The S2 subunit of spike encodes diverse targets for functional antibody responses to SARS-CoV-2.

The SARS-CoV-2 virus responsible for the COVID-19 global pandemic has exhibited a striking capacity for viral evolution that drives continued evasion from vaccine and infection-induced immune responses. Mutations in the receptor binding domain of the S1 subunit of the spike glycoprotein have led to considerable escape from antibody responses, reducing the efficacy of vaccines and monoclonal antibody (mAb) therapies. Therefore, there is a need to interrogate more constrained regions of spike, such as the S2 subdomain. Here, we present a collection of S2 mAbs from two SARS-CoV-2 convalescent individuals that target multiple regions in S2, including regions outside of those commonly reported. One of the S2 mAbs, C20.119, which bound to a highly conserved epitope in the fusion peptide, was able to broadly neutralize across SARS-CoV-2 variants, SARS-CoV-1, and closely related zoonotic sarbecoviruses. The majority of the mAbs were non-neutralizing; however, many of them could mediate antibody-dependent cellular cytotoxicity (ADCC) at levels similar to the S1-targeting mAb S309 that was previously authorized for treatment of SARS-CoV-2 infections. Several of the mAbs with ADCC function also bound to spike trimers from other human coronaviruses (HCoVs), such as MERS-CoV and HCoV-HKU1. Our findings suggest S2 mAbs can target diverse epitopes in S2, including functional mAbs with HCoV and sarbecovirus breadth that likely target functionally constrained regions of spike. These mAbs could be developed for potential future pandemics, while also providing insight into ideal epitopes for eliciting a broad HCoV response.

Enhanced intrinsic photovoltaic effect in tungsten disulfide nanotubes.

The photovoltaic effect in traditional p-n junctions-where a p-type material (with an excess of holes) abuts an n-type material (with an excess of electrons)-involves the light-induced creation of electron-hole pairs and their subsequent separation, generating a current. This photovoltaic effect is particularly important for environmentally benign energy harvesting, and its efficiency has been increased dramatically, almost reaching the theoretical limit1. Further progress is anticipated by making use of the bulk photovoltaic effect (BPVE)2, which does not require a junction and occurs only in crystals with broken inversion symmetry3. However, the practical implementation of the BPVE is hampered by its low efficiency in existing materials4-10. Semiconductors with reduced dimensionality2 or a smaller bandgap4,5 have been suggested to be more efficient. Transition-metal dichalcogenides (TMDs) are exemplary small-bandgap, two-dimensional semiconductors11,12 in which various effects have been observed by breaking the inversion symmetry inherent in their bulk crystals13-15, but the BPVE has not been investigated. Here we report the discovery of the BPVE in devices based on tungsten disulfide, a member of the TMD family. We find that systematically reducing the crystal symmetry beyond mere broken inversion symmetry-moving from a two-dimensional monolayer to a nanotube with polar properties-greatly enhances the BPVE. The photocurrent density thus generated is orders of magnitude larger than that of other BPVE materials. Our findings highlight not only the potential of TMD-based nanomaterials, but also more generally the importance of crystal symmetry reduction in enhancing the efficiency of converting solar to electric power.

phippery: a software suite for PhIP-Seq data analysis.

SUMMARY: We present the phippery software suite for analyzing data from phage display methods that use immunoprecipitation and deep sequencing to capture antibody binding to peptides, often referred to as PhIP-Seq. It has three main components that can be used separately or in conjunction: (i) a Nextflow pipeline, phip-flow, to process raw sequencing data into a compact, multidimensional dataset format and allows for end-to-end automation of reproducible workflows. (ii) a Python API, phippery, which provides interfaces for tasks such as count normalization, enrichment calculation, multidimensional scaling, and more, and (iii) a Streamlit application, phip-viz, as an interactive interface for visualizing the data as a heatmap in a flexible manner. AVAILABILITY AND IMPLEMENTATION: All software packages are publicly available under the MIT License. The phip-flow pipeline: https://github.com/matsengrp/phip-flow. The phippery library: https://github.com/matsengrp/phippery. The phip-viz Streamlit application: https://github.com/matsengrp/phip-viz.

