tbuckley/cabot-search huggingface dataset:
Microglia as hackers of the matrix: sculpting synapses and the extracellular space
Authors: Joshua D. Crapser, Miguel A. Arreola, Kate I. Tsourmas, Kim N. Green
Journal: Cellular and Molecular Immunology (2021)

Abstract Microglia shape the synaptic environment in health and disease, but synapses do not exist in a vacuum. Instead, pre- and postsynaptic terminals are surrounded by extracellular matrix (ECM), which together with glia comprise the four elements of the contemporary tetrapartite synapse model. While research in this area is still just beginning, accumulating evidence points toward a novel role for microglia in regulating the ECM during normal brain homeostasis, and such processes may, in turn, become dysfunctional in disease. As it relates to synapses, microglia are reported to modify the perisynaptic matrix, which is the diffuse matrix that surrounds dendritic and axonal terminals, as well as perineuronal nets (PNNs), specialized reticular formations of compact ECM that enwrap neuronal subsets and stabilize proximal synapses. The interconnected relationship between synapses and the ECM in which they are embedded suggests that alterations in one structure necessarily affect the dynamics of the other, and microglia may need to sculpt the matrix to modify the synapses within. Here, we provide an overview of the microglial regulation of synapses, perisynaptic matrix, and PNNs, propose candidate mechanisms by which these structures may be modified, and present the implications of such modifications in normal brain homeostasis and in disease.
Endoscopic submucosal dissection vs. endoscopic mucosal resection for early Barrett's neoplasia in the West: a retrospective study
Authors: Lady Katherine Mejia Perez, Dennis Yang, Peter V. Draganov, Salmaan Jawaid, Amitabh Chak, John Dumot, Omar Alaber, John J. Vargo, Sunguk Jang, Neal Mehta, Norio Fukami, Tiffany Chua, Moamen Gabr, Praneeth Kudaravalli, Hiroyuki Aihara, Fauze Maluf-Filho, Saowanee Ngamruengphong, Milad Pourmousavi Khoshknab, Amit Bhatt
Journal: Endoscopy (2021)

The difference in clinical outcomes after endoscopic submucosal dissection (ESD) and endoscopic mucosal resection (EMR) for early Barrett's esophagus (BE) neoplasia remains unclear. We compared the recurrence/residual tissue rates, resection outcomes, and adverse events after ESD and EMR for early BE neoplasia.We included patients who underwent EMR or ESD for BE-associated high grade dysplasia (HGD) or T1a esophageal adenocarcinoma (EAC) at eight academic hospitals. We compared demographic, procedural, and histologic characteristics, and follow-up data. A time-to-event analysis was performed to evaluate recurrence/residual disease and a Kaplan-Meier curve was used to compare the groups.243 patients (150 EMR; 93 ESD) were included. EMR had lower en bloc (43 % vs. 89 %; P < 0.001) and R0 (56 % vs. 73 %; P = 0.01) rates than ESD. There was no difference in the rates of perforation (0.7 % vs. 0; P > 0.99), early bleeding (0.7 % vs. 1 %; P > 0.99), delayed bleeding (3.3 % vs. 2.1 %; P = 0.71), and stricture (10 % vs. 16 %; P = 0.16) between EMR and ESD. Patients with non-curative resections who underwent further therapy were excluded from the recurrence analysis. Recurrent/residual disease was 31.4 % [44/140] for EMR and 3.5 % [3/85] for ESD during a median (interquartile range) follow-up of 15.5 (6.75-30) and 8 (2-18) months, respectively. Recurrence-/residual disease-free survival was significantly higher in the ESD group. More patients required additional endoscopic resection procedures to treat recurrent/residual disease after EMR (EMR 24.2 % vs. ESD 3.5 %; P < 0.001).ESD is safe and results in more definitive treatment of early BE neoplasia, with significantly lower recurrence/residual disease rates and less need for repeat endoscopic treatments than with EMR.
A human forebrain organoid model of fragile X syndrome exhibits altered neurogenesis and highlights new treatment strategies
Authors: Yunhee Kang, Ying Zhou, Yujing Li, Yanfei Han, Jie Xu, Weibo Niu, Ziyi Li, Shiying Liu, Hao Feng, Wen Huang, Ranhui Duan, Tianmin Xu, Nisha Raj, Feiran Zhang, Juan Dou, Chongchong Xu, Hao Wu, Gary J. Bassell, Stephen T. Warren, Emily G. Allen, Peng Jin, Zhexing Wen
Journal: Nature Neuroscience (2021)
Validation of a Predictive Model for Survival in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome Receiving Hematopoietic Stem Cell Transplantation
Authors: Piyanuch Kongtim, Simrit Parmar, Denái R. Milton, Gabriela Rondon, Julianne Chen, Betul Oran, Uday Popat, Chitra Hosing, Qaiser Bashir, Partow Kebriaei, Issa F. Khouri, Richard E. Champlin, Stefan O. Ciurea
Journal: Blood (2017)
Expedition of sulfur‐containing heterocyclic derivatives as cytotoxic agents in medicinal chemistry: A decade update
Authors: Kritika Laxmikeshav, Pooja Kumari, Nagula Shankaraiah
Journal: Medicinal Research Reviews (2021)

