Comparing the effect of imputation reference panel composition in four distinct Latin American cohorts.

Genome-wide association studies have been useful in identifying genetic risk factors for various phenotypes. These studies rely on imputation and many existing panels are largely composed of individuals of European ancestry, resulting in lower levels of imputation quality in underrepresented populations. We aim to analyze how the composition of imputation reference panels affects imputation quality in four target Latin American cohorts. We compared imputation quality for chromosomes 7 and X when altering the imputation reference panel by: 1) increasing the number of Latin American individuals; 2) excluding either Latin American, African, or European individuals, or 3) increasing the Indigenous American (IA) admixture proportions of included Latin Americans. We found that increasing the number of Latin Americans in the reference panel improved imputation quality in the four populations; however, there were differences between chromosomes 7 and X in some cohorts. Excluding Latin Americans from analysis resulted in worse imputation quality in every cohort, while differential effects were seen when excluding Europeans and Africans between and within cohorts and between chromosomes 7 and X. Finally, increasing IA-like admixture proportions in the reference panel increased imputation quality at different levels in different populations. The difference in results between populations and chromosomes suggests that existing and future reference panels containing Latin American individuals are likely to perform differently in different Latin American populations.

Ligand-dependent interactions between SR-B1 and S1PR1 in macrophages and atherosclerotic plaques.

HDLs carry sphingosine-1-phosphate (S1P) and stimulate signaling pathways in different cells including macrophages and endothelial cells, involved in atherosclerotic plaque development. HDL signaling via S1P relies on the HDL receptor scavenger receptor class B, type I (SR-B1) and the sphingosine-1-phosphate receptor 1 (S1PR1), which interact when both are heterologously overexpressed in the HEK293 cell line. In this study, we set out to test if SR-B1 and S1PR1 interacted in primary murine macrophages in culture and atherosclerotic plaques. We used knock-in mice that endogenously expressed S1PR1 tagged with eGFP-(S1pr1eGFP/eGFP mice), combined with proximity ligation analysis to demonstrate that HDL stimulates the physical interaction between SR-B1 and S1PR1 in primary macrophages, that this is dependent on HDL-associated S1P and can be blocked by an inhibitor of SR-B1's lipid transfer activity or an antagonist of S1PR1. We also demonstrate that a synthetic S1PR1-selective agonist, SEW2871, stimulates the interaction between SR-B1 and S1PR1 and that this was also blocked by an inhibitor of SR-B1's lipid transport activity. Furthermore, we detected abundant SR-B1/S1PR1 complexes in atherosclerotic plaques of S1pr1eGFP/eGFP mice that also lacked apolipoprotein E. Treatment of mice with the S1PR1 antagonist, Ex26, for 12 h disrupted the SR-B1-S1PR1 interaction in atherosclerotic plaques. These findings demonstrate that SR-B1 and S1PR1 form ligand-dependent complexes both in cultured primary macrophages and within atherosclerotic plaques in mice and provide mechanistic insight into how SR-B1 and S1PR1 participate in mediating HDL signaling to activate atheroprotective responses in macrophages.

Breastfeeding moderates the association of maternal pre-pregnancy nutritional status with offspring body composition at 30 years.

Maternal pre-pregnancy body mass index is positively associated with offspring obesity, even at adulthood, whereas breastfeeding decreases the risk of obesity. The present study was aimed at assessing whether breastfeeding moderates the association of maternal pre-pregnancy body mass index with offspring body composition at adulthood, using data from 3439 subjects enrolled in a southern Brazilian birth cohort. At 30 years of age, maternal pre-pregnancy body mass index was positively associated with offspring prevalence of obesity, abdominal obesity, as well as body mass index and fat and lean mass index. Breastfeeding moderated the association of maternal pre-pregnancy obesity with offspring adiposity at 30 years of age. For those breastfed<6 months, body mass index was 4.13 kg/m2 (95% confidence interval: 2.98; 5.28) higher among offspring of obese mothers, in relation to offspring of normal weight mothers, whereas among those breastfed≥6 months the magnitude of the difference was small [2.95 kg/m2 (95% confidence interval: 1.17; 4.73)], p-value for interaction = 0.03. Concerning obesity, among those who had been breastfed < 6 months, the prevalence of obesity was 2.56 (95% confidence interval: 1.98; 3.31) times higher among offspring of obese mothers. On the other hand, among those who were breastfed ≥ 6 months, the prevalence of obesity was 1.82 (95% confidence interval: 1.09; 3.04) times higher among offspring of obese mothers. Therefore, among overweight mothers breastfeeding for more than 6 months should be supported, as it may mitigate the consequences of maternal overweight on offspring body composition.

