Search

We measure the gas-phase abundances of the elements He, N, O, Ne, S, Ar, and Fe in an individual H ii region known to be leaking Lyman-continuum photons in the Sunburst Arc, a highly magnified galaxy at redshift z = 2.37. We detect the temperature-sensitive auroral lines [S ii ] λλ 4070, 4076, [O iii ] λ 4363, [S iii ] λ 6314, [O ii ] λλ 7320, 7330, and [Ne iii ] λ 3343 in a stacked spectrum of five multiple images of the Lyman-continuum emitter (LCE), from which we directly measure the electron temperature in the low-, intermediate-, and high-ionization zones. We also detect the density-sensitive doublets of [O ii ] λλ 3727, 3730, [S ii ] λλ 6718, 6733, and [Ar iv ] λλ 4713, 4741, which constrain the density in both the low- and high-ionization gas. With these temperature and density measurements, we measure gas-phase abundances with similar rigor as studies of local galaxies and H ii regions. We measure a gas-phase metallicity for the LCE of $12+\mathrm{log}({\rm{O}}/{\rm{H}})=7.97\pm 0.05$ , and find an enhanced nitrogen abundance $\mathrm{log}({\rm{N}}/{\rm{O}})=-0.6{5}_{-0.25}^{+0.16}$ . This nitrogen abundance is consistent with enrichment from a population of Wolf–Rayet stars, additional signatures of which are reported in a companion paper. Abundances of sulfur, argon, neon, and iron are consistent with local low-metallicity H ii regions and low-redshift galaxies. This study represents the most complete chemical abundance analysis of an individual H ii region at Cosmic Noon to date, which enables direct comparisons between local H ii regions and those in the distant Universe.

Abstract Background The COVID-19 pandemic had a profound impact on healthcare and ophthalmology services globally. Numerous studies amongst various medical and surgical specialties showed a reduction in patient attendance and surgical procedures performed. Prior published ophthalmic literature focused on specific types of procedures and were usually single centre. The current study attempts to quantify the impact on a larger scale, namely that of sub-Saharan Africa, and to include all ophthalmic subspecialties. Methods This is a retrospective analysis of the surgical records from 17 ophthalmology centres in seven countries located in East, Central, West and Southern Africa. The date of declaration of the first lockdown was used as the beginning of the pandemic and the pivot point to compare theatre records one year prior to the pandemic and the first year of the pandemic. We examined the total number of surgical procedures over the two year period and categorized them according to ophthalmic subspecialty and type of procedure performed. We then compared the pre-pandemic and pandemic surgical numbers over the two year period. Results There were 26,357 ophthalmic surgical procedures performed with a significant decrease in the first year of the pandemic (n = 8942) compared to the year prior to the pandemic (n = 17,415). The number of surgical procedures performed was lower in the first year of the pandemic compared to the year prior to the pandemic by 49% [Incidence rate ratio (IRR) 0.51, 95% CI 0.41–0.64), 27% (0.73, 0.55–0.99), 46% (0.54, 0.30–0.99), 40% (0.60, 0.39–0.92) and 59% (0.41, 0.29–0.57) in sub-Saharan Africa (4 regions combined), West, Central, East and Southern Africa, respectively]. The number of surgical procedures in the different sub-specialty categories in sub-Saharan Africa (4 regions combined) was significantly lower in the first year of the pandemic compared to the year prior to the pandemic, except for glaucoma (IRR 0.72, 95% CI 0.52–1.01), oncology (0.71, 0.48–1.05), trauma (0.90, 0.63–1.28) and vitreoretinal (0.67, 0.42–1.08) categories. Conclusion This study provides insight into the impact of the COVID-19 pandemic in multiple regions and countries on the African continent. The identification of which surgical subspecialty was most affected by the COVID-19 pandemic in each region allows for better planning and resource allocation to address these backlogs.

Plant oil supplements have been used in ruminant feedlot diets as alternative high-density energy source.However, feeding ruminants with high levels of oil may adversely affect the rumen microbiome and function, negatively impacting performance and production. Plant oils high in polyunsaturated fatty acids (PUFA) may also affect animal products quality when PUFA escape or partially escape biohydrogenation. This study investigated the effects of a low inclusion level (1.62%) of a plant oil (commercial sunflower-soybean blend) on the physicochemical attributes, fatty acid profile, and shelf-display stability of longissimus thoracis et lumborum muscle of lambs fed high-energy starch-based diets. In addition, either a natural or synthetic antioxidant were included in the plant oil containing diets to evaluate their effects on maintenance of shelf-display stability with or without natural or synthetic antioxidants. Forty [n=40; average weight (± standard error of mean) 28 (± 0.836 kg)] were blocked by weight and randomly allocated to 4 dietary treatment groups [(1) control (Grain); (2) grain plus plant oil only (Oil); (3) grain plus plant oil with synthetic antioxidant (OilCaps); and (4) grain plus plant oil with natural antioxidant (OilNat)]. Feeding lambs with grain-based diets supplemented with plant oil, with or without natural or synthetic antioxidants, had no effects on meat physicochemical attributes (P>0.050) or color stability over 7 d of shelf display (P>0.050). Regardless of antioxidant inclusion, oil supplementation increased conjugated linoleic acid (CLA) composition in lamb longissimus muscle (P=0.028). Overall, results from this study suggest that grain-based feedlot diets supplemented with low inclusion levels of plant oil did not significantly affect shelf stability of lamb meat during display while both oil supplement and antioxidants increased the CLA content of longissimus muscle.

