Miracle-dz/UniFAR-FTUs huggingface dataset:
Anti-CELA1 antibody KF4 prevents emphysema by inhibiting stretch-mediated remodeling

There are no therapies to prevent emphysema progression. Chymotrypsin-like elastase 1 (CELA1) is a serine protease that binds and cleaves lung elastin in a stretch-dependent manner and is required for emphysema in a murine antisense oligonucleotide model of α-1 antitrypsin (AAT) deficiency. This study tested whether CELA1 is important in strain-mediated lung matrix destruction in non–AAT-deficient emphysema and the efficacy of CELA1 neutralization. Airspace simplification was quantified after administration of tracheal porcine pancreatic elastase (PPE), after 8 months of cigarette smoke (CS) exposure, and in aging. In all 3 models, Cela1–/– mice had less emphysema and preserved lung elastin despite increased lung immune cells. A CELA1-neutralizing antibody was developed (KF4), and it inhibited stretch-inducible lung elastase in ex vivo mouse and human lung and immunoprecipitated CELA1 from human lung. In mice, systemically administered KF4 penetrated lung tissue in a dose-dependent manner and 5 mg/kg weekly prevented emphysema in the PPE model with both pre- and postinjury initiation and in the CS model. KF4 did not increase lung immune cells. CELA1-mediated lung matrix remodeling in response to strain is an important contributor to postnatal airspace simplification, and we believe that KF4 could be developed as a lung matrix–stabilizing therapy in emphysema.
Mutations accumulated in the Spike of SARS-CoV-2 Omicron allow for more efficient counteraction of the restriction factor BST2/Tetherin

BST2/Tetherin is a restriction factor with broad antiviral activity against enveloped viruses, including coronaviruses. Specifically, BST2 traps nascent particles to membrane compartments, preventing their release and spread. In turn, viruses have evolved multiple mechanisms to counteract BST2. Here, we examined the interactions between BST2 and SARS-CoV-2. Our study shows that BST2 reduces SARS-CoV-2 virion release. However, the virus uses the Spike (S) protein to downregulate BST2. This requires a physical interaction between S and BST2, which routes BST2 for lysosomal degradation in a Clathtin- and ubiquitination-dependent manner. By surveying different SARS-CoV-2 variants of concern (Alpha-Omicron), we found that Omicron is more efficient at counteracting BST2, and that mutations in S account for its enhanced anti-BST2 activity. Mapping analyses revealed that several surfaces in the extracellular region of BST2 are required for an interaction with the Spike, and that the Omicron variant has changed its patterns of association with BST2 to improve its counteraction. Therefore, our study suggests that, besides enhancing receptor binding and evasion of neutralizing antibodies, mutations accumulated in the Spike afford more efficient counteraction of BST2, which highlights that BST2 antagonism is important for SARS-CoV-2 infectivity and spread.
Downward Wave Reflection as a Mechanism for the Stratosphere–Troposphere Response to the 11-Yr Solar Cycle

AbstractThe effects of solar activity on the stratospheric waveguides and downward reflection of planetary waves during NH early to midwinter are examined. Under high solar (HS) conditions, enhanced westerly winds in the subtropical upper stratosphere and the associated changes in the zonal wind curvature led to an altered waveguide geometry across the winter period in the upper stratosphere. In particular, the condition for barotropic instability was more frequently met at 1 hPa near the polar-night jet centered at about 55°N. In early winter, the corresponding change in wave forcing was characterized by a vertical dipole pattern of the Eliassen–Palm (E–P) flux divergent anomalies in the high-latitude upper stratosphere accompanied by poleward E–P flux anomalies. These wave forcing anomalies corresponded with negative vertical shear of zonal mean winds and the formation of a vertical reflecting surface. Enhanced downward E–P flux anomalies appeared below the negative shear zone; they coincided with more .
Reduction in Breast Cancer Death With Adjuvant Chemotherapy Among US Women According to Race, Ethnicity, and the 21-Gene Recurrence Score.

