The 3D ultrastructure of the chordotonal organs in the antenna of a microwasp remains complex although simplified.

Insect antennae are astonishingly versatile and have multiple sensory modalities. Audition, detection of airflow, and graviception are combined in the antennal chordotonal organs. The miniaturization of these complex multisensory organs has never been investigated.

In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1.

Lipoyl synthase (LS) catalyzes the last step in the biosynthesis of the lipoyl cofactor, which is the attachment of sulfur atoms at C6 and C8 of an -octanoyllysyl side chain of a lipoyl carrier protein (LCP). The protein is a member of the radical -adenosylmethionine (SAM) superfamily of enzymes, which use SAM as a precursor to a 5'-deoxyadenosyl 5'-radical (5'-dA·). The role of the 5'-dA· in the LS reaction is to abstract hydrogen atoms from C6 and C8 of the octanoyl moiety of the substrate to initiate subsequent sulfur attachment.

Functional spectrum and specificity of mitochondrial ferredoxins FDX1 and FDX2.

Ferredoxins comprise a large family of iron-sulfur (Fe-S) proteins that shuttle electrons in diverse biological processes. Human mitochondria contain two isoforms of [2Fe-2S] ferredoxins, FDX1 (aka adrenodoxin) and FDX2, with known functions in cytochrome P450-dependent steroid transformations and Fe-S protein biogenesis. Here, we show that only FDX2, but not FDX1, is involved in Fe-S protein maturation.

Quorum-sensing control of matrix protein production drives fractal wrinkling and interfacial localization of Vibrio cholerae pellicles.

Bacterial cells at fluid interfaces can self-assemble into collective communities with stunning macroscopic morphologies. Within these soft, living materials, called pellicles, constituent cells gain group-level survival advantages including increased antibiotic resistance. However, the regulatory and structural components that drive pellicle self-patterning are not well defined.

Quorum-sensing- and type VI secretion-mediated spatiotemporal cell death drives genetic diversity in Vibrio cholerae.

Bacterial colonies composed of genetically identical individuals can diversify to yield variant cells with distinct genotypes. Variant outgrowth manifests as sectors. Here, we show that Type VI secretion system (T6SS)-driven cell death in Vibrio cholerae colonies imposes a selective pressure for the emergence of variant strains that can evade T6SS-mediated killing.

Synergy between c-di-GMP and Quorum-Sensing Signaling in Vibrio cholerae Biofilm Morphogenesis.

Transitions between individual and communal lifestyles allow bacteria to adapt to changing environments. Bacteria must integrate information encoded in multiple sensory cues to appropriately undertake these transitions. Here, we investigate how two prevalent sensory inputs converge on biofilm morphogenesis: quorum sensing, which endows bacteria with the ability to communicate and coordinate group behaviors, and second messenger c-di-GMP signaling, which allows bacteria to detect and respond to environmental stimuli.

Grouping T-Cell Antigen Receptors by Specificity.

Grouping TCRs on the similarity of CDR3 sequences could effectively cluster them by specificity. Three versions of the GLIPH algorithm are described briefly here, with instructions to use GLIPH algorithms to cluster TCRs by specificity.

A High-Throughput Strategy for T-Cell Receptor Cloning and Expression.

Expression of T-cell receptor (TCR) genes is a critical step for TCR characterization and epitope identification. The recent interest in using specific TCRs for cancer immunotherapy has further increased the demand for practical and robust methods to rapidly clone and express TCRs. We show that a recombination-based cloning protocol facilitates simple and rapid transfer of the TCR transgene into different expression systems.

Characterization of KIRCD8 Regulatory T Cells in Humans by scRNA- and TCR-seq.

Previous studies have demonstrated the regulatory functions of Ly49CD8 T cells toward self-reactive CD4 T cells in mice. Recently, we found KIRCD8 T cells are the equivalent of mouse Ly49CD8 T cells in humans. They are increased in patients with autoimmune or infectious diseases as a negative feedback mechanism to suppress the arising pathogenic cells and maintain peripheral tolerance.