This paper gives an overview of Targeting Extremely Magnified Panchromatic Lensed Arcs and Their Extended Star formation (TEMPLATES), a JWST Early Release Science program that targeted four extremely bright, gravitationally lensed galaxies, two extremely dusty and two with low attenuation, as templates for galaxy evolution studies with JWST. TEMPLATES obtains a common set of spectral diagnostics for these 1.3 ≤ z ≤ 4.2 galaxies, in particular H α , Paschen α , and the rest-frame optical and near-infrared continua. In addition, two of the four targets have JWST coverage of [O iii ] 5007 Å and H β ; the other two targets have JWST coverage of polycyclic aromatic hydrocarbon 3.3 μ m and complementary Atacama Large Millimeter/submillimeter Array data covering the [C ii ] 158 μ m emission line. The science goals of TEMPLATES are to demonstrate attenuation-robust diagnostics of star formation, map the distribution of star formation, compare the young and old stellar populations, and measure the physical conditions of star formation and their spatial variation across the galaxies. In addition, TEMPLATES has the technical goal to establish best practices for the integral field units within the NIRSpec and MIRI instruments, both in terms of observing strategy and in terms of data reduction. The paper describes TEMPLATES’s observing program, scientific and technical goals, data reduction methods, and deliverables, including high-level data products and data reduction cookbooks.

The variations of oxygen abundance and ionization parameter in H ii regions are usually thought to be the dominant factors that produced variations seen in observed emission-line spectra. However, if and how these two quantities are physically related is hotly debated in the literature. Using emission line data of NGC 628 observed with SITELLE as part of the Star formation, Ionized Gas, and Nebular Abundances Legacy Survey (SIGNALS), we use a suite of photoionization models to constrain the abundance and ionization parameters for over 1500 H ii regions throughout its disk. We measure an anticorrelation between these two properties, consistent with expectations, although with considerable scatter. Secondary trends with dust extinction and star formation rate surface density potentially explain the large scatter observed. We raise concerns throughout regarding various modeling assumptions and their impact on the observed correlations presented in the literature.

We present the first Chandra X-ray observations of H72.97–69.39, a highly embedded, potential superstar cluster in its infancy located in the star-forming complex N79 of the Large Magellanic Cloud. We detect particularly hard, diffuse X-ray emission that is coincident with the young stellar objects identified with JWST, and the hot gas fills cavities in the dense gas mapped by the Atacama Large Millimeter/submillimeter Array. The X-ray spectra are best fit with either a thermal plasma or power-law model, and assuming the former, we show that the X-ray luminosity of L _X = (1.0 ± 0.3) × 10 ^34 erg s ^−1 is a factor of ∼20 below the expectation for a fully confined wind bubble. Our results suggest that stellar wind feedback produces diffuse hot gas in the earliest stages of massive star cluster formation and that wind energy can be lost quickly via either turbulent mixing followed by radiative cooling or by physical leakage.

Using integrated spectra for two gravitationally lensed galaxies from the JWST TEMPLATES Early Release Science program, we analyze faint auroral lines, which provide direct measurements of the gas-phase chemical abundance. For the brighter galaxy, SGAS1723+34 ( z = 1.3293), we detect the [O iii ] λ 4363, [S iii ] λ 6312, and [O ii ] λ λ 7320, 7330 auroral emission lines, and set an upper limit for the [N ii ] λ 5755 line. For the second galaxy, SGAS1226+21 ( z = 2.925), we do not detect any auroral lines, and report upper limits. With these measurements and upper limits, we constrain the electron temperatures in different ionization zones within both of these galaxies. For SGAS1723+34, where auroral lines are detected, we calculate direct oxygen and nitrogen abundances, finding an N/O ratio consistent with observations of nearby ( z ∼ 0) galaxies. These observations highlight the potent combination of JWST and gravitational lensing to measure faint emission lines in individual distant galaxies and to directly study the chemical abundance patterns in those galaxies.

We present the first spatially resolved maps of gas-phase metallicity for two dust-obscured star-forming galaxies at z ∼ 4, from the JWST TEMPLATES Early Release Science program, derived from NIRSpec integral field unit spectroscopy of the H α and [N ii ] emission lines. Empirical optical line calibrations are used to determine that the sources are globally enriched to near-solar levels. While one source shows elevated [N ii ]/H α ratios and broad H α emission consistent with the presence of an active galactic nucleus in a ≳1 kpc region, we argue that both systems have already undergone significant metal enrichment as a result of their extremely high star formation rates. Utilizing Atacama Large Millimeter/submillimeter Array rest-frame 380 μ m continuum and [C i ]( ^3 P _2 – ^3 P _1 ) line maps we compare the spatial variation of the metallicity and gas-to-dust ratio in the two galaxies, finding the two properties to be anticorrelated on highly resolved spatial scales, consistent with various literature studies of z ∼ 0 galaxies. The data are indicative of the enormous potential of JWST to probe the enrichment of the interstellar medium on ∼kpc scales in extremely dust-obscured systems at z ∼ 4 and beyond.

