Browse Articles

A Paleoarchaean impact crater in the Pilbara Craton, Western Australia

Mitral Regurgitation from Ischemic Papillary-Muscle Rupture

Creating a retinal image database to develop an automated screening tool for diabetic retinopathy in India

The essential clathrin adapter protein complex-2 is tumor suppressive specifically in vivo

Abstract The microenvironment is a rich source of new cancer targets. We thus used a targeted single-guide RNA library to screen a panel of human pancreatic cancer lines for genes uniquely affecting tumorigenesis. Here we show inactivation of the Adapter Protein complex-2 of clathrin-mediated endocytosis reduces cell growth in vitro, but completely oppositely, promotes tumor growth in vivo. In culture, loss of the complex reduces transferrin endocytosis and iron import required for cell fitness. In tumors, alternative iron transport pathways allow pro-tumor effects of Adapter Protein complex-2 loss to manifest. In the most sensitive case, this is attributed to reprogramming the plasma membrane proteome, retaining integrins on the surface leading to Focal Adhesion Kinase phosphorylation and induction of proliferative signals. Adapter Protein complex-2 function in tumorigenesis is thus dependent upon the microenvironment, behaving as a common essential gene in culture via iron import, but as a tumor suppressor in tumors via integrin trafficking.

Supporting the Development of Drugs for Rare Diseases — The Importance of Regulatory Transparency

A CE-GAN based approach to address data imbalance in network intrusion detection systems

Structures of complete HIV-1 TAR RNA portray a dynamic platform poised for protein binding and structural remodeling

Abstract The HIV-1 TAR RNA plays key roles in viral genome architecture, transcription and replication. Previous structural analyses focused on its upper stem loop, which has served as a paradigm to study RNA structural dynamics. However, an imperfectly paired lower stem immediately abuts and stacks with the upper half, both of which are required for efficient HIV replication. Here, we report crystal structures of the full-length HIV-1 TAR which reveal substantial conformational mobility in its three conserved bulges and in its lower stem, which coordinately maintain the structural fluidity of the entire RNA. We find that TAR RNA is a robust inhibitor of PKR, and primarily uses its lower stem to capture and sequester PKR monomers, preventing their dimerization and activation. The lower stem exhibits transient conformational excursions detected by a ligation assay. Time-resolved fluorescence spectroscopy reveals local and global TAR structural remodeling by HIV-1 nucleocapsid, Tat, and PKR. This study portrays the structure, dynamics, and interactions of a complete TAR RNA, uncovers a convergent RNA-based viral strategy to evade innate immunity, and provides avenues to develop antivirals that target a dynamic, multifunctional viral RNA.

NEJM at AHA — Phase 1 Study of AAV9.LAMP2B Gene Therapy in Danon Disease

Influence of landscape characteristics and submerged aquatic vegetation on sediment carbon and nitrogen storage in shallow brackish water habitats

Abstract While marine seagrass habitats are acknowledged as sinks for carbon and nutrients, much less is known about sequestration in brackish-water vegetation. Here, we quantify the amount of organic carbon (Corg) and total nitrogen (TN) in shallow bay sediments (0–25 cm) in the brackish Baltic Sea and assess how it varies with morphometric isolation from the sea, catchment characteristics and abundance of brackish-water vegetation. The sedimentary Corg and TN content per surface area varied across the bay isolation gradient (mean Corg: 2500–4600 g/m2; mean TN: 320–570 g/m2), with enclosed bays having the highest percentage content of Corg and TN, but low sediment density (< 0.1 g cm3), while open bays had more compact sediment with lower percentage content of Corg and TN. The influence of catchment and vegetation characteristics on the sediment Corg and TN content was less clear, suggesting that coastal morphology affecting hydrodynamic exposure is an important determinant of C and TN accumulation in brackish-water bays. The results show that morphometrically isolated shallow coastal areas constitute significant sinks for carbon and nitrogen, which should be considered in management and in any regional estimates of blue carbon and nutrient sequestration functions.

The influence of subglacial lake discharge on Thwaites Glacier ice-shelf melting and grounding-line retreat

Abstract The retreat of the Antarctic Ice Sheet is conventionally attributed to increased ocean melting of ice shelves, potentially enhanced by internal instability from grounding lines near retrograde bed slopes. Ocean melting is enhanced by increased intrusion of modified Circumpolar Deep Water (mCDW) into ice shelf cavities. Upwelling from the release of subglacial meltwater can enhance mCDW’s melting ability, though its efficacy is not well understood and is not represented in current ice sheet loss projections. Here we quantify this process during an exceptional subglacial lake drainage event under Thwaites Glacier. We found that the buoyant plume from the subglacial discharge temporarily doubled the rate of ocean melting under Thwaites, thinning the ice shelf. These events likely contributed to Thwaites’ rapid thinning and grounding line retreat during that period. However, simulations and observations indicate that a steady subglacial water release would more efficiently enhance basal melt rates at Thwaites, with melt rate increasing like the square root of the subglacial discharge. Thus, it remains unclear whether increased subglacial flooding events provide a stabilizing influence on West Antarctic ice loss by reducing the impact of subglacial water on ocean melting, or a destabilizing influence by triggering rapid changes at the grounding zone.

