Design, Synthesis, and Unprecedented Interactions of Covalent Dipeptide-Based Inhibitors of SARS-CoV-2 Main Protease and Its Variants Displaying Potent Antiviral Activity.

The main protease (M) of SARS-CoV-2 is a key drug target for the development of antiviral therapeutics. Here, we designed and synthesized a series of small-molecule peptidomimetics with various cysteine-reactive electrophiles. Several compounds were identified as potent SARS-CoV-2 M inhibitors, including compounds (IC = 0.

Molecular basis for the enzymatic inactivity of class III glutaredoxin ROXY9 on standard glutathionylated substrates.

Class I glutaredoxins (GRXs) are nearly ubiquitous proteins that catalyse the glutathione (GSH)-dependent reduction of mainly glutathionylated substrates. In land plants, a third class of GRXs has evolved (class III). Class III GRXs regulate the activity of TGA transcription factors through yet unexplored mechanisms.

Host cell lectins ASGR1 and DC-SIGN jointly with TMEM106B confer ACE2 independence and imdevimab resistance to SARS-CoV-2 pseudovirus with spike mutation E484D.

The naturally occurring mutation E484D in the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can render viral entry ACE2 independent and imdevimab resistant. Here, we investigated whether the cellular proteins ASGR1, DC-SIGN, and TMEM106B, which interact with the viral S protein, can contribute to these processes. Employing S protein-pseudotyped particles, we found that expression of ASGR1 or DC-SIGN jointly with TMEM106B allowed for robust entry of mutant E484D into otherwise non-susceptible cells, while this effect was not observed upon separate expression of the single proteins and upon infection with SARS-CoV-2 wild type (WT).

Environmental enrichment is associated with favorable memory-related functional brain activity patterns in older adults.

Background: In humans, environmental enrichment (EE), as measured by the engagement in a variety of leisure activities, has been associated with larger hippocampal structure and better memory function. The present cross-sectional study assessed whether EE during early life (13-30 years) and midlife (30-65 years) is associated with better preserved memory-related brain activity patterns in older age.

Methods: In total, 372 cognitively unimpaired older adults (aged ≥60 years old) of the DZNE-Longitudinal Study on Cognitive Impairment and Dementia (DELCODE; DRKS00007966) were investigated.

Immune Response to SARS-CoV-2 XBB.1.5 and JN.1 Variants Following XBB.1.5 Booster Vaccination in Liver Transplant Recipients.

Background/objectives: The efficacy of monovalent BNT162b2 Omicron XBB.1.5 booster vaccination in liver transplant recipients (LTRs) has yet to be described, particularly regarding the immune response to emerging variants like JN.

Affinity maturation endows potent activity onto class 6 SARS-CoV-2 broadly neutralizing antibodies.

The emergence of SARS-CoV-2 variants of concern (VOCs) has greatly diminished the neutralizing activity of previously FDA-approved monoclonal antibodies (mAbs), including that of antibody cocktails and of first-generation broadly neutralizing antibodies such as S309 (Sotrovimab). In contrast, antibodies targeting cryptic conformational epitopes of the receptor binding domain (RBD) have demonstrated broad activity against emerging variants, but exert only moderate neutralizing activity, which has so far hindered clinical development. Here, we utilize in vitro display technology to identify and affinity-mature antibodies targeting the cryptic class 6 epitope, accessible only in the "up" conformation of the SARS-CoV-2 spike trimer.

Prolonged survival by combination treatment with a standardized herbal extract from Japanese Kampo-medicine (Juzentaihoto) and gemcitabine in an orthotopic transplantation pancreatic cancer model.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by its poor prognosis. Traditional Japanese herbal medicine (Kampo), such as Juzentaihoto (a standardized combination of 10 herbal extracts), has shown immune modulatory effects, modulation of microcirculation, and amelioration of fatigue. It is administered to patients to prevent deterioration of cachexia and counteract side effects of chemotherapy.

Cardiovascular PET imaging of fibroblast activation A review of the current literature.

Fibrosis is one of the key healing responses to injury, especially within the heart where it helps to maintain structural integrity following acute insults such as myocardial infarction. However, if it becomes dysregulated then fibrosis can become maladaptive leading to adverse remodelling, impaired cardiac function and heart failure. Fibroblast activation protein is exclusively expressed by activated fibroblasts, the key effector cells of fibrogenesis, and has a unique extracellular domain that is an ideal ligand for novel molecular imaging probes.