BACKGROUND We previously showed the 21-gene breast recurrence score (RS) has lower prognostic accuracy for non-Hispanic Black (NHB) compared with non-Hispanic White (NHW) women with estrogen receptor (ER)-positive/HER2-negative breast cancer. The purpose of this study was to determine the clinical validity of the RS for predicting chemotherapy benefit as recommended in the current NCCN Guidelines for Breast Cancer among women from diverse racial/ethnic groups. METHODS Using the SEER Oncotype database, we estimated propensity score-weighted hazard ratios (HRs) and 95% confidence intervals for breast cancer death with chemotherapy for women with ER-positive/HER2-negative, AJCC stages I-II, axillary node-negative, invasive breast cancer according to race/ethnicity. RESULTS We included 6,033 (8.2%) Asian/Pacific Islander (API), 5,697 (7.8%) NHB, 6,688 (9.1%) Hispanic, and 54,945 (74.9%) NHW women. Breast cancer death was reduced with chemotherapy for NHB (HR, 0.48, 95% CI, 0.28-0.81), Hispanic (HR, 0.48; 95% CI, 0.25-0.94), and NHW (HR, 0.80; 95% CI, 0.65-0.99) women with an RS of 26 to 100. There was a nonsignificant reduction for API women (HR, 0.59; 95% CI, 0.28-1.24). For women with an RS of 11 to 25, there was no reduction in death for any racial/ethnic group. Among women aged ≤50 years, the reduction in breast cancer death with chemotherapy differed according to race (NHB: HR, 0.37 [95% CI, 0.20-0.67]; NHW: HR, 0.56 [95% CI, 0.44-0.74]; Pinteraction for chemotherapy * race <.0499). An exploratory subgroup analysis found that young NHB women may benefit from chemotherapy at a lower RS cutoff than other women. CONCLUSIONS The RS was clinically validated as a predictive biomarker for NHB, Hispanic, and NHW women with ER-positive, axillary node-negative breast cancer, but it may underestimate the benefit of chemotherapy for young NHB women. If this finding is confirmed, the RS cutoff for recommending adjuvant chemotherapy for young NHB women with ER-positive, axillary node-negative breast cancer may need to be lower than for other women.
Desempenho de cultivares elites de mandioca industrial em área de cerrado do Mato Grosso do Sul Performance of elite cultivars of industrial cassava in savannah area of Mato Grosso do Sul State, Brazil

The work was carried out to evaluate the performance of industrial type of the elite cassava cultivars, in Sao Gabriel do Oeste, MS, Brazil, in typical area of savannah vegetation. The IAC 12, IAC 13, IAC 14, IAC 15, IAC 576, Fecula Branca, Espeto and Fibra cultivars were evaluated on plant height, fresh mass of shoots, fresh mass of planting stub, number of root, root production, starch content and harvest index. The experimental design was a randomized block with eight treatments (cultivars) and five replications. The crop was installed using spacing of 0,90m x 0,70m between lines. The harvest was done six months after the planting date. The cultivar IAC 14 presented the highest plant height. IAC14 and IAC 15 presented the highest fresh matter production of the shoot. The cultivars IAC 12, IAC 13, IAC 14, IAC 15 and Fibra presented the highest yields. The cultivars IAC 576 and Espeto had the lowest root production. The highest contents of starch, in decreasing order, were observed to IAC 13, IAC 12, IAC 14, Fiber and IAC 15.
The Migrant-Local Difference in the Relationship Between Social Support, Sleep Disturbance, and Loneliness Among Older Adults in China: Cross-Sectional Study