Despite a complete lack of microsomal triglyceride transfer protein (MTP), L35 rat hepatoma cells secrete triglyceride-containing lipoproteins, albeit at a rate 25% of that of parental FAO hepatoma cells, which express high levels of MTP. The inability to express MTP was associated with a complete block in the secretion of both apolipoprotein (apo)B-100 and apoB-48. Stable expression of a MTP transgene restored the secretion of both apoB-100 and apoB-48 in L35 cells, indicating that MTP is essential for the secretion of both forms of apoB. Treatment with the MTP inhibitor BMS-200150 reduced the secretion of triglyceride by 70% in FAO cells, whereas the inhibitor did not affect the secretion of triglycerides by L35 cells. Thus, in the presence of the MTP inhibitor, both cell types secreted triglycerides at similar rates. Essentially, all of the triglycerides secreted by L35 cells were associated with HDL containing apoA-IV and apoE but devoid of apoB-100 or apoB-48. These results suggest that these triglyceride-containing lipoproteins are assembled and secreted via a pathway that is independent of both apoB and MTP. Our findings support the concept that apoB and MTP co-evolved and provided a means to augment the secretion of triglyceride through the formation of lipoproteins containing large hydrophobic cores enriched with triglycerides.—Hui, T. Y., L. M. Olivier, S. Kang, and R. A. Davis. Microsomal triglyceride transfer protein is essential for hepatic secretion of apoB-100 and apoB-48 but not triglyceride. J. Lipid Res. 2002. 43: 785–793.

At least three different subcellular compartments, including peroxisomes, are involved in cholesterol synthesis. The peroxisomal targeting signals for phosphomevalonate kinase and isopentenyl diphosphate isomerase have been identified. In the current study we identify the peroxisomal targeting signals required for four other enzymes of the cholesterol biosynthetic pathway: acetoacetyl-CoA (AA-CoA) thiolase, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase, mevalonate diphosphate decarboxylase (MPPD), and farnesyl diphosphate (FPP) synthase. Data are presented that demonstrate that mitochondrial AA-CoA thiolase contains both a mitochondrial targeting signal at the amino terminus and a peroxisomal targeting signal (PTS-1) at the carboxy terminus. We also analyze a new variation of PTS-2 sequences required to target HMG-CoA synthase and MPPD to peroxisomes. In addition, we show that FPP synthase import into peroxisomes is dependent on the PTS-2 receptor and identify at the amino terminus of the protein a 20-amino acid region that is required for the peroxisomal localization of the enzyme. These data provide further support for the conclusion that peroxisomes play a critical role in cholesterol biosynthesis.—Olivier, L. M., W. Kovacs, K. Masuda, G-A. Keller, and S. K. Krisans. Identification of peroxisomal targeting signals in cholesterol biosynthetic enzymes: AA-CoA thiolase, HMG-CoA synthase, MPPD, and FPP synthase. J. Lipid Res. 2000. 41: 1921–1935.

Phosphomevalonate kinase catalyzes the conversion of mevalonate-5-phosphate to mevalonate-5-diphosphate and was originally believed to be a cytosolic enzyme. In this study we have localized the phosphomevalonate kinase gene to chromosome 1p13–1q22–23 and present a genomic map indicating that the gene spans more than 8.4 kb in the human genome. Furthermore, we show that message levels and enzyme activity of rat liver phosphomevalonate kinase are regulated in response to dietary sterol levels and that this regulation is coordinate with 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme of cholesterol biosynthesis. In addition, we demonstrate that phosphomevalonate kinase is a peroxisomal protein which requires the C-terminal peroxisomal targeting signal, Ser-Arg-Leu, for localization to the organelle.—Olivier, L. M., K. L. Chambliss, K. M. Gibson, and S. K. Krisans. Characterization of phosphomevalonate kinase: chromosomal localization, regulation, and subcellular targeting. J. Lipid Res. 1999. 40: 672–679.

We report on an experimental study with UV and visible ultrafast time-gated emission and transient absorption of the early photodynamics of horse heart Cytochrome cin both ferric and ferrous redox states. A clear separation in time and energy of tryptophan and haem emission is observed. Excitation of the haem via resonant energy transfer from the tryptophan residue is observed in the subsequent haem electronic relaxation. Different Trp–haem energy transfer time constants of the ferrous and ferric forms are obtained. An almost instantaneous relaxation to the lowest singlet excited state (corresponding to the so-called Q band) characterizes the earliest electronic dynamics of the haem, independent of excitation energy, while dark intermediate states govern the ground-state recovery. The information gathered in these two experiments and in the literature allows us to propose a simple scheme for the electronic relaxation leading to ligand dissociation. [ABSTRACT FROM AUTHOR]

