bluuebunny/crossref_metadata_2025 huggingface dataset:
Obesity and risk for liver disease: a two-sample Mendelian randomisation study
Authors: An Wen , Luo Jing , Yu Zhe , Li Mengqi , Wei Herui , Song Aqian , Mao Yuanpeng , Bian Hao , He Lingling , Xiao Fan , Wei Hongshan
Published: November 2024

The associations between obesity and liver diseases are complex and diverse. To explore the causal relationships between obesity and liver diseases, we applied two-sample Mendelian randomisation (MR) and multivariable MR analysis. The data of exposures (BMI and WHRadjBMI) and outcomes (liver diseases and liver function biomarker) were obtained from the open genome-wide association study database. A two-sample MR study revealed that the genetically predicted BMI and WHRadjBMI were associated with non-alcoholic fatty liver disease, liver fibrosis and autoimmune hepatitis. Obesity was not associated with primary biliary cholangitis, liver failure, liver cell carcinoma, viral hepatitis and secondary malignant neoplasm of liver. A higher WHRadjBMI was associated with higher levels of biomarkers of lipid accumulation and metabolic disorders. These findings indicated independent causal roles of obesity in non-alcoholic fatty liver disease, liver fibrosis and impaired liver metabolic function rather than in viral or autoimmune liver disease.
Are food and beverage purchases reflective of dietary intake? Validity of supermarket purchases as indicator of diet quality in the Supreme Nudge Trial
Authors: Colizzi Chiara , Stuber Josine M. , van der Schouw Yvonne T. , Beulens Joline W. J.
Published: November 2024

Dietary intake assessment is often complicated by intrinsic bias. This study investigated whether food purchase data could constitute a valid indication of dietary intake, by evaluating the extent to which diet quality as measured by supermarket food purchases is correlated with diet quality as measured by reported dietary intake. We used data from the Supreme Nudge cluster-randomised controlled supermarket trial (n 227). Data were collected at baseline from supermarket purchases (loyalty cards) and a dietary questionnaire (short forty-item FFQ) to compute two scores reflecting diet quality from purchasing data (purchased diet quality) and FFQ (consumed diet quality). Both scores constituted thirteen food groups and could theoretically range from 0 (low diet quality) to 130 (high diet quality). The relationship between purchased diet quality and consumed diet quality was assessed using correlation coefficients and the Bland–Altman limits-of-agreement method. Multiple linear regression was fitted between purchased diet quality and consumed diet quality, adjusted for age, sex, waist circumference, educational level and household size. Consumed and purchased diet qualities were modestly positively correlated (Pearson’s ρ = 0·31, 95 % CI 0·18, 0·42). A positive association from linear regression was found after confounding adjustments (βbaseline = 0·22, 95 % CI 0·10, 0·34). The purchased diet quality was systematically lower than the consumed diet quality. This study found that diet quality as measured by supermarket purchases provided a reasonable indication of diet quality as reported by short-FFQ, albeit modest.
Kernels of minimal characters of solvable groups
Authors: Moretó Alexander
Published: November 2024

Let G be a finite solvable group. We prove that if $\chi\in{{\operatorname{Irr}}}(G)$ has odd degree and $\chi(1)$ is the minimal degree of the nonlinear irreducible characters of G, then $G/\operatorname{Ker}\chi$ is nilpotent-by-abelian.
The Brun–Hooley sieve for 𝔽2[X] and squarefree shifts of integer polynomials
Authors: Banerjee Pradipto , Kundu Amit
Published: November 2024

Let f(x) and g(x) be polynomials in $\mathbb F_{2}[x]$ with ${\rm deg}\text{ } f=n$. It is shown that for $n\gg 1$, there is an $g_{1}(x)\in \mathbb F_{2}[x]$ with ${\rm deg}\text{ } g_{1}\leqslant \max\{{\rm deg}\text{ } g, 6.7\log n\}$ and $g(x)-g_{1}(x)$ having $ \lt 6.7\log n$ terms such that $\gcd(f(x), g_{1}(x))=1$. As an application, it is established using a result of Dubickas and Sha that given $f(x)\in \mathbb F_{2}[x]$ of degree $n\geqslant 1$, there is a separable $g(x)\in 2[x]$ with ${\rm deg}\text{ } g= {\rm deg}\text{ } f$ and satisfying that $f(x)-g(x)$ has $\leqslant 6.7\log n$ terms. As a simple consequence, the latter result holds in $\mathbb Z[x]$ after replacing ‘number of terms’ by the L1-norm of a polynomial and $6.7\log n$ by $6.8\log n$. This improves the bound $(\log n)^{\log 4 +\operatorname{\varepsilon}}$ obtained by Filaseta and Moy.
Estimation of dominance genetic effects on pre-weaning efficiency-related traits in Baluchi sheep
Authors: Ghafouri-Kesbi Farhad , Gholizadeh Mohsen
Published: November 2024

