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This Review critically discusses how activation and metabolic reprogramming of lymphocytes, that is, T cells and B cells, triggers the onset, development and progression of obesity and T2DM. We also consider the role of immunity in under-appreciated comorbidities of obesity and/or T2DM, such as oral cavity inflammation, neuroinflammation in Alzheimer disease and gut microbiome dysbiosis. Finally, we discuss previous clinical trials of anti-inflammatory medications in T2DM and consider the path forward.The comorbidity between physical and mental health conditions is challenging and frequently goes unrecognized in practice. Associations between Attention-Deficit/Hyperactivity Disorder (ADHD) and physical conditions have been reported in youth. However, prior research failed to (1) address the patterns of associations in early childhood, middle childhood, and adolescence within the same population sample; (2) consider a large set of physical disorders at the same time; (3) take confounders into account. Our goal was to assess the associations between ADHD symptoms and a broad set of physical conditions across developmental periods. This birth cohort study (n = 2057) is the first to explore the associations between ADHD and a wide range of medical conditions by encompassing the whole early development from 5 months to 17 years in the same sample and relying on innovative network analyses. We found significant associations between ADHD symptoms and several physical conditions, some of which were observed in early childhood, middle childhood, and adolescence (e.g., asthma, sleep problems) or were confounded by socioeconomic status or psychiatric comorbidities (e.g., body mass index, dental caries). The study calls for an effective integrated care model encompassing mental and general healthcare across the developmental period.Neurosurgical interventions including deep brain stimulation (DBS) and capsulotomy have been demonstrated effective for refractory obsessive-compulsive disorder (OCD), although treatment-shared/-specific network mechanisms remain largely unclear. We retrospectively analyzed resting-state fMRI data from three cohorts a cross-sectional dataset of 186 subjects (104 OCD and 82 healthy controls), and two longitudinal datasets of refractory patients receiving ventral capsule/ventral striatum DBS (14 OCD) and anterior capsulotomy (27 OCD). We developed a machine learning model predictive of OCD symptoms (indexed by the Yale-Brown Obsessive Compulsive Scale, Y-BOCS) based on functional connectivity profiles and used graphic measures of network communication to characterize treatment-induced profile changes. We applied a linear model on 2 levels treatments (DBS or capsulotomy) and outcome to identify whether pre-surgical network communication was associated with differential treatment outcomes. We identified 54 functional connectivities within fronto-subcortical networks significantly predictive of Y-BOCS score in patients across 3 independent cohorts, and observed a coexisting pattern of downregulated cortico-subcortical and upregulated cortico-cortical network communication commonly shared by DBS and capsulotomy. Furthermore, increased cortico-cortical communication at ventrolateral and centrolateral prefrontal cortices induced by DBS and capsulotomy contributed to improvement of mood and anxiety symptoms, respectively (p  less then  0.05). Importantly, pretreatment communication of ventrolateral and centrolateral prefrontal cortices were differentially predictive of mood and anxiety improvements by DBS and capsulotomy (effect sizes = 0.45 and 0.41, respectively). These findings unravel treatment-shared and treatment-specific network characteristics induced by DBS and capsulotomy, which may facilitate the search of potential evidence-based markers for optimally selecting among treatment options for a patient.Cerebral organoids offer an opportunity to bioengineer experimental avatars of the developing human brain and have already begun garnering relevant insights into complex neurobiological processes and disease. Thus far, investigations into their heterogeneous cellular composition and developmental trajectories have been largely limited to transcriptional readouts. Recent advances in global proteomic technologies have enabled a new range of techniques to explore dynamic and non-overlapping spatiotemporal protein-level programs operational in these humanoid neural structures. Here we discuss these early protein-based studies and their potentially essential role for unraveling critical secreted paracrine signals, processes with poor proteogenomic correlations, or neurodevelopmental proteins requiring post-translational modification for biological activity. Integrating emerging proteomic tools with these faithful human-derived neurodevelopmental models could transform our understanding of complex neural cell phenotypes and neurobiological processes, not exclusively driven by transcriptional regulation. These insights, less accessible by exclusive RNA-based approaches, could reveal new knowledge into human brain development and guide improvements in neural regenerative medicine efforts.Postpartum adversity is among the strongest predictors for the emergence of postpartum depression (PPD) in humans and a translational risk factor employed in rodent models. Parental care is disturbed under conditions of environmental adversity, including low resource environments, and in PPD. Nonetheless, the neural changes associated with these adversity-induced maladaptive behavioral states remain poorly understood. Postpartum scarcity-adversity can be modeled in rats by providing the dam with limited bedding and nesting (LBN) materials, which mimics the effects of a stressful low resource environment in potentiating maltreatment/neglect in humans. Indeed, LBN exposure from postpartum days (PD) 2-9 increased adverse maternal behaviors, impaired pup retrieval, and increased passive stress coping responses. Since mesolimbic dopamine (DA) activity is an important mechanism for motivated maternal behavior and is implicated in PPD, we assessed the impact of postpartum scarcity-adversity on in vivo electrophysiological properties of ventral tegmental area (VTA) DA neurons at two timepoints. We found reduced numbers of active VTA DA neurons in LBN dams at PD 9-10 but not PD-21, suggesting a transient impact on VTA population activity in LBN dams. Finally, we assessed the impact of early life scarcity-adversity on VTA DA function by conducting VTA recordings in adult female offspring and found a long-lasting attenuation in DA activity. These findings highlight a link between adversity-induced deficits in DA function and disrupted maternal behavior, suggesting the VTA/mesolimbic DA system as a potential mechanism by which postpartum scarcity-adversity drives aberrant maternal behavior, and early postnatal programming of adult VTA function in the offspring.Human genetic sequencing has implicated epigenetic and synaptic aberrations as the most prominent risk factors for autism. Here we show that autistic patients exhibit the significantly lower histone acetylation and elevated HDAC2 expression in prefrontal cortex (PFC). The diminished histone acetylation is also recaptured in an autism mouse model with the deficiency of the Shank3 gene encoding a synaptic scaffolding protein. Treating young (5-week-old) Shank3-deficient mice with a 4-week ketogenic diet, which can act as an endogenous inhibitor of class I HDACs via the major product β-hydroxybutyrate, elevates the level of histone acetylation in PFC neurons. Behavioral assays indicate that ketogenic diet treatment leads to the prolonged rescue of social preference deficits in Shank3-deficient mice. The HDAC downstream target genes encoding NMDA receptor subunits, GRIN2A and GRIN2B, are significantly reduced in PFC of autistic humans. Ketogenic diet treatment of Shank3-deficient mice elevates the transcription and histone acetylation of Grin2a and Grin2b, and restores the diminished NMDAR synaptic function in PFC neurons. These results suggest that the ketogenic diet provides a promising therapeutic strategy for social deficits in autism via the restoration of histone acetylation and gene expression in the brain.