Capillary forces generated by biomolecular condensates.

Liquid-liquid phase separation and related phase transitions have emerged as generic mechanisms in living cells for the formation of membraneless compartments or biomolecular condensates. The surface between two immiscible phases has an interfacial tension, generating capillary forces that can perform work on the surrounding environment. Here we present the physical principles of capillarity, including examples of how capillary forces structure multiphase condensates and remodel biological substrates.

Discovery, structure and mechanism of a tetraether lipid synthase.

Archaea synthesize isoprenoid-based ether-linked membrane lipids, which enable them to withstand extreme environmental conditions, such as high temperatures, high salinity, and low or high pH values. In some archaea, such as Methanocaldococcus jannaschii, these lipids are further modified by forming carbon-carbon bonds between the termini of two lipid tails within one glycerophospholipid to generate the macrocyclic archaeol or forming two carbon-carbon bonds between the termini of two lipid tails from two glycerophospholipids to generate the macrocycle glycerol dibiphytanyl glycerol tetraether (GDGT). GDGT contains two 40-carbon lipid chains (biphytanyl chains) that span both leaflets of the membrane, providing enhanced stability to extreme conditions.

Gene Structure-Based Homology Search Identifies Highly Divergent Putative Effector Gene Family.

Homology of highly divergent genes often cannot be determined from sequence similarity alone. For example, we recently identified in the aphid Hormaphis cornu a family of rapidly evolving bicycle genes, which encode novel proteins implicated as plant gall effectors, and sequence similarity search methods yielded few putative bicycle homologs in other species. Coding sequence-independent features of genes, such as intron-exon boundaries, often evolve more slowly than coding sequences, however, and can provide complementary evidence for homology.

Circulating Tumor DNA Analysis Guiding Adjuvant Therapy in Stage II Colon Cancer.

Background: The role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood.

Structural characterization of cobalamin-dependent radical S-adenosylmethionine methylases.

Cobalamin-dependent radical S-adenosylmethionine (SAM) methylases catalyze key steps in the biosynthesis of numerous biomolecules, including protein cofactors, antibiotics, herbicides, and other natural products, but have remained a relatively understudied subclass of radical SAM enzymes due to their inherent insolubility upon overproduction in Escherichia coli. These enzymes contain two cofactors: a [4Fe-4S] cluster that is ligated by three cysteine residues, and a cobalamin cofactor typically bound by residues in the N-terminal portion of the enzyme. Recent advances in the expression and purification of these enzymes in their active states and with both cofactors present has allowed for more detailed biochemical studies as well as structure determination by X-ray crystallography.

Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain.

Second-order spinal cord excitatory neurons play a key role in spinal processing and transmission of pain signals to the brain. Exogenously induced change in developmentally imprinted excitatory neurotransmitter phenotypes of these neurons to inhibitory has not yet been achieved. Here, we use a subpial dorsal horn-targeted delivery of AAV (adeno-associated virus) vector(s) encoding GABA (gamma-aminobutyric acid) synthesizing-releasing inhibitory machinery in mice with neuropathic pain.

Genome-wide Analysis Reflects Novel 5-Hydroxymethylcytosines Implicated in Diabetic Nephropathy and the Biomarker Potential.

Aim: Diabetic nephropathy (DN) has become the most common cause of end-stage renal disease (ESRD) in most countries. Elucidating novel epigenetic contributors to DN can not only enhance our understanding of this complex disorder, but also lay the foundation for developing more effective monitoring tools and preventive interventions in the future, thus contributing to our ultimate goal of improving patient care.

Methods: The 5hmC-Seal, a highly selective, chemical labeling technique, was used to profile genome-wide 5-hydroxymethylcytosines (5hmC), a stable cytosine modification type marking gene activation, in circulating cell-free DNA (cfDNA) samples from a cohort of patients recruited at Zhongnan Hospital, including T2D patients with nephropathy (DN, n = 12), T2D patients with non-DN vascular complications (non-DN, n = 29), and T2D patients without any complication (controls, n = 14).

