Miracle-dz/UniFAR-FTUs huggingface dataset:
Preclinical advances and the immunophysiology of a new therapeutic Chagas disease vaccine

ABSTRACT Introduction Chronic infection with the protozoal parasite Trypanosoma cruzi leads to a progressive cardiac disease, known as chronic Chagasic cardiomyopathy (CCC). A new therapeutic Chagas disease vaccine is in development to augment the existing antiparasitic chemotherapy drugs. Areas Covered We report on our current understanding of the underlying immunologic and physiologic mechanisms that lead to CCC, including parasite immune escape mechanisms that allow persistence and the subsequent inflammatory and fibrotic processes that lead to clinical disease. We report on vaccine design and the observed immunotherapeutic effects including induction of a balanced TH1/TH2/TH17 immune response that leads to reduced parasite burdens and tissue pathology. Furthermore, we report vaccine-linked chemotherapy, a dose-sparing strategy to further reduce parasite burdens and tissue pathology. Expert Opinion Our vaccine-linked chemotherapeutic approach is a multimodal treatment strategy, addressing both the parasite persistence and the underlying deleterious host inflammatory and fibrotic responses that lead to cardiac dysfunction. In targeting treatment towards patients with chronic indeterminate or early determinate Chagas disease, this vaccine-linked chemotherapeutic approach will be highly economical and will reduce the global disease burden and deaths due to CCC.
The cotranscriptional folding landscape for two cyclic di-nucleotide-sensing riboswitches with highly homologous aptamer domains acting either as ON- or OFF-switches

Abstract Riboswitches are gene regulatory elements located in untranslated mRNA regions. They bind inducer molecules with high affinity and specificity. Cyclic-di-nucleotide-sensing riboswitches are major regulators of genes for the environment, membranes and motility (GEMM) of bacteria. Up to now, structural probing assays or crystal structures have provided insight into the interaction between cyclic-di-nucleotides and their corresponding riboswitches. ITC analysis, NMR analysis and computational modeling allowed us to gain a detailed understanding of the gene regulation mechanisms for the Cd1 (Clostridium difficile) and for the pilM (Geobacter metallireducens) riboswitches and their respective di-nucleotides c-di-GMP and c-GAMP. Binding capability showed a 25 nucleotide (nt) long window for pilM and a 61 nt window for Cd1. Within this window, binding affinities ranged from 35 μM to 0.25 μM spanning two orders of magnitude for Cd1 and pilM showing a strong dependence on competing riboswitch folds. Experimental results were incorporated into a Markov simulation to further our understanding of the transcriptional folding pathways of riboswitches. Our model showed the ability to predict riboswitch gene regulation and its dependence on transcription speed, pausing and ligand concentration.
Intact high‐resolution working memory binding in a patient with developmental amnesia and selective hippocampal damage

Debate continues regarding the possible role of the hippocampus across short‐term and working memory tasks. The current study examined the possibility of a hippocampal contribution to precise, high‐resolution cognition and conjunctive memory. We administered visual working memory tasks featuring a continuous response component to a well‐established developmental amnesic patient with relatively selective bilateral hippocampal damage (Jon) and healthy controls. The patient was able to produce highly accurate response judgments regarding conjunctions of color and orientation or color and location, using simultaneous or sequential presentation of stimuli, with no evidence of any impairment in working memory binding, categorical accuracy, or continuous precision. These findings indicate that hippocampal damage does not necessarily lead to deficits in high‐resolution cognitive performance, even when the damage is severe and bilateral.
Reduction in the Treatment Gap for Breast Cancer in Mexico under Seguro Popular, 2007 to 2016

ABSTRACT As Mexico’s government restructures the health system, a comprehensive assessment of Seguro Popular’s Fund for Protection against Catastrophic Expenses (FPGC) can help inform decision makers to improve breast cancer outcomes and health system performance. This study aimed to estimate the treatment gap for breast cancer patients treated under FPGC and assess changes in this gap between 2007 (when coverage started for breast cancer treatment) and 2016. We used a nationwide administrative claims database for patients whose breast cancer treatment was financed by FPGC in this period (56,847 women), Global Burden of Disease breast cancer incidence estimates, and other databases to estimate the population not covered by social security. We compared the observed number of patients who received treatment under FPGC to the expected number of breast cancer cases among women not covered by social security to estimate the treatment gap. Nationwide, the treatment gap was reduced by more than half: from 0.71, 95% CI (0.69, 0.73) in 2007 to 0.15, 95%CI (0.09, 0.22) in 2016. Reductions were observed across all states . This is the first study to assess the treatment gap for breast cancer patients covered under Seguro Popular. Expanded financing through FPGC sharply increased access to treatment for breast cancer. This was an important step toward improving breast cancer care, but high mortality remains a problem in Mexico. Increased access to treatment needs to be coupled with effective interventions to assure earlier cancer diagnosis and earlier initiation of high-quality treatment.
Layer-specific distribution and expression pattern of AMPA- and NMDA-type glutamate receptors in the barrel field of the adult rat somatosensory cortex: a quantitative electron microscopic analysis