Patient-reported symptom monitoring: using (big) data to improve supportive care at the macro-, meso-, and micro-levels.

PURPOSE: This paper aims to provide a comprehensive understanding of the need for continued development of symptom monitoring (SM) implementation, utilization, and data usage at the macro-, meso-, and micro-levels. METHODS: Discussions from a patient-reported SM workshop at the MASCC/ISSO 2022 annual meeting were analyzed using a macro-meso-micro analytical framework of cancer care delivery. The workshop categories "initiation and implementation, barriers to adoption and utilization, and data usage" were integrated for each level. RESULTS: At the macro-level, policy development could encourage data sharing and international collaboration, including the exchange of SM methods, supportive care models, and self-management modules. At the meso-level, institutions should adjust clinical workflow and service delivery and promote a thorough technical and clinical integration of SM. At the micro-level, SM should be individualized, with timely feedback for patients, and should foster trust and understanding of AI decision support tools amongst clinicians to improve supportive care. CONCLUSIONS: The workshop reached a consensus among international experts on providing guidance on SM implementation, utilization, and (big) data usage pathways in cancer survivors across the cancer continuum and on macro-meso-micro levels.

Filgrastim biosimilar (EP2006): A review of 15 years' post-approval evidence.

Filgrastim is approved for several indications, including reduction of the incidence and duration of chemotherapy-induced neutropenia and for stem cell mobilization. The filgrastim biosimilar, EP2006, has been available in Europe since 2009, and in the United States since 2015. In this time, preclinical and clinical data used to support the approval of EP2006 have been published. These data established the biosimilarity of EP2006 to reference filgrastim in terms of structure, pharmacokinetics, pharmacodynamics, efficacy, safety, and immunogenicity. Additional real-world evidence studies have also demonstrated equivalent efficacy and safety of EP2006 compared with reference filgrastim, both in the reduction of neutropenia and in stem cell mobilization in clinical practice. This review summarizes these preclinical, clinical, and real-world data, as well as the available cost-effectiveness data, for EP2006 since its approval 15 years ago.

Transforming growth factor-ß1 and soluble co-inhibitory immune checkpoints as putative drivers of immune suppression in patients with basal cell carcinoma.

The current study compared the levels and possible associations between systemic soluble immune checkpoints (sICPs, n = 17) and a group of humoral modulators of immune suppressor cells (n = 7) in a cohort of patients with basal cell carcinoma (BCC, n = 40) and a group of healthy control subjects (n = 20). The seven humoral modulators of immunosuppressor cells were represented by the enzymes, arginase 1 and fibroblast activation protein (FAP), the chemokine, RANTES (CCL5) and the cytokines, interleukin-10 and transforming growth factor-ß1 (TGF-ß1), as well as the M2-type macrophage markers, soluble CD163 (sCD163) and sCD206. The plasma levels of six co-inhibitory sICPs, sCTLA-4, sLAG-3, sPD-1, sPD-L1, sTIM-3 and sPD-L2 were significantly elevated in the cohort of BCC patients (p<0.001-p<0.00001), while that of sBTLA was significantly decreased (p<0.006). Of the co-stimulatory sICPs, sCD27 and sGITR were significantly increased (p<0.0002 and p<0.0538) in the cohort of BCC patients, while the others were essentially comparable with those of the control participants; of the dual active sICPs, sHVEM was significantly elevated (p<0.00001) and TLR2 comparable with the control group. A correlation heat map revealed selective, strong associations of TGF-ß1 with seven co-stimulatory (z = 0.618468-0.768131) and four co-inhibitory (z = 0.674040-0.808365) sICPs, as well as with sTLR2 (z = 0.696431). Notwithstanding the association of BCC with selective elevations in the levels of a large group of co-inhibitory sICPs, our novel findings also imply the probable involvement of TGF-ß1 in driving immunosuppression in this malignancy, possibly via activation of regulatory T cells. Notably, these abnormalities were present in patients with either newly diagnosed or recurrent disease.