Macrocyclization and Backbone Modification in RiPP Biosynthesis.

The past decade has seen impressive advances in understanding the biosynthesis of ribosomally synthesized and posttranslationally modified peptides (RiPPs). One of the most common modifications found in these natural products is macrocyclization, a strategy also used by medicinal chemists to improve metabolic stability and target affinity and specificity. Another tool of the peptide chemist, modification of the amides in a peptide backbone, has also been observed in RiPPs.

Quantitative input-output dynamics of a c-di-GMP signal transduction cascade in Vibrio cholerae.

Bacterial biofilms are multicellular communities that collectively overcome environmental threats and clinical treatments. To regulate the biofilm lifecycle, bacteria commonly transduce sensory information via the second messenger molecule cyclic diguanylate (c-di-GMP). Using experimental and modeling approaches, we quantitatively capture c-di-GMP signal transmission via the bifunctional polyamine receptor NspS-MbaA, from ligand binding to output, in the pathogen Vibrio cholerae.

Inpatient Administration of Alpha-1-Adrenergic Receptor Blocking Agents Reduces Mortality in Male COVID-19 Patients.

Apha-1-adrenergic receptor antagonists (α-blockers) can suppress pro-inflammatory cytokines, thereby potentially improving outcomes among patients with COVID-19. Accordingly, we evaluated the association between α-blocker exposure (before or during hospitalization) and COVID-19 in-hospital mortality. We identified 2,627 men aged 45 or older who were admitted to Mount Sinai hospitals with COVID-19 between February 24 and May 31, 2020, in New York.

KIRCD8 T cells suppress pathogenic T cells and are active in autoimmune diseases and COVID-19.

In this work, we find that CD8 T cells expressing inhibitory killer cell immunoglobulin-like receptors (KIRs) are the human equivalent of Ly49CD8 regulatory T cells in mice and are increased in the blood and inflamed tissues of patients with a variety of autoimmune diseases. Moreover, these CD8 T cells efficiently eliminated pathogenic gliadin-specific CD4 T cells from the leukocytes of celiac disease patients in vitro. We also find elevated levels of KIRCD8 T cells, but not CD4 regulatory T cells, in COVID-19 patients, correlating with disease severity and vasculitis.

Multiple early factors anticipate post-acute COVID-19 sequelae.

Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2-3 months later), integrated with clinical data and patient-reported symptoms.

XFEL serial crystallography reveals the room temperature structure of methyl-coenzyme M reductase.

Methyl-Coenzyme M Reductase (MCR) catalyzes the biosynthesis of methane in methanogenic archaea, using a catalytic Ni-centered Cofactor F430 in its active site. It also catalyzes the reverse reaction, that is, the anaerobic activation and oxidation, including the cleavage of the CH bond in methane. Because methanogenesis is the major source of methane on earth, understanding the reaction mechanism of this enzyme can have massive implications in global energy balances.

Translating science to medicine: The case for physician-scientists.

As the number of physician-scientists continues to decline, action must be taken to support them as they embark on their careers.

Structure of a B-dependent radical SAM enzyme in carbapenem biosynthesis.

Carbapenems are antibiotics of last resort in the clinic. Owing to their potency and broad-spectrum activity, they are an important part of the antibiotic arsenal. The vital role of carbapenems is exemplified by the approval acquired by Merck from the US Food and Drug Administration (FDA) for the use of an imipenem combination therapy to treat the increased levels of hospital-acquired and ventilator-associated bacterial pneumonia that have occurred during the COVID-19 pandemic.

Singlet Oxygen Leads to Structural Changes to Chloroplasts during their Degradation in the Arabidopsis thaliana plastid ferrochelatase two Mutant.

During stress, chloroplasts produce large amounts of reactive oxygen species (ROS). Chloroplasts also contain many nutrients, including 80% of a leaf's nitrogen supply. Therefore, to protect cells from photo-oxidative damage and to redistribute nutrients to sink tissues, chloroplasts are prime targets for degradation.