Synthesis of Graphene Quantum Dots Decorated With Se, Eu and Ag As Photosensitizer and Study of Their Potential to Use in Photodynamic Therapy.

GQDs decorated with europium (Eu), silver (Ag) and selenium (Se) at molar ratios of 0.1%, 0.3% and 0.5% were produced for the first time at different temperatures of 180 °C, 200 °C and 220 °C. Surface passivation was carried out with polyethylene glycol (PEG) to increase the intensity of photoluminescence (PL) of the produced samples. The prepared quantum dots were characterized by X-Ray diffraction (XRD), Fourier transformed infrared spectroscopy (FTIR), transmission electron microscopy (TEM), PL and ultraviolet-visible spectroscopy. GQDs synthesized at 180 °C and decorated with Se (0.3%) had maximum PL intensity along with long lasted afterglow over 90 min compared with other samples. Excitation wavelength at 360 nm produced maximum emission at 600-900 nm and resulted in high singlet oxygen (1O 2) generation which makes it a good candidate for photodynamic therapy applications.

Preparation and characterization of selenium-decorated graphene quantum dots with high afterglow for application in photodynamic therapy.

Graphene quantum dots (GQDs) was synthesized using a simple, rapid and affordable method and decorated with selenium at different molar ratios for the first time to obtain an efficient sample for use in photodynamic therapy. Surface modification of GQDs was carried out using polyethylene glycol (PEG) for conjugation with protoporphyrin IX (PpIX). Synthesized GQDs (Se: 0.3%) at 180°C had an emission spectrum that fairly coincided with the absorption profile of PpIX. A relative decrease of about 62.48% in the emission intensity of anthracene was recorded under illumination with UVC light in the presence of GQDs (Se: 0.3%) and the reduction for clung GQDs (Se: 0.3%) and PpIX during 90 min was about 70.68%. Singlet oxygen (1 O2 ) generation was examined using a chemical method that showed significant enhancement in decomposition rate constant in clung GQDs-PEG-PpIX compared with GQDs and PpIX alone. Afterglow over 600 s showed that GQDs (Se: 0.3%) could be effective for near skin and even deep tumours.

Polymorphisms rs2167444 and rs508384 in the SCD1 Gene Are Linked with High ApoB-48 Levels and Adverse Profile of Cardiometabolic Risk Factors.

Elevated plasma concentration of apolipoprotein B-48 (apoB-48) is an independent risk factor of cardiovascular disease. Stearoyl-CoA desaturase-1 (SCD1) is a rate-limiting lipogenic enzyme and a key regulator of fuel metabolism. The aim of this study was to analyse associations between clinical, biochemical, and genetic factors and different apoB-48 levels in subjects at increased cardiometabolic risk. We examined 220 subjects exhibiting at least one metabolic syndrome (MetS) component. In conjunction with basic clinical, anthropometric and laboratory measurements, we analysed various polymorphisms of stearoyl-CoA desaturase-1 (SCD1). Subjects were divided into two groups according to the median apoB-48 level: (1) high apoB-48 (≥ 7.9 mg/l, N = 112) and (2) low apoB-48 (< 7.9 mg/l, N = 108). Neither group differed significantly in anthropometric measures. High plasma apoB-48 levels were associated with increased systolic blood pressure (+3 %; P < 0.05), MetS prevalence (59.8 vs. 32.4 %; P < 0.001), small-dense LDL frequency (46.4 vs. 20.4 %; P < 0.001), triglycerides (+97 %; P < 0.001), non-HDLcholesterol (+27 %; P < 0.001), and lower concentrations of HDL-cholesterol (-11 %; P < 0.01). This group was further characterized by a higher HOMA-IR index (+54 %; P < 0.001) and increased concentrations of conjugated dienes (+11 %; P < 0.001) and oxidatively modified LDL (+ 38 %; P < 0.05). Lower frequencies of SCD1 minor genotypes (rs2167444, rs508384, P < 0.05) were observed in subjects with elevated plasma concentrations of apoB-48. Elevated plasma concentrations of apoB-48 are associated with an adverse lipid profile, higher systolic blood pressure, insulin resistance, and oxidative stress. Lower proportions of minor SCD1 genotypes (rs2167444, rs508384) implicate the role of genetic factors in the pathogenesis of elevated levels of apoB-48.