Background Driven by the accelerated aging of the population of China, the number of older adults has increased rapidly in the country. Meanwhile, following children, migrant older adults (MOA) have emerged as a vulnerable group in the process of fast urbanization. Existed studies have illustrated the association between social support and loneliness and the relationship between sleep disturbance and loneliness; however, the underlying mechanisms and the migrant-local difference in the association between social support, sleep disturbance, and loneliness have not been identified. Objective This study aimed to clarify the migrant-local difference in the relationship between social support, sleep disturbance, and loneliness in older adults in China. Methods Multistage cluster random sampling was used to select participants: 1205 older adults (n=613, 50.9%, MOA and n=592, 49.1%, local older adults [LOA]) were selected in Weifang City, China, in August 2021. Loneliness was assessed with the 6-item short-form University of California, Los Angeles Loneliness Scale, social support was evaluated with the Social Support Rating Scale, and sleep disturbance was measured with the Pittsburgh Sleep Quality Index. The chi-square test, t test, and structural equation modeling (SEM) were adopted to explore the migrant-local difference between social support, sleep disturbance, and loneliness among the MOA and LOA. Results The mean score of loneliness was 8.58 (SD 3.03) for the MOA and 8.00 (SD 2.79) for the LOA. SEM analysis showed that social support exerts a direct negative effect on both sleep disturbance (standardized coefficient=–0.24 in the MOA and –0.20 in the LOA) and loneliness (standardized coefficient=–0.44 in the MOA and –0.40 in the LOA), while sleep disturbance generates a direct positive effect on loneliness (standardized coefficient=0.13 in the MOA and 0.22 in the LOA). Conclusions Both MOA and LOA have a low level of loneliness, but the MOA show higher loneliness than the LOA. There is a negative correlation between social support and loneliness as well as between social support and sleep disturbance among the MOA and LOA (MOA>LOA), while loneliness is positively associated with sleep disturbance in both populations (MOA
Effectiveness and safety of ivabradine in Chinese patients with chronic heart failure: an observational study

Abstract Aims A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well‐known HR‐lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF. Methods and results This multicentre, single‐arm, prospective, observational study enrolled Chinese patients with chronic HF. The primary outcome was change from baseline in HR at 1 and 6 months, measured by pulse counting. Effectiveness was also evaluated using laboratory tests, the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) and overall summary score (OSS), and New York Heart Association (NYHA) class. Treatment‐emergent adverse events (TEAEs) were assessed. A post hoc analysis examined the effectiveness and safety of ivabradine combined with an angiotensin receptor–neprilysin inhibitor (ARNI) or beta‐blocker. A total of 1003 patients were enrolled [mean age 54.4 ± 15.0 years, 773 male (77.1%), mean baseline HR 88.5 ± 11.3 b.p.m. , mean blood pressure 115.7/74.4 ± 17.2/12.3 mmHg, mean left ventricular ejection fraction 30.9 ± 7.6%, NYHA Classes III and IV in 48.8% and 22.0% of patients, respectively]. HR decreased by a mean of 12.9 and 16.1 b.p.m. after 1 and 6 months, respectively (both P < 0.001). At Month 6, improvements in the KCCQ CSS and OSS of ≥5 points were observed in 72.1% and 74.1% of patients, respectively (both P < 0.001). Left ventricular ejection fraction increased by 12.1 ± 11.6 (P < 0.001), and 66.7% of patients showed improvement in NYHA class (P < 0.001). At Month 6, the overall proportion of patients in NYHA Classes III and IV was reduced to 13.5% and 2.1%, respectively. Serum brain natriuretic peptide (BNP) and N‐terminal pro‐BNP changed by −331.9 ng/L (−1238.6, −134.0) and −1113.8 ng/L (−2202.0, −297.2), respectively (P < 0.001). HR reductions and improvements in NYHA and KCCQ scores with ivabradine were similar with and without use of ARNIs or beta‐blockers. Of 498 TEAEs in 296 patients (29.5%), 73 TEAEs in 55 patients (5.5%) were considered related to ivabradine [most frequent sinus bradycardia (n = 7) and photopsia (n = 7)]. TEAEs were reported in a similar number of patients in ARNI and beta‐blocker subgroups (21.9–35.6%). Conclusions Ivabradine treatment reduced HR and improved cardiac function and health‐related quality of life in Chinese patients with chronic HF. Benefits were seen irrespective of whether or not patients were also taking ARNIs or beta‐blockers. Treatment was well tolerated with a similar profile to previous ivabradine studies.
DNMT3A/TET2/ASXL1 mutations are an age-independent thrombotic risk factor in polycythemia vera patients: an observational study.

