Orthogonal and multiplexable genetic perturbations with an engineered prime editor and a diverse RNA array.

Programmable and modular systems capable of orthogonal genomic and transcriptomic perturbations are crucial for biological research and treating human genetic diseases. Here, we present the minimal versatile genetic perturbation technology (mvGPT), a flexible toolkit designed for simultaneous and orthogonal gene editing, activation, and repression in human cells. The mvGPT combines an engineered compact prime editor (PE), a fusion activator MS2-p65-HSF1 (MPH), and a drive-and-process multiplex array that produces RNAs tailored to different types of genetic perturbation.

Steering acidic oxygen reduction selectivity of single-atom catalysts through the second sphere effect.

Natural enzymes feature distinctive second spheres near their active sites, leading to exquisite catalytic reactivity. However, incumbent synthetic strategies offer limited versatility in functionalizing the second spheres of heterogeneous catalysts. Here, we prepare an enzyme-mimetic single Co-N atom catalyst with an elaborately configured pendant amine group in the second sphere via 1,3-dipolar cycloaddition, which switches the oxygen reduction reaction selectivity from the 4e to the 2e pathway under acidic conditions.

Recycling e-waste into gold-loaded covalent organic framework catalysts for terminal alkyne carboxylation.

The rising demand for gold requires innovative methods for its recovery from e-waste. Here we present the synthesis of two tetrazine-based vinyl-linked covalent organic frameworks: TTF-COF and TPE-COF that adsorb gold ions and nanoparticles and catalyze the carboxylation of terminal alkynes. These covalent organic frameworks have low band gaps and high photocurrent responses.

In vivo imaging of glycogen in human muscle.

Probing regional glycogen metabolism in humans non-invasively has been challenging due to a lack of sensitive approaches. Here we studied human muscle glycogen dynamics post-exercise with a spatial resolution of millimeters and temporal resolution of minutes, using relayed nuclear Overhauser effect (glycoNOE) MRI. Data at 5T showed a homogeneous distribution of glycogen in resting muscle, with an average concentration of 99 ± 13 mM.

Robust and inducible genome editing via an all-in-one prime editor in human pluripotent stem cells.

Prime editing (PE) allows for precise genome editing in human pluripotent stem cells (hPSCs), such as introducing single nucleotide modifications, small insertions or deletions at a specific genomic locus. Here, we systematically compare a panel of prime editing conditions in hPSCs and generate a potent prime editor, "PE-Plus", through co-inhibition of mismatch repair and p53-mediated cellular stress responses. We further establish an inducible prime editing platform in hPSCs by incorporating the PE-Plus into a safe-harbor locus and demonstrated temporal control of precise editing in both hPSCs and differentiated cells.

Neuromorphic-enabled video-activated cell sorting.

Imaging flow cytometry allows image-activated cell sorting (IACS) with enhanced feature dimensions in cellular morphology, structure, and composition. However, existing IACS frameworks suffer from the challenges of 3D information loss and processing latency dilemma in real-time sorting operation. Herein, we establish a neuromorphic-enabled video-activated cell sorter (NEVACS) framework, designed to achieve high-dimensional spatiotemporal characterization content alongside high-throughput sorting of particles in wide field of view.

NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression.

Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane.

Facile synthesis of nanoporous Mg crystalline structure by organic solvent-based reduction for solid-state hydrogen storage.

Nanoporous metals have unique potentials for energy applications with a high surface area despite the percolating structure. Yet, a highly corrosive environment is required for the synthesis of porous metals with conventional dealloying methods, limiting the large-scale fabrication of porous structures for reactive metals. In this study, we synthesize a highly reactive Mg nanoporous system through a facile organic solution-based approach without any harsh etching.

Combining genomics and epidemiology to investigate a zoonotic outbreak of rabies in Romblon Province, Philippines.

Rabies is a viral zoonosis that kills thousands of people annually in low- and middle-income countries across Africa and Asia where domestic dogs are the reservoir. 'Zero by 30', the global strategy to end dog-mediated human rabies, promotes a One Health approach underpinned by mass dog vaccination, post-exposure vaccination of bite victims, robust surveillance and community engagement. Using Integrated Bite Case Management (IBCM) and whole genome sequencing (WGS), we enhanced rabies surveillance to detect an outbreak in a formerly rabies-free island province in the Philippines.