BackgroundSocial anxiousness is a pervasive symptom in both social anxiety disorder and autism spectrum conditions. Binocular rivalry, which occurs when different images are presented to each eye, has been used to explore how visual and cognitive processing differs across various clinical diagnoses. Previous studies have separately explored whether individuals with autism or anxiety experience binocular rivalry in ways that are different from neurotypical individuals.MethodsWe applied rivalry paradigms that are similar to those used in previous studies of autism and general anxiety to individuals experiencing symptoms of social anxiousness at clinical or subclinical levels. We also incorporated rivalrous stimuli featuring neutral and emotional facial valances to explore potential overlap of social processing components in social anxiety and autism.ResultsWe hypothesized that higher levels of social anxiousness would increase binocular rivalry switch rates and that higher levels of autistic traits would decrease switch rates. However, stimulus condition did not affect switch rates in either diagnostic group, and switch rate was not significantly predictive of dimensional measures of either autism or social anxiety.DiscussionThis may suggest a common mechanism for atypical visual cognition styles previously associated with social anxiety and autism. Alternatively, differences in switch rates may only emerge at higher trait levels than reported by the participants in our studies. Furthermore, these findings may be influenced by sex differences in our unique sample.

Space and time analyses of channel changes, especially within large rivers subject to high levels of human impact, are critical to address multiple questions about rivers in the Anthropocene era. The reconstruction of long-term (> 150 year) evolutionary trajectories permits an understanding of how natural and anthropogenic factors impact hydromorphological and ecological processes in rivers, helps with the design of sustainable management and restoration options, and may also help in the assessment of future changes. However, the reconstruction of channel changes can be challenging: historical data are often scattered across many archives, and the quantity and accuracy of information generally decreases as one goes back in time. This data article provides a historical database of 350 cartographic and topo-bathymetric resources on the French Rhône River (530 km in length) compiled from the 17th to mid-20th century, with a temporal focus prior to extensive river training (1860s). The data were collected in 14 national, regional, and departmental archive services. A table describes the properties of each archived data item and its associated iconographic files. Some of the historical maps are available in a georeferenced format. A GIS layer enables one-click identification of all archive data available for a given reach of the French Rhône River. This database provides substantial new material for deeper analyses of channel changes over a longer time period and at a finer time step compared with previously available data. The database has several potential applications in geomorphology, retrospective hydraulic modelling, historical ecology, and river restoration, as well as permitting comparisons with other multi-impacted rivers worldwide. The dataset is available at https://doi.org/10.1594/PANGAEA.922437 (Arnaud et al., 2020a). Iconographic extracts of the 350 archived items are available at http://photo.driihm.fr/index.php/category/52 (last access: 2 May 2021).

We analyze a sample of 25 [Ne v ] ( λ 3426) emission-line galaxies at 1.4 < z < 2.3 using Hubble Space Telescope/Wide Field Camera 3 G102 and G141 grism observations from the CANDELS Ly α Emission at Reionization (CLEAR) survey. [Ne v ] emission probes extremely energetic photoionization (creation potential of 97.11 eV) and is often attributed to energetic radiation from active galactic nuclei (AGNs), shocks from supernovae, or an otherwise very hard ionizing spectrum from the stellar continuum. In this work, we use [Ne v ] in conjunction with other rest-frame UV/optical emission lines ([O ii ] λ λ 3726, 3729, [Ne iii ] λ 3869, H β , [O iii ] λ λ 4959, 5007, H α +[N ii ] λ λ 6548, 6583, [S ii ] λ λ 6716, 6731), deep (2–7 Ms) X-ray observations (from Chandra), and mid-infrared imaging (from Spitzer) to study the origin of this emission and to place constraints on the nature of the ionizing engine. The majority of the [Ne v ]-detected galaxies have properties consistent with ionization from AGNs. However, for our [Ne v ]-selected sample, the X-ray luminosities are consistent with local ( z ≲ 0.1) X-ray-selected Seyferts, but the [Ne v ] luminosities are more consistent with those from z ∼ 1 X-ray-selected QSOs. The excess [Ne v ] emission requires either reduced hard X-rays or a ∼0.1 keV excess. We discuss possible origins of the apparent [Ne v ] excess, which could be related to the “soft (X-ray) excess” observed in some QSOs and Seyferts and/or be a consequence of a complex/anisotropic geometry for the narrow-line region, combined with absorption from a warm, relativistic wind ejected from the accretion disk. We also consider implications for future studies of extreme high-ionization systems in the epoch of reionization ( z ≳ 6) with the James Webb Space Telescope.

