tbuckley/cabot-search huggingface dataset:
Platelet and Megakaryocyte Roles in Innate and Adaptive Immunity
Authors: Milka Koupenova, Alison C. Livada, Craig N. Morrell
Journal: Circulation Research (2022)

Classically, platelets have been described as the cellular blood component that mediates hemostasis and thrombosis. This important platelet function has received significant research attention for >150 years. The immune cell functions of platelets are much less appreciated. Platelets interact with and activate cells of all branches of immunity in response to pathogen exposures and infection, as well as in response to sterile tissue injury. In this review, we focus on innate immune mechanisms of platelet activation, platelet interactions with innate immune cells, as well as the intersection of platelets and adaptive immunity. The immune potential of platelets is dependent in part on their megakaryocyte precursor providing them with the molecular composition to be first responders and immune sentinels in initiating and orchestrating coordinated pathogen immune responses. There is emerging evidence that extramedullary megakaryocytes may be immune differentiated compared with bone marrow megakaryocytes, but the physiological relevance of immunophenotypic differences are just beginning to be explored. These concepts are also discussed in this review. The immune functions of the megakaryocyte/platelet lineage have likely evolved to coordinate the need to repair a vascular breach with the simultaneous need to induce an immune response that may limit pathogen invasion once the blood is exposed to an external environment.
Theory of mind in context: Mental-state representations for social evaluation
Authors: Brandon M. Woo, Enda Tan, J. Kiley Hamlin
Journal: Behavioral and Brain Sciences (2021)

Abstract Whereas Phillips and colleagues argue that knowledge representations are more basic than belief representations, we argue that an accurate analysis of what is fundamental to theory of mind may depend crucially on the context in which mental-state reasoning occurs. Specifically, we call for increased study of the developmental trajectory of mental-state reasoning within socially evaluative contexts.
Impacts of heat stress on global cattle production during the 21st century: a modelling study
Authors: Philip Thornton, Gerald Nelson, Dianne Mayberry, Mario Herrero
Journal: The Lancet Planetary Health (2022)

Heat stress in animals is one of the major climate change impacts on domesticated livestock raised in both intensive and extensive production systems. At temperatures higher than an animal's thermoneutral zone, heat stress can affect liveweight gain, milk yield, and fertility. Animal welfare may also be negatively affected by heat stress even in the absence of effects on productivity, at least in the short term.We estimated the comparative statics change in the value of cattle milk and meat production from heat stress-induced losses at the global level, using climate scenario outputs for the middle (2045) and end of the century (2085). The loss estimates are based on bioenergetic equations that relate changes in dry matter intake (DMI) to both cold and hot, humid weather. DMI changes were estimated using CMIP6 climate data and linked to a global dataset containing information on livestock production systems, animal numbers, and region-specific and system-specific animal diets. Changes in DMI were converted to changes in milk and meat production and valued using early 20th century world prices (ie, constant 2005 US dollars).For a high greenhouse-gas emission scenario (SSP5-8.5), production losses from heat stress were estimated to amount to $39·94 billion (95% CI 34·39-45·49 billion) per year by the end of the century, or 9·8% of the value of production of meat and milk from cattle in 2005. For a low emission scenario (SSP1-2.6), the value of production losses was $14·89 billion (12·62-16·95 billion) per year, or 3·7% of 2005 value. In both scenarios, losses in most tropical regions were projected to be far greater than they were in temperate regions.Our results highlight the potential magnitude and extent of the adaptation efforts that will be necessary to combat the effects of increasing heat stress on cattle production during this century if food security challenges are to be minimised. Adaptations include switching to more heat-tolerant breeds and provision of shade, ventilation, and cooling systems.CGIAR Trust Fund and bilateral donors.
Subcortical Cognition: The Fruit Below the Rind
Authors: Karolina Janacsek, Tanya M. Evans, Mariann Kiss, Leela Shah, Hal Blumenfeld, Michael T. Ullman
Journal: Annual Review of Neuroscience (2022)