This study was conducted to estimate the relative contribution of dominance genetic effects to efficiency-related traits including Kleiber ratio (KR), efficiency of growth (EF) and relative growth rate (RGR) in Baluchi sheep. To this end, each trait was analysed with a series of 12 animal models which were identical for fixed and additive genetic effects but differed for combinations of dominance genetic and maternal effects. The Akaike's information criterion (AIC) was used to rank models. (Co)variances between traits were estimated using bivariate analyses. For all traits studied, according to AIC values, models containing the dominance genetic effects provided a better data fit than otherwise identical models. By including dominance genetic effects in the model, additive genetic variance did not change, but a significant decrease was observed in the residual variance (24, 19 and 25% for KR, EF and RGR, respectively). Estimates of dominance heritability $( {\boldsymbol h}_{\boldsymbol d}^ 2 )$ were 0.20 ± 0.05, 0.17 ± 0.05 and 0.19 ± 0.07 for KR, EF and RGR, respectively, more than corresponding estimates of additive heritability ${\bf ( }{\boldsymbol h}_{\boldsymbol a}^{\bf 2} {\bf ) }$ as 0.14 ± 0.02, 0.09 ± 0.03 and 0.13 ± 0.02, respectively. Dominance genetic correlations between traits were 0.89 ± 0.17 (KR-EF), 0.86 ± 0.20 (KR-RGR) and 0.93 ± 0.21 (EF-RGR). Additive genetic correlations between traits were 0.84 ± 0.05 (KR-EF), 0.78 ± 0.04 (KR-RGR) and 0.83 ± 0.04 (EF-RGR). The Spearman correlation between additive breeding values including and excluding dominance genetic effects were close to unity either for all animals or top ranked animals. Since presence of dominance genetic effects increased the model power to fit the data, inclusion of these effects in the genetic evaluation models for Baluchi sheep was recommended.
Adaptive integral terminal sliding mode control of unmanned bicycle via ELM and barrier function
Authors: Chen Long , Jin Zhihui , Shao Ke , Wang Guangyi , He Shuping , Stojanovic Vladimir , Bahri Parisa Arabzadeh , Wang Hai
Published: November 2024

In this paper, an unmanned bicycle (UB) with a reaction wheel is designed, and a second-order mathematical model with uncertainty is established. In order to achieve excellent balancing performance of the UB system, an adaptive controller is designed, which is composed of nominal feedback control, compensating control using extreme learning machine observer and reaching control via integral terminal sliding mode (ITSM) and barrier function (BF)-based adaptive law. Owing to the features of BF-based ITSM (BFITSM), not only any uncertainty or disturbance upper bound is not needed any longer but also the finite-time convergence of the closed-loop system can be ensured with a predefined error bound. Moreover, the BF-based control gain can be adaptively adjusted according to the update of the lumped uncertainty such that the overestimation is removed. The stability analysis of the closed-loop system is given according to Lyapunov theory. Comparable experimental results on an actual UB are carried out to validate the superior balancing performance of the proposed controller.
Express[p] in expressive phonology: analysis of a nicknaming pattern using ‘princess’ in Japanese
Authors: Kumagai Gakuji
Published: November 2024

Recent studies have shown that sound-symbolic patterns can be modelled using phonological theory. The purpose of the current study is to describe a new Japanese nicknaming pattern, pime-yobi, wherein [h] alternates with [p] to express cuteness, and to model it using Maximum Entropy Harmonic Grammar. The current study, building on the analysis of Alderete & Kochetov (2017), proposes a sound-symbolic constraint, Express[p], which requires output forms to contain [p]. The results of two experiments show that Japanese speakers found names containing [p]s to be cuter than those without them and that pime-yobi nicknaming exhibits intra- and inter-speaker variation in acceptability and cuteness. Based on these results, theoretical analysis shows that the weight of Express[p] varies both across different speakers and within the same speaker.
Ireland and the Antarctic Treaty System
Authors: Hughes Kevin A. , Hughes Katherine A.
Published: November 2024

Ireland has a rich Antarctic history, with Bransfield, Crozier, Shackleton, Crean and others acting as key Irish individuals in Antarctic exploration. Recognized as a source of Irish national pride, memorials, stamps, coins and a government research vessel all commemorate their polar feats. Today, a large proportion of Ireland's citizens visit the Antarctic region and Irish researchers produce high levels of academic outputs on Antarctic topics relative to many other nations. However, Ireland has not acceded to any Antarctic Treaty System instruments, despite a 20 year campaign to do so by cross-party Irish politicians. Ireland has the largest population of any nation in the European Union (EU) yet to accede to the Treaty and is much larger than some existing Treaty signatory states. However, Treaty accession provides no entitlement to participate in Antarctic governance, which is reserved for Consultative Parties, and therefore undertaking the associated legal and administrative work may be considered a poor use of available resources. Ireland's attainment of consultative status would be an even more complex and resource-intensive goal, but collaboration with the EU and other global partners could be a cost-effective solution that may also indirectly support Ireland's ambitions for Observer status at the Arctic Council.
Surgical management of a giant left coronary artery aneurysm mimicking cardiac mass
Authors: Zhu Hong , Bu Haisong
Published: November 2024

The giant coronary artery aneurysm is a very rare finding (0.02% of the general population), in which the right coronary artery is most often affected by aneurysms. Herein, we present a rare case of a giant left coronary artery aneurysm involving multiple major coronary arteries and compressing the cardiac cavity. The giant coronary artery aneurysm was opened and explored under cardiopulmonary bypass, and many mixed thrombi and calcified tissue were exposed. The patient was discharged uneventfully 7 days after surgery. The best management strategy at present is based on case reports, small case series, and personal experience. Treatment must be individualized according to the aetiology, location, symptoms, size, disease progression, the existence of infection, and the degree of any coexisting atherosclerosis. Surgery is a good alternative, particularly if a giant coronary artery aneurysm has a high risk of rupture and compressing the cardiac cavity. Even today, the treatment strategy is still open to debate and a clear evidence-based management strategy has not been established.
STABILITY ANALYSIS FOR STOCHASTIC MCKEAN–VLASOV EQUATION
Authors: SHI C. , WANG W.
Published: November 2024