Abstract This review article proposes a comprehensive report of the design strategies engaged in the development of various sulfur‐bearing cytotoxic agents. The outcomes of various studies depict that the sulfur heterocyclic framework is a fundamental structure in diverse synthetic analogs representing a myriad scope of therapeutic activities. A number of five‐, six‐ and seven‐membered sulfur‐containing heterocyclic scaffolds, such as thiazoles, thiadiazoles, thiazolidinediones, thiophenes, thiopyrans, benzothiazoles, benzothiophenes, thienopyrimidines, simple and modified phenothiazines, and thiazepines have been discussed. The subsequent studies of the derivatives unveiled their cytotoxic effects through multiple mechanisms (viz. inhibition of tyrosine kinases, topoisomerase I and II, tubulin, COX, DNA synthesis, and PI3K/Akt and Raf/MEK/ERK signaling pathways), and several others. Thus, our concise illustration explains the design strategy and anticancer potential of these five‐ and six‐membered sulfur‐containing heterocyclic molecules along with a brief outline on seven‐membered sulfur heterocycles. The thorough assessment of antiproliferative activities with the reference drug allows a proficient assessment of the structure–activity relationships (SARs) of the diversely synthesized molecules of the series.
The RAG1 N-terminal region regulates the efficiency and pathways of synapsis for V(D)J recombination
Authors: Helen A. Beilinson, Rebecca A. Glynn, Anurupa Devi Yadavalli, Jianxiong Xiao, Elizabeth Corbett, Huseyin Saribasak, Rahul Arya, Charline Miot, Anamika Bhattacharyya, Jessica M. Jones, Jagan M.R. Pongubala, Craig H. Bassing, David G. Schatz
Journal: The Journal of Experimental Medicine (2021)

Immunoglobulin and T cell receptor gene assembly depends on V(D)J recombination initiated by the RAG1-RAG2 recombinase. The RAG1 N-terminal region (NTR; aa 1–383) has been implicated in regulatory functions whose influence on V(D)J recombination and lymphocyte development in vivo is poorly understood. We generated mice in which RAG1 lacks ubiquitin ligase activity (P326G), the major site of autoubiquitination (K233R), or its first 215 residues (Δ215). While few abnormalities were detected in R1.K233R mice, R1.P326G mice exhibit multiple features indicative of reduced recombination efficiency, including an increased Igκ+:Igλ+ B cell ratio and decreased recombination of Igh, Igκ, Igλ, and Tcrb loci. Previous studies indicate that synapsis of recombining partners during Igh recombination occurs through two pathways: long-range scanning and short-range collision. We find that R1Δ215 mice exhibit reduced short-range Igh and Tcrb D-to-J recombination. Our findings indicate that the RAG1 NTR regulates V(D)J recombination and lymphocyte development by multiple pathways, including control of the balance between short- and long-range recombination.
27030 Extended safety analysis of baricitinib 2-mg in adult patients with atopic dermatitis: An integrated analysis from 8 randomized clinical trials
Authors: Brett King, Catherine Maari, Edward Lain, Jonathan I. Silverberg, Maher Issa, Katrin Holzwarth, Dennis Brinker, Tracy Cardillo, Fabio P. Nunes, Eric L. Simpson
Journal: Journal of the American Academy of Dermatology (2021)
Combinatorial technology revitalized by DNA‐encoding
Authors: Árpád Furka
Journal: MedComm (2021)

Combinatorial chemistry invented nearly 40 years ago was welcomed with enthusiasm in the drug research community. The method offered access to a practically unlimited number of new compounds. The new compounds however are mixtures, and methods had to be developed for the identification of the bioactive components. This was one of the reasons why the method could not providethe expected cornucopia of new drugs. Among the different screening methods, two approaches seem to offer the best results. One of them is based on the intrinsic property of the combinatorial split and pool solid-phase synthesis: One compound forms on each bead of the solid support. Different methods have been developed to encode the beads and identify the structure of compounds formed on them. The most important method applies DNA oligomers for encoding. As a second approach in screening, DNA-encoded combinatorial libraries are synthesized omitting the solid support and the mixtures are screened in solution using affinity binding methods. Libraries containing billions and even trillions of components are synthesized and successfully tested, which led to the identification of a significant number of new leads.
Ancient Gene Duplications, Rather Than Polyploidization, Facilitate Diversification of Petal Pigmentation Patterns in <i>Clarkia gracilis</i> (Onagraceae)
Authors: Rong-Chien Lin, Mark D Rausher
Journal: Molecular Biology and Evolution (2021)