From evidence to care delivery: Opportunities and risks in health and science policy. A position paper of the Association of the Scientific Medical Societies in Germany (AWMF).

Objective: After over 25 years of developing clinical practice guidelines, the Association of the Scientific Medical Societies in Germany (AWMF) held a symposium to discuss the following topics in order to improve the way evidence is implemented in the delivery of care: expansion of the data pool for guideline development, the regulatory policy framework for this expansion, the transfer of clinical practice guideline statements to medical practice, the associated opportunities and risks resulting from the European legislation.

Methods: The AWMF held its Berlin Forum on 27 April 2022 where experts from scientific medical societies and national institutions in the healthcare sector reported their experiences and perceptions on the topics mentioned. Three writing groups compiled the key statements from these contributions to and discussions made at the Berlin Forum into a position paper.

Feasibility of hand disinfection in paediatric advanced life support (PALS): A simulation study.

Background: Hand disinfection is often omitted during emergencies because it may delay life-saving treatments. As healthcare-associated infections significantly worsen patient outcomes, the categorical omission of hand disinfection in emergencies should be re-evaluated. Real-world observations on this subject tentatively indicate compliance rates of <10%.

Local Hydrogen Concentration and Distribution in Pd Nanoparticles: An In Situ STEM-EELS Approach.

Local detection of hydrogen concentration in metals is of central importance for many areas of hydrogen technology, such as hydrogen storage, detection, catalysis, and hydrogen embrittlement. A novel approach to measure the hydrogen concentration in a model system consisting of cubic palladium nanoparticles (Pd NPs), with a lateral resolution down to 4 nm is demonstrated. By measuring the shift of the Pd bulk plasmon peak with scanning transmission electron microscopy (STEM) combined with energy electron loss spectroscopy (EELS) during in situ hydrogen gas loading and unloading, local detection of the hydrogen concentration is achieved in TEM.

PSMA - Targeted Clinical Molecular Imaging of Atherosclerosis: Correlation with Cardiovascular Risk Factors.

Aim: The early diagnosis of atherosclerotic changes to prevent ischemic events represents a clinical challenge.Prostate-specific membrane antigen (PSMA) as an established diagnostic in the field of prostate cancer also appears to detect neovascularization and inflammation in other diseases. We hypothesized that it might be also suited for detection of inflammation in atherosclerosis.

Enzymatic Upgrading of Biomass-Derived Aldoses to Rare Deoxy Ketoses Catalyzed by Transketolase Variants.

A sustainable, convenient, scalable, one-step method for the two-carbon chain elongation of cheap and biomass-derived pentoses (l-arabinose, and 2-deoxy-d-ribose) and hexose l-rhamnose was developed to produce C deoxy ketoses (C-7 and C-8) using transketolase, an enzyme catalyzing the quasi-irreversible transfer of a ketol group from an α-keto acid to an aldehyde. Deoxygenated ketoses - commonly obtained by chemical synthesis - were afforded through a suitable combination of both nucleophile and electrophile substrates in the presence of rationally designed TK variants. Pyruvate as nucleophile with pentose l-arabinose (C-5) as electrophile gave 1-deoxy-L-gluco-heptulose (C-7), while ß-hydroxypyruvate (HPA) as nucleophile with acceptors 2-deoxy-d-ribose (C-5) and 6-deoxy-l-mannose (l-rhamnose) (C-6) led to formation of 4-deoxy-d-altro-heptulose (C-7) and 8-deoxy-l-glycero-l-galacto-octulose (C-8), respectively.

Urinary Dickkopf-3 as a Potential Marker for Estimated Glomerular Filtration Rate Decline in Patients With Heart Failure.

Background: Patients with chronic heart failure (HF) show an increased risk for the occurrence of chronic kidney disease and cardiorenal syndrome. Urinary Dickkopf-3 (uDKK3), a stress-induced, tubular profibrotic glycoprotein, may be elevated in HF as early as in New York Heart Association class I HF and may indicate subsequent decline in estimated glomerular filtration rate (eGFR).

Methods And Results: uDKK3 levels in patients with HF and controls were measured by enzyme-linked immunosorbent assay.

Comparative Analysis of Host Cell Entry Efficiency and Neutralization Sensitivity of Emerging SARS-CoV-2 Lineages KP.2, KP.2.3, KP.3, and LB.1.

