OCA-B/Pou2af1 is sufficient to promote CD4+ T cell memory and prospectively identifies memory precursors.

The molecular mechanisms leading to the establishment of immunological memory are inadequately understood, limiting the development of effective vaccines and durable antitumor immune therapies. Here, we show that ectopic OCA-B expression is sufficient to improve antiviral memory recall responses, while having minimal effects on primary effector responses. At peak viral response, short-lived effector T cell populations are expanded but show increased Gadd45b and Socs2 expression, while memory precursor effector cells show increased expression of Bcl2, Il7r, and Tcf7 on a per-cell basis. Using an OCA-B mCherry reporter mouse line, we observe high OCA-B expression in CD4+ central memory T cells. We show that early in viral infection, endogenously elevated OCA-B expression prospectively identifies memory precursor cells with increased survival capability and memory recall potential. Cumulatively, the results demonstrate that OCA-B is both necessary and sufficient to promote CD4 T cell memory in vivo and can be used to prospectively identify memory precursor cells.

Association between labor and delivery pain and postpartum pain with symptoms and clinical diagnosis of postpartum depression in patients with overweight and obesity.

PURPOSE: Childbirth pain has been associated with the risk for postpartum depression. However, existing studies have been limited by the use of depression screening tools as outcomes, and none to date have used a structured clinical interview for DSM-V (SCID), which is considered the gold standard for psychiatric diagnoses. This study aimed to quantify the relationships between labor and postpartum pain and postpartum depression diagnosis detected by SCID, as well as depression symptoms detected by the Center for Epidemiological Studies Depression Scale (CESD) screening tool, among a high-risk cohort. METHODS: The study was a secondary analysis of a prospective observational study of a cohort of women enriched for high risk for depression, i.e., pregnant women originally enrolled in a prospective study investigating factors leading to excessive gestational weight gain. Subjects were assessed prospectively for depression using both SCID and CESD at the third trimester and at 6 months postpartum. Overweight and obesity were defined as pre-gravid body mass index (BMI) ≥ 25 kg/m2. Both vaginal and cesarean deliveries were included in the cohort. Pain scores (0-10 numeric rating scale) during childbirth and after delivery were correlated with CESD and SCID. Propensity score matching was performed with propensity groups defined as those with low-moderate postpartum pain and those with high postpartum pain. The relationships between pain measures and 6-month postpartum depression diagnosis by SCID, and between pain measures and 6-month postpartum depression symptoms by CESD, were assessed by unweighted logistic regression and by logistic regression weighted by propensity score derived by average treatment effect (ATE) adjusted for baseline covariates. RESULTS: There were 237 subjects in the cohort for analysis. Labor and postpartum pain were not associated with depression diagnosis by SCID at 6 months postpartum. However, postpartum pain, but not labor pain, was associated with depressive symptoms on the CESD at 6 months postpartum. Women with higher maximum postpartum pain scores had significantly higher odds of developing clinically significant postpartum depressive symptoms at 6 months, compared to those with lower pain scores in the unweighted model (OR: 1.3, 95% CI 1.0, 1.5; P = 0.005) and ATE-weighted models (OR: 1.2, 95% CI 1.0, 1.5; P = 0.03). Consistent with prior work, SCID and CESD were strongly associated, and 92.9% (13/14) of participants with postpartum depression diagnosis by 6-month SCID also showed high CESD symptomology, P < 0.0001). CONCLUSIONS: Although labor and postpartum pain were not associated with clinical diagnosis of depression (SCID) at 6 months postpartum, postpartum pain was linked to 6-month postpartum depression symptoms. Depressive symptoms are more likely to be exhibited in women with higher postpartum pain, potentially reflecting poorer birth recovery. The contribution of postpartum pain and depressive symptoms to overall patterns of poor recovery after childbirth should be assessed further.

Intraoperative Remifentanil Infusion and Postoperative Pain Outcomes After Cardiac Surgery-Results from Secondary Analysis of a Randomized, Open-Label Clinical Trial.