Spectroscopic studies of extreme-ionization galaxies (EIGs) are critical to our understanding of exotic systems throughout cosmic time. These EIGs exhibit spectral features requiring >54.42 eV photons: the energy needed to ionize helium into He ^2+ fully and emit He ii recombination lines. Spectroscopic studies of EIGs can probe exotic stellar populations or accretion onto intermediate-mass black holes (∼10 ^2 –10 ^5 M _⊙ ), which are the possibly key contributors to the reionization of the Universe. To facilitate the use of EIGs as probes of high-ionization systems, we focus on ratios constructed from several rest-frame UV/optical emission lines: [O iii ] λ 5008, H β , [Ne iii ] λ 3870, [O ii ] λ λ 3727, 3729, and [Ne v ] λ 3427. These lines probe the relative intensity at energies of 35.12, 13.62, 40.96, 13.62, and 97.12 eV, respectively, covering a wider range of ionization than traced by other common rest-frame UV/optical techniques. We use the ratios of these lines ([Ne v ]/[Ne iii ] ≡ Ne53, [O iii ]/H β , and [Ne iii ]/[O ii ]), which are nearby in wavelength, mitigating the effects of dust attenuation and uncertainties in flux calibration. We make predictions from photoionization models constructed from Cloudy that use a broad range of stellar populations and black hole accretion models to explore the sensitivity of these line ratios to changes in the ionizing spectrum. We compare our models to observations from the Hubble Space Telescope and JWST of galaxies with strong high-ionization emission lines at z ∼ 0, z ∼ 2, and 5 < z < 8.5. We show that the Ne53 ratio can separate galaxies with ionization from “normal” stellar populations from those with active galactic nuclei and even “exotic” Population III models. We introduce new selection methods to identify galaxies with photoionization driven by Population III stars or intermediate-mass black hole accretion disks that could be identified in upcoming high-redshift spectroscopic surveys.

Background: Thought disorder and visual-perceptual deficits have been well documented, but their relationships with clinical symptoms and cognitive function remain unclear. Cognitive-perceptual deficits may underscore clinical symptoms in schizophrenia patients. Aim: This study aimed to explore how thought disorder and form perception are related with clinical symptoms and cognitive dysfunction in first-episode schizophrenia. Setting: Forty-two patients with a first-episode of schizophrenia, schizophreniform or schizoaffective disorder were recruited from community clinics and state hospitals in the Cape Town area. Methods: Patients were assessed at baseline with the Rorschach Perceptual Thinking Index (PTI), the Positive and Negative Syndrome Scale (PANSS) and the MATRICS Cognitive Consensus Battery (MCCB). Spearman correlational analyses were conducted to investigate relationships between PTI scores, PANSS factor analysis-derived domain scores and MCCB composite and subscale scores. Multiple regression models explored these relationships further. Results: Unexpectedly, poor form perception (X- %) was inversely correlated with the severity of PANSS positive symptoms (r = -0.42, p = 0.02). Good form perception (XA%) correlated significantly with speed of processing (r = 0.59, p < 0.01), working memory (r = 0.48, p < 0.01) and visual learning (r = 0.55, p < 0.01). PTI measures of thought disorder did not correlate significantly with PANSS symptom scores or cognitive performance. Conclusions: Form perception is associated with positive symptoms and impairment in executive function during acute psychosis. These findings suggest that there may be clinical value in including sensory-perceptual processing tasks in cognitive remediation and social cognitive training programmes for schizophrenia patients.

In our analysis of a quantitative trait locus (QTL) for plasma triglyceride (TG) levels [logarithm of odds (LOD) = 3.7] on human chromosome 7q36, we examined 29 single nucleotide polymorphisms (SNPs) across INSIG1, a biological candidate gene in the region. Insulin-induced genes (INSIGs) are feedback mediators of cholesterol and fatty acid synthesis in animals, but their role in human lipid regulation is unclear. In our cohort, the INSIG1 promoter SNP rs2721 was associated with TG levels (P = 2 × 10−3 in 1,560 individuals of the original linkage cohort, P = 8 × 10−4 in 920 unrelated individuals of the replication cohort, combined P = 9.9 × 10−6). Individuals homozygous for the T allele had 9% higher TG levels and 2-fold lower expression of INSIG1 in surgical liver biopsy samples when compared with individuals homozygous for the G allele. Also, the T allele showed additional binding of nuclear proteins from HepG2 liver cells in gel shift assays. Finally, the variant rs7566605 in INSIG2, the only homolog of INSIG1, enhances the effect of rs2721 (P = 0.00117). The variant rs2721 alone explains 5.4% of the observed linkage in our cohort, suggesting that additional, yet-undiscovered genes and sequence variants in the QTL interval also contribute to alterations in TG levels in humans.

Background: Sarcomatoid renal cell carcinoma (RCC) is associated with an aggressive biology and a poor prognosis. Poor-risk RCC is defined by clinical prognostic factors and demonstrates similarly aggressive behavior. No standard treatment exists for patients with sarcomatoid RCC, and treatment options for patients with poor-risk disease are of limited benefit. The objective of this study was to investigate the efficacy of antiangiogenic therapy in combination with cytotoxic chemotherapy in clinically aggressive RCC. Methods: This was a phase 2, single-arm trial of sunitinib and gemcitabine in patients with sarcomatoid or poor-risk RCC. The primary end point was the objective response rate (ORR). Secondary end points included the time to progression (TTP), overall survival (OS), safety, and biomarker correlatives. Results: Overall, 39 patients had sarcomatoid RCC, and 33 had poor-risk RCC. The ORR was 26% for patients with sarcomatoid RCC and 24% for patients with poor-risk RCC. The median TTP and OS for patients with sarcomatoid RCC were 5 and 10 months, respectively. For patients with poor-risk disease, the median TTP and OS were 5.5 and 15 months, respectively. Patients whose tumors had >10% sarcomatoid histology had a higher clinical benefit rate (ORR plus stable disease) than those with ≤ 10% sarcomatoid histology (P = 0.04). The most common grade 3 or higher treatment-related adverse events included neutropenia (n = 20), anemia (n = 10), and fatigue (rt = 7). Conclusions: These results suggest that antiangiogenic therapy and cytotoxic chemotherapy are an active and well-tolerated combination for patients with aggressive RCC. The combination may be more efficacious than either therapy alone and is currently under further investigation. [ABSTRACT FROM AUTHOR]