Identifying families with an underlying inherited cancer predisposition is a major goal of cancer prevention efforts. Mendelian risk models have been developed to better predict the risk associated with a pathogenic variant of developing breast/ovarian cancer (with BRCAPRO) and the risk of developing pancreatic cancer (PANCPRO). Given that pathogenic variants involving BRCA2 and BRCA1 predispose to all three of these cancers, we developed a joint risk model to capture shared susceptibility.

We expanded the existing framework for PANCPRO and BRCAPRO to jointly model risk of pancreatic, breast, and ovarian cancer and validated this new model, BRCAPANCPRO on three data sets each reflecting the common target populations.

BRCAPANCPRO outperformed the prior BRCAPRO and PANCPRO models and yielded good discrimination for differentiating BRCA1 and BRCA2 carriers from non-carriers (AUCs 0.79, 95% CI 0.73-0.84 and 0.70, 95% CI 0.60-0.80) in families seen in high-risk clinics and pancreatic cancer family registries, respectively. In addition, BRCAPANCPRO was reasonably well calibrated for predicting future risk of pancreatic cancer (observed-to-expected (O/E) ratio = 0.81 [0.69, 0.94]).

The BRCAPANCPRO model provides improved risk assessment over our previous risk models, particularly for pedigrees with a co-occurrence of pancreatic cancer and breast and/or ovarian cancer.

The BRCAPANCPRO model provides improved risk assessment over our previous risk models, particularly for pedigrees with a co-occurrence of pancreatic cancer and breast and/or ovarian cancer.

Breast cancer in young women is more likely to have higher risk features and be associated with germline BRCA1/BRCA2 mutations. We present the clinicopathologic features of breast cancers in a prospective cohort of young women, and associations between surrogate molecular subtype and BRCA1/BRCA2 mutation status.

Histopathological features, biomarker status, tumour stage and BRCA status were collected. Invasive tumours were categorised as luminal A-like (ER + and/or PR + , HER2-, grade 1/2), luminal B-like (ER + and/or PR + , HER2 + , or ER + and/or PR + , HER2-, and grade 3), HER2-enriched (ER/PR-, HER2 + ) or triple-negative.

In all, 57.3% (654/1143) of invasive tumours were high grade. In total, 32.9% were luminal A-like, 42.4% luminal B-like, 8.3% HER2-enriched, and 16.4% triple-negative. Among different age groups, there were no differences in molecular phenotype, stage, grade or histopathology. MLN8054 11% (131) of tumours were from BRCA mutation carriers; 64.1% BRCA1 (63.1% triple-negative), and 35.9% BRCA2 (55.3% luminal B-like).

The opportunity to provide comparisons across young age groups, BRCA mutation status, surrogate molecular phenotype, and the identification of more aggressive hormone receptor-positive phenotypes in this population provides direction for future work to further understand and improve disparate outcomes for young women with luminal B-like cancers, particularly BRCA2-associated cancers, with potential implications for tailored prevention and treatment.

The opportunity to provide comparisons across young age groups, BRCA mutation status, surrogate molecular phenotype, and the identification of more aggressive hormone receptor-positive phenotypes in this population provides direction for future work to further understand and improve disparate outcomes for young women with luminal B-like cancers, particularly BRCA2-associated cancers, with potential implications for tailored prevention and treatment.