Cognitive neuroscience has highlighted the cerebral cortex while often overlooking subcortical structures. This cortical proclivity is found in basic and translational research on many aspects of cognition, especially higher cognitive domains such as language, reading, music, and math. We suggest that, for both anatomical and evolutionary reasons, multiple subcortical structures play substantial roles across higher and lower cognition. We present a comprehensive review of existing evidence, which indeed reveals extensive subcortical contributions in multiple cognitive domains. We argue that the findings are overall both real and important. Next, we advance a theoretical framework to capture the nature of (sub)cortical contributions to cognition. Finally, we propose how new subcortical cognitive roles can be identified by leveraging anatomical and evolutionary principles, and we describe specific methods that can be used to reveal subcortical cognition. Altogether, this review aims to advance cognitive neuroscience by highlighting subcortical cognition and facilitating its future investigation.
Mechanism of praziquantel action at a parasitic flatworm ion channel
Authors: Sang-Kyu Park, Lukas Friedrich, Nawal A. Yahya, Claudia M. Rohr, Evgeny G. Chulkov, David Maillard, Friedrich Rippmann, Thomas Spangenberg, Jonathan S. Marchant
Journal: Science Translational Medicine (2021)

Parasitic flatworm sensitivity to praziquantel is determined by amino acid variation in the binding pocket of a TRP channel.
Bioactive hydrogel microcapsules for guiding stem cell fate decisions by release and reloading of growth factors
Authors: Kihak Gwon, Hye Jin Hong, Alan M. Gonzalez-Suarez, Michael Q. Slama, Daheui Choi, Jinkee Hong, Harihara Baskaran, Gulnaz Stybayeva, Quinn P. Peterson, Alexander Revzin
Journal: Bioactive Materials (2021)

Human pluripotent stem cells (hPSC) hold considerable promise as a source of adult cells for treatment of diseases ranging from diabetes to liver failure. Some of the challenges that limit the clinical/translational impact of hPSCs are high cost and difficulty in scaling-up of existing differentiation protocols. In this paper, we sought to address these challenges through the development of bioactive microcapsules. A co-axial flow focusing microfluidic device was used to encapsulate hPSCs in microcapsules comprised of an aqueous core and a hydrogel shell. Importantly, the shell contained heparin moieties for growth factor (GF) binding and release. The aqueous core enabled rapid aggregation of hPSCs into 3D spheroids while the bioactive hydrogel shell was used to load inductive cues driving pluripotency maintenance and endodermal differentiation. Specifically, we demonstrated that one-time, 1 h long loading of pluripotency signals, fibroblast growth factor (FGF)-2 and transforming growth factor (TGF)-β1, into bioactive microcapsules was sufficient to induce and maintain pluripotency of hPSCs over the course of 5 days at levels similar to or better than a standard protocol with soluble GFs. Furthermore, stem cell-carrying microcapsules that previously contained pluripotency signals could be reloaded with an endodermal cue, Nodal, resulting in higher levels of endodermal markers compared to stem cells differentiated in a standard protocol. Overall, bioactive heparin-containing core-shell microcapsules decreased GF usage five-fold while improving stem cell phenotype and are well suited for 3D cultivation of hPSCs.
Targeting Cellular Iron Homeostasis with Ironomycin in Diffuse Large B-cell Lymphoma
Authors: Julie Devin, Tatiana Cañeque, Yea-Lih Lin, Lucie Mondoulet, Jean-Luc Veyrune, Matthieu Abouladze, Elvira Garcia De Paco, Ouissem Karmous Gadacha, Guillaume Cartron, Philippe Pasero, Caroline Bret, Raphaël Rodriguez, Jerome Moreaux
Journal: Cancer Research (2022)