The study of extracellular vesicles has become an incredibly important field of study, but the inherent heterogeneity of these vesicles continues to make their study challenging. The genetic variability and well-documented protocols for the growth and vesicle isolation from Leishmania parasites provide a unique opportunity to compare the heterogeneity of different populations secreted by Leishmania clones. Leishmania mexicana was cultured on solid SDM agar plates and 8 clonal colonies were selected. The EVs collected from the liquid cultures of these 8 clones were assessed by NTA, TEM, and proteomic analysis. We found that all 8 clonal L. mexicana cultures were visually indistinguishable from each other and had similar growth rate, and these physical similarities extended to their EVs. However, proteomic analysis reveals that the EVs collected have unique protein profiles compared to each other and EVs isolated from a heterogeneous liquid culture of L. mexicana . We selected 3 clonal EVs for further mouse infection experiments and found that EVs from CL7 L. mexicana consistently caused reduced footpad swelling in C57BL6 mice footpads compared to EVs from CL1, CL8, and heterogenous L. mexicana . This trend was not observed when infecting Balb/C mice and C57BL6 with the parasites alone, with only CL1 L. mexicana causing significantly increased infection in Balb/c mice. Our results together show that EVs isolated from different clonal colonies of L. mexicana have distinct differences in protein cargo which can lead to varying outcomes on Leishmania infection. Further evaluation will be needed to determine the underlying mechanisms behind this and verify that differences observed in infectivity are directly caused by variations between our L. mexicana clones, especially genetic sequencing and immunoblotting to validate our results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dong, Douanne, Fernandez-Prada and Olivier.)

Purpose: Maintaining physical fitness plays an important role in the management of people with cystic fibrosis (pwCF). Longitudinal data on the course of physical fitness and the potential impact of the introduction of highly effective CFTR modulator therapy with elexacaftor/tezacaftor/ivacaftor (ETI) in adult pwCF are scarce. Methods: Health-related and skill-related components of physical fitness were assessed using an incremental cycle test (Wpeak), plus forward bend (FB), prone bent knee hip extension (HE), plank leg raise (PLR), standing long jump (SLJ), and standing on one leg (OLS). Relevant disease-specific clinical data (body mass index [BMI] and forced expiratory volume in 1 second [FEV1]) were recorded. Results: Twenty-eight adult pwCF (age 26.0 ± 7.8 years) were followed over 5.6 ± 0.9 years; 21 started ETI therapy during this period. Significant improvements from baseline were noted in BMI ( p < 0.001) and health-related fitness components (HE, p = 0.002; PLR, p = < 0.001), whereas Wpeak and FB remained stable over time (all p > 0.05). Skill-related components (SLJ, OLS) showed no change (all p > 0.05). Subgroup analysis revealed significant improvements in BMI, FEV1, and health-related fitness measures of muscular strength and endurance (HE, p = 0.009; PLR, p < 0.001) only in pwCF using ETI. Conclusion: Despite the improvements, the impact of ETI on the individual parameters was small. Other factors than implementation of ETI alone need to be considered on the way to a high level of physical fitness in adult pwCF.

Previous studies in rodents suggest that mismatch between fetal and postnatal nutrition predisposes individuals to metabolic diseases. We hypothesized that in nonhuman primates (NHP), fetal programming of maternal undernutrition (MUN) persists postnatally with a dietary mismatch altering metabolic molecular systems that precede standard clinical measures. We used unbiased molecular approaches to examine response to a high fat, high-carbohydrate diet plus sugar drink (HFCS) challenge in NHP juvenile offspring of MUN pregnancies compared with controls (CON). Pregnant baboons were fed ad libitum (CON) or 30% calorie reduction from 0.16 gestation through lactation; weaned offspring were fed chow ad libitum . MUN offspring were growth restricted at birth. Liver, omental fat, and skeletal muscle gene expression, and liver glycogen, muscle mitochondria, and fat cell size were quantified. Before challenge, MUN offspring had lower body mass index (BMI) and liver glycogen, and consumed more sugar drink than CON. After HFCS challenge, MUN and CON BMIs were similar. Molecular analyses showed HFCS response differences between CON and MUN for muscle and liver, including hepatic splicing and unfolded protein response. Altered liver signaling pathways and glycogen content between MUN and CON at baseline indicate in utero programming persists in MUN juveniles. MUN catchup growth during consumption of HFCS suggests increased risk of obesity, diabetes, and cardiovascular disease. Greater sugar drink consumption in MUN demonstrates altered appetitive drive due to programming. Differences in blood leptin, liver glycogen, and tissue-specific molecular response to HFCS suggest MUN significantly impacts juvenile offspring ability to manage an energy rich diet.

