Measurement of the axial vector form factor from antineutrino-proton scattering.

Scattering of high energy particles from nucleons probes their structure, as was done in the experiments that established the non-zero size of the proton using electron beams1. The use of charged leptons as scattering probes enables measuring the distribution of electric charges, which is encoded in the vector form factors of the nucleon2. Scattering weakly interacting neutrinos gives the opportunity to measure both vector and axial vector form factors of the nucleon, providing an additional, complementary probe of their structure. The nucleon transition axial form factor, FA, can be measured from neutrino scattering from free nucleons, νµn → µ-p and [Formula: see text], as a function of the negative four-momentum transfer squared (Q2). Up to now, FA(Q2) has been extracted from the bound nucleons in neutrino-deuterium scattering3-9, which requires uncertain nuclear corrections10. Here we report the first high-statistics measurement, to our knowledge, of the [Formula: see text] cross-section from the hydrogen atom, using the plastic scintillator target of the MINERvA11 experiment, extracting FA from free proton targets and measuring the nucleon axial charge radius, rA, to be 0.73 ± 0.17 fm. The antineutrino-hydrogen scattering presented here can access the axial form factor without the need for nuclear theory corrections, and enables direct comparisons with the increasingly precise lattice quantum chromodynamics computations12-15. Finally, the tools developed for this analysis and the result presented are substantial advancements in our capabilities to understand the nucleon structure in the weak sector, and also help the current and future neutrino oscillation experiments16-20 to better constrain neutrino interaction models.

Management of glioblastoma: State of the art and future directions.

Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.

Rational design of a new antibiotic class for drug-resistant infections.

The development of new antibiotics to treat infections caused by drug-resistant Gram-negative pathogens is of paramount importance as antibiotic resistance continues to increase worldwide1. Here we describe a strategy for the rational design of diazabicyclooctane inhibitors of penicillin-binding proteins from Gram-negative bacteria to overcome multiple mechanisms of resistance, including ß-lactamase enzymes, stringent response and outer membrane permeation. Diazabicyclooctane inhibitors retain activity in the presence of ß-lactamases, the primary resistance mechanism associated with ß-lactam therapy in Gram-negative bacteria2,3. Although the target spectrum of an initial lead was successfully re-engineered to gain in vivo efficacy, its ability to permeate across bacterial outer membranes was insufficient for further development. Notably, the features that enhanced target potency were found to preclude compound uptake. An improved optimization strategy leveraged porin permeation properties concomitant with biochemical potency in the lead-optimization stage. This resulted in ETX0462, which has potent in vitro and in vivo activity against Pseudomonas aeruginosa plus all other Gram-negative ESKAPE pathogens, Stenotrophomonas maltophilia and biothreat pathogens. These attributes, along with a favourable preclinical safety profile, hold promise for the successful clinical development of the first novel Gram-negative chemotype to treat life-threatening antibiotic-resistant infections in more than 25 years.

FAM222A, Part of the BET-Regulated Basal Endothelial Transcriptome, Is a Novel Determinant of Endothelial Biology and Angiogenesis-Brief Report.