Diffuse large B-cell lymphoma (DLBCL) is the most common hematological malignancy. Although more than half of patients with DLBCL achieve long-term remission, the majority of remaining patients succumb to the disease. As abnormal iron homeostasis is implicated in carcinogenesis and the progression of many tumors, we searched for alterations in iron metabolism in DLBCL that could be exploited to develop novel therapeutic strategies. Analysis of the iron metabolism gene expression profile of large cohorts of patients with DLBCL established the iron score (IS), a gene expression-based risk score enabling identification of patients with DLBCL with a poor outcome who might benefit from a suitable targeted therapy. In a panel of 16 DLBCL cell lines, ironomycin, a promising lysosomal iron-targeting small molecule, inhibited DLBCL cell proliferation at nanomolar concentrations compared with typical iron chelators. Ironomycin also induced significant cell growth inhibition, ferroptosis, and autophagy. Ironomycin treatment resulted in accumulation of DNA double-strand breaks, delayed progression of replication forks, and increased RPA2 phosphorylation, a marker of replication stress. Ironomycin significantly reduced the median number of viable primary DLBCL cells of patients without major toxicity for nontumor cells from the microenvironment and presented low toxicity in hematopoietic progenitors compared with conventional treatments. Significant synergistic effects were also observed by combining ironomycin with doxorubicin, BH3 mimetics, BTK inhibitors, or Syk inhibitors. Altogether, these data demonstrate that a subgroup of high-risk patients with DLBCL can be identified with the IS that can potentially benefit from targeting iron homeostasis.Iron homeostasis represents a potential therapeutic target for high-risk patients with DLBCL that can be targeted with ironomycin to induce cell death and to sensitize tumor cells to conventional treatments.
Sec13 promotes oligodendrocyte differentiation and myelin repair through autocrine pleiotrophin signaling
Authors: Zhixiong Liu, Minbiao Yan, Wanying Lei, Rencai Jiang, Wenxiu Dai, Jialin Chen, Chaomeng Wang, Li Li, Mei Wu, Ximing Nian, Daopeng Li, Di Sun, Xiaoqi Lv, Chaoying Wang, Changchuan Xie, Luming Yao, Caiming Wu, Jin Hu, Naian Xiao, Wei Mo, Zhanxiang Wang, Liang Zhang
Journal: Journal of Clinical Investigation (2022)

Dysfunction of protein trafficking has been intensively associated with neurological diseases, including neurodegeneration, but whether and how protein transport contributes to oligodendrocyte (OL) maturation and myelin repair in white matter injury remains unclear. ER-to-Golgi trafficking of newly synthesized proteins is mediated by coat protein complex II (COPII). Here, we demonstrate that the COPII component Sec13 was essential for OL differentiation and postnatal myelination. Ablation of Sec13 in the OL lineage prevented OPC differentiation and inhibited myelination and remyelination after demyelinating injury in the central nervous system (CNS), while improving protein trafficking by tauroursodeoxycholic acid (TUDCA) or ectopic expression of COPII components accelerated myelination. COPII components were upregulated in OL lineage cells after demyelinating injury. Loss of Sec13 altered the secretome of OLs and inhibited the secretion of pleiotrophin (PTN), which was found to function as an autocrine factor to promote OL differentiation and myelin repair. These data suggest that Sec13-dependent protein transport is essential for OL differentiation and that Sec13-mediated PTN autocrine signaling is required for proper myelination and remyelination.
The BMJ Interview: Rahul Gupta on being in charge of “one of the worst health crises in America”
Authors: Joanne Silberner
Journal: BMJ (2022)

The first physician to serve as America’s drug tsar and a big supporter of harm reduction approaches, Rahul Gupta tells <b>Joanne Silberner</b> that the battle against the opioid epidemic will be won with science
Abstract 066: A Healthy Plant-based Diet Was Associated With Slower Cognitive Decline In African Americans: A Biracial Community-based Cohort Of Older Adults
Authors: Xiaoran Liu, Klodian Dhana, Lisa Barnes, Christy Tangney, Puja Aggarwal, Neelum Agarwal, Thomas Holland, Kumar Rajan
Journal: Circulation (2022)