Gold nanoparticle-decorated graphene as a nonlinear optical material in the visible and near-infrared spectral range.

There have been numerous reports of boosting nonlinear optical phenomena in plasmonic nanostructures through local-field enhancement as well as through intrinsic metal nonlinearities. Here, we study the possibility of plasmonic enhancement of graphene's nonlinear absorption by creating a composite material: gold nanoparticle-decorated graphene dispersed in water. To evaluate the additive effect of combining the two materials on the saturable absorption efficiency we performed a series of f-scan (modified Z-scan) measurements using femtosecond laser pulses in the broad spectral range from 530 to 1600 nm. These studies are supplemented by TEM, UV-vis, ATR and Raman spectroscopy, revealing the mechanisms behind the formation of the composite material.

The detection of capsaicin and dihydrocapsaicin in horse serum following long-term local administration.

BACKGROUND: Capsaicin and dihydrocapsaicin are alkaloids with analgesic effects in humans and animals. When used locally, both of them minimalise pain sensation by defunctionalising nerve endings. According to the Federation Equestrian International Prohibited Substances List, these are substance banned in horse competitions. The aim of the study was to determine the detection time of capsaicin in both plasma and serum after long-term use of a gel recommended for commercial use and applied as intended. The objective of the study was to select the best material for the detection of capsaicin as a doping substance in horses. METHODS: Nine healthy mature horses were administered 0.1% capsaicin topically in the form of a commercial analgesic gel (15 g of the gel per limb) to the front limbs every 24 hours for five days with a polar fleece bandage. Blood serum and plasma were collected prior to gel application and in the 12th, 18th, 24th, 36th, 42nd, 48th, 60th, 84th, 108th, 132nd, 156th hour after the gel application. Qualitative and quantitative analysis was performed using ultra-high performance liquid chromatography coupled with a triple quadrupole mass spectrometry (UHPLC-QqQ-MS/MS). RESULTS: The concentration of capsaicin in the serum samples did not exceed the lower limit of quantification. Capsaicin was not detected in the plasma samples during the entire study period. Dihydrocapsaicin was not detected in blood serum or plasma. CONCLUSION: The presented results suggest that capsaicin is not detected in horse serum in the 24-hour-periodfollowing its last application according to the dosage regimen used by owners and veterinarians for therapy rather than doping, based on a five day gel application and a polar bandage.

Conjunctival aerobic bacterial flora in healthy Silesian foals and adult horses in Poland.

BACKGROUND: Commensal bacterial and fungal flora of the conjunctival sac has been described in horses and other animals. The identification of commensal flora of the conjunctival sac may aid in the diagnosis of ocular inflammatory diseases, such as conjunctivitis or more severe ulcerative keratitis, common in horses. Moreover, damage of ocular protective barriers may lead to an opportunistic infection. The study was carried out in Silesian horses kept at a single breeding center in South-western Poland, in order to limit any breed-dependant and climate-dependant variables affecting the results. Following an ophthalmic examination that revealed no abnormalities, sterile swabs were collected from conjunctival sac in 26 adult horses and 11 foals. The obtained swabs were subjected to bacterial culture testing. In case of Staphylococcus spp. isolation, susceptibility to methicillin was evaluated. RESULTS: Forty- three bacterial isolates, representing eleven genera of bacteria were cultured from 30 (81%) horses. Gram-positive bacteria were the dominant isolates (72%) (p < 0.001). The most commonly isolated Gram-positive bacteria were Staphylococcus spp., while Moraxella spp. were the most frequently isolated Gram-negative bacteria. There was no significant influence of sex and age on the frequency and type of microbial isolates. CONCLUSIONS: Commensal flora is present in the conjunctival sac of healthy horses in Poland. Age does not affect the abundance and type of microbial isolates.

Morphology and elemental analysis of free range and stabled Polish Konik horses hair using Energy-dispersive X-ray spectroscopy (EDS).