Bystander activated CD8+ T cells mediate neuropathology during viral infection via antigen-independent cytotoxicity.

Although many viral infections are linked to the development of neurological disorders, the mechanism governing virus-induced neuropathology remains poorly understood, particularly when the virus is not directly neuropathic. Using a mouse model of Zika virus (ZIKV) infection, we found that the severity of neurological disease did not correlate with brain ZIKV titers, but rather with infiltration of bystander activated NKG2D+CD8+ T cells. Antibody depletion of CD8 or blockade of NKG2D prevented ZIKV-associated paralysis, suggesting that CD8+ T cells induce neurological disease independent of TCR signaling. Furthermore, spleen and brain CD8+ T cells exhibited antigen-independent cytotoxicity that correlated with NKG2D expression. Finally, viral infection and inflammation in the brain was necessary but not sufficient to induce neurological damage. We demonstrate that CD8+ T cells mediate virus-induced neuropathology via antigen-independent, NKG2D-mediated cytotoxicity, which may serve as a therapeutic target for treatment of virus-induced neurological disease.

A Cre-dependent reporter mouse for quantitative real-time imaging of protein kinase A activity dynamics.

Intracellular signaling dynamics play a crucial role in cell function. Protein kinase A (PKA) is a key signaling molecule that has diverse functions, from regulating metabolism and brain activity to guiding development and cancer progression. We previously developed an optical reporter, FLIM-AKAR, that allows for quantitative imaging of PKA activity via fluorescence lifetime imaging microscopy and photometry. However, using viral infection or electroporation for the delivery of FLIM-AKAR is invasive and results in variable expression. Here, we developed a reporter mouse, FL-AK, which expresses FLIM-AKAR in a Cre-dependent manner from the ROSA26 locus. FL-AK provides robust and consistent expression of FLIM-AKAR over time. Functionally, the mouse line reports an increase in PKA activity in response to activation of both Gαs and Gαq-coupled receptors in brain slices. In vivo, FL-AK reports PKA phosphorylation in response to neuromodulator receptor activation. Thus, FL-AK provides a quantitative, robust, and flexible method to reveal the dynamics of PKA activity in diverse cell types.

Longevity, demographic characteristics, and socio-economic status are linked to triiodothyronine levels in the general population.

The hypothalamic-pituitary-thyroid (HPT) axis is fundamental to human biology, exerting central control over energy expenditure and body temperature. However, the consequences of normal physiologic HPT-axis variation in populations without diagnosed thyroid disease are poorly understood. Using nationally representative data from the 2007 to 2012 National Health and Nutrition Examination Survey, we explore relationships with demographic characteristics, longevity, and socio-economic factors. We find much larger variation across age in free T3 than other HPT-axis hormones. T3 and T4 have opposite relationships to mortality: free T3 is inversely related and free T4 is positively related to the likelihood of death. Free T3 and household income are negatively related, particularly at lower incomes. Finally, free T3 among older adults is associated with labor both in terms of unemployment and hours worked. Physiologic TSH/T4 explain only 1.7% of T3 variation, and neither are appreciably correlated to socio-economic outcomes. Taken together, our data suggest an unappreciated complexity of the HPT-axis signaling cascade broadly such that TSH and T4 may not be accurate surrogates of free T3. Furthermore, we find that subclinical variation in the HPT-axis effector hormone T3 is an important and overlooked factor linking socio-economic forces, human biology, and aging.

Cortical reactivations predict future sensory responses.

Many theories of offline memory consolidation posit that the pattern of neurons activated during a salient sensory experience will be faithfully reactivated, thereby stabilizing the pattern1,2. However, sensory-evoked patterns are not stable but, instead, drift across repeated experiences3-6. Here, to investigate the relationship between reactivations and the drift of sensory representations, we imaged the calcium activity of thousands of excitatory neurons in the mouse lateral visual cortex. During the minute after a visual stimulus, we observed transient, stimulus-specific reactivations, often coupled with hippocampal sharp-wave ripples. Stimulus-specific reactivations were abolished by local cortical silencing during the preceding stimulus. Reactivations early in a session systematically differed from the pattern evoked by the previous stimulus-they were more similar to future stimulus response patterns, thereby predicting both within-day and across-day representational drift. In particular, neurons that participated proportionally more or less in early stimulus reactivations than in stimulus response patterns gradually increased or decreased their future stimulus responses, respectively. Indeed, we could accurately predict future changes in stimulus responses and the separation of responses to distinct stimuli using only the rate and content of reactivations. Thus, reactivations may contribute to a gradual drift and separation in sensory cortical response patterns, thereby enhancing sensory discrimination7.

