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Here we report a human intellectual disability disease locus on chromosome 14q31.3 corresponding to mutation of the ZC3H14 gene that encodes a conserved polyadenosine RNA binding protein. We identify ZC3H14 mRNA transcripts in the human central nervous system, and we find that rodent ZC3H14 protein is expressed in hippocampal neurons and colocalizes with poly(A) RNA in neuronal cell bodies. A Drosophila melanogaster model of this disease created by mutation of the gene encoding the ZC3H14 ortholog dNab2, which also binds polyadenosine RNA, reveals that dNab2 is essential for development and required in neurons for normal locomotion and flight. Biochemical and genetic data indicate that dNab2 restricts bulk poly(A) tail length in vivo, suggesting that this function may underlie its role in development and disease. These studies reveal a conserved requirement for ZC3H14/dNab2 in the metazoan nervous system and identify a poly(A) RNA binding protein associated with a human brain disorder.

Control of self-renewal and differentiation of human ES cells (hESCs) remains a challenge. This is largely due to the use of culture systems that involve poorly defined animal products and do not mimic the normal developmental milieu. Routine protocols involve the propagation of hESCs on mouse fibroblast or human feeder layers, enzymatic cell removal, and spontaneous differentiation in cultures of embryoid bodies, and each of these steps involves significant variability of culture conditions. We report that a completely synthetic hydrogel matrix can support (i) long-term self-renewal of hESCs in the presence of conditioned medium from mouse embryonic fibroblast feeder layers, and (ii) direct cell differentiation. Hyaluronic acid (HA) hydrogels were selected because of the role of HA in early development and feeder layer cultures of hESCs and the controllability of hydrogel architecture, mechanics, and degradation. When encapsulated in 3D HA hydrogels (but not within other hydrogels or in monolayer cultures on HA), hESCs maintained their undifferentiated state, preserved their normal karyotype, and maintained their full differentiation capacity as indicated by embryoid body formation. Differentiation could be induced within the same hydrogel by simply altering soluble factors. We therefore propose that HA hydrogels, with their developmentally relevant composition and tunable physical properties, provide a unique microenvironment for the self-renewal and differentiation of hESCs.

Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection. Here, Dillard and Taft-Benz et al. show in a female mouse model how different adjuvants affect inactivated vaccine-mediated protection against homologous SARS-CoV-2 and heterologous SARS-CoV-1-like coronaviruses. They find that an aluminum hydroxide-adjuvanted vaccine can increase risk of adverse outcomes during heterologous infection.

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N  = 300,486; age 16–102) and find 148 genome-wide significant independent loci ( P  < 5 × 10 −8 ) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function. Cognitive function is associated with health and important life outcomes. Here, the authors perform a genome-wide association study for general cognitive function in 300,486 individuals and identify genetic loci that implicate neural and cell developmental pathways in this trait.