Hair is a more biologically stable material than other tissues and contains a relatively constant level of minerals, drugs or toxins. The content of essential elements in hair depends on dietary and non-dietary factors. The aim of this study was to assess and compare the effect of diet on the elemental composition and morphological properties of the hair of healthy Polish Konik horses. Mane hair was collected from 19 horses living in The National Park in Popielno in Poland. Six of these horses were free-ranged all year with permanent access to pasture, while 13 horses were kept in the stable and fed oats, hay and straw. The samples were analyzed using a Scanning Electron Microscope combined with Energy-dispersive X-ray spectroscopy (SEM-EDS). Each hair was analyzed for its microscopic appearance and elemental Mg, Si, S, Ca, Mn, Co, Zn and Se content. No significant changes in the morphological properties and elemental composition were observed. There was inter- individual variability in element content between horses in both groups, but this did not affect their health. The comparison of the present results with other studies shows that the level of elements in the hair of Polish Konik horses is significantly lower than in healthy horses of other breeds. The traditional feeding plan containing pasture, oats and hay does not contain a sufficient amount of main mineral elements. Further investigation is needed to explain the effect of diet and maintenance on the mineral balance of horses.

Searching for ivermectin resistance in a Strongylidae population of horses stabled in Poland.

BACKGROUND: There are no available studies describing the possible resistance of strongyles to ivermectin in horses in Poland. One hundred seventy three horses from nine stud farms from South-Western Poland were studied. The effectiveness of ivermectin was studied on the 14th day after ivermectin administration using the fecal egg count reduction test, and a long-term observation of the egg reappearance period was carried out. The fecal study was carried out using a modified McMaster method, which typically detects 20 eggs per gram of stool. The results were subjected to statistical analysis that enabled quantification of the eggs in the stool samples. RESULTS: The study revealed high efficacy of ivermectin on the 14th day after administration without a shortening of the egg reappearance period. CONCLUSION: The results indicate that strongyles resistance to ivermectin in Poland is not a serious problem.

High Pressure Vibrational Properties of WS2 Nanotubes.

We bring together synchrotron-based infrared and Raman spectroscopies, diamond anvil cell techniques, and an analysis of frequency shifts and lattice dynamics to unveil the vibrational properties of multiwall WS2 nanotubes under compression. While most of the vibrational modes display similar hardening trends, the Raman-active A1g breathing mode is almost twice as responsive, suggesting that the nanotube breakdown pathway under strain proceeds through this displacement. At the same time, the previously unexplored high pressure infrared response provides unexpected insight into the electronic properties of the multiwall WS2 tubes. The development of the localized absorption is fit to a percolation model, indicating that the nanotubes display a modest macroscopic conductivity due to hopping from tube to tube.

Enhanced field emission of WS2 nanotubes.

Results on electron field emission from free standing tungsten disulfide (WS2) nanotubes (NTs) are presented. Experiments show that the NTs protruding on top of microstructures are efficient cold emitters with turn-on fields as low as 1 V/µm and field enhancement of few thousands. Furthermore, the emission current shows remarkable stability over more than eighteen hours of continuous operation. Such performance and long-term stability of the WS2 cathodes is comparable to that reported for optimized carbon nanotube (CNTs) based emitters. Besides this, it is found that the WS2 cathodes prepared are less sensitive than CNTs in chemical reactive ambients. The high field enhancement and superior reliability achieved indicates a potential for vacuum nanoelectronics and flat panel display applications.

Human catalase, its polymorphisms, regulation and changes of its activity in different diseases.

Catalase (CAT) is a well-studied enzyme that plays an important role in protecting cells against the toxic effects of hydrogen peroxide. In human, it has been implicated in different physiological and pathological conditions. This review summarizes the information available on the function and role of CAT polymorphisms in pathogenesis of various pathophysiological states as well as on the regulation of CAT gene expression. Numerous studies have described the CAT polymorphisms and their link with various diseases. Changes in the CAT levels were reported in many different diseases and polymorphisms in the CAT gene were shown to be associated with different pathophysiological states, e.g. hypertension, diabetes mellitus, insulin resistance, dyslipidaemia, asthma, bone metabolism or vitiligo. Regulation of the CAT gene expression plays an important role in the levels of CAT. The catalase gene expression is regulated by various mechanisms involving e.g. peroxisome proliferator-activated receptor γ (PPARγ), tumour necrosis factor α (TNF-α), p53 protein and hypermethylation of CpG islands in the catalase promoter. Transcription of the CAT gene is mainly influenced by the -262 C/T and -844 A/G polymorphisms. A common polymorphism -262 C/T in the promoter region has been found to be associated with altered CAT activities. Apart from genetic factors, the activities of CAT may be affected by age, seasonal variations, physical activity, or a number of chemical compounds. Future investigations are necessary to elucidate the role of CAT in pathogenesis of oxidative stress-related diseases.

