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Background A survey was developed to characterize disease incidence, common pathology lesions, environmental characteristics, and nutrition programs within captive research marmoset colonies. Methods Seventeen research facilities completed the electronic survey. Results Nutritional management programs varied amongst research institutions housing marmosets; eight primary base diets were reported. The most common clinical syndromes reported were gastrointestinal disease (i.e. inflammatory bowel disease like disease, chronic lymphocytic enteritis, chronic malabsorption, chronic diarrhea), metabolic bone disease or fracture, infectious diarrhea, and oral disease (tooth root abscesses, gingivitis, tooth root resorption). The five most common pathology morphologic diagnoses were colitis, nephropathy/nephritis, enteritis, chronic lymphoplasmacytic enteritis, and cholecystitis. Obesity was more common (average 20% of a reporting institution's population) than thin body condition (average 5%). Conclusions Through review of current practices, we aim to inspire development of evidence-based practices to standardize husbandry and nutrition practices for marmoset research colonies.

Recent advances in synthetic human embryology has provided a previously inexistent molecular portrait of human development. Models of synthetic human embryonic tissues capitalize on the self-organizing capabilities of human embryonic stem cells when they are cultured on biomimetic conditions that simulate in vivo human development. In this Review, we discuss these models and how they have shed light on the early stages of human development including amniotic sac development, gastrulation and neurulation. We discuss the mechanisms underlying the molecular logic of embryonic tissue self-organization that have been dissected using synthetic models of human embryology and explore future challenges in the field. Geared with technological advances in bioengineering, high resolution gene expression and imaging tools, these models are set to transform our understanding of the mechanistic basis of embryonic tissue self-organization during human development and how they may go awry in disease.

Contact guidance is a powerful topographical cue that induces persistent directional cell migration. Healthy tissue stroma is characterized by a meshwork of wavy extracellular matrix (ECM) fiber bundles, whereas metastasis-prone stroma exhibit less wavy, more linear fibers. The latter topography correlates with poor prognosis, whereas more wavy bundles correlate with benign tumors. We designed nanotopographic ECM-coated substrates that mimic collagen fibril waveforms seen in tumors and healthy tissues to determine how these nanotopographies may regulate cancer cell polarization and migration machineries. Cell polarization and directional migration were inhibited by fibril-like wave substrates above a threshold amplitude. Although polarity signals and actin nucleation factors were required for polarization and migration on low-amplitude wave substrates, they did not localize to cell leading edges. Instead, these factors localized to wave peaks, creating multiple "cryptic leading edges" within cells. On high amplitude wave substrates, retrograde flow from large cryptic leading edges depolarized stress fibers and focal adhesions and inhibited cell migration. On low-amplitude wave substrates, actomyosin contractility overrode the small cryptic leading edges and drove stress fiber and focal adhesion orientation along the wave axis to mediate directional migration. Cancer cells of different intrinsic contractility depolarized at different wave amplitudes, and cell polarization response to wavy substrates could be tuned by manipulating contractility. We propose that ECM fibril waveforms with sufficiently high amplitude around tumors may serve as "cell polarization barriers," decreasing directional migration of tumor cells, which could be overcome by up-regulation of tumor cell contractility.

Hypertension susceptibility in women increases at the transition to menopause, termed perimenopause, a state characterized by erratic estrogen fluctuation and extended hormone cycles. Elucidating the role of estrogen signaling in the emergence of hypertension during perimenopause has been hindered by animal models that are confounded by abrupt estrogen cessation or effects of aging. In the present study, accelerated ovarian failure (AOF) in estrogen receptor beta (ER beta) reporter mice was induced by 4-vinylcyclohexene diepoxide in young mice to model early-stage ovarian failure (peri-AOF) characteristic of peri-menopause. It was found that administering ER beta agonists suppressed elevated blood pressure in a model of neurogenic hypertension induced by angiotensin II (AngII) in peri-AOF, but not in age-matched male mice. It was also found that ERb agonist administration in peri-AOF females, but not males, suppressed the heightened NMDAR signaling and reactive oxygen production in ER beta neurons in the hypothalamic paraventricular nucleus (PVN), a critical neural regulator of blood pressure. It was further shown that deleting ER beta in the PVN of gonadally intact females produced a phenotype marked by a sensitivity to AngII hypertension. These results suggest that ER beta signaling in the PVN plays an important role in blood pressure regulation in female mice and contributes to hypertension susceptibility in females at an early stage of ovarian failure comparable to human perimenopause.