Age is a prominent risk factor for cardiometabolic disease, often leading to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction exclusively resulting from physiological aging remain elusive. Previous research demonstrated age-related functional alterations in baboons, analogous to humans. The goal of this study is to identify early cardiac molecular alterations preceding functional adaptations, shedding light on the regulation of age-associated changes. Unbiased transcriptomics of left ventricle samples are performed from female baboons aged 7.5-22.1 years (human equivalent ≈30-88 years). Weighted-gene correlation network and pathway enrichment analyses are performed, with histological validation. Modules of transcripts negatively correlated with age implicated declined metabolism-oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid β-oxidation. Transcripts positively correlated with age suggested a metabolic shift toward glucose-dependent anabolic pathways, including hexosamine biosynthetic pathway (HBP). This shift is associated with increased glycosaminoglycan synthesis, modification, precursor synthesis via HBP, and extracellular matrix accumulation, verified histologically. Upregulated extracellular matrix-induced signaling coincided with glycosaminoglycan accumulation, followed by cardiac hypertrophy-related pathways. Overall, these findings revealed a transcriptional shift in metabolism favoring glycosaminoglycan accumulation through HBP before cardiac hypertrophy. Unveiling this metabolic shift provides potential targets for age-related cardiac diseases, offering novel insights into early age-related mechanisms., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Giving birth prematurely is a traumatic event that has many consequences for the mother but also for her baby and their family. Studies have shown that about a quarter of these mothers will suffer from post-traumatic stress disorder (PTSD) as a result. This study aims to identify internal personality factors associated with the development of PTSD in mothers who gave birth before 33 weeks. The results revealed significant correlations between two personality dimensions (neuroticism and extraversion) and the likeliness of developing PTSD in mothers who gave birth prematurely. Neuroticism is positively liked with the disorder while extraversion is negatively correlated with it. Studies should now focus on early detection of PTSD and better interventions for these mothers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Grand et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Recently, there is increasing evidence that the proportion of odontogenic brain abscesses is greater than previously known. In this study, we aim to differentiate the oral infections as triggers more precisely and to classify them in the clinical setting., Methods: For analysis, we conducted a retrospective single center study. We reviewed patients with brain abscesses who have undergone treatment in the University Hospital of Freiburg, Germany in the period between 2000-2021. Inclusion required two main criteria: 1. The brain abscess must not have an other focus than odontogenic. 2. The microbial spectrum identified in the brain abscess must be consistent with an odontogenic origin., Results: Of 217 brain abscess patients, 26 met the inclusion criteria. 42% (11 patients) suffered from immunosuppressive conditions. Odontogenic foci were diagnosed in 18 cases (69%). Neurologic deficits included vigilance reduction and hemiparesis. Pathogens of the Streptococcus anginosus group were the most frequent causative agent (21 cases, 81%). Metronidazole (54%) and ceftriaxone (42%) were part of the targeted antibiotic therapy. All brain abscesses were surgically treated. Teeth were extracted in 14 of 17 cases for focus control. 18 cases (72%) showed complete or partial resolution of neurologic symptoms and 3 cases were fatal., Conclusion: Apparently silent or chronic oral infections are sufficient to cause bacterial colonization of the brain, especially in immunocompromised patients. Therefore, special care should be taken to maintain good oral health. An interdisciplinary management should become a standard to prevent and treat the occurrence of brain abscesses., (© 2024. The Author(s).)

Introduction: Exosomes produced by the protozoan parasite Leishmania (LeishEXO) are well-established drivers of virulence, though mechanisms underlying their exacerbation of experimental leishmaniasis remain elusive. Expression of Annexin A1 (ANXA1), a protein implicated in exosome-mediated pathologies and viral internalization, has been shown to correlate with cutaneous leishmaniasis severity. Given ANXA1's regulation of myeloid cells - the canonical hosts for Leishmania - we studied the potential role of ANXA1 and its receptors FPR1/2 in exerting LeishEXO's effects., Methods: Murine and in vitro ANXA1 -/- models were used to study the generation of protective T H 1 responses during experimental L. major infection with and without LeishEXO. Recruitment of inflammatory cells was assessed using a peritoneal cell recruitment assay and immunophenotyping, and production of inflammatory mediators was measured using a cytokine and chemokine array. Treatment of experimental models with FPR2 antagonist WRW4 and FPR1/2 agonist WKYMVm was used to delineate the role of the FPR/ANXA1 axis in LeishEXO-mediated hyperpathogenesis., Results: We established that ANXA1 deficiency prohibits LeishEXO-mediated pathogenesis and myeloid cell infection, with minimal alterations to adaptive and innate immune phenotypes. FPR2 blockade with WRW4 similarly inhibited leishmanial hyperpathogenesis, while direct activation of FPRs with WKYMVm enhanced infection and recapitulated the LeishEXO-mediated phenotype. This research describes LeishEXO's utilization of the ANXA1/FPR axis to facilitate parasitic internalization and pathogenesis, which may be leveraged in the development of therapeutics for leishmaniasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 da Silva Lira Filho, Lafleur, Alvarez, Piccirillo and Olivier.)