BACKGROUND: BETs (bromodomain and extraterminal domain-containing epigenetic reader proteins), including BRD4 (bromodomain-containing protein 4), orchestrate transcriptional programs induced by pathogenic stimuli, as intensively studied in cardiovascular disease and elsewhere. In endothelial cells (ECs), BRD4 directs induced proinflammatory, proatherosclerotic transcriptional responses; BET inhibitors, like JQ1, repress these effects and decrease atherosclerosis. While BET effects in pathogenic conditions have prompted therapeutic BET inhibitor development, BET action under basal conditions, including ECs, has remained understudied. To understand BET action in basal endothelial transcriptional programs, we first analyzed EC RNA-Seq data in the absence versus presence of JQ1 before using BET regulation to identify novel determinants of EC biology and function. METHODS: RNA-Seq datasets of human umbilical vein ECs without and with JQ1 treatment were analyzed. After identifying C12orf34, also known as FAM222A (family with sequence similarity 222 member A), as a previously unreported, basally expressed, potently JQ1-induced EC gene, FAM222A was studied in endothelial and angiogenic responses in vitro using small-interference RNA silencing and lentiviral overexpression, in vitro, ex vivo and in vivo, including aortic sprouting, matrigel plug assays, and murine neonatal oxygen-induced retinopathy. RESULTS: Resting EC RNA-Seq data indicate BETs direct transcriptional programs underlying core endothelial properties including migration, proliferation, and angiogenesis. BET inhibition in resting ECs also significantly induced a subset of mRNAs, including FAM222A-a unique BRD4-regulated gene with no reported EC role. Silencing endothelial FAM222A significantly decreased cellular proliferation, migration, network formation, aorta sprouting, and Matrigel plug vascularization through coordinated modulation of VEGF (vascular endothelial growth factor) and NOTCH mediator expression in vitro, ex vivo, in vivo; lentiviral FAM222A overexpression had opposite effects. In vivo, siFAM222A significantly repressed retinal revascularization in neonatal murine oxygen-induced retinopathy through similar angiogenic signaling modulation. CONCLUSIONS: BET control over the basal endothelial transcriptome includes FAM222A, a novel, BRD4-regulated, key determinant of endothelial biology and angiogenesis.

In community-acquired pneumonia, adding oral clarithromycin to standard care increased early clinical response.

SOURCE CITATION: Giamarellos-Bourboulis EJ, Siampanos A, Bolanou A, et al. Clarithromycin for early anti-inflammatory responses in community-acquired pneumonia in Greece (ACCESS): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2024;12:294-304. 38184008.

Long-term monitoring reveals widespread and severe declines of understory birds in a protected Neotropical forest.

Long-term studies on the population dynamics of tropical resident birds are few, and it remains poorly understood how their populations have fared in recent decades. Here, we analyzed a 44-y population study of a Neotropical understory bird assemblage from a protected forest reserve in central Panama to determine if and how populations have changed from 1977 to 2020. Using the number of birds captured in mist nets as an index of local abundance, we estimated trends over time for a diverse suite of 57 resident species that comprised a broad range of ecological and behavioral traits. Estimated abundances of 40 (∼70%) species declined over the sampling period, whereas only 2 increased. Furthermore, declines were severe: 35 of the 40 declining species exhibited large proportional losses in estimated abundance, amounting to ≥50% of their initial estimated abundances. Declines were largely independent of ecology (i.e., body mass, foraging guild, or initial abundance) or phylogenetic affiliation. These widespread, severe declines are particularly alarming, given that they occurred in a relatively large (∼22,000-ha) forested area in the absence of local fragmentation or recent land-use change. Our findings provide robust evidence of tropical bird declines in intact forests and bolster a large body of literature from temperate regions suggesting that bird populations may be declining at a global scale. Identifying the ecological mechanisms underlying these declines should be an urgent conservation priority.

Overdestabilization vs Overstabilization in the Theoretical Analysis of f-Orbital Covalency.

The complex nature of the f-orbital electronic structures and their interaction with the chemical environment pose significant computational challenges. Advanced computational techniques that variationally include scalar relativities and spin-orbit coupling directly at the molecular orbital level have been developed to address this complexity. Among these, variational relativistic multiconfigurational multireference methods stand out for their high accuracy and systematic improvement in studies of f-block complexes. Additionally, these advanced methods offer the potential for calibrating low-scaling electronic structure methods such as density functional theory. However, studies on the Cl K-edge X-ray absorption spectra of the [Ce(III)Cl6]3- and [Ce(IV)Cl6]2- complexes show that time-dependent density functional theory with approximate exchange-correlation kernels can lead to inaccuracies, resulting in an overstabilization of 4f orbitals and incorrect assessments of covalency. In contrast, approaches utilizing small active space wave function methods may understate the stability of these orbitals. The results herein demonstrate the need for large active space, multireference, and variational relativistic methods in studying f-block complexes.