The pth (

$p\geq 1$

) moment exponential stability, almost surely exponential stability and stability in distribution for stochastic McKean–Vlasov equation are derived based on some distribution-dependent Lyapunov function techniques.
An Intersectional Approach to Family Life: Reflections on Same-Sex Marriage, Familisation Risks, and Defamilisation Risks in Mainland China
Authors: Liu Emma H. , Lo Iris Po Yee , Yue Jack Wai Chik
Published: November 2024

This article focuses on how the policy on same-sex marriage and a person’s social locations impact upon Chinese lesbians’ life chances and welfare. Bringing the familisation and defamilisation literature, which has predominantly focused on heterosexual populations and families, into dialogue with an intersectionality perspective, we map the ways in which gender, sexuality, and class intersect in shaping lesbians’ experiences of defamilisation and familisation risks. The findings, drawn from interviews conducted in Beijing, China, reveal that the absence of legalised same-sex marriage, coupled with a lack of familial and societal recognition of same-sex relationships, exposes lesbians to both defamilisation and familisation risks, leading to difficulties in choosing whether and how to participate in the family. The intersectionality lens guides us to move beyond the heterosexual/homosexual boundary and to rethink the possibility of welfare alliances that can improve the welfare of not only lesbians but also other groups of women and minorities.
A New GRACE Downscaling Approach for Deriving High‐Resolution Groundwater Storage Changes Using Ground‐Based Scaling Factors
Authors: Li Huixiang , Pan Yun , Yeh Pat J.‐F. , Zhang Chong , Huang Zhiyong , Xu Li , Wang Haigang , Zeng Linghai , Gong Huili , Famiglietti James S.
Published: November 2024

To compensate for the coarse resolution of groundwater storage (GWS) estimation by the Gravity Recovery and Climate Experiment (GRACE) satellites and make better use of available observed groundwater‐level (GWL) data in some aquifers, a ground‐based scaling factor (SF) method is proposed here to derive high‐resolution GRACE GWS estimates. Improvement is achieved by using the gridded SF derived from assimilating ground‐based GWL observations. The proposed SF method is tested on the North China Plain (NCP, ∼140,000 km2), where a dense network of observation wells and a consistently estimated specific yield (SY) data set are available, to demonstrate its effectiveness and practical applications. The sensitivities of SF‐estimated GWS accuracy to the specification of SY and the assimilation of GWL observation data are explored through four designed numerical experiments. Results show that this novel ground‐based method can reduce the impact of SY uncertainty on GWS estimates, particularly in regions with more pronounced regional GWS trends. The accuracy of SF‐estimated GWS is primarily determined by whether the assimilated wells can reflect the regionally averaged GWS trend. GWS accuracy is less dependent on the number of available wells assimilated. The estimated GWS trend (2004–2015) in NCP is −32.6 ± 1.3 mm/yr (−4.6 ± 0.2 km3/yr), with contrasting GWS trends found in the west Piedmont Plain (∼54,000 km2, with a loss of −66.8 mm/yr) and the coastal Eastern Plain (∼20,000 km2, and a gain of +7.2 mm/yr). Despite the limitations of regional and time scale dependence inherent in SF method, this study highlights the benefits of assimilating in situ observed GWL data instead of using model simulations in estimating SF to downscale GRACE GWS to the higher‐resolution that is desired by local water resources management.
Spatially Compounding Drought Events in Brazil
Authors: Gesualdo Gabriela C. , Benso Marcos R. , Mendiondo Eduardo M. , Brunner Manuela I.
Published: November 2024

Spatially compounding drought events affect multiple locations simultaneously, severely affecting food, water, energy, human health, and infrastructure sectors. Despite the cascading impacts and challenges compound droughts impose on society, we still lack an in‐depth understanding of spatially connected drought occurrences. Given the complexity and costs of droughts in Brazil, identifying regions prone to co‐experiencing droughts is critical for developing effective adaptation measures. Here, we develop a novel framework to assess the spatial co‐occurrence of hydrological drought events, which can be adapted for global applications to evaluate spatially compounding drought. This framework involves extracting drought data from individual catchments and calculating the co‐occurrence of droughts across all catchments. We apply this method to investigate the spatial connectedness of droughts in 511 Brazilian catchments over 39 years (1983–2022). Additionally, we classify catchments based on drought duration, intensity, deficit, number of events, and spatial connectedness to identify regions with similar drought behavior. Our findings reveal significant variability in drought characteristics and connectedness across Brazil, with the Central‐Northeast and Northwest Amazon regions being most affected by multiple and widespread droughts. We identify five distinct regions in Brazil that exhibit common drought behaviors, sharing attributes such as aridity, catchment area, and precipitation seasonality. These regions hold the potential to guide future adaptation plans for managing hydrological compound extremes at both the catchment and regional scales, including the development of risk pool networks. Our results underscore the importance of considering the interactions of spatially compounding hydrological droughts in risk assessments and adaptation strategies.
Land Reclamation Controls on Multi‐Centennial Estuarine Evolution
Authors: Schrijvershof R. A. , van Maren D. S. , Van der Wegen M. , Hoitink A. J. F.
Published: November 2024