Background: African Americans (AAs) are about twice as likely to develop dementia compared to non-Hispanic whites (NHWs). Dietary modification is an effective preventive strategy to reduce the rate of cognitive decline, a hallmark feature of dementia; however, evidence from diverse populations focusing on AAs is minimal. Objective: To evaluate the association between a plant-based diet and the rate of cognitive decline in a population-based sample of AAs and NHWs. Method: This study consisted of 4753 participants (62% African American, 63% female) in a biracial population-based study in the United States (Chicago Health and Aging Project, 1993 to 2012). Plant-based diet quality was evaluated by the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI). Global cognition was assessed using a composite score of four tests of cognition. We used mixed models to examine the association between PDI, hPDI, and uPDI with the rate of decline in global cognition, perceptual speed, and episodic memory. Models were adjusted for age, sex, apoE genotype, education, cognitive activities, smoking status, calorie intake, risk factors of cardiovascular disease, time, and an interaction term of time with each covariate. Results: We demonstrated that there were distinct differences in the association of dietary patterns with cognitive decline in AAs and NHWs. AAs had higher intakes of egg, fish or seafood, sugar-sweetened beverages, and whole grains compared to NHWs (p&lt;0.001 for all). Higher hPDI was associated with a slower rate of decline in global cognition, perceptual speed, and episodic memory in AAs but not NHWs. AAs in the highest quintile of hPDI had significantly slower rates of decline in global cognition, β = 0.0183 (p=0.032), perceptual speed β = 0.0179 (p=0.04), and episodic memory β=0.0183 (p=0.04) compared to individuals in the lowest quintile of hPDI. The rate of global cognitive decline in the highest quintile was slowed by 28.4% when compared to individuals in the lowest quintile of hPDI in AAs. There were no associations with either PDI or uPDI and the rate of cognitive decline in either racial group. Conclusion: AAs and NHWs have distinct dietary patterns. A healthy plant-based diet was associated with a slower rate of decline in global cognition, perceptual speed, and episodic memory in AAs. These results are informative in facilitating the development of tailored dietary recommendations for the prevention of cognitive decline in diverse populations.
From more testing to smart testing: data-guided SARS-CoV-2 testing choices, the Netherlands, May to September 2020
Authors: Janko van Beek, Zsofia Igloi, Timo Boelsums, Ewout Fanoy, Hannelore Gotz, Richard Molenkamp, Jeroen van Kampen, Corine GeurtsvanKessel, Annemiek A van der Eijk, David van de Vijver, Marion Koopmans
Journal: Eurosurveillance (2022)

BackgroundSARS-CoV-2 RT-PCR assays are more sensitive than rapid antigen detection assays (RDT) and can detect viral RNA even after an individual is no longer infectious. RDT can reduce the time to test and the results might better correlate with infectiousness.AimWe assessed the ability of five RDT to identify infectious COVID-19 cases and systematically recorded the turnaround time of RT-PCR testing.MethodsSensitivity of RDT was determined using a serially diluted SARS-CoV-2 stock with known viral RNA concentration. The probability of detecting infectious virus at a given viral load was calculated using logistic regression of viral RNA concentration and matched culture results of 78 specimens from randomly selected non-hospitalised cases. The probability of each RDT to detect infectious cases was calculated as the sum of the projected probabilities for viral isolation success for every viral RNA load found at the time of diagnosis in 1,739 confirmed non-hospitalised COVID-19 cases.ResultsThe distribution of quantification cycle values and estimated RNA loads for patients reporting to drive-through testing was skewed to high RNA loads. With the most sensitive RDT (Abbott and SD Biosensor), 97.30% (range: 88.65-99.77) of infectious individuals would be detected. This decreased to 92.73% (range: 60.30-99.77) for Coris BioConcept and GenBody, and 75.53% (range: 17.55-99.77) for RapiGEN. Only 32.9% of RT-PCR results were available on the same day as specimen collection.ConclusionThe most sensitive RDT detected infectious COVID-19 cases with high sensitivity and may considerably improve containment through more rapid isolation and contact tracing.
Targeting the anti-apoptotic Bcl-2 family proteins: machine learning virtual screening and biological evaluation of new small molecules
Authors: Elisabetta Valentini, Simona D'Aguanno, Marta Di Martile, Camilla Montesano, Virginia Ferraresi, Alexandros Patsilinakos, Manuela Sabatino, Lorenzo Antonini, Martina Chiacchiarini, Sergio Valente, Antonello Mai, Gianni Colotti, Rino Ragno, Daniela Trisciuoglio, Donatella Del Bufalo
Journal: Theranostics (2022)