Tetravalent Cerium Alkyl and Benzyl Complexes.

High-valent cerium complexes of alkyl and benzyl ligands are unprecedented due to the incompatibility of the typically highly oxidizing Ce4+ ion and the reducing alkyl or benzyl ligand. Herein we report the synthesis and isolation of the first tetravalent cerium alkyl and benzyl complexes supported by the tri-tert-butyl imidophosphorane ligand, [NP(tBu)3]1-. The Ce4+ monoiodide complex, [Ce4+I(NP(tert-butyl)3)3] (1-CeI), serves as a precursor to the alkyl and benzyl complexes, [Ce4+(Npt)(NP(tert-butyl)3)3] (2-CeNpt) (Npt = neopentyl, CH2C(CH3)3) and [Ce4+(Bn)(NP(tert-butyl)3)3] (2-CeBn) (Bn = benzyl, CH2Ph). The bonding and structure of these complexes are characterized by single-crystal XRD, NMR and UV-vis-NIR spectroscopy, cyclic voltammetry, and DFT studies.

Intervalence Charge Transfer in Nonbonding, Mixed-Valence, Homobimetallic Ytterbium Complexes.

There are several reports of compounds containing lanthanide ions in two different formal oxidation states; however, there are strikingly few examples of intervalence charge transfer (IVCT) transitions observed for these complexes, with those few occurrences limited to extended solids rather than molecular species. Herein, we report the synthesis, characterization, and computational analysis for a series of ytterbium complexes including a mixed-valence Yb25+ complex featuring a remarkably short Yb···Yb distance of 2.9507(8) Å. In contrast to recent reports of short Ln···Ln distances attributed to bonding through 5d orbitals, the formally Yb25+ complex presented here displays clear localization of Ln2+ and Ln3+ character and yet still displays an IVCT in the visible spectrum. These results demonstrate the ability to tune the electronic structure of formally mixed oxidation state lanthanide complexes: the high exchange stabilization of the Yb2+ 4f14 configuration disfavors the formation of a 5d1 bonding configuration, and the short metal-metal distance enforced by the ligand framework allows for the first observed lanthanide IVCT in a molecular system.

Genomic Landscape of Adenocarcinomas Across the Gastroesophageal Junction: Moving on from the Siewert Classification.

OBJECTIVE: To investigate how the Siewert classification of gastroesophageal junction adenocarcinomas correlates with genomic profiles. SUMMARY/BACKGROUND DATA: Current staging and treatment guidelines recommend that tumors with an epicenter less than 2 cm into the gastric cardia be treated as esophageal cancers, while tumors with epicenter greater than 2 cm into the cardia be staged and treated as gastric cancers. To date, however, few studies have compared the genomic profiles of the 3 Siewert classification groups to validate this distinction. METHODS: Using targeted tumor sequencing data on patients with adenocarcinoma of the gastroesophageal junction previously treated with surgery at our institution, we compared genomic features across Siewert classification groups. RESULTS: A total of 350 patients were included: 121 had Siewert type I, 170 type II, and 59 type III. Comparisons by Siewert location revealed that Siewert type I and II were primarily characterized as the chromosomal instability (CIN) molecular subtype and displayed Barrett's metaplasia and p53 and cell cycle pathway dysregulation. Siewert type III tumors, by contrast, were more heterogeneous, including higher proportions of microsatellite instability (MSI) and genomically stable (GS) tumors and more frequently displayed ARID1A and somatic CDH1 alterations, signet ring cell features, and poor differentiation. Overall, Siewert type I and II tumors demonstrated greater genomic overlap with lower esophageal tumors, while Siewert type III tumors shared genomic features with gastric tumors. CONCLUSIONS: Overall, our results support recent updates in treatment and staging guidelines. Ultimately, however, molecular rather than anatomic classification may prove more valuable in determining staging, treatment, and prognosis.

Investigation of the Electrocatalytic Reduction of Peroxydisulfate Using Scanning Electrochemical Microscopy.