The politicizing clinic: insights on 'the social' for mental health policy and practice.

PURPOSE: In this paper, we explore how Brazilian socially sensitive therapy can respond to care-users' desire to change the social and political forces shaping their lives. We use this case to demonstrate the limits of the "social determinants of health" agenda which, when operationalized, tends to leave questions of lasting structural change aside. METHODS: We report on mixed methods ethnographic and epidemiological results from the 1982 Pelotas (Brazil) birth cohort study, a prospective study of 5914 children. Ethnographic analysis explored the cyclical relationship between schooling, mental health care, conceptualizations of mental distress, social and political engagement, and experiences with diverse forms of discrimination. Epidemiological bivariate and multivariate analyses examined differences in socio-political participation and the reporting of discrimination at different time-points for participants who used therapy with those who did not. Effect modification analysis tested the hypothesis that the socially empowering effects of therapy were greater for marginalized and minoritized youth. RESULTS: Most young people living in situations of precarity experienced therapy, particularly when based in schools, to be a blame-inducing process. A more fulfilling and impactful therapeutic experience took shape when young people were able to shift the focus away from symptom reduction and behavioral management toward narrative life analyses, social debate, and political agency. Use of socially sensitive therapy was statistically associated with increased political participation and reporting of discrimination after controlling for confounders. The empowering effects of therapy were greater for those with less formal education and family income, but not for young people who identified as black, brown, or non-white. CONCLUSION: The findings underscore the importance of considering agency, sociality, and politics when theorizing "the social" in clinical practice, and health and social policy.

A Cre-dependent reporter mouse for quantitative real-time imaging of Protein Kinase A activity dynamics.

Intracellular signaling dynamics play a crucial role in cell function. Protein kinase A (PKA) is a key signaling molecule that has diverse functions, from regulating metabolism and brain activity to guiding development and cancer progression. We previously developed an optical reporter, FLIM-AKAR, that allows for quantitative imaging of PKA activity via fluorescence lifetime imaging microscopy and photometry. However, using viral infection or electroporation for the delivery of FLIM-AKAR is invasive, cannot easily target sparse or hard-to-transfect/infect cell types, and results in variable expression. Here, we developed a reporter mouse, FL-AK, which expresses FLIM-AKAR in a Cre-dependent manner from the ROSA26 locus. FL-AK provides robust and consistent expression of FLIM-AKAR over time. Functionally, the mouse line reports an increase in PKA activity in response to activation of both Gαs and Gαq-coupled receptors in brain slices. In vivo, FL-AK reports PKA phosphorylation in response to neuromodulator receptor activation. Thus, FL-AK provides a quantitative, robust, and flexible method to reveal the dynamics of PKA activity in diverse cell types.

Striatum supports fast learning but not memory recall.

Animals learn to carry out motor actions in specific sensory contexts to achieve goals. The striatum has been implicated in producing sensory-motor associations, yet its contribution to memory formation or recall is not clear. To investigate the contribution of striatum to these processes, mice were taught to associate a cue, consisting of optogenetic activation of striatum-projecting neurons in visual cortex, with forelimb reaches to access food pellets. As necessary to direct learning, striatal neural activity encoded both the sensory context and outcome of reaching. With training, the rate of cued reaching increased, but brief optogenetic inhibition of striatal activity arrested learning and prevented trial-to-trial improvements in performance. However, the same manipulation did not affect performance improvements already consolidated into short- (within an hour) or long-term (across days) memories. Hence, striatal activity is necessary for trial-to-trial improvements in task performance, leading to plasticity in other brain areas that mediate memory recall.

