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Injectable biomimetic hydrogels have great potential for use in regenerative medicine as cellular delivery vectors. However, they can suffer from issues relating to hypoxia, including poor cell survival, differentiation, and functional integration owing to the lack of an established vascular network. Here we engineer a hybrid myoglobin:peptide hydrogel that can concomitantly deliver stem cells and oxygen to the brain to support engraftment until vascularisation can occur naturally. We show that this hybrid hydrogel can modulate cell fate specification within progenitor cell grafts, resulting in a significant increase in neuronal differentiation. We find that the addition of myoglobin to the hydrogel results in more extensive innervation within the host tissue from the grafted cells, which is essential for neuronal replacement strategies to ensure functional synaptic connectivity. This approach could result in greater functional integration of stem cell-derived grafts for the treatment of neural injuries and diseases affecting the central and peripheral nervous systems. Injectable biomimetic hydrogels hold significant promise for tissue engineering applications. Here, the authors present a hybrid myoglobin:peptide hydrogel to overcome a critical oxygen shortage following neural stem cell transplantation, thus increasing cell survival and integration.

Vitamins play an essential role in a variety of metabolic pathways involved in energy metabolism and neuronal function and hence, contribute to metabolic, mental and overall health and wellbeing. Women become more susceptible to vitamin deficiencies when transitioning into midlife due to changes in hormonal levels, nutrition, and lifestyle. These factors can potentially predispose them to changes in physical and mental health. The objective of this study is to examine associations between vitamins and health outcomes, including metabolic, mental and muscle health, among Asian women. Women were from the Growing Up in Singapore Towards healthy Outcomes (GUSTO) a prospective longitudinal cohort study. The study measurements were performed in 662 women at postnatal 8–8.5 years study visits at a mean age of 39.9 years. Plasma vitamin concentrations were measured using liquid chromatography-tandem mass spectrometry (A, D, E, K, B) and microbiological assays (B12 and folate). Body mass index (BMI), blood pressure, fasting and post-oral glucose tolerance test 120-min glucose, insulin, HbA1c, triglycerides and HDL-cholesterol were measured. A composite metabolic syndrome (MetS) score was calculated. Self-administered Beck’s Depression Inventory, State-Trait Anxiety Inventory and Perceived Stress Scale questionnaires were used to assess mental well-being. Hand grip strength (HGS) was measured using a dynamometer at year 11 study visits. Multivariable regression analyses were used to study the associations between plasma vitamins and metabolic, musculoskeletal and mental health outcomes. Thiamine monophosphate, pyridoxal-5’-phosphate, and cholecalciferol showed a positive association with favourable metabolic health outcomes such as reduced fasting insulin, increased HDL-cholesterol and reduced MetS scores. Plasma all-trans retinol, α-tocopherol, γ-tocopherol, and phylloquinone showed a positive association with increased MetS scores, however this was attenuated by taking into account triglyceride concentrations. Folate showed a positive association with decreased perceived stress. The significant inverse associations of the B-vitamers and cholecalciferol with MetS scores were only present in women with BMI ≥ 23 kg/m 2 . Our analysis demonstrated significant associations of plasma vitamins with metabolic and mental health outcomes in the Asian women.

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.

How viruses evolve within hosts can dictate infection outcomes; however, reconstructing this process is challenging. We evaluate our multiplexed amplicon approach, PrimalSeq, to demonstrate how virus concentration, sequencing coverage, primer mismatches, and replicates influence the accuracy of measuring intrahost virus diversity. We develop an experimental protocol and computational tool, iVar, for using PrimalSeq to measure virus diversity using Illumina and compare the results to Oxford Nanopore sequencing. We demonstrate the utility of PrimalSeq by measuring Zika and West Nile virus diversity from varied sample types and show that the accumulation of genetic diversity is influenced by experimental and biological systems.

CRISPR techniques are allowing the development of technologies for nucleic acid detection (see the Perspective by Chertow). Taking advantages of the distinctive enzymatic properties of CRISPR enzymes, Gootenberg et al. developed an improved nucleic acid detection technology for multiplexed quantitative and highly sensitive detection, combined with lateral flow for visual readout. Myhrvold et al. added a sample preparation protocol to create a field-deployable viral diagnostic platform for rapid detection of specific strains of pathogens in clinical samples. Cas12a (also known as Cpf1), a type V CRISPR protein, cleaves double-stranded DNA and has been adapted for genome editing. Chen et al. discovered that Cas12a also processes single-stranded DNA threading activity. A technology platform based on this activity detected human papillomavirus in patient samples with high sensitivity. Science , this issue p. 439 , p. 444 , p. 436 ; see also p. 381 A nucleic acid detection technology identifies viruses with minimal equipment and sample processing requirements. Mitigating global infectious disease requires diagnostic tools that are sensitive, specific, and rapidly field deployable. In this study, we demonstrate that the Cas13-based SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) platform can detect Zika virus (ZIKV) and dengue virus (DENV) in patient samples at concentrations as low as 1 copy per microliter. We developed HUDSON (heating unextracted diagnostic samples to obliterate nucleases), a protocol that pairs with SHERLOCK for viral detection directly from bodily fluids, enabling instrument-free DENV detection directly from patient samples in <2 hours. We further demonstrate that SHERLOCK can distinguish the four DENV serotypes, as well as region-specific strains of ZIKV from the 2015–2016 pandemic. Finally, we report the rapid (<1 week) design and testing of instrument-free assays to detect clinically relevant viral single-nucleotide polymorphisms.