The elementary steps of the electrocatalytic reduction of S2O82- using the Ru(NH3)63+/2+ redox couple were investigated using scanning electrochemical microscopy (SECM) and steady-state voltammetry (SSV). SECM investigations were carried out in a 0.1 M KCl solution using a 3.5 µm radius carbon ultramicroelectrode (UME) as the SECM tip and a 25 µm radius platinum UME as the substrate electrode. Approach curves were recorded in the positive feedback mode of SECM by reducing Ru(NH3)63+ at the tip electrode and oxidizing Ru(NH3)62+ at the substrate electrode, as a function of the tip-substrate separation and S2O82- concentration. The one-electron reaction between electrogenerated Ru(NH3)62+ and S2O82- yields the unstable S2O83•-, which rapidly dissociates to produce highly oxidizing SO4•-. Because SO4•- is such a strongly oxidizing species, it can be further reduced at both the tip and the substrate, or it can react with Ru(NH3)62+ to regenerate Ru(NH3)63+. SECM approach curves display a complex dependence on the tip-substrate distance, d, due to redox mediation reactions at both the tip and the substrate. Finite element method (FEM) simulations of both SECM approach curves and SSV confirm a previously proposed mechanism for the mediated reduction of S2O82- using the Ru(NH3)63+/2+ redox couple. Our results provide a lower limit for dissociation rate constant of S2O83•- (∼1 × 106 s-1), as well as the rate constants for electron transfer between SO4•- and Ru(NH3)62+ (∼1 × 109 M-1 s-1) and between S2O82- and Ru(NH3)62+ (∼7 × 105 M-1 s-1).

Electrocatalytic Reduction of Benzyl Bromide during Single Ag Nanoparticle Collisions.

Previous reports of the electrocatalytic activity of Ag nanoparticles (AgNPs) toward the reduction of organic halides have been limited to measurements of immobilized nanoparticle ensembles. Here, we have investigated the electrochemical reduction of benzyl bromide (PhCH2Br) occurring at single AgNPs (4.2 to 37 nm radius) in methanol, where the effects of nanoparticle size on catalytic behavior can be more thoroughly examined and rigorously quantified. AgNP collisions at a 6.3 µm radius Au ultramicroelectrode (UME) result in measurable electrocatalytic amplification currents from the reduction of PhCH2Br, where collision events are indicated by a sudden step increase in the reduction current recorded in the current-time trace. The dependence of the height of these steps on the applied potential allowed for an analysis of reaction kinetics based on the Butler-Volmer model, resulting in an estimation of the standard rate constant (k0) as a function of AgNP size. Measured values of k0 range from 4.0 × 10-4 to 8.0 × 10-4 cm/s on AgNPs with radii of 14, 29, and 37 nm, whereas k0 was found to be 6.2 × 10-4 cm/s at a 12.3 µm radius Ag disk UME. The results indicate that the kinetics of PhCH2Br reduction are independent of AgNP size and are similar to the reaction kinetics observed at a Ag UME. The frequency of observed particle collisions was found to be dependent on particle size, where 14 nm radius AgNPs resulted in the highest-frequency collisions. The potential- and size-dependent interactions of AgNPs with the Au UME are discussed in terms of the DLVO theory.

Perivascular Fibrosis Is Mediated by a KLF10-IL-9 Signaling Axis in CD4+ T Cells.