In order to survive and replicate, Salmonella has evolved mechanisms to gain access to intestinal epithelial cells of the crypt. However, the impact of Salmonella Typhimurium on stem cells and progenitors, which are responsible for the ability of the intestinal epithelium to renew and protect itself, remains unclear. Given that intestinal organoids growth is sustained by stem cells and progenitors activity, we have used this model to document the effects of Salmonella Typhimurium infection on epithelial proliferation and differentiation, and compared it to an in vivo model of Salmonella infection in mice. Among gut segments, the caecum was preferentially targeted by Salmonella. Analysis of infected crypts and organoids demonstrated increased length and size, respectively. mRNA transcription profiles of infected crypts and organoids pointed to upregulated EGFR-dependent signals, associated with a decrease in secretory cell lineage differentiation. To conclude, we show that organoids are suited to mimic the impact of Salmonella on stem cells and progenitors cells, carrying a great potential to drastically reduce the use of animals for scientific studies on that topic. In both models, the EGFR pathway, crucial to stem cells and progenitors proliferation and differentiation, is dysregulated by Salmonella, suggesting that repeated infections might have consequences on crypt integrity and further oncogenesis., (© 2024. The Author(s).)

Objective: To investigate the outcomes of cochlear implantation in patients with TMTC2 -associated sensorineural hearing loss and auditory neuropathy/auditory dys-synchrony., Patients: Adult and pediatric cochlear implant (CI) patients followed in an academic center who tested positive for TMTC2 genetic variant rs35725509., Intervention: Cochlear implantation., Main Outcome Measures: Speech perception scores in quiet., Results: Ten CI patients were identified with TMTC2 variant rs35725509 out of 157 patients who underwent genetic testing (i.e., 6.3% of patients tested). All demonstrated progressive, bilateral hearing loss with severe-to-profound audiometric thresholds preoperatively. Pre-CI and 1-year post-CI speech recognition percent correct scores were compared. Post-CI speech perception (mean 61.0%, standard deviation 31.4%) was significantly higher than pre-CI speech perception (mean 21.0%, standard deviation 27.0%) ( p = 0.002). Individually, 9 of the 10 subjects experienced significant improvements in speech perception pre- to post-CI ( p < 0.05). Electrically evoked compound action potential measures were available for five patients, and all showed normal electrically evoked compound action potential thresholds., Conclusion: Patients with TMTC2 -associated sensorineural hearing loss and auditory neuropathy/auditory dys-synchrony have significantly improved speech perception outcomes with cochlear implantation and should be considered candidates for this intervention if there are no other contraindications., Competing Interests: The authors disclose no conflicts of interest., (Copyright © 2024, Otology & Neurotology, Inc.)

A cost-effective fiber laser architecture is introduced in which the output seed pulse is stretched and then returned in the oscillator for an additional single-pass amplification without spectral broadening. It is implemented in an all-PM-fiber configuration based on a Mamyshev oscillator with a low repetition rate of 1 MHz. It features a linear oscillator bounded by two offset chirped fiber Bragg gratings accompanied by a third one acting as a pulse recycling filter. The latter tailors the pulse profile in amplitude and phase to seed femtosecond chirped-pulse amplification systems without additional pre-amplification nor pulse stretching. A single-pump prototype generating 200-nJ, 100-ps pulses compressible to 290 fs at 1030 nm and at 960 kHz is demonstrated. Furthermore, simulations show how this new oscillator architecture can provide tailored seed pulses with high enough spectral energy density and low enough nonlinear phase to generate sub-200 fs, 40 µJ, > 180 MW pulses from an all-fiber setup involving a single tapered-fiber power amplifier, without pulse picking.

Malaria is a serious vector-borne disease characterized by periodic episodes of high fever and strong immune responses that are coordinated with the daily synchronized parasite replication cycle inside RBCs. As immune cells harbor an autonomous circadian clock that controls various aspects of the immune response, we sought to determine whether the intensity of the immune response to Plasmodium spp., the parasite causing malaria, depends on time of infection. To do this, we developed a culture model in which mouse bone marrow-derived macrophages are stimulated with RBCs infected with Plasmodium berghei ANKA (iRBCs). Lysed iRBCs, but not intact iRBCs or uninfected RBCs, triggered an inflammatory immune response in bone marrow-derived macrophages. By stimulating at four different circadian time points (16, 22, 28, or 34 h postsynchronization of the cells' clock), 24-h rhythms in reactive oxygen species and cytokines/chemokines were found. Furthermore, the analysis of the macrophage proteome and phosphoproteome revealed global changes in response to iRBCs that varied according to circadian time. This included many proteins and signaling pathways known to be involved in the response to Plasmodium infection. In summary, our findings show that the circadian clock within macrophages determines the magnitude of the inflammatory response upon stimulation with ruptured iRBCs, along with changes of the cell proteome and phosphoproteome., (Copyright © 2024 The Authors.)