DESIGN: Report of secondary pain outcomes from a prospective, randomized, open-label clinical trial that compared remifentanil and fentanyl on perioperative hyperglycemic response in cardiac surgery. SETTING: Single institution, tertiary university hospital. PARTICIPANTS: The study comprised 116 adult elective cardiac surgical patients. INTERVENTIONS: Participants were randomly assigned to receive either intermittent fentanyl boluses (F) or continuous remifentanil infusion (R) intraoperatively. MEASUREMENTS AND MAIN RESULTS: Postoperative pain was evaluated with pain scores every 6 hours for 48 hours. Pain threshold to mechanical stimuli was measured around the sternotomy incision at 48 and 96 hours. The development of chronic pain was assessed using the numeric rating scale at 1, 3, 6, and 12 months after discharge. The final analysis included 106 patients. Pain scores and wound hyperalgesia were not significantly different postoperatively between the groups. The incidence of chronic pain at 3 months was comparable in both groups (61% in group F v 58% in group R; p = 0.79). Pain of more-than-mild degree was seen in 13 (32%) patients in group F and 8 (19%) in group R (p = 0.25) at 3 months. Median pain scores were not significantly different between the groups at 1, 3, 6, and 12 months after discharge from the hospital. CONCLUSIONS: The present study's findings suggested that intraoperative remifentanil infusion does not significantly worsen pain outcomes in patients undergoing elective cardiac surgery.

The impact of socioeconomic status in patients with left ventricular assist devices (LVADs).

BACKGROUND: Socioeconomic status (SES) can be a powerful predictor of adverse outcomes among heart failure patients but its impact on survival and readmission following left ventricular assist device (LVAD) implantation surgery is poorly understood. We investigated if the LVAD recipients from more deprived neighborhoods experienced higher mortality and readmission rate after device implantation as compared to those from less deprived areas. METHODS: This is a single center, retrospective analysis evaluating adults who received Heartmate III and Heartware HVAD implants between 2009 and 2018. SES indicators were area of deprivation index (ADI), race and income. Our cohort was grouped by ADI quartiles from least deprived (Q1), Q2, Q3 to the most deprived (Q4). Outcomes included overall mortality and readmission following surgery. RESULTS: A total of 191 patients were included in the study. Demographics by SES indicators demonstrated that least deprived (Q1) patients were older than the most deprived (65 vs. 57, p < .01), African-American patients originated from more deprived neighborhoods than Caucasians (ADI 87 vs. 62, p < .001), and high-income patients had higher preoperative BUN and creatinine. Outcome differences included a decreased risk of death in most deprived patients (Q4) compared to the least deprived (Q1), however after adjusting for age, LVAD indication, and INTERMACS profile this was no longer significant. No differences in survival or readmission by race or income was observed CONCLUSION: SES does not independently impact survival and readmission after Heartware HVAD and Heartmate III LVAD implantation. More studies are needed to evaluate if other SES factors affect these outcomes.

Recent advances in microfluidic platforms for single-cell analysis in cancer biology, diagnosis and therapy.

Understanding molecular, cellular, genetic and functional heterogeneity of tumors at the single-cell level has become a major challenge for cancer research. The microfluidic technique has emerged as an important tool that offers advantages in analyzing single-cells with the capability to integrate time-consuming and labour-intensive experimental procedures such as single-cell capture into a single microdevice at ease and in a high-throughput fashion. Single-cell manipulation and analysis can be implemented within a multi-functional microfluidic device for various applications in cancer research. Here, we present recent advances of microfluidic devices for single-cell analysis pertaining to cancer biology, diagnostics, and therapeutics. We first concisely introduce various microfluidic platforms used for single-cell analysis, followed with different microfluidic techniques for single-cell manipulation. Then, we highlight their various applications in cancer research, with an emphasis on cancer biology, diagnosis, and therapy. Current limitations and prospective trends of microfluidic single-cell analysis are discussed at the end.

Light-Oxygen-Voltage (LOV)-sensing Domains: Activation Mechanism and Optogenetic Stimulation.