[Birth conditions and attention deficit/hyperactivity disorders (ADHD) in adults in the Pelotas (Brazil) birth cohorts of 1982 and 1993]. / Condições de nascimento e transtorno do déficit de atenção com hiperatividade (TDAH) em adultos nas coortes de nascimento de Pelotas, Rio Grande do Sul, Brasil, de 1982 e 1993.

This study evaluates the association of birth conditions with attention deficit/hyperactivity disorders (ADHD) in adults using data from two birth cohorts in the city of Pelotas Rio Grande do Sul State, Brazil. In 1982 and 1993 all births in the city were identified and have been prospectively monitored. In the follow-ups at 30 and 22 years of the 1982 (n = 3,574) and 1993 (n = 3,780) cohorts, respectively, participants were examined, and trained psychologists applied the Mini-International Neuropsychiatric Interview (M.I.N.I.). Those individuals who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria were defined as positive for ADHD. Poisson regression with robust variance adjustment was used to estimate the prevalence ratio (PR) adjusted for sex, maternal skin color, family income, maternal age, maternal schooling during pregnancy, maternal marital status, parity, and maternal smoking during pregnancy. The prevalence of adult ADHD was 4.4% and 4.5% in the 1982 and 1993 cohorts, respectively. The prevalence of ADHD was higher in those born with lower weight, but no linear trend was observed, and those born with weight between 3,000 and 3,499 grams (PR = 1.40; 95%CI: 1.05-1.86) had the highest risk. For gestational age, we observed an inversely proportional relationship for the presence of ADHD: preterm infants had a 33% higher risk (95%CI: 0.90-1.96) of being considered as having ADHD than those born at 39 or more weeks, but as the confidence interval included nullity, this association may have occurred at random. These results indicate that birth weight and gestational age may be associated with adult ADHD.

Este artigo avaliou a associação das condições de nascimento com o transtorno do déficit de atenção com hiperatividade (TDAH) em adultos utilizando dados de duas coorte de nascimento da cidade de Pelotas, Rio Grande do Sul, Brasil. Em 1982 e 1993, todos os nascimentos ocorridos na cidade foram identificados e prospectivamente acompanhados. Nos acompanhamentos aos 30 e 22 anos das coortes 1982 (n = 3.574) e 1993 (n = 3.780), respectivamente, os participantes foram examinados e psicólogos treinados aplicaram a Mini-International Neuropsychiatric Interview (M.I.N.I.). Aqueles indivíduos que preencheram os critérios diagnósticos do Manual Diagnóstico e Estatístico de Transtornos Mentais (DSM-5) foram definidos como positivos para TDAH. A regressão de Poisson com ajuste robusto da variância foi usada para estimar a razão de prevalência (RP) ajustadas para sexo, cor da pele materna, renda familiar, idade materna, escolaridade materna durante a gestação, estado civil materno, paridade e tabagismo materno durante a gestação. A prevalência do TDAH adulto foi de 4,4% e 4,5% nas coortes de 1982 e 1993, respectivamente. A prevalência de TDAH foi maior naqueles que nasceram com menor peso, mas não foi observada tendencia linear. Além disso, aqueles que nasceram com peso entre 3.000 e 3.499 gramas (g) (RP = 1,40, IC95%: 1,05-1,86) apresentaram maior risco para o transtorno. Para a idade gestacional, observamos uma relação inversamente proporcional acerca da presença de TDAH, os pré-termos apresentaram risco 33% maior (IC95%: 0,90-1,96) de ser considerado com TDAH do que os nascidos com 39 ou mais semanas, mas como o intervalo de confiança incluiu a nulidade, essa associação pode ter ocorrido ao acaso. Tais resultados indicam que o peso ao nascer e a idade gestacional podem estar associados ao TDAH adulto.