Land reclamations influence the morphodynamic evolution of estuaries and tidal basins, because an altered planform changes tidal dynamics and associated residual sediment transport. The morphodynamic response time to land reclamation is long, impacting the system for decades to centuries. Other human interventions (e.g., deepening of fairways or port construction) will add more morphodynamic adaptation timescales. Our understanding of the cumulative effects of anthropogenic interference with estuaries is limited because observations usually do not cover the complete morphological adaptation period. We aim to assess the impact of land reclamation works and other human interventions on an estuarine system by means of digital reconstructions of historical morphologies of the Ems Estuary over the past 500 years. Our analysis demonstrates that the intertidal‐subtidal area ratio altered due to land reclamation works and that the ratio partly restored after land reclamation ended. The land reclamation works have led to the degeneration of an ebb and flood channel system, transitioning the estuary from a multichannel to a single channel system. We infer that the 20th‐century intensification of channel dredging and re‐alignment works accelerated rather than caused this development. The centennial‐scale observations show that the Ems estuary evolution corresponds to a land reclamation response following tidal asymmetry‐based stability theory as it moves toward a new equilibrium configuration with modified tidal flats and channels. Considering the long history of land reclamation in the Ems Estuary, it provides an analogy for expected developments in comparable tidal systems where land reclamations were recently carried out.
Association of Long‐Term Exposure to PM2.5 Constituents and Green Space With Arthritis and Rheumatoid Arthritis
Authors: He Yi‐Sheng , Xu Yi‐Qing , Cao Fan , Gao Zhao‐Xing , Ge Man , He Tian , Zhang Peng , Zhao Chan‐Na , Wang Peng , Xu Zhiwei , Pan Hai‐Feng
Published: November 2024

There is limited evidence regarding the effects of long‐term exposure to PM2.5 constituents on the risk of arthritis and rheumatoid arthritis, and the interaction between PM2.5 and green space remains unclear. This study examined the relationship between long‐term exposure to PM2.5 constituents and the risk of arthritis and rheumatoid arthritis, with the exposure period extending from recruitment until self‐reported outcomes, death, loss to follow‐up, or end of follow‐up. Additionally, the study assessed whether there was an interactive effect between PM2.5 and green space on these risks. We gathered cohort data on 18,649 individuals aged ≥45 years. We applied generalized linear mixed‐effects models to estimate the effects of PM2.5 constituents, NDVI, and their interaction on arthritis and rheumatoid arthritis. The quantile g‐computation and weighted quantile sum regression model were applied to estimate the combined effect of PM2.5 constituents. Our results showed that exposure to single and mixed PM2.5 constituents adversely affected arthritis and rheumatoid arthritis, and was mainly attributed to the black carbon component. We observed “U” or “J” shaped exposure‐response curves for the effects of PM2.5, OM, NO3− and NH4+ exposure on the development of arthritis/rheumatoid arthritis. Additionally, the odds ratio of arthritis for per interquartile range (IQR) increase in PM2.5 was 1.209 (95% CI:1.198, 1.221), per 0.1‐unit decrease in NDVI was 1.091 (95% CI:1.033, 1.151), and the interaction term was 1.005 (95% CI:1.002, 1.007). These findings flesh out the existing evidence for PM2.5 constituents, NDVI and arthritis, rheumatoid arthritis, but the underlying mechanisms still require further exploration.
Retrieving Estimates of the Storm‐Relative Wind Profile From the Vertical Variation of Hydrometeor Size Sorting Signatures
Authors: Loeffler Scott D.
Published: November 2024

Raindrop fall speed increases with raindrop size. Because larger raindrops fall through a given layer of the atmosphere more quickly compared to smaller raindrops, they spend less time in the layer and, therefore, have less time to be acted on and advected by the storm‐relative winds. This results in hydrometeor size sorting which impacts the polarimetric radar variables such as differential reflectivity and specific differential phase . Previous work has shown a strong correlation between the mean storm‐relative wind in the sorting layer and the separation between regions of enhanced and at the bottom of the sorting layer. This study leverages this finding, along with a simple size sorting model, to construct radar‐derived estimates of the storm‐relative wind profile. The radar‐derived “pseudo‐hodographs” are well‐correlated with the magnitude and direction of the corresponding storm‐relative wind profiles. Further, these radar‐derived estimates of the storm‐relative winds are used to calculate estimates of shear and storm‐relative helicity, which also exhibit a strong correlation.
Observed Responses of Gravity Wave Momentum Fluxes to the Madden‒Julian Oscillation Around the Extratropical Mesopause Using Mohe Meteor Radar Observations
Authors: Zhou Xu , Liu Libo , Yue Xinan , Chen Guiwan , Lu Xian
Published: November 2024

The 12‐year continuous observation of gravity wave momentum fluxes (GWMFs) estimated by the Mohe meteor radar (53.5°N, 122.3°E) revealed prominent intraseasonal variability around the extratropical mesopause (82–94 km) during boreal winters. Composite analysis of the December‒January‒February (DJF) season according to the Madden‒Julian Oscillation (MJO) phases revealed that the zonal GWMFs notably increased in MJO Phase 4 (P4) by ∼2–4 m2/s2, and a Monte Carlo test was designed to examine the statistical significance. The response in zonal winds lags behind the GWMF response by two MJO phases (i.e., 1/2π), indicating a “force‒response” interaction between them. Additionally, time‐lagged composites revealed that strengthened westward GWMFs occurred ∼25–35 days after MJO P4, coincident with the MJO impact on the zonal winds in the stratosphere. The analysis results also suggested that the mechanism of MJO by which the MJO influences the stratospheric circulation might involve poleward propagating effects of stationary planetary waves with zonal wavenumber one. This work emphasizes the importance of GW intraseasonal variability, which impacts tropical sources from the troposphere to the extratropical mesopause.
Bifurcation Instability Modulated by a Connecting Channel Leads to Periodic Water Partitioning in a Simple Channel Network
Authors: Gao Weilun , Wang Zheng Bing , Kleinhans Maarten G. , Shao Dongdong , Zhu Zhenchang , Yang Zhifeng
Published: November 2024