Abstract It has been suggested that gene duplication and polyploidization create opportunities for the evolution of novel characters. However, the connections between the effects of polyploidization and morphological novelties have rarely been examined. In this study, we investigated whether petal pigmentation patterning in an allotetraploid Clarkia gracilis has evolved as a result of polyploidization. Clarkia gracilis is thought to be derived through a recent polyploidization event with two diploid species, C. amoena huntiana and an extinct species that is closely related to C. lassenensis. We reconstructed phylogenetic relationships of the R2R3-MYBs (the regulators of petal pigmentation) from two subspecies of C. gracilis and the two purported progenitors, C. a. huntiana and C. lassenensis. The gene tree reveals that these R2R3-MYB genes have arisen through duplications that occurred before the divergence of the two progenitor species, that is, before polyploidization. After polyploidization and subsequent gene loss, only one of the two orthologous copies inherited from the progenitors was retained in the polyploid, turning it to diploid inheritance. We examined evolutionary changes in these R2R3-MYBs and in their expression, which reveals that the changes affecting patterning (including expression domain contraction, loss-of-function mutation, cis-regulatory mutation) occurred after polyploidization within the C. gracilis lineages. Our results thus suggest that polyploidization itself is not necessary in producing novel petal color patterns. By contrast, duplications of R2R3-MYB genes in the common ancestor of the two progenitors have apparently facilitated diversification of petal pigmentation patterns.
Toward Healing and Health Equity for Asian American, Native Hawaiian, and Pacific Islander Populations
Authors: Howard K. Koh, Juliet K. Choi, Jeffrey B. Caballero
Journal: JAMA (2021)

This Viewpoint discusses the racist rhetoric that has been aimed at Asian American, Native Hawaiian, and Pacific Islander individuals throughout the COVID-19 pandemic and highlights the importance of recognizing the special challenges of this population in achieving health equity for all.
Acute depletion of CTCF rewires genome-wide chromatin accessibility
Authors: Beisi Xu, Hong Wang, Shaela Wright, Judith Hyle, Yang Zhang, Ying Shao, Mingming Niu, Yiping Fan, Wojciech Rosikiewicz, Mohamed Nadhir Djekidel, Junmin Peng, Rui Lu, Chunliang Li
Journal: Genome biology (2021)

The transcription factor CTCF appears indispensable in defining topologically associated domain boundaries and maintaining chromatin loop structures within these domains, supported by numerous functional studies. However, acute depletion of CTCF globally reduces chromatin interactions but does not significantly alter transcription.
Promoting leisure-time versus occupational physical activity: socially biased or solutions to closing the socioeconomic gap?
Authors: Leandro Garcia, Sophie Jones, Ruth Hunter
Journal: British Journal of Sports Medicine (2021)

We read with interest Straker et al ’s editorial1 arguing how a focus on leisure-time physical activity is socially biased, and that designing jobs with the right amount and nature of physical activity can correct those biases. We offer here three counterpoints to encourage a wider discussion of this very relevant and important topic.

Our first point is centred on the fact that Straker et al compared two different types of physical activity promotion strategies. They wrote that ‘public health messaging has focused largely on increasing leisure time physical activity’, but suggested changes in how work is designed —largely a structural change—could correct socioeconomic biases. We posit the following: (1) for communication campaigns to be effective, the target audience must have the opportunities and means to act on the information they receive, regardless of being in the leisure or work domain. People from lower socioeconomic backgrounds usually occupy jobs they have …
Time-dependent effect of 1,6-hexanediol on biomolecular condensates and 3D chromatin organization
Authors: Xinyi Liu, Shaoshuai Jiang, Lin Ma, Jiale Qu, Longying Zhao, Xing Zhu, Junjun Ding
Journal: Genome biology (2021)

