Browse Articles

High-performance Ag2Se-based thermoelectrics for wearable electronics

Identification and characterization of a dsRNA-degrading nuclease CmdsRNase2 influencing RNAi efficiency in the rice leaffolder Cnaphalocrocis medinalis

Judicial Invalidation of the FDA’s Laboratory-Developed Test Rule — Legal and Public Health Consequences

Cell-context response to germ layer differentiation signals is predetermined by the epigenome in regionalized epiblast populations

Synthesis of a reversible quantum Vedic multiplier on IBM quantum computers

Seeking Multiorgan Benefits with Cardiovascular–Kidney–Metabolic Drug Therapy

Early mucosal responses following a randomised controlled human inhaled infection with attenuated Mycobacterium bovis BCG

Abstract The development of an effective vaccine against Mycobacterium tuberculosis is hampered by an incomplete understanding of immunoprotective mechanisms. We utilise an aerosol human challenge model using attenuated Mycobacterium bovis BCG, in BCG-naïve UK adults. The primary endpoint of this study (NCT03912207) was to characterise the early immune responses induced by aerosol BCG infection, the secondary endpoint was to identify immune markers associated with in-vitro protection. Blinded volunteers were randomised to inhale 1 × 107 CFU aerosolised BCG or 0.9% saline (20:6); and sequentially allocated to bronchoscopy at day 2 or 7 post-inhalation (10 BCG, 3 saline each timepoint). In the bronchoalveolar lavage post-aerosol BCG infection, there was an increase in frequency of eosinophils, neutrophils, NK cells and Donor-Unrestricted T cells at day 7, and the frequency of antigen presenting cells decreased at day 7 compared with day 2. The frequency of interferon-gamma+ BCG-specific CD4+ T cells increased in the BAL and peaked in the blood at day 7 post-BCG infection compared to day 2. BAL cells at day 2 and day 7 upregulated gene pathways related to phagocytosis, MHC-II antigen loading, T cell activation and proliferation. BCG’s lack of key virulence factors and its failure to induce granulomas, may mean the observed immune responses do not fully recapitulate Mycobacterium tuberculosis infection. However, human infection models can provide unique insights into early immune mechanisms, informing vaccine design for complex pathogens.

eHealth literacy and cancer screening attitudes among chronic patients

Oral Semaglutide and Cardiovascular Outcomes in High-Risk Type 2 Diabetes

How and when North America’s deepest river gorge formed

Author Correction: Parvalbumin-expressing basket-cell network plasticity induced by experience regulates adult learning

Structures of the Escherichia coli type 1 pilus during pilus rod assembly and after assembly termination

Abstract Uropathogenic Escherichia coli strains use filamentous type 1 pili to adhere to and invade uroepithelial cells. The pilus consists of a flexible tip fibrillum, formed by the adhesin FimH and the subunits FimG and FimF. The pilus rod is a helical assembly of up to 3000 copies of the main subunit FimA, terminated by a single copy of the subunit FimI that anchors the rod to the assembly platform FimD in the outer membrane. Although type 1 pilus assembly can be completely reconstituted in vitro, the precise mechanism of assembly termination on FimD is still unknown. Here, we present cryo-electron microscopy structures of the fully assembled pilus with all its components prior to and after incorporation of FimI, capped with the assembly chaperone FimC. The structures reveal that FimD positions the proximal end of the pilus rod at an angle of ca. 50 degrees relative to the plane of the outer membrane. Specific interactions between FimI and FimC, absent in the equivalent FimA-FimC interface of the non-terminated pilus, stabilize the assembly-terminated state. In addition, we present structures of the transition region between the tip fibrillum and the helical rod, showing how FimF aligns the tip fibrillum along the rod axis.

Experimental analysis of metamaterial integrated applicator for hyperthermia cancer treatment

Colchicine and Spironolactone in Acute Myocardial Infarction

Efficient mRNA delivery to resting T cells to reverse HIV latency

Abstract A major hurdle to curing HIV is the persistence of integrated proviruses in resting CD4+ T cells that remain in a transcriptionally silent, latent state. One strategy to eradicate latent HIV is to activate viral transcription, followed by elimination of infected cells through virus-mediated cytotoxicity or immune-mediated clearance. We hypothesised that mRNA-lipid nanoparticle (LNP) technology would provide an opportunity to deliver mRNA encoding proteins able to reverse HIV latency in resting CD4+ T cells. Here we develop an LNP formulation (LNP X) with unprecedented potency to deliver mRNA to hard-to-transfect resting CD4+ T cells in the absence of cellular toxicity or activation. Encapsulating an mRNA encoding the HIV Tat protein, an activator of HIV transcription, LNP X enhances HIV transcription in ex vivo CD4+ T cells from people living with HIV. LNP X further enables the delivery of clustered regularly interspaced short palindromic repeats (CRISPR) activation machinery to modulate both viral and host gene transcription. These findings offer potential for the development of a range of nucleic acid-based T cell therapeutics.

Spatially multiplexed single-photon sources based on binary-tree multiplexers with optimized structure

Abstract We develop a method for optimizing the structure of general binary-tree multiplexers realized with asymmetric photon routers aiming at improving the performance of spatially multiplexed single-photon sources. Our procedure systematically considers all possible binary-tree multiplexers that can be constructed using a certain number of photon routers. Using this method one can select the multiplexer structure that leads to the highest single-photon probability for a given set of loss parameters characterizing the system. We determine the optimal general binary-tree multiplexers for experimentally realizable values of the transmission coefficients of the photon routers and that of the detector efficiency. We show that single-photon sources based on such optimal multiplexers yield higher single-photon probabilities than what can be achieved with single-photon sources based on any other spatial multiplexer considered in the literature. Our approach improves the performance of multiplexed single-photon sources even for small system sizes which is the typical situation in current experiments.

Daratumumab in Relapsed or Refractory Pediatric Immune Thrombocytopenia

Distinct ossification trade-offs illuminate the shoulder girdle reconfiguration at the water-to-land transition

High content imaging shows distinct macrophage and dendritic cell phenotypes for psoriasis and atopic dermatitis

Abstract Psoriasis (Pso) and atopic dermatitis (AD) are chronic inflammatory skin diseases with distinct but also shared immunological features. Assessment of the feasibility of high content immunohistochemistry to identify distinct immune responses in skin biopsies from patients with chronic inflammatory skin diseases. While principal component analysis (PCA) based on the inflammatory marker profile discriminated healthy subjects from patients, it did not differ between Pso and AD. Single-cell phenotyping of high content immunohistochemistry images showed modest disease-specific differences for T cell populations in the number of Th1 T cells and γδT cells. Strong differences in macrophage and dendritic cell (DC) populations were observed whereby in AD disease-specific DCs with antiviral properties and anti-inflammatory macrophages were seen. Additional differences between Pso and AD were seen with the more frequent epidermal localization of CD8+ T cells in Pso and DCs in AD. Consequently, high content immunohistochemistry clearly discriminated AD from Pso based on macrophage and DC phenotype. Due to their phenotypic flexibility macrophages and DCs strongly reflect the immunological environment and serve to highlight disease-specific and -defining pathomechanisms and may serve to identify new drug targets.

Loss of Subsidized Drug Coverage and Mortality among Medicare Beneficiaries