The light-oxygen-voltage (LOV) domains of phototropins emerged as essential constituents of light-sensitive proteins, helping initiate blue light-triggered responses. Moreover, these domains have been identified across all kingdoms of life. LOV domains utilize flavin nucleotides as co-factors and undergo structural rearrangements upon exposure to blue light, which activates an effector domain that executes the final output of the photoreaction. LOV domains are versatile photoreceptors that play critical roles in cellular signaling and environmental adaptation; additionally, they can noninvasively sense and control intracellular processes with high spatiotemporal precision, making them ideal candidates for use in optogenetics, where a light signal is linked to a cellular process through a photoreceptor. The ongoing development of LOV-based optogenetic tools, driven by advances in structural biology, spectroscopy, computational methods, and synthetic biology, has the potential to revolutionize the study of biological systems and enable the development of novel therapeutic strategies.

Review of racial/ethnic disparities in obstetrics-related anesthesia administration and pain management.

While racial/ethnic disparities in maternal outcomes including mortality and severe maternal morbidity are well documented, there is limited information on disparities in obstetric anesthesia practices. This paper reviews literature on racial/ethnic disparities in peripartum anesthesia administration and postpartum pain management. Current literature demonstrates racial/ethnic disparities in several aspects of obstetric anesthesia care including neuraxial administration for vaginal labor pain, neuraxial versus general anesthesia for cesarean delivery, post neuraxial anesthesia complications, postpartum pain management and postdural puncture headache treatment practices. However, many studies are dated or have limited data from single institutions or states. More research on nation-wide racial/ethnic disparities in obstetric anesthesia is needed to understand its broader practice and management in the USA.

While racial/ethnic disparities in maternal mortality and morbidity are well documented, there is limited information on disparities in anesthesia practices for pregnant women. Consequently, this paper reviews literature on racial/ethnic disparities in maternal pain management during and after delivery. Current literature demonstrates racial/ethnic disparities in several aspects of obstetric pain management care including epidural use for vaginal labor pain, regional versus general anesthesia for cesarean delivery, epidural anesthesia complications, pain management after delivery and postural puncture headache treatment practices. However, many available studies are dated or limited to single institutions or states. Therefore, more research on nation-wide racial/ethnic disparities in obstetric pain management is needed to understand its broader practice and management in the USA.

Translational research updates in female health anesthesiology: a narrative review.

Background and Objective: Females represent 49.6% of the global population and constitute a significant proportion of surgical patients and hospital admissions. Little is known about the bi-directional effects of sex and anesthetics or the impact of anesthetic interventions on long-term female health outcomes. Sex differences in pain pathways can influence pain experience and treatment effectiveness. The impact of anesthetic management on the recurrence of breast cancer is poorly understood, as are the long-term consequences of cardiovascular disease and safe and effective treatments in pregnancy. This review aims to outline recent advances in translational science in female health anesthesiology research and highlight critical research opportunities in pain, cancer outcomes, and cardiovascular disorders. Methods: We searched PubMed and summarized relevant articles published in English between December 2021 and June 2022. Key Content and Findings: Studies reveal sex differences in pain pathways and highlight the importance of sex as a biological variable in experimental designs and translational medicine. Sex differences have also been observed in side effects attributed to opioid analgesics. We summarize some of the neural circuits that might underlie these differences. In the perioperative setting, specific anesthetics are implicated in metastatic seeding potential and acute and chronic pain outcomes, suggesting the importance of anesthetic selection in comprehensive care during oncologic surgery. In the peridelivery setting, preeclampsia, a cardiovascular disorder of pregnancy, affects maternal outcomes; however, biomarkers can risk-stratify females at risk for preeclampsia and hold promise for identifying the risk of adverse neurological and other health outcomes. Conclusions: Research that builds diagnostic and predictive tools in pain and cardiovascular disease will help anesthesiologists minimize sex-related risks and side effects associated with anesthetics and peri-hospital treatments. Sex-specific anesthesia care will improve outcomes, as will the provision of practical information to patients and clinicians about the effectiveness of therapies and behavioral interventions. However, more research studies and specific analytic plans are needed to continue addressing sex-based outcomes in anesthesiology.