The human genetic dissection of clinical phenotypes is complicated by genetic heterogeneity. Gene burden approaches that detect genetic signals in case-control studies are underpowered in genetically heterogeneous cohorts. We therefore developed a genome-wide computational method, network-based heterogeneity clustering (NHC), to detect physiological homogeneity in the midst of genetic heterogeneity. Simulation studies showed our method to be capable of systematically converging genes in biological proximity on the background biological interaction network, and capturing gene clusters harboring presumably deleterious variants, in an efficient and unbiased manner. We applied NHC to whole-exome sequencing data from a cohort of 122 individuals with herpes simplex encephalitis (HSE), including 13 individuals with previously published monogenic inborn errors of TLR3-dependent IFN-alpha/beta immunity. The top gene cluster identified by our approach successfully detected and prioritized all causal variants of five TLR3 pathway genes in the 13 previously reported individuals. This approach also suggested candidate variants of three reported genes and four candidate genes from the same pathway in another ten previously unstudied individuals. TLR3 responsiveness was impaired in dermal fibroblasts from four of the five individuals tested, suggesting that the variants detected were causal for HSE. NHC is, therefore, an effective and unbiased approach for unraveling genetic heterogeneity by detecting physiological homogeneity.

Dysregulated immune features in a patient with a homozygous loss-of-function mutation in PDCD1 suggest that IL-6, IL-23, STAT3 and ROR gamma T might be potential targets for treatment of PD-1 blockade-induced autoimmunity. The pathophysiology of adverse events following programmed cell death protein 1 (PD-1) blockade, including tuberculosis (TB) and autoimmunity, remains poorly characterized. We studied a patient with inherited PD-1 deficiency and TB who died of pulmonary autoimmunity. The patient's leukocytes did not express PD-1 or respond to PD-1-mediated suppression. The patient's lymphocytes produced only small amounts of interferon (IFN)-gamma upon mycobacterial stimuli, similarly to patients with inborn errors of IFN-gamma production who are vulnerable to TB. This phenotype resulted from a combined depletion of V delta 2(+) gamma delta T, mucosal-associated invariant T and CD56(bright) natural killer lymphocytes and dysfunction of other T lymphocyte subsets. Moreover, the patient displayed hepatosplenomegaly and an expansion of total, activated and ROR gamma T+ CD4(-)CD8(-) double-negative alpha beta T cells, similar to patients with STAT3 gain-of-function mutations who display lymphoproliferative autoimmunity. This phenotype resulted from excessive amounts of STAT3-activating cytokines interleukin (IL)-6 and IL-23 produced by activated T lymphocytes and monocytes, and the STAT3-dependent expression of ROR gamma T by activated T lymphocytes. Our work highlights the indispensable role of human PD-1 in governing both antimycobacterial immunity and self-tolerance, while identifying potentially actionable molecular targets for the diagnostic and therapeutic management of TB and autoimmunity in patients on PD-1 blockade.

The flexible control of sequential behavior is a fundamental aspect of speech, enabling endless reordering of a limited set of learned vocal elements (syllables or words). Songbirds are phylogenetically distant from humans but share both the capacity for vocal learning and neural circuitry for vocal control that includes direct pallial-brainstem projections. Based on these similarities, we hypothesized that songbirds might likewise be able to learn flexible, moment-by-moment control over vocalizations. Here, we demonstrate that Bengalese finches (Lonchura striata domestica), which sing variable syllable sequences, can learn to rapidly modify the probability of specific sequences (e.g. 'ab-c' versus 'ab-d') in response to arbitrary visual cues. Moreover, once learned, this modulation of sequencing occurs immediately following changes in contextual cues and persists without external reinforcement. Our findings reveal a capacity in songbirds for learned contextual control over syllable sequencing that parallels human cognitive control over syllable sequencing in speech.

Quiescent neural stem cells (NSCs) in the adult mouse ventricular-subventricular zone (V-SVZ) undergo activation to generate neurons and some glia. Here we show that platelet-derived growth factor receptor beta (PDGFR beta) is expressed by adult V-SVZ NSCs that generate olfactory bulb interneurons and glia. Selective deletion of PDGFRb in adult V-SVZ NSCs leads to their release from quiescence, uncovering gliogenic domains for different glial cell types. These domains are also recruited upon injury. We identify an intraventricular oligodendrocyte progenitor derived from NSCs inside the brain ventricles that contacts supraependymal axons. Together, our findings reveal that the adult V-SVZ contains spatial domains for gliogenesis, in addition to those for neurogenesis. These gliogenic NSC domains tend to be quiescent under homeostasis and may contribute to brain plasticity.

Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.