BACKGROUND Polycythemia vera (PV) patients are classified as high or low thrombotic risk based on age and prior history of thrombosis. Despite adherence to treatment recommendations, vascular events remain frequent, leading us to question whether thrombotic risk stratification could be improved. We previously reported an association between thrombotic events and mutations in DTA genes (DNMT3A, TET2 and ASXL1). The objective of this study was to confirm this observation in a larger series of PV patients. METHODS PV patients with a minimum follow-up of 3 years were recruited from 8 European centers. Medical history was searched for thrombotic event recorded at any time and next-generation sequencing carried out with a myeloid panel. Multivariable logistic regression evaluated the impact of variables on thrombotic risk. Kaplan-Meier thrombosis-free survival curves were compared by the Log Rank test. Associations in the total cohort were confirmed in a case-control study to exclude selection bias. RESULTS Of the 136 patients recruited, 74 (56.1%) had a thrombotic event, with an incidence density of 2.83/100 person-years. In multivariable analysis, age ≥60 years was not a risk factor for thrombotic event while presence of DTA mutation was, also being predictive for shorter thrombosis-free survival (p=0.007). A gender- and age-matched case-control study confirmed the association between thrombotic event and DTA mutation, including in a subgroup of patients aged≤ 60 years. CONCLUSIONS Our results support the use of molecular testing at diagnosis to help predict which PV patients are at higher risk of developing thrombosis.
Cholestatic Drug-Induced Liver Injury in a Patient Taking High-Dose Niacin for Hyperlipidemia

Niacin, an important component of a balanced diet, is central to lipid metabolism. Occasionally used to treat hyperlipidemia, niacin is widely available without a prescription, making its use often unknown to treating physicians. Severe hepatotoxicity has been reported with niacin use. In the following report, we describe a case of hospitalization for acute decompensated cirrhosis with cholestatic morphology in a patient taking self-initiated large quantities of extended-release niacin. Despite medical management and support, the patient unfortunately expired on day 16 of hospitalization. Given ease of access and unclear long-term benefit in hyperlipidemia, the current case serves to raise awareness of niacin’s potential hepatotoxicity through highlighting a severe outcome. Although mode of liver injury remains unknown, the use of extended-release niacin formulations and prolonged high-dose supplementation is associated with enhanced hepatotoxicity. Careful review and counseling of commonly available supplements remains an important task of both hospital and primary care physicians.
SH2 domain protein E and ABL signaling regulate blood vessel size

Blood vessels in different vascular beds vary in size, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood. Src homology 2 domain containing E (She) protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vessel size in zebrafish embryos and human endothelial cell culture. Zebrafish she mutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow, eventually leading to the DA collapse. Vascular endothelial specific overexpression of she resulted in a reduced diameter of the DA, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated the she mutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA size in she mutants correlated with an increased endothelial expression of claudin 5a (cldn5a), which encodes a protein enriched in tight junctions. Inhibition of cldn5a expression partially rescued the enlarged DA in she mutants, suggesting that She regulates DA size, in part, by promoting cldn5a expression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates vessel and lumen size during vascular tubulogenesis.
Mechanisms of thyrotropin receptor-mediated phenotype variability deciphered by gene mutations and M453T knock-in model.

The clinical spectrum of thyrotropin receptor (TSHR)-mediated diseases varies from loss-of-function mutations causing congenital hypothyroidism to constitutively active mutations (CAMs) leading to nonautoimmune hyperthyroidism (NAH). Variation at the TSHR locus has also been associated with altered lipid and bone metabolism and autoimmune thyroid diseases. However, the extrathyroidal roles of TSHR, and the mechanisms underlying phenotypic variability among TSHR-mediated diseases remain unclear. Here we identified and characterized TSHR variants and factors involved in phenotypic variability in different patient cohorts, the FinnGen database, and a mouse model. TSHR CAMs were found in all 16 patients with NAH, with one CAM in an unexpected location in the extracellular leucine-rich repeat domain (p.S237N) and another in the transmembrane domain (p.I640V) in two families with distinct hyperthyroid phenotypes. In addition, screening of the FinnGen database revealed rare functional variants, as well as distinct common non-coding TSHR SNPs significantly associated with thyroid phenotypes, but no other significant association between TSHR variants and over 2,000 non-thyroid disease endpoints. Finally, our TSHR M453T knock-in model revealed that the phenotype was dependent on the mutation´s signaling properties and was ameliorated by increased iodine intake. In summary, our data shows that TSHR-mediated disease risk can be modified by variants at the TSHR locus both inside and outside the coding region, and by altered TSHR-signaling and dietary iodine, supporting the need for personalized treatment strategies.
Ketone ester supplementation of Atkins-type diet prolongs survival in an orthotopic xenograft model of glioblastoma