El presente estudio evaluó la asociación de las condiciones de nacimiento con el trastorno por déficit de atención con hiperactividad (TDAH) en adultos utilizando datos de dos cohortes de nacimiento de la ciudad de Pelotas. En 1982 y 1993 se identificaron todos los nacimientos de la ciudad y se les ha hecho un seguimiento prospectivo. En los seguimientos a los 30 y 22 años de las cohortes de 1982 (n = 3.574) y 1993 (n = 3.780), respectivamente, los participantes fueron examinados y psicólogos capacitados aplicaron la Mini-International Neuropsychiatric Interview (M.I.N.I.). Aquellas personas que cumplieron con los criterios de diagnóstico del Manual Diagnóstico y Estadístico de los Trastornos Mentales (DSM-5) se definieron como positivos para TDAH. Se utilizó la regresión de Poisson con ajuste robusto de la varianza para estimar la razón de prevalencia (RP) ajustada por sexo, color de piel materna, ingreso familiar, edad materna, educación materna en la gestación, estado civil materno, paridad y tabaquismo materno en la gestación. La prevalencia del TDAH en adultos fue de 4,4% y 4,5 %, en las cohortes de 1982 y 1993, respectivamente. La prevalencia de TDAH fue mayor en aquellos que nacieron con menor peso, pero no se observó una tendencia lineal, y aquellos que nacieron con peso entre 3.000 y 3.499 gramos (RP = 1,40; IC95%: 1,05-1,86) presentaron el mayor riesgo. Para la edad gestacional, se observó una relación inversamente proporcional para la presencia de TDAH, los niños prematuros presentaron un 33 % más de riesgo (IC95 %: 0,90-1,96), de ser considerado como teniendo TDAH que los nacidos con 39 o más semanas, pero como el intervalo de confianza incluyó la nulidad, esa asociación puede haber ocurrido al azar. Tales resultados indican que el peso al nacer y la edad gestacional pueden estar asociados con el TDAH en adultos.

PAR4 Inhibition Reduces Coronary Artery Atherosclerosis and Myocardial Fibrosis in SR-B1/LDLR Double Knockout Mice.

BACKGROUND: SR-B1 (scavenger receptor class B type 1)/LDLR (low-density lipoprotein receptor) double knockout mice fed a high-fat, high-cholesterol diet containing cholate exhibit coronary artery disease characterized by occlusive coronary artery atherosclerosis, platelet accumulation in coronary arteries, and myocardial fibrosis. Platelets are involved in atherosclerosis development, and PAR (protease-activated receptor) 4 has a prominent role in platelet function in mice. However, the role of PAR4 on coronary artery disease in mice has not been tested. METHODS: We tested the effects of a PAR4 inhibitory pepducin (RAG8) on diet-induced aortic sinus and coronary artery atherosclerosis, platelet accumulation in atherosclerotic coronary arteries, and myocardial fibrosis in SR-B1/LDLR double knockout mice. SR-B1/LDLR double knockout mice were fed a high-fat, high-cholesterol diet containing cholate and injected daily with 20 mg/kg of either the RAG8 pepducin or a control reverse-sequence pepducin (SRQ8) for 20 days. RESULTS: Platelets from the RAG8-treated mice exhibited reduced thrombin and PAR4 agonist peptide-mediated activation compared with those from control SRQ8-treated mice when tested ex vivo. Although aortic sinus atherosclerosis levels did not differ, RAG8-treated mice exhibited reduced coronary artery atherosclerosis, reduced platelet accumulation in atherosclerotic coronary arteries, and reduced myocardial fibrosis. These protective effects were not accompanied by changes in circulating lipids, inflammatory cytokines, or immune cells. However, RAG8-treated mice exhibited reduced VCAM-1 (vascular cell adhesion molecule 1) protein levels in nonatherosclerotic coronary artery cross sections and reduced leukocyte accumulation in atherosclerotic coronary artery cross sections compared with those from SRQ8-treated mice. CONCLUSIONS: The PAR4 inhibitory RAG8 pepducin reduced coronary artery atherosclerosis and myocardial fibrosis in SR-B1/LDLR double knockout mice fed a high-fat, high-cholesterol diet containing cholate. Furthermore, RAG8 reduced VCAM-1 in nonatherosclerotic coronary arteries and reduced leukocyte and platelet accumulation in atherosclerotic coronary arteries. These findings identify PAR4 as an attractive target in reducing coronary artery disease development, and the use of RAG8 may potentially be beneficial in cardiovascular disease.

Thyroid hormone rewires cortical circuits to coordinate body-wide metabolism and exploratory drive.