Metamaterial-based injection molding for the cost-effective production of whole cuts.

The escalating global demand for meat products has intensified ecological concerns, underscoring the need for sustainable meat alternatives. Although current methods effectively imitate ground meat, mimicking whole cuts, which constitute 54% of the global market, remains challenging due to the lack of scalable technology. Injection molding is a massively scalable manufacturing technology developed for the polymer industry.

Cas12e orthologs evolve variable structural elements to facilitate dsDNA cleavage.

Exceptionally diverse type V CRISPR-Cas systems provide numerous RNA-guided nucleases as powerful tools for DNA manipulation. Two known Cas12e nucleases, DpbCas12e and PlmCas12e, are both effective in genome editing. However, many differences exist in their in vitro dsDNA cleavage activities, reflecting the diversity in Cas12e's enzymatic properties.

Deep-learning enabled generalized inverse design of multi-port radio-frequency and sub-terahertz passives and integrated circuits.

Millimeter-wave and terahertz integrated circuits and chips are expected to serve as the backbone for future wireless networks and high resolution sensing. However, design of these integrated circuits and chips can be quite complex, requiring years of human expertise, careful tailoring of hand crafted circuit topologies and co-design with parameterized and pre-selected templates of electromagnetic structures. These structures (radiative and non-radiative, single-port and multi-ports) are subsequently optimized through ad-hoc methods and parameter sweeps.

PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: a phase 1 dose escalation trial.

Here we report results of a phase 1 multi-institutional, open-label, dose-escalation trial (NCT02744287) of BPX-601, an investigational autologous PSCA-directed GoCAR-T® cell product containing an inducible MyD88/CD40 ON-switch responsive to the activating dimerizer rimiducid, in patients with metastatic pancreatic (mPDAC) or castration-resistant prostate cancer (mCRPC). Primary objectives were to evaluate safety and tolerability and determine the recommended phase 2 dose/schedule (RP2D). Secondary objectives included the assessment of efficacy and characterization of the pharmacokinetics of rimiducid.

Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids.

AAV vectors show promise for gene therapy; however, kidney gene transfer remains challenging. Here we conduct a barcode-seq-based comparison of 47 AAV capsids administered through different routes in mice, followed by individual validation. We find that local delivery of AAV-KP1, but not AAV9, via the renal vein or pelvis effectively transduces proximal tubules with minimal off-target liver transduction, while systemic AAV9, but not AAV-KP1, enhances proximal tubule and podocyte transduction in chronic kidney disease.

Neoadjuvant anti-PD1 immunotherapy for surgically accessible recurrent glioblastoma: clinical and molecular outcomes of a stage 2 single-arm expansion cohort.

Glioblastoma is immunologically "cold" and resistant to single-agent immune-checkpoint inhibitors (ICI). Our previous study of neoadjuvant pembrolizumab in surgically-accessible recurrent glioblastoma identified a molecular signature of response to ICI and suggested that neoadjuvant pembrolizumab may improve survival. To increase the power of this observation, we enrolled an additional 25 patients with a primary endpoint of evaluating the cell cycle gene signature associated with neoadjuvant pembrolizumab and performed bulk-RNA seq on resected tumor tissue (NCT02852655).

The genetic and observational nexus between diabetes and arthritis: a national health survey and mendelian randomization analysis.

Background: Diabetes mellitus (DM) and arthritis are prevalent conditions worldwide. The intricate relationship between these two conditions, especially in the context of various subtypes of arthritis, remains a topic of interest.

Objective: To investigate the relationship between diabetes and arthritis, with a focus on Rheumatoid Arthritis (RA), using data from the National Health and Nutrition Examination Survey (NHANES) and Mendelian Randomization (MR) analysis.

Synergistic effects of colistin-rifampin-based triple antimicrobial combination therapy against Carbapenem-resistant Pseudomonas aeruginosa: a time-kill assay.

Background: Our research aimed to investigate the potential of in vitro triple antimicrobial synergism against carbapenem-resistant Pseudomonas aeruginosa (CRPA) as a strategy to overcome antimicrobial resistance.