Heavy reliance on glucose metabolism and a reduced capacity to use ketone bodies makes glioblastoma (GBM) a promising candidate for ketone-based therapies. Ketogenic diet (KD) is well-known for its promising effects in controlling tumor growth in GBM. Moreover, synthetic ketone ester (KE) has demonstrated to increase blood ketone levels and enhance animal survival in a metastatic VM-M3 murine tumor model. Here, we compared the efficacy of a KE-supplemented Atkins-type diet (ATD-KE) to a classic KD in controlling tumor progression and enhancing survival in a clinically relevant orthotopic patient-derived xenograft GBM model. Our findings demonstrate that ATD-KE preserves body weight (percent change from the baseline; 112±2.99 vs. 116.9±2.52 and 104.8±3.67), decreases blood glucose (80.55±0.86 vs. 118.6±9.51 and 52.35±3.89 mg/dl), and increases ketone bodies in blood (1.15±0.03 mM vs. 0.55±0.04 and 2.66±0.21 mM) and brain tumor tissue (3.35±0.30 mM vs. 2.04±0.3 and 4.25±0.25 mM) comparable to the KD (results presented for ATD-KE vs. standard diet [STD] and KD, respectively). Importantly, the ATD-KE treatment significantly enhanced survival compared to the STD and was indistinguishable from the KD (47 days in STD vs. 56 days in KD and ATD-KE), suggesting that a nutritionally balanced low carbohydrate ATD combined with KE may be as effective as the KD alone in reducing brain tumor progression. Overall, these data support the rationale for clinical testing of KE-supplemented low-carb diet as an adjunct treatment for brain tumor patients.
Key Challenges for Respiratory Virus Surveillance while Transitioning out of Acute Phase of COVID-19 Pandemic

To support the ongoing management of viral respiratory diseases while transitioning out of the acute phase of the COVID-19 pandemic, many countries are moving toward an integrated model of surveillance for SARS-CoV-2, influenza virus, and other respiratory pathogens. Although many surveillance approaches catalyzed by the COVID-19 pandemic provide novel epidemiologic insight, continuing them as implemented during the pandemic is unlikely to be feasible for nonemergency surveillance, and many have already been scaled back. Furthermore, given anticipated cocirculation of SARS-CoV-2 and influenza virus, surveillance activities in place before the pandemic require review and adjustment to ensure their ongoing value for public health. In this report, we highlight key challenges for the development of integrated models of surveillance. We discuss the relative strengths and limitations of different surveillance practices and studies as well as their contribution to epidemiologic assessment, forecasting, and public health decision-making.
Widespread Neogene volcanism on Central Kerguelen Plateau, Southern Indian Ocean

ABSTRACT We report new age determinations and compositions for rocks from 18 dredge hauls collected from eight submarine areas across Central Kerguelen Plateau (CKP). Sea knolls and volcanic fields with multiple small cones were targeted over a ∼125 000 km2 region that includes Heard and McDonald Islands. Large early Miocene (22–16 Ma) sea knolls rise from the western margin of the CKP and are part of a NNW–SSE line of volcanic centres that lie between Îles Kerguelen and Heard and McDonald Islands. These are probably related to hotspot activity now underlying the Heard Island area. We see evidence of much younger activity (5 Ma to present) in volcanic fields to the north of, and up to 300 km NE of, Heard Island. Compositions include basanite, basalt and trachybasalt, which are broadly similar to plateau lava flows from nearby Ocean Drilling Program Site 1138, lower Miocene lavas at Îles Kerguelen, dredged rocks from the early Miocene sea knolls, and Big Ben lavas from Heard Island. Geochemical data indicate decreasing fractions of mantle source melting with time. We propose that a broad region of the CKP became volcanically active in Neogene time owing to incubation of plume material at the base of the relatively stationary overlying plateau. The presence of pre-existing crustal faults gave access for melts from the Heard mantle plume to rise to the surface.