Our objective was to examine immunosuppression induced by dexamethasone (DEX) administration in cattle on immunological responses to a multivalent respiratory vaccine containing replicating and nonreplicating agents. Steers ( = 32; 209 ± 8 kg) seronegative to infectious bovine rhinotracheitis virus (IBRV), bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), and parainfluenza-3 virus (PI3V) were stratified by BW and randomly assigned to 1 of 3 treatments: 1) acute immunosuppression (ACU; 0.5 mg/kg BW DEX intravenously at 1000 h only on d 0), 2) chronic immunosuppression (CHR; 0.5 mg/kg BW DEX intravenously at 1000 h on d -3 to 0), or 3) a control (CON; no DEX). On d -4, steers were fitted with intravenous catheters in the jugular vein and placed into individual stanchions. At 1200 h on d 0, steers were administered a respiratory vaccine containing modified-live virus (MLV) isolates of IBRV, BVDV, BRSV, and PI3V and a (MH) toxoid. On d 4, cattle were transported (177 km) and housed in an isolated outdoor pen. Serum was harvested on d 0, 7, 14, 21, 28, 35, 42, and 56 to determine IBRV-, BVDV-, BRSV-, and PI3V-specific antibody titers and MH whole cell and leukotoxin antibody concentrations. Sera from d -2, 0, 1, 3, 7, and 14 were used to quantify haptoglobin (Hp) concentration and ceruloplasmin (Cp) activity. Nasal swab specimens were collected on d 0, 3, and 14 to determine the presence of IBRV, BVDV, BRSV, and PI3V via PCR analysis. There was a treatment × day interaction ( < 0.01) such that CHR steers had a greater ( ≤ 0.07) BVDV antibody titer on d 14, 21, and 28. Moreover, IBRV-specific antibodies increased beginning on d 14 for CHR and on d 28 for ACU and remained greater through d 56 compared with CON ( ≤ 0.03). Conversely, serum MH whole cell antibody concentration was least ( ≤ 0.06) for CHR from d 7 to 28 and greatest for CON ( ≤ 0.04) on d 56. Treatment altered Hp such that CON exhibited a greater ( < 0.01) Hp concentration than CHR but was not different from ACU ( = 0.16). On d 3, Cp was greatest for CON, intermediate for ACU, and least for CHR (treatment × day; ≤ 0.01). The prevalence of IBRV and BVDV in nasal swabs on d 14 was 67 and 56%, respectively, for CHR; 10 and 10%, respectively, for CON; and 9 and 0%, respectively, for ACU ( ≤ 0.006). Results suggest that CHR allowed increased replication of MLV vaccine agents. Conversely, DEX-induced immunosuppression blunted the acute phase protein and antibody response against the nonreplicating MH toxoid.

This study assessed the functionality and durability of engineered human vasculatures from endothelial progenitors when implanted in a mouse deep burn‐wound model. Human vascular networks, derived from endothelial colony‐forming cells in hyaluronic acid hydrogels, were transplanted into third‐degree burns. Collectively, the findings suggest that human vasculature engineered from endothelial colony‐forming cells can integrate with the host vessels in a deep third‐degree burn model and that hyaluronic acid hydrogels that support the precise formation of human vasculature in vitro can be successfully delivered to the site of injury, where they can survive and integrate with the host vasculature. The ability of vascularized constructs to integrate with tissues may depend on the kinetics and stability of vascular structure development. This study assessed the functionality and durability of engineered human vasculatures from endothelial progenitors when implanted in a mouse deep burn‐wound model. Human vascular networks, derived from endothelial colony‐forming cells in hyaluronic acid hydrogels, were transplanted into third‐degree burns. On day 3 following transplantation, macrophages rapidly degraded the hydrogel during a period of inflammation; through the transitions from inflammation to proliferation (days 5–7), the host's vasculatures infiltrated the construct, connecting with the human vessels within the wound area. The growth of mouse vessels near the wound area supported further integration with the implanted human vasculatures. During this period, the majority of the vessels (∼60%) in the treated wound area were human. Although no increase in the density of human vessels was detected during the proliferative phase, they temporarily increased in size. This growth peaked at day 7, the middle of the proliferation stage, and then decreased by the end of the proliferation stage. As the wound reached the remodeling period during the second week after transplantation, the vasculatures including the transplanted human vessels generally regressed, and few microvessels, wrapped by mouse smooth muscle cells and with a vessel area less than 200 μm2 (including the human ones), remained in the healed wound. Overall, this study offers useful insights for the development of vascularization strategies for wound healing and ischemic conditions, for tissue‐engineered constructs, and for tissue regeneration.