BACKGROUND: Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Ang II (angiotensin II) contributes to vascular disease and end-organ damage via promoting T-cell activation. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood. METHODS: TF (transcription factor) profiling was performed in peripheral blood mononuclear cells of hypertensive patients. CD4-targeted KLF10 (Kruppel like factor 10)-deficient (Klf10fl/flCD4Cre+; [TKO]) and CD4-Cre (Klf10+/+CD4Cre+; [Cre]) control mice were subjected to Ang II infusion. End point characterization included cardiac echocardiography, aortic imaging, multiorgan histology, flow cytometry, cytokine analysis, aorta and fibroblast transcriptomic analysis, and aortic single-cell RNA-sequencing. RESULTS: TF profiling identified increased KLF10 expression in hypertensive human subjects and in CD4+ T cells in Ang II-treated mice. TKO mice showed enhanced perivascular fibrosis, but not interstitial fibrosis, in aorta, heart, and kidney in response to Ang II, accompanied by alterations in global longitudinal strain, arterial stiffness, and kidney function compared with Cre control mice. However, blood pressure was unchanged between the 2 groups. Mechanistically, KLF10 bound to the IL (interleukin)-9 promoter and interacted with HDAC1 (histone deacetylase 1) inhibit IL-9 transcription. Increased IL-9 in TKO mice induced fibroblast intracellular calcium mobilization, fibroblast activation, and differentiation and increased production of collagen and extracellular matrix, thereby promoting the progression of perivascular fibrosis and impairing target organ function. Remarkably, injection of anti-IL9 antibodies reversed perivascular fibrosis in Ang II-infused TKO mice and C57BL/6 mice. Single-cell RNA-sequencing revealed fibroblast heterogeneity with activated signatures associated with robust ECM (extracellular matrix) and perivascular fibrosis in Ang II-treated TKO mice. CONCLUSIONS: CD4+ T cell deficiency of Klf10 exacerbated perivascular fibrosis and multi-organ dysfunction in response to Ang II via upregulation of IL-9. Klf10 or IL-9 in T cells might represent novel therapeutic targets for treatment of vascular or fibrotic diseases.

Outbreak of Human Trichinellosis - Arizona, Minnesota, and South Dakota, 2022.

Trichinellosis is a parasitic zoonotic disease transmitted through the consumption of meat from animals infected with Trichinella spp. nematodes. In North America, human trichinellosis is rare and is most commonly acquired through consumption of wild game meat. In July 2022, a hospitalized patient with suspected trichinellosis was reported to the Minnesota Department of Health. One week before symptom onset, the patient and eight other persons shared a meal that included bear meat that had been frozen for 45 days before being grilled and served rare with vegetables that had been cooked with the meat. Investigation identified six trichinellosis cases, including two in persons who consumed only the vegetables. Motile Trichinella larvae were found in remaining bear meat that had been frozen for >15 weeks. Molecular testing identified larvae from the bear meat as Trichinella nativa, a freeze-resistant species. Persons who consume meat from wild game animals should be aware that that adequate cooking is the only reliable way to kill Trichinella parasites and that infected meat can cross-contaminate other foods.

Coordination Modes and Binding Patterns in Lanthanum Phosphoramide Complexes.

A monoanionic phosphoramide ligand is introduced, which forms a series of lanthanum complexes with the ligand in both anionic and neutral forms. Stoichiometric control alone provides monometallic complexes with either two or three phosphoramide ligands. Alternatively, a combination of anionic and neutral proteo ligands featuring intramolecular hydrogen bonding can be obtained. The anionic form of the ligand binds lanthanum as a bi- or monodentate ligand, depending on the steric demand at the metal center, while the protonated ligand binds exclusively through the phosphoramide oxygen donor.

Testing a health baseline during a bivalve mollusc mortality event: An investigation into die-offs of pipi Paphies australis from Aotearoa New Zealand.

Disease is a major threat to the economic, ecological and cultural services provided by wild bivalve populations. Over the past decade anecdotal reports on declining health of native bivalve populations around Aotearoa New Zealand have been supported by increasing observations of mass die-offs. Causes of declining health and mass die-offs of wild bivalves are not clear and could be due to a number of interactive and cumulative factors, including declining water quality, climate change, or disease. Pipi/kokota (Paphies australis) within the Whangarei area (northern New Zealand) have suffered repeated die-offs and declining health since at least 2009. Baseline health data for wild native bivalve populations are scarce making it difficult to identify changes in pathogen infection prevalence and intensity and infer their importance to host health. This research aimed to examine and document the health of pipi in Whangarei with the objective of identifying factors that may contribute to their ill health and lack of population recovery. We sampled pipi from four sites within Whangarei, eight times across two years (total n = 640) to establish a health baseline using histopathology, general bacteriology, and qPCR for the intracellular bacteria Endozoicomonas spp. Three pipi mass die-offs occurred during the sampling window that were opportunistically sampled to compare against the health baseline established using healthy pipi. An increase in bacterial growth and a decrease in the abundance of Endozoicomonas spp. in mortality pipi was observed compared with the health baseline. Establishing a health baseline for pipi from Whangarei provided a benchmark to assess changes in a pipi population experiencing high mortality. Such data can help identify factors contributing to die-offs and to help inform what mitigation, if any, is possible in wild shellfish populations.