Longitudinal cognitive evaluation before and after delivery among people with preeclampsia.

BACKGROUND: Cognitive impairments related to preeclampsia after pregnancy have been reported; however, it is not known if weaknesses in cognition occur before and shortly after delivery. OBJECTIVE: This study aimed to assess the feasibility of longitudinal cognitive testing before and after delivery, and to investigate whether those with preeclampsia have cognitive weaknesses during the third trimester of pregnancy and at 1 and 3 months postpartum. We hypothesized that people with preeclampsia would have lower cognition scores across all time points compared with normotensive people. STUDY DESIGN: This longitudinal, prospective, observational study in a single institution enrolled people (N=30) at ≥28 weeks of gestation with preeclampsia (N=16) or normotension (N=14). People with chronic hypertension, neurologic or developmental disabilities, moderate or severe depression or anxiety, or current substance use were excluded. Subjective (Everyday Cognition Scale) and objective assessment of executive function (Stroop Color-Word Interference Test, Trail-Making Test), attention and working memory (Digit Span subtest), and information processing speed (Digit Symbol Substitution Test) was conducted, and Z-scores were calculated. Baseline characteristics (eg, prepregnancy body mass index) were collected from the medical record. Generalized linear models were used to estimate associations. RESULTS: We enrolled 37% (30/81) of eligible people and retained 80% (24/30) and 53% (16/30) at 1 and 3 months postpartum, respectively. People with preeclampsia reported more memory problems (ß=0.87; 95% confidence interval, 0.44-1.31), and scored worse on attention and working memory (ß=-0.94; 95% confidence interval, -1.42 to -0.45) and executive function (Stroop test ß=-0.86; 95% confidence interval, -1.53 to -0.19) domains compared with normotensive people after adjusting for time, age, education, and prepregnancy body mass index. CONCLUSION: Longitudinal assessment of cognition in pregnant preeclamptic and normotensive people is feasible. People with preeclampsia reported worse subjective memory and had lower scores in attention, working memory, and executive function.

Patient safety and public health concerns: poor dissolution rate of pioglitazone tablets obtained from China, Myanmar and internet sites.

BACKGROUND: Poor quality medicines have serious implications for public health. The aim of this study was to explore the quality of the antidiabetic pioglitazone, using samples collected in China and Myanmar, and samples purchased online. METHODS: In this cross-sectional study, we examined samples (n = 163) collected from hospitals in Shanghai, China in 2012 (n = 44), products purchased via the internet and imported into Japan in 2013 (n = 59), and samples purchased in shops in Yangon, Myanmar in 2015 (n = 60). Collected samples were subjected to visual inspection, authenticity investigation and quality testing (potency, content uniformity and dissolution test) by high-performance liquid chromatography. Samples were rated as compliant or non-compliant based on the relevant pharmacopoeial acceptance criteria. RESULTS: Visual inspection of all samples revealed compliant products. However, responses from manufacturers during authenticity investigation were poor. Among the n = 44 samples from China, one was non-compliant in the potency test. Among the n = 59 samples personally imported into Japan, 38% of generic samples were found to be non-compliant. In Myanmar, 13.3% of samples were non-compliant. Non-compliant samples predominantly failed in the dissolution test. All non-compliant samples were generic. CONCLUSIONS: Despite the apparent satisfactory outcome on the samples from China, pioglitazone samples collected in Myanmar and purchased online for personal import into Japan included many substandard products, which failed quality assessment predominantly because of poor dissolution. Internet providers did not comply with Japanese regulations in various respects.

Targeting transcriptional coregulator OCA-B/Pou2af1 blocks activated autoreactive T cells in the pancreas and type 1 diabetes.