The objective of this study was to determine the dose response effects of supplementing Saccharomyces cerevisiae fermentation product prototype on leukocyte functionality and ex vivo cytokine production during a dexamethasone (DEX) challenge. Holstein steers (125.1 ± 8.16 kg; N = 32) were assigned to treatments including 0, 20, 40, or 60 g/head/d of prototype (n = 8). Calves were housed for 21 d in dry lot corrals with four calves per pen (2 pens/treatment). Calves were offered ad libitum access to a 50/50 TMR of a commercially available 16% crude protein pelleted grower and 18% CP chopped alfalfa hay. Treatments were top dressed. The quantity of feed offered and orts were measured daily. After the 21 d adjustment to diets, calves were jugularly catheterized and moved into individual stations (2.13 × 0.76 cm) in an environmentally controlled barn and allowed 48 h to adapt before the first DEX injection. Blood samples were collected at -24, -6, 0, 6, 12, 18, 24, 48, and 72 h relative to the first DEX injection. DEX was administered via jugular catheter at 0.1 mg/kg BW at 0, 6, and 12 h. Peripheral blood neutrophil (PMN) concentrations increased (P < 0.001) at 6 h and remained elevated through 72 h in all steers. Neutrophil L-selectin and PMN and monocyte (MONO) oxidative burst (OB) and phagocytosis (PHAG) of an environmental Escherichia coli decreased (P < 0.059) at 6 h in all steers. L-selectin returned to baseline at 72 h while OB and PHAG failed to return to baseline by 72 h. Total leukocyte counts (P < 0.001) and PMN concentrations (P = 0.001) increased linearly with prototype dose. PMN L-selectin concentrations did not differ (P = 0.684) among treatments. Oxidative burst intensity in PMN (P = 0.025) and MONO (P = 0.003) increased linearly with prototype dose at 72 h, as well as in MONO PHAG intensity (P = 0.004) at 6 h. The percentage of PMN (P = 0.012) and MONO (P = 0.013) that were both PHAG and OB positive increased linearly with prototype at 72 h. Ex vivo whole blood lipopolysaccharide stimulated TNF-a concentrations was greater (P = 0.026) in prototype steers than control steers at -24 h. Overall, these data demonstrate that the dexamethasone challenge induced severe leukocyte dysfunction, and prototype supplementation influenced plasma neutrophil concentrations and may have increased recovery of neutrophil and monocyte function.

The objective of this study was to determine the effects of supplementing a Saccharomyces cerevisiae fermentation product prototype (Prototype) on the pathophysiological response during a combined viral-bacterial respiratory challenge. Holstein steer calves (126.5 ± 6.11kg; N= 16) were completely randomized to treatments including 0 (CON) or 20 g/head/d of Prototype (n = 8). Calves were housed in open, dry lot corrals with four calves per pen (2 pens/treatment). Calves were offered ad libitum access to a 50:50 total mixed ration of a commercially available 16% CP pelleted calf grower and 18% CP chopped alfalfa hay Treatments were top dressed for 30 d. Orts were measured daily and the quantity of feed was adjusted for approximately 10% orts. Calves were moved to individual stanchions (2.13 x 0.76 cm) in an enclosed bam. fitted with rectal temperature monitoring devices, and allowed 24 h adaptation before initiating the respiratory challenge. All calves were challenged with 1.5 x 108 PFU.mL-1.nostril-1 of bovine herpesvirus-1 cooper strain at -72 h using a mucosal atomizer and with 106 CFU of M. haemolytica (MH) intratracheal at 0 h. Blood samples were collected via jugular venipuncture at -96, -72, -48, -24, 0, 6, 24, 48, 72, 120, 168, and 240 h relative to the MH challenge. Total leukocytes counts tended (P = 0.063) to be greater at 24 h among CON steers. Neutrophil:lymphocyte also tended to be greater (P < 0.095) at 24 and 72 h among CON steers. Monocyte phagocytosis of an environmental Escherichia coli tended (P = 0.056) to be greater in steers fed the Prototype at 24 h. Neutrophil oxidative burst to an environmental Escherichia coli tended (P = 0.071) to be greater at 6 h and was greater (P = 0.011) at 168 h among steers fed the Prototype. However, monocyte oxidative burst tended (P = 0.052) to be greater among CON at 72h. Neutrophil L-selectin did not differ between treatments (P = 0.515). Neither serum haptoglobin concentrations (P = 0.773) nor rectal temperature (P = 0.985) differed between treatments. These data demonstrate that the Saccharomyces cerevisiae fermentation product prototype may influence some acute leukocyte responses during a viral-bacterial respiratory challenge, but did not have strong influences on measures of inflammation or disease.