Abstract AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) and NMDA (N-methyl-d-aspartate) glutamate receptors are driving forces for synaptic transmission and plasticity at neocortical synapses. However, their distribution pattern in the adult rat neocortex is largely unknown and was quantified using freeze fracture replication combined with postimmunogold-labeling. Both receptors were co-localized at layer (L)4 and L5 postsynaptic densities (PSDs). At L4 dendritic shaft and spine PSDs, the number of gold grains detecting AMPA was similar, whereas at L5 shaft PSDs AMPA-receptors outnumbered those on spine PSDs. Their number was significantly higher at L5 vs. L4 PSDs. At L4 and L5 dendritic shaft PSDs, the number of gold grains detecting GluN1 was ~2-fold higher than at spine PSDs. The number of gold grains detecting the GluN1-subunit was higher for both shaft and spine PSDs in L5 vs. L4. Both receptors showed a large variability in L4 and L5. A high correlation between the number of gold grains and PSD size for both receptors and targets was observed. Both receptors were distributed over the entire PSD but showed a layer- and target-specific distribution pattern. The layer- and target-specific distribution of AMPA and GluN1 glutamate receptors partially contribute to the observed functional differences in synaptic transmission and plasticity in the neocortex.
Role of post-translational modifications on the alpha-synuclein aggregation-related pathogenesis of Parkinson’s disease

Together with neuronal loss, the existence of insoluble inclusions of alpha-synuclein (α-syn) in the brain is widely accepted as a hallmark of synucleinopathies including Parkinson’s disease (PD), multiple system atrophy, and dementia with Lewy body. Because the α-syn aggregates are deeply involved in the pathogenesis, there have been many attempts to demonstrate the mechanism of the aggregation and its potential causative factors including post-translational modifications (PTMs). Although no concrete conclusions have been made based on the previous study results, growing evidence suggests that modifications such as phosphorylation and ubiquitination can alter α-syn characteristics to have certain effects on the aggregation process in PD; either facilitating or inhibiting fibrillization. In the present work, we reviewed studies showing the significant impacts of PTMs on α-syn aggregation. Furthermore, the PTMs modulating α-syn aggregation-induced cell death have been discussed.
Dance for Chronic Pain Conditions: A Systematic Review

Abstract Objectives Globally, 20–25% of people will experience chronic pain in their lifetimes. Dance is a physical activity with psychosocial benefits that might positively impact pain. This review aimed to investigate the effect of dance interventions on the experience of pain by quantitative measures and qualitative themes. Methods Seven major databases were searched from inception to January 2021. Two independent reviewers screened articles at each stage. Qualitative and quantitative studies were included if the dance interventions lasted more than 6 weeks, participants reported pain of duration longer than 3 months, and pain was an outcome of the study. All articles were critically appraised with appropriate Joanna Briggs Institute tools, and data were collated through the use of results-based convergent synthesis. Results From 23,628 articles, 34 full papers were included, with a total of 1,254 participants (75.2% female). Studies predominantly investigated individuals with fibromyalgia (26%) and generalized chronic pain (14%), with aerobic dance (20.7%) and Biodanza (20.7%) being the most common dance genres investigated. Overall, 74% of studies noted either reduced pain through quantitative pain measures or qualitative themes of improved pain experience (88% for chronic primary pain and 80% for chronic secondary musculoskeletal pain). Discussion There were positive effects of dance on chronic primary and secondary musculoskeletal pain across diverse populations. A variety of study designs and interventions noted improved pain measures and themes around pain coping and acceptance, with all dance therapies showing improvements, particularly when performed for 60–150 minutes’ duration weekly. Dance should be considered as an effective adjunct in the management of chronic pain.
Daily discrimination, church support, personal mastery, and psychological distress in black people in the United States

ABSTRACT Objective This study used the stress process model to test the mediating effects of personal mastery and moderating effects of church-based social support on the relationship between daily discrimination and psychological distress across three age groups of African American and Afro-Caribbean adults. Methods Using a national sample of 5008 African Americans and Afro-Caribbean adults from the National Survey of American Life Study, this study employs structural equation modeling to investigate the relationships between daily discrimination, personal mastery, church-based social support, and psychological distress. Results Daily discrimination was an independent predictor of psychological distress across all groups. Group- and age-specific comparisons revealed significant differences in the experience of daily discrimination and psychological distress. Mastery was a partial mediator of the relationship between discrimination and psychological distress among Afro-Caribbeans while church support was a significant moderator only among the young and older African Americans. Implications Together, our study findings provide useful first steps towards developing interventions to reduce the adverse psychological impacts of daily discrimination on African Americans and Afro-Caribbeans. Intervention efforts such as individual psychotherapy aimed to improve Afro-Caribbean individuals’ sense of mastery would be a partial solution to alleviating the adverse effects of discrimination on their psychological health.
The relation of blood cell division control protein 42 level with disease risk, comorbidity, tumor features/markers, and prognosis in colorectal cancer patients