Water and mass transport in distributary channel networks play an important role in nourishing fluvial and coastal wetlands, and are largely determined by the morphological configurations of channel bifurcations. While the morphological equilibrium of a single channel bifurcation has been extensively studied, the equilibrium configurations of channel networks with connecting channels linking the bifurcating branches, that is, the “bifurcation‐connecting channel” units that are commonly found in rivers, deltas and estuaries, remain elusive. In this simple yet representative channel network of the “bifurcation‐connecting channel” unit, we observed through numerical simulations an oscillatory water partitioning under moderate Shields stress and channel aspect ratio, in addition to the steady‐state solutions reported in previous studies. The oscillatory water partitioning indicates a newly discovered periodic solution, which is an emergent behavior under constant boundary conditions. We found that the periodic solution is primarily due to the dynamic interactions between bifurcation instability and water surface slope advantage in the two branches modulated by the reversable discharges through the connecting channel, under moderate Shields stress and channel aspect ratio. In such cases, the developed slope advantage in the subordinate branch can suppress the deepening of the dominant branch and eventually lead to the shifting of the dominant branch. In contrast, the channel network attains a steady‐state solution when the slope advantage or the bifurcation instability is dominant with relatively low and high Shields stress (or channel aspect ratio). Our results improve the understanding on the evolution and restoration of channel networks under increasing human interventions in global deltas.
The Importance of Impoundment interception in Simulating Riverine Dissolved Organic Carbon
Authors: Liu JiaoJiao , Liu JunZhi , Du XinZhong , Guo RenKui , Duan Zheng , Yuan BinJie , Liu YongQin
Published: November 2024

Modeling of riverine dissolved organic carbon (DOC) dynamics is of great importance for the global carbon budget. Impoundment interception changes the travel time of water and DOC from upslope contributing areas, exerting substantial influence on riverine DOC dynamics in the catchments with many impoundments. However, the impact of impoundment interception representation on riverine DOC modeling has not been evaluated so far. This study investigated to what extent impoundment interception representation affects DOC simulations using a newly developed catchment‐scale DOC model, which can represent the upslope contributing areas of impoundments and the impoundment interception process. The results showed that streamflow and DOC load simulation were well simulated regardless of whether impoundment interception was represented, but the simulation of DOC concentrations was satisfiable only when impoundment interception was taken into account. The simulation without impoundment interception produced unrealistic fluctuation of DOC concentration due to the direct mixing of DOC from different sources with contrasting concentration gradients. These results underscored the significance of employing an appropriate model structure for riverine DOC simulation. It is strongly recommended that DOC concentration be utilized for model evaluation in order to attain robust simulation outcomes. Moreover, the newly developed model in this study keeps a balance between the completeness of process presentation and model complexity, occupying a unique “ecological niche” among catchment‐scale riverine DOC models.
Genome-first determination of the prevalence and penetrance of eight germline myeloid malignancy predisposition genes: a study of two population-based cohorts
Authors: Hendricks Rachel M. , Kim Jung , Haley Jeremy S. , Ramos Mark Louie , Mirshahi Uyenlinh L. , Carey David J. , Stewart Douglas R. , McReynolds Lisa J.
Published: November 2024

It is estimated that 10% of individuals with a myeloid malignancy carry a germline susceptibility. Using the genome-first approach, in which individuals were ascertained on genotype alone, rather than clinical phenotype, we quantified the prevalence and penetrance of pathogenic germline variants in eight myeloid malignancy predisposition (gMMP) genes. ANKRD26, CEBPA, DDX41, MECOM, SRP72, ETV6, RUNX1 and GATA2, were analyzed from the Geisinger MyCode DiscovEHR (n = 170,503) and the United Kingdom Biobank (UKBB, n = 469,595). We identified a high risk of myeloid malignancies (MM) (odds ratio[OR] all genes: DiscovEHR, 4.6 [95% confidential interval (CI) 2.1–9.7], p < 0.0001; UKBB, 6.0 [95% CI 4.3–8.2], p = 3.1 × 10-27), and decreased overall survival (hazard ratio [HR] DiscovEHR, 1.8 [95% CI 1.3–2.6], p = 0.00049; UKBB, 1.4 [95% CI 1.2–1.8], p = 8.4 × 10-5) amongst heterozygotes. Pathogenic DDX41 variants were the most commonly identified, and in UKBB showed a significantly increased risk of MM (OR 5.7 [95% CI 3.9–8.3], p = 6.0 × 10-20) and increased all-cause mortality (HR 1.35 [95% CI 1.1–1.7], p = 0.0063). Through a genome-first approach, this study genetically ascertained individuals with a gMMP and determined their MM risk and survival.
Biallelic variants in CCN2 underlie an autosomal recessive kyphomelic dysplasia
Authors: Singh Swati , Danda Sumita , Sharma Neetu , Shah Hitesh , Madhuri Vrisha , Mir Tariq Altaf , Padala Nadia Zipporah , Medishetti Raghavender , Ekbote Alka , Bhavani Gandham SriLakshmi , Sevilimedu Aarti , Girisha Katta M.
Published: November 2024