Investigation of genetic determinants of cognitive change in later life.

Cognitive decline is a major health concern and identification of genes that may serve as drug targets to slow decline is important to adequately support an aging population. Whilst genetic studies of cross-sectional cognition have been carried out, cognitive change is less well-understood. Here, using data from the TOMMORROW trial, we investigate genetic associations with cognitive change in a cognitively normal older cohort. We conducted a genome-wide association study of trajectories of repeated cognitive measures (using generalised estimating equation (GEE) modelling) and tested associations with polygenic risk scores (PRS) of potential risk factors. We identified two genetic variants associated with change in attention domain scores, rs534221751 (p = 1 × 10-8 with slope 1) and rs34743896 (p = 5 × 10-10 with slope 2), implicating NCAM2 and CRIPT/ATP6V1E2 genes, respectively. We also found evidence for the association between an education PRS and baseline cognition (at >65 years of age), particularly in the language domain. We demonstrate the feasibility of conducting GWAS of cognitive change using GEE modelling and our results suggest that there may be novel genetic associations for cognitive change that have not previously been associated with cross-sectional cognition. We also show the importance of the education PRS on cognition much later in life. These findings warrant further investigation and demonstrate the potential value of using trial data and trajectory modelling to identify genetic variants associated with cognitive change.

Reconstruction of a polyclonal ADCC antibody repertoire from an HIV-1 non-transmitting mother.

Human natural history and vaccine studies support a protective role of antibody dependent cellular cytotoxicity (ADCC) activity against many infectious diseases. One setting where this has consistently been observed is in HIV-1 vertical transmission, where passively acquired ADCC activity in HIV-exposed infants has correlated with reduced acquisition risk and reduced pathogenesis in HIV+ infants. However, the characteristics of HIV-specific antibodies comprising a maternal plasma ADCC response are not well understood. Here, we reconstructed monoclonal antibodies (mAbs) from memory B cells from late pregnancy in mother MG540, who did not transmit HIV to her infant despite several high-risk factors. Twenty mAbs representing 14 clonal families were reconstructed, which mediated ADCC and recognized multiple HIV Envelope epitopes. In experiments using Fc-defective variants, only combinations of several mAbs accounted for the majority of plasma ADCC of MG540 and her infant. We present these mAbs as evidence of a polyclonal repertoire with potent HIV-directed ADCC activity.

Genomic landscape and actionable mutations of brain metastases derived from non-small cell lung cancer: A systematic review.

Background: Brain metastases derived from non-small cell lung cancer (NSCLC) represent a significant clinical problem. We aim to characterize the genomic landscape of brain metastases derived from NSCLC and assess clinical actionability. Methods: We searched Embase, MEDLINE, Web of Science, and BIOSIS from inception to 18/19 May 2022. We extracted information on patient demographics, smoking status, genomic data, matched primary NSCLC, and programmed cell death ligand 1 expression. Results: We found 72 included papers and data on 2346 patients. The most frequently mutated genes from our data were EGFR (n = 559), TP53 (n = 331), KRAS (n = 328), CDKN2A (n = 97), and STK11 (n = 72). Common missense mutations included EGFR L858R (n = 80) and KRAS G12C (n = 17). Brain metastases of ever versus never smokers had differing missense mutations in TP53 and EGFR, except for L858R and T790M in EGFR, which were seen in both subgroups. Of the top 10 frequently mutated genes that had primary NSCLC data, we found 37% of the specific mutations assessed to be discordant between the primary NSCLC and brain metastases. Conclusions: To our knowledge, this is the first systematic review to describe the genomic landscape of brain metastases derived from NSCLC. These results provide a comprehensive outline of frequently mutated genes and missense mutations that could be clinically actionable. These data also provide evidence of differing genomic landscapes between ever versus never smokers and primary NSCLC compared to the BM. This information could have important consequences for the selection and development of targeted drugs for these patients.