Animals adapt to varying environmental conditions by modifying the function of their internal organs, including the brain. To be adaptive, alterations in behavior must be coordinated with the functional state of organs throughout the body. Here we find that thyroid hormone- a prominent regulator of metabolism in many peripheral organs- activates cell-type specific transcriptional programs in anterior regions of cortex of adult mice via direct activation of thyroid hormone receptors. These programs are enriched for axon-guidance genes in glutamatergic projection neurons, synaptic regulators across both astrocytes and neurons, and pro-myelination factors in oligodendrocytes, suggesting widespread remodeling of cortical circuits. Indeed, whole-cell electrophysiology recordings revealed that thyroid hormone induces local transcriptional programs that rewire cortical neural circuits via pre-synaptic mechanisms, resulting in increased excitatory drive with a concomitant sensitization of recruited inhibition. We find that thyroid hormone bidirectionally regulates innate exploratory behaviors and that the transcriptionally mediated circuit changes in anterior cortex causally promote exploratory decision-making. Thus, thyroid hormone acts directly on adult cerebral cortex to coordinate exploratory behaviors with whole-body metabolic state.

Dopamine and glutamate regulate striatal acetylcholine in decision-making.

Striatal dopamine and acetylcholine are essential for the selection and reinforcement of motor actions and decision-making1. In vitro studies have revealed an intrastriatal circuit in which acetylcholine, released by cholinergic interneurons (CINs), drives the release of dopamine, and dopamine, in turn, inhibits the activity of CINs through dopamine D2 receptors (D2Rs). Whether and how this circuit contributes to striatal function in vivo is largely unknown. Here, to define the role of this circuit in a living system, we monitored acetylcholine and dopamine signals in the ventrolateral striatum of mice performing a reward-based decision-making task. We establish that dopamine and acetylcholine exhibit multiphasic and anticorrelated transients that are modulated by decision history and reward outcome. Dopamine dynamics and reward encoding do not require the release of acetylcholine by CINs. However, dopamine inhibits acetylcholine transients in a D2R-dependent manner, and loss of this regulation impairs decision-making. To determine how other striatal inputs shape acetylcholine signals, we assessed the contribution of cortical and thalamic projections, and found that glutamate release from both sources is required for acetylcholine release. Altogether, we uncover a dynamic relationship between dopamine and acetylcholine during decision-making, and reveal multiple modes of CIN regulation. These findings deepen our understanding of the neurochemical basis of decision-making and behaviour.

Pro-Tumorigenic and Thrombotic Activities of Platelets in Lung Cancer.

Aside from their key protective roles in hemostasis and innate immunity, platelets are now recognized as having multifaceted, adverse roles in the pathogenesis, progression and outcome of many types of human malignancy. The most consistent and compelling evidence in this context has been derived from the notable association of elevated circulating platelet counts with the onset and prognosis of various human malignancies, particularly lung cancer, which represents the primary focus of the current review. Key topics include an overview of the association of lung cancer with the circulating platelet count, as well as the mechanisms of platelet-mediated, pro-tumorigenic immunosuppression, particularly the role of transforming growth factor beta 1. These issues are followed by a discussion regarding the pro-tumorigenic role of platelet-derived microparticles (PMPs), the most abundant type of microparticles (MPs) in human blood. In this context, the presence of increased levels of PMPs in the blood of lung cancer patients has been associated with tumor growth, invasion, angiogenesis and metastasis, which correlate with disease progression and decreased survival times. The final section of the review addresses, firstly, the role of cancer-related platelet activation and thrombosis in the pathogenesis of secondary cardiovascular disorders and the associated mortality, particularly in lung cancer, which is second only to disease progression; secondly, the review addresses the potential role of antiplatelet agents in the adjunctive therapy of cancer.

Experimental charge density and topological analysis of tetraaquabis(hydrogenmaleato)nickel(II): a comparison with Hirshfeld atom refinement.

Experimental charge density analysis is conducted on the coordination compound tetraaquabis(hydrogenmaleato)nickel(II), which exhibits a short intramolecular hydrogen bond. Through topological analysis, the nature of Ni-O bonds is concluded to be intermediate between ionic and covalent, but mainly presenting an ionic character, while the short hydrogen bond is classified as covalent in nature. The compound was also analysed after Hirshfeld atom refinement performed using NoSpherA2. A topological analysis was conducted on the molecular wavefunction and the results are compared with those obtained from experiment. In general, there is good agreement between the refinements, and the chemical bonds involving H atoms are in better agreement with what is expected from neutron data after HAR than they are after multipole refinement.