Kyphomelic dysplasia is a rare heterogenous group of skeletal dysplasia, characterized by bowing of the limbs, severely affecting femora with distinct facial features. Despite its first description nearly four decades ago, the precise molecular basis of this condition remained elusive until the recent discovery of de novo variants in the KIF5B-related kyphomelic dysplasia. We ascertained two unrelated consanguineous families with kyphomelic dysplasia. They had six affected offsprings and we performed a detailed clinical evaluation, skeletal survey, and exome sequencing in three probands. All the probands had short stature, cleft palate, and micro-retrognathia. Radiographs revealed kyphomelic femora, bowing of long bones, radial head dislocations and mild platyspondyly. We noted two novel homozygous variants in CCN2 as possible candidates that segregated with the phenotype in the families: a missense variant c.443G>A; p.(Cys148Tyr) in exon 3 and a frameshift variant, c.779_786del; p.(Pro260LeufsTer7) in exon 5. CCN2 is crucial for proliferation and differentiation of chondrocytes. Earlier studies have shown that Ccn2-deficient mice exhibit twisted limbs, short and kinked sterna, broad vertebrae, domed cranial vault, shorter mandibles, and cleft palate. We studied the impact of CCN2 knockout in zebrafish models via CRISPR-Cas9 gene editing. F0 knockouts of ccn2a in zebrafish showed altered body curvature, impaired cartilage formation in craniofacial region and either bent or missing tails. Our observations in humans and zebrafish combined with previously described skeletal phenotype of Ccn2 knock out mice, confirm that biallelic loss of function variants in CCN2 result in an autosomal recessive kyphomelic dysplasia.
Four putative pathogenic ARHGAP29 variants in patients with non-syndromic orofacial clefts (NsOFC)
Authors: Ranji Peyman , Pairet Eleonore , Helaers Raphael , Bayet Bénédicte , Gerdom Alexander , Gil-da-Silva-Lopes Vera Lúcia , Revencu Nicole , Vikkula Miikka
Published: November 2024

The pathophysiological basis of non-syndromic orofacial cleft (NsOFC) is still largely unclear. However, exome sequencing (ES) has led to identify several causative genes, often with reduced penetrance. Among these, the Rho GTPase activating protein 29 (ARHGAP29) has been previously implicated in 7 families with NsOFC. We investigated a cohort of 224 NsOFCs for which no genetic pathogenic variant had been identified by diagnostic testing. We used ES and bioinformatic variant filtering and identified four novel putative pathogenic variants in ARHGAP29 in four families. One was a missense variant leading to the substitution of the first methionine with threonine, two were heterozygous frameshift variants leading to a premature termination codon, and one was a nonsense variant. All variants were predicted to result in loss of function, either through mRNA decay, truncated ARHGAP29, or abnormal N-terminal initiation of translation of ARHGAP29. The truncated ARHGAP29 proteins would lack the important RhoGAP domain. The variants were either absent or rare in the control population databases, and the loss of intolerance score (pLI) of ARHGAP29 is 1.0, suggesting that ARHGAP29 haploinsufficiency is not tolerated. Phenotypes ranged from microform cleft lip (CL) to complete bilateral cleft lip and palate (CLP), with one unaffected mutation carrier. These results extend the mutational spectrum of ARHGAP29 and show that it is an important gene underlying variable NsOFC phenotypes. ARHGAP29 should be included in diagnostic genetic testing for NsOFC, especially familial cases, as it may be mutated in ∼4% of them (4/97 in our cohort) with high penetrance (89%).
Effectiveness of the intelligent hypertension excellence centers (iHEC) therapy model in the blood pressure management of older hypertensive patients: a randomized controlled trial
Authors: Jiang Yuqin , Zheng Lijun , Zhang Yunhe , Fan Zhen , Guo Jianshu , Yang Junling , Liu Peng , Zhong Ping , Xie Dili
Published: November 2024

Intelligent hypertension excellence centers (iHEC) may improve blood pressure (BP) management in older hypertensive patients. However, this has not yet been rigorously evaluated, so we conducted a prospective randomized open-label clinical trial to verify this hypothesis. Older patients with hypertension were recruited between January and June 2022. The control group received conventional treatment and visited doctors in clinic. The intervention group received the iHEC therapy model, including remote BP management, online consultation, and follow-up services with support from the internet. Both groups received 12 months follow-up. Finally, 540 older patients with hypertension participated in the study; of these, 517 completed the follow-up. The average age was 71.4 ± 3.7years, 81 patients with frailty (15.7%). When follow-up was terminated, the SBP of the intervention group was 4.2 mmHg lower than that of the control group (95% CI, 2.0 to 6.4, P < 0.001), and the overall BP control rate in the intervention group was higher than that in the control group (60.2% vs. 48.1%, P < 0.05). During follow-up, the new-onset rate of excessive BP lowering in the intervention group was lower than that in the control group (3.8% vs. 9.0%, P < 0.05). Patients with a median age or above and high school education or above had higher numbers of online consultations and home BP measurements (P < 0.05).Our study confirmed those who received the iHEC therapy model achieved better BP reduction, higher rates of BP control, and alleviated the risk of excessive BP reduction.
3D chromatin maps of a brown alga reveal U/V sex chromosome spatial organization
Authors: Liu Pengfei , Vigneau Jeromine , Craig Rory J. , Barrera-Redondo Josué , Avdievich Elena , Martinho Claudia , Borg Michael , Haas Fabian B. , Liu Chang , Coelho Susana M.
Published: November 2024