Passively Acquired Constant Region 5-Specific Antibodies Associated With Improved Survival in Infants Who Acquire Human Immunodeficiency Virus.

Studying vertical human immunodeficiency virus (HIV) transmission enables the impact of passively transferred antibodies on HIV transmission and pathogenesis to be examined. Using phage display of HIV envelope peptides and peptide enzyme-linked immunosorbent assay (ELISA), we found that, in infants who acquired HIV, passive antibody responses to constant region 5 (C5) were associated with improved survival in 2 cohorts. In a combined analysis, C5 peptide ELISA activity was correlated directly with survival and estimated infection time and inversely with set point viral load. These results suggest that preexisting C5-specific antibodies may be correlated with the survival of infants living with HIV, motivating additional research into their protective potential.

Higher HIV-1 Env gp120-Specific Antibody-Dependent Cellular Cytotoxicity (ADCC) Activity Is Associated with Lower Levels of Defective HIV-1 Provirus.

A cure for HIV-1 (HIV) remains unrealized due to a reservoir of latently infected cells that persist during antiretroviral therapy (ART), with reservoir size associated with adverse health outcomes and inversely with time to viral rebound upon ART cessation. Once established during ART, the HIV reservoir decays minimally over time; thus, understanding factors that impact the size of the HIV reservoir near its establishment is key to improving the health of people living with HIV and for the development of novel cure strategies. Yet, to date, few correlates of HIV reservoir size have been identified, particularly in pediatric populations. Here, we employed a cross-subtype intact proviral DNA assay (CS-IPDA) to quantify HIV provirus between one- and two-years post-ART initiation in a cohort of Kenyan children (n = 72), which had a median of 99 intact (range: 0-2469), 1340 defective (range: 172-3.84 × 104), and 1729 total (range: 178-5.11 × 104) HIV proviral copies per one million T cells. Additionally, pre-ART plasma was tested for HIV Env-specific antibody-dependent cellular cytotoxicity (ADCC) activity. We found that pre-ART gp120-specific ADCC activity inversely correlated with defective provirus levels (n = 68, r = -0.285, p = 0.0214) but not the intact reservoir (n = 68, r = -0.0321, p-value = 0.800). Pre-ART gp41-specific ADCC did not significantly correlate with either proviral population (n = 68; intact: r = -0.0512, p-value = 0.686; defective: r = -0.109, p-value = 0.389). This suggests specific host immune factors prior to ART initiation can impact proviruses that persist during ART.

Elevated binding and functional antibody responses to SARS-CoV-2 in infants versus mothers.

Infant antibody responses to viral infection can differ from those in adults. However, data on the specificity and function of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in infants, and direct comparisons between infants and adults are limited. Here, we characterize antibody binding and functionality against Wuhan-Hu-1 (B lineage) strain SARS-CoV-2 in convalescent plasma from 36 postpartum women and 14 of their infants infected with SARS-CoV-2 from a vaccine-naïve prospective cohort in Nairobi, Kenya. We find significantly higher antibody titers against SARS-CoV-2 Spike, receptor binding domain and N-terminal domain, and Spike-expressing cell-surface staining levels in infants versus mothers. Plasma antibodies from mothers and infants bind to similar regions of the Spike S2 subunit, including the fusion peptide (FP) and stem helix-heptad repeat 2. However, infants display higher antibody levels and more consistent antibody escape pathways in the FP region compared to mothers. Finally, infants have significantly higher levels of antibody-dependent cellular cytotoxicity (ADCC), though, surprisingly, Spike pseudovirus neutralization titers between infants and mothers are similar. These results suggest infants develop distinct SARS-CoV-2 binding and functional antibody activities and reveal age-related differences in humoral immunity to SARS-CoV-2 infection that could be relevant to protection and COVID-19 disease outcomes.