The transcriptional coregulator OCA-B promotes expression of T cell target genes in cases of repeated antigen exposure, a necessary feature of autoimmunity. We hypothesized that T cell-specific OCA-B deletion and pharmacologic OCA-B inhibition would protect mice from autoimmune diabetes. We developed an Ocab conditional allele and backcrossed it onto a diabetes-prone NOD/ShiLtJ strain background. T cell-specific OCA-B loss protected mice from spontaneous disease. Protection was associated with large reductions in islet CD8+ T cell receptor specificities associated with diabetes pathogenesis. CD4+ clones associated with diabetes were present but associated with anergic phenotypes. The protective effect of OCA-B loss was recapitulated using autoantigen-specific NY8.3 mice but diminished in monoclonal models specific to artificial or neoantigens. Rationally designed membrane-penetrating OCA-B peptide inhibitors normalized glucose levels and reduced T cell infiltration and proinflammatory cytokine expression in newly diabetic NOD mice. Together, the results indicate that OCA-B is a potent autoimmune regulator and a promising target for pharmacologic inhibition.

Echocardiographic Guidance of AMPLATZER Amulet Left Atrial Appendage Occlusion Device Placement.

In this report, we provided details of periprocedural echocardiographic guidance for patients undergoing Amplatzer-Amulet device left atrial closure. Familiarity with left atrial appendage (LAA) occlusion devices and the required left atrial examination and measurements are key before device placement. Device placement is assisted by transesophageal echocardiography (TEE) and fluoroscopy, but TEE will be the main guide for patients with renal insufficiency in whom contrast dye use needs to be minimal. TEE is also used to confirm LAA occlusion with the device and finally detect complications throughout the procedure and into the postoperative period.

Transcription factor Oct1 protects against hematopoietic stress and promotes acute myeloid leukemia.

A better understanding of the development and progression of acute myelogenous leukemia (AML) is necessary to improve patient outcome. Here we define roles for the transcription factor Oct1/Pou2f1 in AML and normal hematopoiesis. Inappropriate reactivation of the CDX2 gene is widely observed in leukemia patients and in leukemia mouse models. We show that Oct1 associates with the CDX2 promoter in both normal and AML primary patient samples, but recruits the histone demethylase Jmjd1a/Kdm3a to remove the repressive H3K9me2 mark only in malignant specimens. The CpG DNA immediately adjacent to the Oct1 binding site within the CDX2 promoter exhibits variable DNA methylation in healthy control blood and bone marrow samples, but complete demethylation in AML samples. In MLL-AF9-driven mouse models, partial loss of Oct1 protects from myeloid leukemia. Complete Oct1 loss completely suppresses leukemia but results in lethality from bone marrow failure. Loss of Oct1 in normal hematopoietic transplants results in superficially normal long-term reconstitution; however, animals become acutely sensitive to 5-fluorouracil, indicating that Oct1 is dispensable for normal hematopoiesis but protects blood progenitor cells against external chemotoxic stress. These findings elucidate a novel and important role for Oct1 in AML.

Crystallization of a human galectin-3 variant with two ordered segments in the shortened N-terminal tail.

Among members of the family of adhesion/growth-regulatory galectins, galectin-3 (Gal-3) bears a unique modular architecture. A N-terminal tail (NT) consisting of the N-terminal segment (NTS) and nine collagen-like repeats is linked to the canonical lectin domain. In contrast to bivalent proto- and tandem-repeat-type galectins, Gal-3 is monomeric in solution, capable to self-associate in the presence of bi- to multivalent ligands, and the NTS is involved in cellular compartmentalization. Since no crystallographic information on Gal-3 beyond the lectin domain is available, we used a shortened variant with NTS and repeats VII-IX. This protein crystallized as tetramers with contacts between the lectin domains. The region from Tyr101 (in repeat IX) to Leu114 (in the CRD) formed a hairpin. The NTS extends the canonical ß-sheet of F1-F5 strands with two new ß-strands on the F face. Together, crystallographic and SAXS data reveal a mode of intramolecular structure building involving the highly flexible Gal-3's NT.