Male-Partner Treatment to Prevent Recurrence of Bacterial Vaginosis

Development of a high-throughput MassARRAY-based single assay for the characterization of Streptococcus suis species and serotypes

A bioinspired in-materia analog photoelectronic reservoir computing for human action processing

Micronutrients — Assessment, Requirements, Deficiencies, and Interventions

Author Correction: Evaluation of antibiofilm properties of dehydroacetic acid (DHA) grafted spiro-oxindolopyrrolidines synthesized via multicomponent 1,3-dipolar cycloaddition reaction

A prenatal window for enhancing spatial resolution of cortical barrel maps

Unveiling the silent threat: Investigating asymptomatic plasmodium infections in Gorgora, Ethiopia through microscopy and loop-mediated isothermal amplification

Background The asymptomatic carriers of the Plasmodium parasite represent a large hidden reservoir of Plasmodium species. These individuals can carry microscopically detectable levels and sub-microscopic levels of Plasmodium parasitemia. As a result, the use of clinical diagnostic methods, such as Rapid Diagnosis Tests (RDTs) and Giemsa microscopy leads to underestimation of the burden of asymptomatic malaria. Thus, the use of highly sensitive molecular methods such as loop-mediated isothermal amplification techniques (LAMP) helps to overcome these limitations and is crucial to reporting the true burden of the disease. Objective This study aimed to determine the prevalence of Asymptomatic Plasmodium infections (APIs), and evaluate light microscopy for the detection of APIs using the LAMP method as a reference in Gorgora, Western Dembia district, Northwest Ethiopia. Method A community-based cross-sectional survey was carried out from May 17 to June 30, 2023, among households located in particular kebeles at Gorgora. The study participants were chosen using a multi-stage sampling technique. One Hundred Fifteen households and one household member from each household were selected using systematic random and simple random sampling techniques, respectively. To gather sociodemographic data, semi-structured questionnaires were used. Capillary blood samples were obtained from each study participant and screened for Plasmodium species infections using a LAMP kit and light microscopy. The data were entered into Epi Data version 4.6 and exported to SPSS version 25 for analysis. Results The prevalence of APIs through light microscopy examination and LAMP analysis was 6.1% (95%CI: 2.5-12.1) and 11.3% (95%CI: 6.2-18.6) respectively. Using LAMP as a reference, the sensitivity and specificity of microscopy were 53.8% and 100% respectively. Microscopy examination missed six Plasmodium infections that were positive by LAMP analysis. A measure of agreement between LAMP and Microscopy was found to be 0.67(k = 0.67). Conclusions A significant proportion of APIs was found which likely act as a reservoir of transmission. This study also showed a significant number of APIs were missed by microscopy techniques. Thus, efforts to control and eliminate malaria should also consider these sub-microscopic infections.

A deep learning approach to understanding controlled ovarian stimulation and in vitro fertilization dynamics

Dynamic multimodal information encryption combining programmable structural coloration and switchable circularly polarized luminescence

Predictors of clozapine concentration and psychiatric symptoms in patients with schizophrenia

Clozapine has superior efficacy to other antipsychotics, especially in patients with treatment-resistant schizophrenia. However, its pharmacokinetics and pharmacodynamics vary largely among patients. We aimed to evaluate the clinical and genetic factors associated with the pharmacokinetics and pharmacodynamics of clozapine in patients with schizophrenia. Blood samples for clozapine pharmacokinetic assessment were collected from patients with schizophrenia at weeks 2 (visit 2), 8 (visit 3), and 18 (visit 4) from the initiation of clozapine treatment. The Positive and Negative Syndrome Scale (PANSS) score was assessed at baseline (visit 1) and visits 3 and 4. Linear mixed models were used to identify the clinical and genetic variables associated with the clozapine concentration and total PANSS score. A total of 45 patients were included in the pharmacogenomic analysis. Owing to the small sample size, we categorized concomitant medications into four groups. However, individual drugs may have different effects on clozapine concentration. Clozapine concentration was significantly associated with smoking status and cumulative clozapine dose. Clozapine concentration was significantly associated with five single nucleotide polymorphisms (SNPs) in three genes (rs28371726 and rs202102799 in CYP2D6, rs4148323 and rs34946978 in UGT1A1, and rs2011404 in UGT1A4). Furthermore, follow-up time, body mass index, and total bilirubin levels were significantly associated with the total PANSS scores. The PANSS score was significantly associated with four SNPs in two genes (rs7787082 and rs10248420 in ABCB1 and rs2133251840 and rs762502 in DRD4). This study suggests potential clinical and genetic predictors of clozapine concentration and psychiatric symptoms in patients with schizophrenia treated with clozapine. With further investigations in diverse populations, our findings may provide important information on variables to be considered in individualized clozapine treatment.