Nuclear three dimensional (3D) folding of chromatin structure has been linked to gene expression regulation and correct developmental programs, but little is known about the 3D architecture of sex chromosomes within the nucleus, and how that impacts their role in sex determination. Here, we determine the sex-specific 3D organization of the model brown alga Ectocarpus chromosomes at 2 kb resolution, by mapping long-range chromosomal interactions using Hi-C coupled with Oxford Nanopore long reads. We report that Ectocarpus interphase chromatin exhibits a non-Rabl conformation, with strong contacts among telomeres and among centromeres, which feature centromere-specific LTR retrotransposons. The Ectocarpus chromosomes do not contain large local interactive domains that resemble TADs described in animals, but their 3D genome organization is largely shaped by post-translational modifications of histone proteins. We show that the sex determining region (SDR) within the U and V chromosomes are insulated and span the centromeres and we link sex-specific chromatin dynamics and gene expression levels to the 3D chromatin structure of the U and V chromosomes. Finally, we uncover the unique conformation of a large genomic region on chromosome 6 harboring an endogenous viral element, providing insights regarding the impact of a latent giant dsDNA virus on the host genome’s 3D chromosomal folding.
Fine-mapping and molecular characterisation of primary sclerosing cholangitis genetic risk loci
Authors: Goode Elizabeth C. , Fachal Laura , Panousis Nikolaos , Moutsianas Loukas , McIntyre Rebecca E. , Bai Benjamin Yu Hang , Kawasaki Norihito , Wittmann Alexandra , Raine Tim , Rushbrook Simon M. , Anderson Carl A.
Published: November 2024

Genome-wide association studies of primary sclerosing cholangitis have identified 23 susceptibility loci. The majority of these loci reside in non-coding regions of the genome and are thought to exert their effect by perturbing the regulation of nearby genes. Here, we aim to identify these genes to improve the biological understanding of primary sclerosing cholangitis, and nominate potential drug targets. We first build an eQTL map for six primary sclerosing cholangitis-relevant T-cell subsets obtained from the peripheral blood of primary sclerosing cholangitis and ulcerative colitis patients. These maps identify 10,459 unique eGenes, 87% of which are shared across all six primary sclerosing cholangitis T-cell types. We then search for colocalisations between primary sclerosing cholangitis loci and eQTLs and undertake Bayesian fine-mapping to identify disease-causing variants. In this work, colocalisation analyses nominate likely primary sclerosing cholangitis effector genes and biological mechanisms at five non-coding (UBASH3A, PRKD2, ETS2 and AP003774.1/CCDC88B) and one coding (SH2B3) primary sclerosing cholangitis loci. Through fine-mapping we identify likely causal variants for a third of all primary sclerosing cholangitis-associated loci, including two to single variant resolution.
Nucleotidyltransferase toxin MenT extends aminoacyl acceptor ends of serine tRNAs to control Mycobacterium tuberculosis growth
Authors: Xu Xibing , Barriot Roland , Voisin Bertille , Arrowsmith Tom J. , Usher Ben , Gutierrez Claude , Han Xue , Pagès Carine , Redder Peter , Blower Tim R. , Neyrolles Olivier , Genevaux Pierre
Published: November 2024

Toxins of toxin-antitoxin systems use diverse mechanisms to inhibit bacterial growth. In this study, we characterize the translation inhibitor toxin MenT3 of Mycobacterium tuberculosis, the bacterium responsible for tuberculosis in humans. We show that MenT3 is a robust cytidine specific tRNA nucleotidyltransferase in vitro, capable of modifying the aminoacyl acceptor ends of most tRNA but with a marked preference for tRNASer, to which long stretches of cytidines are added. Furthermore, transcriptomic-wide analysis of MenT3 targets in M. tuberculosis identifies tRNASer as the sole target of MenT3 and reveals significant detoxification attempts by the essential CCA-adding enzyme PcnA in response to MenT3. Finally, under physiological conditions, only in the presence the native menAT3 operon, an active pool of endogenous MenT3 targeting tRNASer in M. tuberculosis is detected, likely reflecting the importance of MenT3 during infection.
Why models underestimate West African tropical forest primary productivity
Authors: Zhang-Zheng Huanyuan , Deng Xiongjie , Aguirre-Gutiérrez Jesús , Stocker Benjamin D. , Thomson Eleanor , Ding Ruijie , Adu-Bredu Stephen , Duah-Gyamfi Akwasi , Gvozdevaite Agne , Moore Sam , Oliveras Menor Imma , Prentice I. Colin , Malhi Yadvinder
Published: November 2024

Tropical forests dominate terrestrial photosynthesis, yet there are major contradictions in our understanding due to a lack of field studies, especially outside the tropical Americas. A recent field study indicated that West African forests have among the highest forests gross primary productivity (GPP) yet observed, contradicting models that rank them lower than Amazonian forests. Here, we show possible reasons for this data-model mismatch. We found that biometric GPP measurements are on average 56.3% higher than multiple global GPP products at the study sites. The underestimation of GPP largely disappears when a standard photosynthesis model is informed by local field-measured values of (a) fractional absorbed photosynthetic radiation (fAPAR), and (b) photosynthetic traits. Remote sensing products systematically underestimate fAPAR (33.9% on average at study sites) due to cloud contamination issues. The study highlights the potential widespread underestimation of tropical forests GPP and carbon cycling and hints at the ways forward for model and input data improvement.
Cohort studies on 71 outcomes among people with atopic eczema in UK primary care data
Authors: Matthewman Julian , Schultze Anna , Strongman Helen , Bhaskaran Krishnan , Roberts Amanda , Denaxas Spiros , Mansfield Kathryn E. , Langan Sinéad M.
Published: November 2024