Biomolecular condensates have been implicated in multiple cellular processes. However, the global role played by condensates in 3D chromatin organization remains unclear. At present, 1,6-hexanediol (1,6-HD) is the only available tool to globally disrupt condensates, yet the conditions of 1,6-HD vary considerably between studies and may even trigger apoptosis.In this study, we first analyzed the effects of different concentrations and treatment durations of 1,6-HD and found that short-term exposure to 1.5% 1,6-HD dissolved biomolecular condensates whereas long-term exposure caused aberrant aggregation without affecting cell viability. Based on this condition, we drew a time-resolved map of 3D chromatin organization and found that short-term treatment with 1.5% 1,6-HD resulted in reduced long-range interactions, strengthened compartmentalization, homogenized A-A interactions, B-to-A compartment switch and TAD reorganization, whereas longer exposure had the opposite effects. Furthermore, the long-range interactions between condensate-component-enriched regions were markedly weakened following 1,6-HD treatment.In conclusion, our study finds a proper 1,6-HD condition and provides a resource for exploring the role of biomolecular condensates in 3D chromatin organization.
26200 Tumor burden in patients with locally advanced basal cell carcinoma and metastatic basal cell carcinoma following treatment with sonidegib: Results of the 42-month BOLT study
Authors: Michael Migden, Aaron S. Farberg, James Spencer, Felix Kiecker, Alexander Guminski, Kurt Gebauer, Carmen Loquai, Caroline Robert, Nicholas Squittieri, Reinhard Dummer
Journal: Journal of the American Academy of Dermatology (2021)
COVID-19: Inflammatory Profile
Authors: Yuhang Wang, Stanley Perlman
Journal: Annual Review of Medicine (2021)

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), has resulted in a pandemic that has had widespread effects on human activities. The clinical presentation of severe COVID-19 includes a broad spectrum of clinical disease, most notably acute respiratory distress syndrome, cytokine release syndrome (CRS), multiorgan failure, and death. Direct viral damage and uncontrolled inflammation have been suggested as contributory factors in COVID-19 disease severity. The COVID-19 pandemic has emphasized the critical role of an effective host immune response in controlling a virus infection and demonstrated the devastating effect of immune dysregulation. Understanding the nature of the immune response to SARS-CoV-2 pathogenesis is key to developing effective treatments for COVID-19. Here, we describe the nature of the dysregulated host immune response in COVID-19, identify potential mechanisms involved in CRS, and discuss potential strategies that can be used to manage immune dysregulation in COVID-19.
Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle
Authors: Joseph A. Willson, Simone Arienti, Pranvera Sadiku, Leila Reyes, Patricia Coelho, Tyler Morrison, Giulia Rinaldi, David H. Dockrell, Moira K. B. Whyte, Sarah R. Walmsley
Journal: Blood (2021)
The Normal Anatomy of the Brain Pathways: What the Neuroradiologist Needs to Know (Literature Review)
Authors: A. S. Filatov, E. I. Kremneva, M. S. Matrosova, V. V. Trubitsyna, L. A. Dobrynina, M. V. Krotenkova
Journal: Radiology - Practice (2021)

Diffusion-tensor magnetic resonance imaging (DT-MRI) allows imaging of most brain pathways, quantifying their integrity and even suggesting a leading mechanism of damage (demyelination or ischemia). However, it is difficult to use this technique without a good knowledge of the anatomy. This article provides an overview of the literature on the structure and function of the main brain pathways.
Parallel Genomic Alterations of Antigen and Payload Targets Mediate Polyclonal Acquired Clinical Resistance to Sacituzumab Govitecan in Triple-Negative Breast Cancer
Authors: James T. Coates, Sheng Sun, Ignaty Leshchiner, Nayana Thimmiah, Elizabeth E. Martin, Daniel McLoughlin, Brian P. Danysh, Kara Slowik, Raquel A. Jacobs, Kahn Rhrissorrakrai, Filippo Utro, Chaya Levovitz, Elyssa Denault, Charlotte S. Walmsley, Avinash Kambadakone, James R. Stone, Steven J. Isakoff, Laxmi Parida, Dejan Juric, Gad Getz, Aditya Bardia, Leif W. Ellisen
Journal: Cancer Discovery (2021)

