and Lactobacillus increased, while the abundance of harmful bacteria like Candidatus Bacilloplasma decreased. Meanwhile, the series of butyrate-producing yeast significantly improved trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice by restoring butyrate content. Among the series of engineered yeasts, the strain with the second-highest butyrate synthesis ability showed the most significant regulatory and the best therapeutic effect on the gut microbiota from IBD patients and the colitis mouse model. This study confirmed the existence of a therapeutic window for IBD treatment by supplementing butyrate, and it is necessary to restore butyrate levels according to the actual situation of patients to restore intestinal flora.
Evaluating the Effects of Chronic Oral Exposure to the Food Additive Silicon Dioxide on Oral Tolerance Induction and Food Sensitivities in Mice
Authors: Bruno Lamas, Natalia Martins Breyner, Yann Malaisé, Mark Wulczynski, Heather J. Galipeau, Eric Gaultier, Christel Cartier, Elena F. Verdu, Eric Houdeau
Journal: Environmental Health Perspectives (2024)

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Tetrasulfide bond boosts the anti-tumor efficacy of dimeric prodrug nanoassemblies
Authors: Shiyi Zuo, Tian Liu, Lingxiao Li, Hezhen Xu, Jiayu Guo, Qing Wang, Yinxian Yang, Zhonggui He, Jin Sun, Bingjun Sun
Journal: Cell Reports Medicine (2024)

Dimeric prodrug nanoassemblies (DPNAs) stand out as promising strategies for improving the efficiency and safety of chemotherapeutic drugs. The success of trisulfide bonds (-SSS-) in DPNAs makes polysulfide bonds a worthwhile focus. Here, we explore the comprehensive role of tetrasulfide bonds (-SSSS-) in constructing superior DPNAs. Compared to trisulfide and disulfide bonds, tetrasulfide bonds endow DPNAs with superlative self-assembly stability, prolonged blood circulation, and high tumor accumulation. Notably, the ultra-high reduction responsivity of tetrasulfide bonds make DPNAs a highly selective "tumor bomb" that can be ignited by endogenous reducing agents in tumor cells. Furthermore, we present an "add fuel to the flames" strategy to intensify the reductive stress at tumor sites by replenishing exogenous reducing agents, making considerable progress in selective tumor inhibition. This work elucidates the crucial role of tetrasulfide bonds in establishing intelligent DPNAs, alongside the combination methodology, propelling DPNAs to new heights in potent cancer therapy.