Atopic eczema may be related to multiple subsequent adverse health outcomes. Here, we provide evidence to judge and compare associations between eczema and a comprehensive set of outcomes. We conducted 71 cohort studies (age, sex, general practice-matched) using Clinical Practice Research Datalink Aurum primary care records (1997−2023), comparing up to 3.6 million people with eczema to 16.8 million without. Eczema was associated with subsequent diagnosis of outcomes with adjusted hazard ratios (99% confidence intervals) from Cox regression of up to 4.02(3.95–4.10) for food allergy (rate difference [RD] per 1,000 person-years of 1.5). Besides strong associations with atopic and allergic conditions (e.g., asthma 1.87[1.39–1.82], RD5.4) and skin infections (e.g., molluscum contagiosum 1.81[1.64–1.96], RD1.8), the strongest associations were with Hodgkin’s lymphoma (1.85[1.66–2.06], RD0.02), Alopecia Areata (1.77[1.71–1.83], RD0.2), Crohn’s disease (1.62[1.54–1.69], RD0.1), Urticaria (1.58[1.57–1.60], RD1.9), Coeliac disease (1.42[1.37–1.47], RD0.1), Ulcerative colitis (1.40[1.34–1.46], RD0.1), Autoimmune liver disease (1.32[1.21–1.43], RD0.01), and Irritable bowel syndrome (1.31[1.29–1.32], RD0.7). Sensitivity analyses revealed the impact of consultation bias or choice of cohort age cut-off on findings. Comparatively large HRs in severe eczema were seen for some liver, gastrointestinal and cardiovascular conditions, osteoporosis, and fractures. Most cancers and neurological conditions were not associated with eczema.
Coordinated inheritance of extrachromosomal DNAs in cancer cells
Authors: Hung King L. , Jones Matthew G. , Wong Ivy Tsz-Lo , Curtis Ellis J. , Lange Joshua T. , He Britney Jiayu , Luebeck Jens , Schmargon Rachel , Scanu Elisa , Brückner Lotte , Yan Xiaowei , Li Rui , Gnanasekar Aditi , Chamorro González Rocío , Belk Julia A. , Liu Zhonglin , Melillo Bruno , Bafna Vineet , Dörr Jan R. , Werner Benjamin , Huang Weini , Cravatt Benjamin F. , Henssen Anton G. , Mischel Paul S. , Chang Howard Y.
Published: November 2024

The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently1. Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division2,3. Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells4. How multiple ecDNA species within a tumour cell are assorted and maintained across somatic cell generations is unclear. Here we show that cooperative ecDNA species are coordinately inherited through mitotic co-segregation. Imaging and single-cell analyses show that multiple ecDNAs encoding distinct oncogenes co-occur and are correlated in copy number in human cancer cells. ecDNA species are coordinately segregated asymmetrically during mitosis, resulting in daughter cells with simultaneous copy-number gains in multiple ecDNA species before any selection. Intermolecular proximity and active transcription at the start of mitosis facilitate the coordinated segregation of ecDNA species, and transcription inhibition reduces co-segregation. Computational modelling reveals the quantitative principles of ecDNA co-segregation and co-selection, predicting their observed distributions in cancer cells. Coordinated inheritance of ecDNAs enables co-amplification of specialized ecDNAs containing only enhancer elements and guides therapeutic strategies to jointly deplete cooperating ecDNA oncogenes. Coordinated inheritance of ecDNAs confers stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations.
Selective ion transport through hydrated micropores in polymer membranes
Authors: Wang Anqi , Breakwell Charlotte , Foglia Fabrizia , Tan Rui , Lovell Louie , Wei Xiaochu , Wong Toby , Meng Naiqi , Li Haodong , Seel Andrew , Sarter Mona , Smith Keenan , Alvarez‐Fernandez Alberto , Furedi Mate , Guldin Stefan , Britton Melanie M. , McKeown Neil B. , Jelfs Kim E. , Song Qilei
Published: November 2024

Ion-conducting polymer membranes are essential in many separation processes and electrochemical devices, including electrodialysis1, redox flow batteries2, fuel cells3 and electrolysers4,5. Controlling ion transport and selectivity in these membranes largely hinges on the manipulation of pore size. Although membrane pore structures can be designed in the dry state6, they are redefined upon hydration owing to swelling in electrolyte solutions. Strategies to control pore hydration and a deeper understanding of pore structure evolution are vital for accurate pore size tuning. Here we report polymer membranes containing pendant groups of varying hydrophobicity, strategically positioned near charged groups to regulate their hydration capacity and pore swelling. Modulation of the hydrated micropore size (less than two nanometres) enables direct control over water and ion transport across broad length scales, as quantified by spectroscopic and computational methods. Ion selectivity improves in hydration-restrained pores created by more hydrophobic pendant groups. These highly interconnected ion transport channels, with tuned pore gate sizes, show higher ionic conductivity and orders-of-magnitude lower permeation rates of redox-active species compared with conventional membranes, enabling stable cycling of energy-dense aqueous organic redox flow batteries. This pore size tailoring approach provides a promising avenue to membranes with precisely controlled ionic and molecular transport functions.