New SARS-CoV-2 lineages continue to evolve and may exhibit new characteristics regarding host cell entry efficiency and potential for antibody evasion. Here, employing pseudotyped particles, we compared the host cell entry efficiency, ACE2 receptor usage, and sensitivity to antibody-mediated neutralization of four emerging SARS-CoV-2 lineages, KP.2, KP.

Effect of mechanical stirring on sonoluminescence and sonochemiluminescence.

Light emissions from cavitating liquids serve as a diagnostic tool for chemical activity, bubble collapse conditions, or excited species. Here we demonstrate the influence of mechanical stirring on sonoluminescence (SL) and sonochemiluminescence (SCL) emissions emerging in the presence of dissolved sodium salts and luminol in different sonicated liquids. In the systems investigated, driven in the 20-40 kHz range, stirring can change the spatial distribution of blue/white broadband SL emissions and of the orange sodium D-line emission, as well as their relative intensities.

Transcriptional profiling of the M. complexus in naked neck chickens suggest a direct pleiotropic effect of GDF7 on feathering and reduced hatchability.

Background: The locus for naked neck (Na) in chickens reduces feather coverage and leads to increased heat dissipation from the body surface resulting in better adaptability to hot conditions. However, the Na gene is linked to significantly lower hatchability due to an increased late embryonic mortality. It has been argued that the causative gene GDF7 may have a direct pleiotropic effect on hatchability via its effect on muscle development.

ACE2-independent sarbecovirus cell entry can be supported by TMPRSS2-related enzymes and can reduce sensitivity to antibody-mediated neutralization.

The COVID-19 pandemic, caused by SARS-CoV-2, demonstrated that zoonotic transmission of animal sarbecoviruses threatens human health but the determinants of transmission are incompletely understood. Here, we show that most spike (S) proteins of horseshoe bat and Malayan pangolin sarbecoviruses employ ACE2 for entry, with human and raccoon dog ACE2 exhibiting broad receptor activity. The insertion of a multibasic cleavage site into the S proteins increased entry into human lung cells driven by most S proteins tested, suggesting that acquisition of a multibasic cleavage site might increase infectivity of diverse animal sarbecoviruses for the human respiratory tract.

A longitudinal investigation of the acoustic properties of infant-directed speech from 6 to 18 months.

Caregivers often modulate their speech when interacting with infants, adapting a register that has been suggested to have attentional, affective and didactic purposes. The present preregistered study examined the longitudinal trajectories of a diverse range of acoustic features of infant-directed speech (IDS) and compared these with adult-directed speech (ADS), in Norwegian parents of 6- to 18-month-old infants. Sixty-nine families participated.

Biodiversity and anthropogenic disturbances predominantly drive carbon sequestration rates across temporal scales in temperate forests.

Addressing the escalating challenges of climate change necessitates a comprehensive understanding of the factors influencing carbon sequestration rates (CSRs) in forest ecosystems. Although the impact of various biotic factors, environmental, and anthropogenic factors on CSRs over different time scales is well recognized, their precise roles remain poorly defined. This study aims to clarify the mechanistic relationships between CSRs and these factors in large-scale natural temperate forests in northeastern China.

Axon demyelination and degeneration in a zebrafish model of hereditary spastic paraplegia.

Hereditary spastic paraplegias (HSPs) are a diverse set of neurological disorders characterized by progressive spasticity and weakness in the lower limbs caused by damage to the axons of the corticospinal tract. More than 88 genetic mutations have been associated with HSP, yet the mechanisms underlying these disorders are not well understood. We replicated the pathophysiology of one form of HSP known as spastic paraplegia 15 (SPG15) in zebrafish.

Assessing plasmatic transport inhibitors of thyroid hormone in mammals in the Xenopus Eleutheroembryonic Thyroid Assay (XETA).

The Xenopus Eleutheroembryonic Thyroid Assay (XETA, OECD TG 248) was established as an alternative to the Amphibian Metamorphosis Assay (AMA, OECD TG 231) for the analysis of (anti-)thyroid activity of chemicals. The XETA is a New Approach Method (NAM) since the embryonic life stages used in the assay are not yet feeding independently, which renders the assay to be considered a non-animal test under many national laws. Physiologically, the used embryos are not fully developed yet, and thus there are limitations to the XETA for detecting certain mechanisms along the hypothalamic-pituitary-thyroid (HPT) axis.