Silicon is the most scalable optoelectronic material but has suffered from its inability to generate directly and efficiently classical or quantum light on-chip. Scaling and integration are the most fundamental challenges facing quantum science and technology. We report an all-silicon quantum light source based on a single atomic emissive center embedded in a silicon-based nanophotonic cavity. We observe a more than 30-fold enhancement of luminescence, a near-unity atom-cavity coupling efficiency, and an 8-fold acceleration of the emission from the all-silicon quantum emissive center. Our work opens immediate avenues for large-scale integrated cavity quantum electrodynamics and quantum light-matter interfaces with applications in quantum communication and networking, sensing, imaging, and computing. The use of silicon for integrated quantum photonic technologies is currently hindered by the lack of suitable on-demand quantum light sources. Here, the authors fill this gap by demonstrating the creation of single atomic emissive centers in silicon and their efficient coupling with nanophotonic cavities.

The current investigation analyses the convective heat transfer performance, entropy generation, and entransy evaluation of swirl flows generated by distorted radial fins (DRF). As swirl flows and various vortical structures induce large temperature gradients, second law and entransy analyses are necessary to thoroughly evaluate their true thermodynamic influence on heat transfer enhancement. The results indicated that due to the influence of swirl flows and vortices, all angles of the DRF were capable of inducing intense fluid mixing, thinner thermal boundary layers, and turbulent eddies. It was found that overaggressive swirl flows may hinder local heat transfer performances, by enclosing low-velocity heated fluids within the thermal boundary layers. However, as these overaggressive swirl flows and strong vortices propagate downstream, beneficial fluid mixing was eventuated, favouring heat transport over large regions. In terms of thermal performances, the maximum heat transfer enhancement was exhibited by the α=45° DRF, improving the Nusselt numbers up to 59.3%. Accordingly, the highest performance evaluation criterion (PEC) of 1.269 was obtained by the α=45° DRF at the Reynolds number 2389, attributed to the centrifugal effects of the swirl flows. Optimal entropy generation numbers were also exhibited by the α=45° DRF at the highest studied Reynolds number, reducing total entropy generation by 36.81%. Lower entransy thermal resistances were also accredited to greater DRF angles due to the intense swirl effects. In essence, the study concludes that the effects of swirl flows and vortices significantly enhance heat transfer, whilst reducing both entropy generation and entransy dissipation rates, leading to optimal thermal performances.

Intrinsic apoptosis is critical to prevent tumor formation and is engaged by many anti-cancer agents to eliminate tumor cells. BAX and BAK, the two essential mediators of apoptosis, are thought to be regulated through similar mechanisms and act redundantly to drive apoptotic cell death. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as important for BAX, but not BAK, to function. Genetic deletion of VDAC2 abrogated the association of BAX and BAK with mitochondrial complexes containing VDAC1, VDAC2, and VDAC3, but only inhibited BAX apoptotic function. Deleting VDAC2 phenocopied the loss of BAX in impairing both the killing of tumor cells by anti-cancer agents and the ability to suppress tumor formation. Together, our studies show that efficient BAX-mediated apoptosis depends on VDAC2, and reveal a striking difference in how BAX and BAK are functionally impacted by their interactions with VDAC2. BAX and BAK are pro-apoptotic proteins whose activity is essential for the action of many anti-cancer drugs and to suppress tumorigenesis. Here, the authors perform a genome-wide CRISPR/Cas9 screen and identify VDAC2 as a promoter of BAX-mediated apoptosis that is important for an efficient chemotherapeutic response and to suppress tumor formation.

The current work involves optimization of the thermohydraulic performance and field synergy when employing various streamlined conical fins and clove-treated graphene nanoplatelets (CGNP) nanofluids. The results were compared with conventional fins and a smooth pipe, under identical working conditions. Findings revealed that all fin designs were capable of inducing recirculations comprised of secondary flows and vortices, that intensified fluid mixing and thinner thermal boundary layers, resulting in heat transfer enhancement. Utilizing the steep fin (SF), maximum heat transfer coefficient and Nusselt number were found to be enhanced up to 37.5%. In terms of hydraulic effects, the streamlined conical fins were capable of reducing frictional losses compared to the conventional fins, attributed to diminishing fluid stagnation and pressure drag. The results indicated that the addition of CGNP nanoparticles had enhanced heat transfer coefficient; however, it deteriorated Nusselt numbers, due to relatively greater enhancement in conductive heat transfer compared to the convective heat transfer in the thermal system. The combined efforts of the SF and the 0.1 mass% CGNP nanofluid achieved a maximum average heat transfer of 42.71% compared to distilled water within a smooth channel, under identical flowrates. Due to the low nanoparticle concentration employed, influence on the base fluid viscosity and wall shear stress was minimal, leading to negligible effects on the friction factors when employing the CGNP nanofluids. The study concluded that the utilization of the nanofluids and fins significantly improved field synergy numbers, implying enhanced synergy between the velocity and temperature fields, corresponding to optimal convective heat transfer.