In TB, an 8-wk, 5-drug regimen was noninferior to a standard 24-wk, 4-drug regimen for clinical outcomes at 96 wk.

SOURCE CITATION: Paton NI, Cousins C, Suresh C, et al; TRUNCATE-TB Trial Team. Treatment strategy for rifampin-susceptible tuberculosis. N Engl J Med. 2023;388:873-887. 36808186.

Increased Crystal Field Drives Intermediate Coupling and Minimizes Decoherence in Tetravalent Praseodymium Qubits.

Crystal field (CF) control of rare-earth (RE) ions has been employed to minimize decoherence in qubits and to enhance the effective barrier of single-molecule magnets. The CF approach has been focused on the effects of symmetry on dynamic magnetic properties. Herein, the magnitude of the CF is increased via control of the RE oxidation state. The enhanced 4f metal-ligand covalency in Pr4+ gives rise to CF energy scales that compete with the spin-orbit coupling of Pr4+ and thereby shifts the paradigm from the ionic ζSOC ≫ VCF limit, used to describe trivalent RE-ion, to an intermediate coupling (IC) regime. We examine Pr4+-doped perovskite oxide lattices (BaSnO3 and BaZrO3). These systems are defined by IC which quenches orbital angular momentum. Therefore, the single-ion spin-orbit coupled states in Pr4+ can be chemically tuned. We demonstrate a relatively large hyperfine interaction of Aiso = 1800 MHz for Pr4+, coherent manipulation of the spin with QM = 2ΩRTm, reaching up to ∼400 for 0.1Pr:BSO at T = 5 K, and significant improvement of the temperature at which Tm is limited by T1 (T* = 60 K) compared to other RE ion qubits.

Electrocatalytic Hydrogen Evolution at Full Atomic Utilization over ITO-Supported Sub-nano-Ptn Clusters: High, Size-Dependent Activity Controlled by Fluxional Pt Hydride Species.

A combination of density functional theory (DFT) and experiments with atomically size-selected Ptn clusters deposited on indium-tin oxide (ITO) electrodes was used to examine the effects of applied potential and Ptn size on the electrocatalytic activity of Ptn (n = 1, 4, 7, and 8) for the hydrogen evolution reaction (HER). Activity is found to be negligible for isolated Pt atoms on ITO, increasing rapidly with Ptn size such that Pt7/ITO and Pt8/ITO have roughly double the activity per Pt atom compared to atoms in the surface layer of polycrystalline Pt. Both the DFT and experiment find that hydrogen under-potential deposition (Hupd) results in Ptn/ITO (n = 4, 7, and 8) adsorbing ∼2H atoms/Pt atom at the HER threshold potential, equal to ca. double the Hupd observed for Pt bulk or nanoparticles. The cluster catalysts under electrocatalytic conditions are hence best described as a Pt hydride compound, significantly departing from a metallic Pt cluster. The exception is Pt1/ITO, where H adsorption at the HER threshold potential is energetically unfavorable. The theory combines global optimization with grand canonical approaches for the influence of potential, uncovering the fact that several metastable structures contribute to the HER, changing with the applied potential. It is hence critical to include reactions of the ensemble of energetically accessible PtnHx/ITO structures to correctly predict the activity vs Ptn size and applied potential. For the small clusters, spillover of Hads from the clusters to the ITO support is significant, resulting in a competing channel for loss of Hads, particularly at slow potential scan rates.