Sacituzumab govitecan (SG), the first antibody-drug conjugate (ADC) approved for triple-negative breast cancer, incorporates the anti-TROP2 antibody hRS7 conjugated to a topoisomerase-1 (TOP1) inhibitor payload. We sought to identify mechanisms of SG resistance through RNA and whole-exome sequencing of pretreatment and postprogression specimens. One patient exhibiting de novo progression lacked TROP2 expression, in contrast to robust TROP2 expression and focal genomic amplification of TACSTD2/TROP2 observed in a patient with a deep, prolonged response to SG. Analysis of acquired genomic resistance in this case revealed one phylogenetic branch harboring a canonical TOP1 E418K resistance mutation and subsequent frameshift TOP1 mutation, whereas a distinct branch exhibited a novel TACSTD2/TROP2 T256R missense mutation. Reconstitution experiments demonstrated that TROP2T256R confers SG resistance via defective plasma membrane localization and reduced cell-surface binding by hRS7. These findings highlight parallel genomic alterations in both antibody and payload targets associated with resistance to SG. SIGNIFICANCE: These findings underscore TROP2 as a response determinant and reveal acquired SG resistance mechanisms involving the direct antibody and drug payload targets in distinct metastatic subclones of an individual patient. This study highlights the specificity of SG and illustrates how such mechanisms will inform therapeutic strategies to overcome ADC resistance.This article is highlighted in the In This Issue feature, p. 2355.
Seek and Ye Shall Find: COVID-19 and Bacterial Superinfection
Authors: Georgios D. Kitsios, Alison Morris
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Seek and Ye Shall Find: COVID-19 and Bacterial SuperinfectionSince the onset of the coronavirus disease (COVID-19) pandemic and the massive influx of sick patients requiring mechanical ventilation in ICUs around the globe, frontline clinicians have repeatedly faced the same question: "Is it all just COVID-19 or does my patient have a secondary bacterial pneumonia?"Providing a timely and concrete answer at the bedside has proven difficult.COVID-19 pneumonia shares many of the radiographic, physiologic, and clinical features of severe bacterial pneumonias, often with a protracted course and variable evolution of severity, making objective microbiologic data necessary for the diagnosis of superinfections.However, dedicated diagnostic workup with lower respiratory tract (LRT) sampling has been variably performed, and earlier in the pandemic, it was often avoided because of (now largely allayed) concerns of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission.Consistent with clinical practice guidelines (1), about 85% of critically ill patients with COVID-19 receive systemic antibiotics (2, 3), which are often empiric and of broad spectrum.Such management guided by well-intentioned "best guesses" is destined to offer no benefit in many patients and may even cause harm in some.Empiric antibiotics given to patients with an isolated SARS-CoV-2 infection are not only unnecessary, but may also expose patients to unwarranted adverse effects and promote the selection of resistant pathogens.Furthermore, premature diagnostic closure on presumed secondary pneumonia will neglect investigation of competing etiologies for respiratory decline (e.g., pulmonary embolism or congestive heart failure).On the other hand, patients with COVID-19 with a true superinfecting pathogen require the timely initiation of targeted antibiotics of appropriate spectrum and duration (Figure 1).Given these uncertainties, in this issue of the Journal, Pickens and the NU COVID (Northwestern University COVID-19) Investigators (pp.921-932) provide influential and practiceinforming data on bacterial superinfection in mechanically ventilated patients with COVID-19 (4).Capitalizing on an institutional practice of routine bronchoscopic sampling in patients after intubation or with clinical suspicion of ventilator-associated pneumonia (VAP), the authors enrolled 179 patients with COVID-19 and captured a comprehensive data set of 389 BAL samples.These samples were collected either early (within 48 h of intubation, n = 133), while looking for a community-or hospital-acquired superinfection, or late (.48 h, n = 246), while looking for an incident VAP (Figure 1).BAL fluid was analyzed for host cellular composition, as well as for
Sure Start children’s centres prevented 13 000 hospital admissions a year, study estimates
Authors: Adrian O’Dowd
Journal: BMJ (2021)

Around 13 000 admissions of children to hospital each year were likely to have been prevented by the work of the Sure Start children’s centres that were set up across England in 1999 to support parents of young children, the Institute for Fiscal Studies has concluded.

In a report published on 16 August the institute examined the effects of the Sure Start scheme to see how it had affected children’s health up to the age of 15.1 The centres were set up to bring together health, parenting support, childcare, and parental employment services into one place for families with children under the age of 5 years.

At its peak in 2010 Sure Start received more than …
25572 Impact of risankizumab on the duration of PASI90 achievement: A post hoc analysis of 4 phase III clinical trials
Authors: Mark G. Lebwohl, Ahmed M. Soliman, Hongbo Yang, Jessie Wang, Sarah H. Koenigsberg, Annika Anderson, Bryon Padilla, Andreas Pinter
Journal: Journal of the American Academy of Dermatology (2021)
26580 Efficacy of treatment with brodalumab after treatment failure of previous interleukin 17A inhibitors in patients with psoriasis
Authors: Nikolai Loft, Anne Bregnhøj, Simon Fage, Claus Henrik Nielsen, Christian Enevold, Claus Zachariae, Lars Iversen, Lone Skov
Journal: Journal of the American Academy of Dermatology (2021)