Bcl-2 family anti-apoptotic proteins are overexpressed in several hematological and solid tumors, and contribute to tumor formation, progression, and resistance to therapy.They represent a promising therapeutic avenue to explore for cancer treatment.Venetoclax, a Bcl-2 inhibitor is currently used for hematological malignancies or is undergoing clinical trials for either hematological or solid tumors.Despite these progresses, ongoing efforts are focusing on the identification and development of new molecules targeting Bcl-2 protein and/or other family members.Methods: Machine learning guided virtual screening followed by surface plasmon resonance, molecular docking and pharmacokinetic analyses were performed to identify new inhibitors of anti-apoptotic members of Bcl-2 family and their pharmacokinetic profile.The sensitivity of cancer cells from different origin to the identified compounds was evaluated both in in vitro (cell survival, apoptosis, autophagy) and in vivo (tumor growth in nude mice) preclinical models.Results: IS20 and IS21 were identified as potential new lead compounds able to bind Bcl-2, Bcl-xL and Mcl-1 recombinant proteins.Molecular docking investigation indicated IS20 and IS21 could bind into the Beclin-1 BH3 binding site of wild type Bcl-2, Bcl-xL and Mcl-1 proteins.In particular, although the IS21 docked conformation did not show a unique binding mode, it clearly showed its ability in flexibly adapting to either BH3 binding sites.Moreover, both IS20 and IS21 reduced cell viability, clonogenic ability and tumor sphere formation, and induced apoptosis in leukemic, melanoma and lung cancer cells.Autophagosome formation and maturation assays demonstrated induction of autophagic flux after treatment with IS20 or IS21.Experiments with z-VAD-fmk, a pan-caspase inhibitor, and chloroquine, a late-stage autophagy inhibitor, demonstrated the ability of the two compounds to promote apoptosis by autophagy.IS21 also reduced in vivo tumor growth of both human leukemia and melanoma models. Conclusion:Virtual screening coupled with in vitro and in vivo experimental data led to the identification of two new promising inhibitors of anti-apoptotic proteins with good efficacy in the binding to recombinant Bcl-2, Bcl-xL and Mcl-1 proteins, and against different tumor histotypes.
Consciousness generates agent action
Authors: Jonathan Delafield-Butt, Colwyn Trevarthen
Journal: Behavioral and Brain Sciences (2022)

Abstract Consciousness directs the actions of the agent for its own purposive gains. It re-organises a stimulus-response linear causality to deliver generative, creative agent action that evaluates the subsequent experience prospectively. This inversion of causality affords special properties of control that are not accounted for in integrated information theory (IIT), which is predicated on a linear, deterministic cause-effect model. IIT remains an incomplete, abstract, and disembodied theory without explanation of the psychobiology of consciousness that serves the vital agency the organism.
Abstract 11048: Serotonin Transporter Deficiency Leads to a Specific Fibrotic Pattern in Valvular and Myocardial Tissue
Authors: Estibaliz Castillero, Alex D'Angelo, Mangesh Kurade, Robert LEVY, Giovanni Ferrari
Journal: Circulation (2021)

Introduction: Increased serotonin (5HT) levels can lead to heart valve disease. This mechanism is observed in patients with 5HT-secreting carcinoid tumors and after treatment with the diet drug Dexfenfluoramine, which acts as a 5HT receptor (HTR)-2B agonist and as an inhibitor of the 5HT transporter (SERT). SERT internalizes 5HT, limiting HTR signaling (Figure 1A). We showed that SERT reduction on human mitral valve (MV) contributes to the progression of MV regurgitation. We investigated the impact of SERT deficiency on cardiac substructures in a SERT-/- murine model. Methods: SERT-/- and wild type (WT) C57BL/6J mice (n≥8/group) were sacrificed at 16 weeks of age, after echocardiography (Fig. 1B). Cardiac substructures (left ventricle (LV) apex, MV leaflets, aortic valve (AV) leaflets and aortic-mitral (AM curtain) were isolated in three animals/group (Fig. 1E). Results: Ventricular dimensions were significantly larger in SERT-/- mice vs. WT at end-systole and end-diastole (Fig. 1C). Fractional shortening was significantly reduced in SERT-/- mice vs. WT. Pricosirius staining of collagen showed that SERT-/- mice had increased MV leaflet fibrosis, MV and AV sub-valvular fibrosis at leaflet attachment points (AM curtain, Fig. 1D), and epicardial fibrosis. PCR (Fig. 1F) showed significantly increased COL1A1 expression in the LV myocardium, MV, AV and AM curtain in SERT-/- mice vs. WT. Fibrosis marker alpha smooth muscle actin (αSMA) was significantly increased in the myocardium and AM curtain of SERT-/- mice, but not in the valve leaflets. HTR2B expression was significantly increased in the MV and AM curtain of SERT-/- mice. Conclusions: SERT-/- mice have decreased cardiac function, and cardiac fibrosis that is associated with HTR2B upregulation in the MV leaflets and valve leaflet attachment points. Our results support the hypothesis that decreased 5HT clearance by SERT downregulation may increase HTR2B signaling in the MV leading to remodeling and regurgitation.