Cell division control protein 42 (CDC42) is involved in colorectal cancer (CRC) progression by modulating CD8+ T cell activation, immune escape, and direct oncogenetic biological processes. This study aimed to explore the correlation of blood CDC42 with disease risk, comorbidities, disease features, tumor markers, and prognosis among CRC patients.
Expression profiling of immune genes associated with black pepper (Piper nigrum) powder supplementation in the diets of broiler chickens

Abstract The present study was conducted on three hundred commercial broiler chicks with the aim to evaluate the effect of black pepper supplementation on expression of TLR gene where the negative control (T1) group was given basal diet without antibiotic and in the control group (T2) basal diet with antibiotic was fed, third (T3), fourth (T4), fifth (T5) and sixth (T6) groups were supplemented with black pepper powder (BPP) at levels 0.25, 0.5, 0.75 and 1%, respectively in diet. After 42 days, a significant reduction (p < 0.05) in ileal E. coli count and a higher value of Lactobacilli was recorded in the various black pepper powder supplemented groups, and they differed significantly (p < 0.05) from negative control. The mRNA expression levels of Toll-like receptors (TLR 2 and TLR 4) had shown significant (p < 0.05) changes in experimental groups. The TLR 2 and TLR 4 genes revealed differential expression in all black pepper supplemented groups in comparison to negative control and control group, while TLR 7 did not show any significant change. Thus, supplementation of black pepper powder can be exploited as an immunomodulator to enhance adaptive immune response of broiler chicks after validation on large number of samples.
B cell targeting in CAR T cell therapy: Side effect or driver of CAR T cell function?

Chimeric antigen receptor (CAR) T cell therapies targeting CD19 and CD22 have been successful for treating B cell cancers, but CAR T cells targeting non–B cell cancers remain unsuccessful. We propose that rather than being strictly a side effect of therapy, the large number of CAR interactions with normal B cells may be a key contributor to clinical CAR T cell responses. Description Targeting normal B cells may be a key driver of CAR T cell function.
Concurrent intraventricular intracranial myxoid mesenchymal tumor and ependymoma in a long‐term Ewing sarcoma survivor

Intracranial myxoid mesenchymal tumor, FET::CREB fusion positive is a rare, recently described central nervous system neoplasm. It is characterized by EWSR1::CREB family transcription factor fusion, typically arises in children and adolescents, and is locally aggressive even after gross total resection. Currently, there are little data available to guide management and gauge long‐term prognosis. Furthermore, there have been no reports of these lesions occurring simultaneously with other intracranial neoplasms or in patients with a history of malignancy. Here we describe the first case of a very unusual patient with intracranial myxoid mesenchymal tumor of the right lateral ventricle with a concurrent fourth ventricular ependymoma who had a remote history of Ewing sarcoma of the right fibula.
Diagnosis, treatment and supportive management of chronic lymphocytic leukemia: recommendations of the Dutch HOVON CLL working group

Abstract Management of patients with chronic lymphocytic leukemia (CLL) is changing due to considerable advances in the therapeutic armamentarium, and new therapies will possibly continue to emerge in the near future. Therefore, the CLL working group of the Dutch-Belgium Haemato-Oncology Cooperative Group for Adults in the Netherlands (HOVON) necessitated revising the Dutch CLL guidelines. The current guideline is based on the expert opinion of the HOVON CLL working group members and focusses on well-designed clinical trials taking into account efficacy with special emphasis on toxicity, treatment duration and treatment intensity. This article provides recommendations on diagnosis, treatment strategies in front-line and relapsed setting and provides supportive care measurements during novel-based therapies as well as for infectious CLL-related complications. The recommendations presented here are intended to provide guidance for the management of CLL patients in the Netherlands, and take into account the availability of treatment strategies at the time of this publication.
Prognostic and Biologic Significance of ERBB2-Low Expression in Early-Stage Breast Cancer.