Methods: We used 12 CRPA blood isolates stocked in the Asian Bacterial Bank between 2016 and 2018. All isolates were tested by multi-locus sequencing and carbapenemase multiplex PCR.

Current perspectives on the dynamic culture of mesenchymal stromal/stem cell spheroids.

Mesenchymal stromal/stem cells (MSCs) are promising candidates for regenerative medicine owing to their self-renewal properties, multilineage differentiation, immunomodulatory effects, and angiogenic potential. MSC spheroids fabricated by 3D culture have recently shown enhanced therapeutic potential. MSC spheroids create a specialized niche with tight cell-cell and cell-extracellular matrix interactions, optimizing their cellular function by mimicking the in vivo environment.

Juvenile Incarceration in an Adult Facility and Violent Victimization During Adulthood.

Introduction: A growing body of research indicates that being incarcerated in an adult jail or prison as a juvenile can elevate one's exposure to adverse childhood experiences, including violent and sexual victimization and neglect, and may lead to several long-term difficulties. This study investigates the relationship between being confined in an adult jail or prison as a minor and experiencing violent victimization as an adult.

Methods: Data from the National Longitudinal Survey of Youth-1997 cohort were used in the study.

Mortality in Haemophilia Patients in India: A National Cohort Study.

Introduction: Mortality and morbidity in persons with haemophilia (PWH) have decreased due to improved diagnosis and treatment along with comprehensive population outreach efforts, but the impact is not uniform in different countries.

Aim: The study aims to assess all-cause and intracranial haemorrhage (ICH)-specific mortality of PWH in India.

Methods: This is a retrospective, observational, multi-centric cohort study of 1020 haemophilia patients from three centres in India.

Update on andrological effects of SARS-CoV-2 infection and COVID-19: An overview review.

Background: Evidence indicates a wide range of andrological alterations in patients with the Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection and Coronavirus Disease 2019 (COVID-19).

Aim: To provide an update on the andrological effects of SARS-CoV-2 infection and COVID-19.

Methods: PubMed/MEDLINE and Institutional websites were searched for randomized clinical trials, non-systematic reviews, systematic reviews, and meta-analyses.

Gut Microbiota-Derived Hyocholic Acid Enhances Type 3 Immunity and Protects Against Salmonella enterica Serovar Typhimurium in Neonatal Rats.

This study investigates how microbiome colonization influences the development of intestinal type 3 immunity in neonates. The results showed that reduced oxygen levels in the small intestine of neonatal rats induced by Saccharomyces boulardii accelerated microbiome colonization and type 3 immunity development, which protected against Salmonella enterica serovar Typhimurium infection. Microbiome maturation increased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and hyocholic acid (HCA) levels.

Evaluation of Perceived Competence and Satisfaction in Neurogastroenterology and Motility Training During the Gastroenterology Fellowship in Spain.

Introduction: We evaluated the level of achievement of the published recommendations of the European and American neurogastroenterology and motility (NGM) Societies, on the competence in managing NGM disorders in a European Country with regulated gastroenterology training program.

Methods: We conducted a nationwide survey to gastroenterologists in Spain. Information regarding demographics, training center characteristics, NGM training, self-reported interest, satisfaction with the Tier 1 skills recommended by the ANMS-ESNM, and perceived competence in the diagnosis and management of diseases in the spectrum of NGM was obtained.

Impact of blood flow restriction intensity on pain perception and muscle recovery post-eccentric exercise.

Background: Delayed onset muscle soreness (DOMS) is a well-established phenomenon characterized by ultrastructural muscle damage that typically develops following unfamiliar or high-intensity exercise. DOMS manifests with a constellation of symptoms, including muscle tenderness, stiffness, edema, mechanical hyperalgesia, and a reduced range of joint motion. In recent years, the application of blood flow restriction (BFR) has garnered attention for its potential impact on DOMS.

Non-Invasive Diagnosis of Moyamoya Disease Using Serum Metabolic Fingerprints and Machine Learning.

Moyamoya disease (MMD) is a progressive cerebrovascular disorder that increases the risk of intracranial ischemia and hemorrhage. Timely diagnosis and intervention can significantly reduce the risk of new-onset stroke in patients with MMD. However, the current diagnostic methods are invasive and expensive, and non-invasive diagnosis using biomarkers of MMD is rarely reported.