Understanding inclusive education in chile: an overview of policy and educational research / Panorama des politiques publiques et des recherches sur léducation inclusive au chili / Para compreender a educação inclusiva chilena: panorama de políticas e pesquisa educativa / Comprender la educación inclusiva chilena: panorama de políticas e investigación educativa

Abstract The development of the concept of inclusive education was based on several sources and surrounded by other notions, such as failure, quality and effectiveness, which influence its interpretation and implementation. This article is a theoretical discussion that seeks to understand, from an educational perspective, how this confluence of ideas was formed. To that end, we establish a historical chronology of international policies, national Chilean policies, and research trends, which are understood as universal concerns, work hypotheses and objects of study, respectively. The discussion reveals the complexity of the concept when we contextualize it and when we clarify its logic in psycho-pedagogical terms and in terms of resource effectiveness, quality and inclusion.

Résumé Le concept d'éducation inclusive a été construit à partir de diverses sources et entouré de notions, telles que l'échec, la qualité et l'efficacité, qui influencent son interprétation et sa mise en œuvre. Cet article vise à comprendre par le biais d'une discussion theorique comment une telle confluence d'idées s'est produite d'un point de vue éducatif. À cette fin, a été réalisée une retrospective chronologique concernant l'histoire des politiques publiques internationales et des politiques nationales chiliennes, aussi bien que les tendances des recherches dans le domaine, vues comme préoccupations universelles, hypothèses de travail et objets d'étude. Cette discussion a dévoilé la complexité du concept son observation contextualisée, mais a aussi rendu plus transparentes les logiques psychopédagogiques, d'efficacité des ressources, de qualité et d'inclusion sur lesquelles il se base.

Resumo O conceito de educação inclusiva foi construído a partir de diversas fontes, cercado de outras noções como fracasso, qualidade e eficácia, que influem em sua interpretação e implementação. Este artigo de discussão teórica tenta compreender a partir de uma perspectiva educativa como foi construída essa confluência de ideias. Para tanto realiza-se uma cronologia de antecedentes de políticas internacionais e nacionais chilenas, bem como de tendências em pesquisas, entendendo-as como preocupações universais, hipóteses de trabalho e objetos de estudo, respectivamente. A discussão nos revela a complexidade do conceito ao observá-lo de maneira contextualizada e torna transparentes as lógicas psicopedagógicas, de eficácia dos recursos e de qualidade e inclusão nas quais se baseia.

Resumen El concepto de educación inclusiva se ha construido desde diversas fuentes rodeado de otras nociones como fracaso, calidad y eficacia que influyen en su interpretación e implementación. Este artículo de discusión teórica busca comprender desde una perspectiva educativa cómo se ha construido esta confluencia de ideas. Para esto se realiza una cronología de antecedentes de políticas internacionales y políticas nacionales chilenas, así como de tendencias en investigaciones, entendiéndolas como preocupaciones universales, hipótesis de trabajo y objetos de estudio, respectivamente. La discusión nos revela la complejidad del concepto al mirarlo de manera contextualizada y transparentar las lógicas psicopedagogistas, de eficacia de los recursos y de calidad e inclusión sobre las que se asienta.

Preliminary X-ray crystallographic analysis of an engineered variant of human chimera-type galectin-3 with a shortened N-terminal domain.

How lectins translate sugar-encoded information into cellular effects not only depends on glycan recognition. Other domains of the protein can contribute to the functional profile of a lectin. Human galectin-3 (Gal-3), an adhesion/growth-regulatory galectin, is composed of three different domains and is thus called a chimera-type protein. In addition to the carbohydrate-recognition domain, this lectin encompasses an N-terminal domain consisting of a peptide harbouring two phosphorylation sites and nine non-triple-helical collagen-like repeats. This region plays an as yet structurally undefined role in Gal-3 aggregation and ligand recognition. To date, crystallization of full-length Gal-3 has not been achieved. With the aim of providing structural insights into this modular organization, a Gal-3 variant was crystallized maintaining the terminal peptide and three of the nine collagen-like repeats. The crystals belonged to the orthorhombic space group P212121, with unit-cell parameters a = 94.04, b = 97.96, c = 236.20 Å, and diffracted to a resolution of 3.3 Å.