Importance It is unclear whether ERBB2-low breast cancer should be considered an individual biologic subtype distinct from ERBB2-0 breast cancer. Objective To investigate whether low ERBB2 expression is associated with distinct clinicopathologic characteristics and prognosis among patients with hormone receptor (HR)-positive and triple-negative breast cancer (TNBC). Design, Setting, and Participants This cohort study was conducted using data from a prospectively maintained institutional database on all consecutive patients with breast cancer undergoing surgery between January 2016 and March 2021 at Dana-Farber Brigham Cancer Center. The study included 5235 patients with stage I through III, ERBB2-negative invasive breast cancer. Tumors were classified as ERBB2-low if they had an ERBB2 immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization assay and ERBB2-0 if they had an ERBB2 IHC score of 0. Data were analyzed from September 2021 through January 2022. Exposures Standard treatment according to institutional guidelines. Main Outcomes and Measures Comparison of clinicopathologic characteristics and disease outcomes (pathologic complete response rate [pCR], disease-free survival, distant disease-free survival, and overall survival) between patients with ERBB2-low and ERBB2-0 breast cancer. Results Among 5235 patients with ERBB2-negative invasive breast cancer (5191 [99.2%] women; median [range] age at primary surgery, 59.0 [21.0-95.0] years), 2917 patients (55.7%) and 2318 patients (44.3%) had ERBB2-low and ERBB2-0 tumors, respectively. Expression of HR was significantly more common among ERBB2-low compared with ERBB2-0 tumors (2643 patients [90.6%] vs 1895 patients [81.8%]; P < .001). The rate of ERBB2-low tumors increased progressively, from 296 of 739 estrogen receptor (ER)-negative tumors (40.1%) to 31 of 67 ER-low (ie, ER 1%-9%) tumors (46.3%), 37 of 67 ER-moderate (ie, ER, 10%-49%) tumors (55.2%), 2047 of 3542 ER-high (ie, ER, 50%-95%) tumors (57.8%), and 499 of 803 ER-very high (ie, ER > 95%) tumors (62.1%) (P < .001). Among 675 patients receiving neoadjuvant chemotherapy, those with ERBB2-0 tumors experienced higher pCR rates (95 patients [26.8%] vs 53 patients [16.6%]; P = .002). However, there were no statistically significant differences in pCR rate between ERBB2-low and ERBB2-0 tumors when separately analyzing HR-positive, ER-low, HR-positive without ER-low, or TNBC tumors. In exploratory survival analysis, no differences by ERBB2-low expression in disease-free survival, distant disease-free survival, or overall survival were observed among patients with HR-positive tumors or TNBC. Conclusions and Relevance The results of this cohort study did not support the interpretation of ERBB2-low breast cancer as a distinct biologic subtype. ERBB2-low expression was positively associated with level of ER expression, and ER-low tumors were enriched among ERBB2-0 tumors, suggesting that, given the worse prognosis of ER-low tumors, they may be associated with confounding of prognostic analyses of ERBB2-low expression.
Functional Genomics Identified Novel Genes Involved in Growth at Low Temperatures in Listeria monocytogenes

Listeria monocytogenes is a Gram-positive pathogen that contributes to foodborne outbreaks due to its ability to survive at low temperatures. However, the genetic determinants of Lm involved in growth at low temperatures have not been fully defined. ABSTRACT Listeria monocytogenes (Lm) is a foodborne pathogen that can cause severe human illness. Standard control measures for restricting bacterial growth, such as refrigeration, are often inadequate as Lm grows well at low temperatures. To identify genes involved in growth at low temperatures, a powerful functional genomics method Tn-seq was performed in this study. This genome-wide screening comprehensively identified the known and novel genetic determinants involved in low-temperature growth. A novel gene lmo1366, encoding rRNA methyltransferase, was identified to play an essential role in Lm growth at 16°C. In contrast, the inactivation of lmo2301, a gene encoding the terminase of phage A118, significantly enhanced the growth of Lm at 16°C. The deletion of lmo1366 or lmo2301 resulted in cell morphology alterations and impaired the growth rate in milk and other conditions at low temperatures. Transcriptomic analysis revealed that the Δlmo1366 and Δlmo2301 mutants exhibited altered transcriptional patterns compared to the wild-type strain at 16°C with significant differences in genes involved in ribosome structural stability and function, and membrane biogenesis, respectively. This work uncovered novel genetic determinants involved in Lm growth at 16°C, which could lead to a better understanding of how bacteria survive and multiply at low temperatures. Furthermore, these findings could potentially contribute to developing novel antibacterial strategies under low-temperature conditions. IMPORTANCE Listeria monocytogenes is a Gram-positive pathogen that contributes to foodborne outbreaks due to its ability to survive at low temperatures. However, the genetic determinants of Lm involved in growth at low temperatures have not been fully defined. Here, the genetic determinants involved in the low-temperature growth of Lm were comprehensively identified on a genome-wide scale by Tn-seq. The gene lmo1366, encoding rRNA methyltransferase, was identified essential for growth under low-temperature conditions. On the other hand, the gene lmo2301, encoding terminase of phage A118, plays a negative role in bacterial growth at low temperatures. The transcriptomic analysis revealed the potential mechanisms. These findings lead to a better understanding of how bacteria survive and multiply at low temperatures and could provide unique targets for novel antibacterial strategies under low-temperature conditions.