bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of dietary intake and physical activity in reducing weight social inequalities among adolescents: an application of G-formula to PRALIMAP-INÈS trial
Authors: Dakin Mohamed , Manneville Florian , Langlois Johanne , Briançon Serge , Lecomte Edith , Spitz Elisabeth , Legrand Karine , Böhme Philip , Guillemin Francis , Omorou Abdou
Published: May 2024

Interventions aiming to reduce social inequalities of weight status in adolescents usually focus on lifestyle behaviours, but their effectiveness is limited. This study analysed the effect of achieving levels of dietary intake (DI) and/or physical activity (PA) guidelines on reducing social inequalities in weight status among adolescents. We included adolescents from the PRomotion de l’ALIMentation et de l’Activité Physique – INÉgalité de Santé (PRALIMAP-INÈS) trial with weight status data available at baseline and 1-year follow-up (n 1130). PA and DI were measured using the International Physical Activity Questionnaire and a validated FFQ, respectively. We estimated the likelihood of a 1-year reduction in BMI z-score (BMIz) and population risk difference (PRD) under hypothetical DI and PA levels and socio-economic status using the parametric G-formula. When advantaged and less advantaged adolescents maintained their baseline DI and PA, we found social inequalities in weight status, with a PRD of a 1-year reduction in BMIz of −1·6 % (–3·0 %, −0·5 %). These inequalities were not observed when less advantaged adolescents increased their proportion of achieving DI guidelines by 30 % (PRD = 2·2 % (–0·5 %, 5·0 %)) unlike the same increase in PA (PRD = −3·9 % (–6·8 %, −1·3 %)). Finally, social inequalities of weight status were not observed when levels of achievement of both PA and DI guidelines increased by 30 % (PRD = 2·2 % (–0·5 %, 4·0 %)). Enhancing DI rather than PA could be effective in reducing social inequalities in weight status among adolescents. Future interventions aiming to reduce these inequalities should mostly target DI to be effective.
Ganoderma lucidum dry extract supplementation modulates T lymphocyte function in older women
Authors: Iser-Bem Patricia Nancy , Lobato Tiago Bertola , Alecrim-Zeza Amanda Lins , dos Santos de Oliveira Laiane Cristina , Passos Maria Elizabeth Pereira , Manuel Richelieau , Diniz Vinícius Leonardo Sousa , Correa Ilana Souza , de Oliveira Sarah Poma , Silva Eliane Borges da , Almeida Mariana Mendes de , Dias Beatriz Belmiro , Gritte Raquel Bragante , Levada-Pires Adriana Cristina , Masi Laureane Nunes , Hatanaka Elaine , Pithon-Curi Tania Cristina , Hirabara Sandro Massao , Fabi João Paulo , Curi Rui , Gorjao Renata
Published: May 2024

Ganoderma lucidum (a mushroom used in traditional Chinese medicine) compounds may attenuate ageing-related physiological changes and restore normal immunity. However, studies on the physiological effects of Ganoderma lucidum dry extract food supplements are few. Therefore, here, we aimed to investigate the effects of Ganoderma lucidum dry extract food supplement on the lymphocyte function of older women. This was a double-blind clinical trial (n 60) with a final 39 older volunteers, divided into two groups Ganoderma lucidum (n 23) and placebo (n 16). The Ganoderma lucidum group received 2000 mg/d of Ganoderma lucidum dry extract for 8 weeks. We used flow cytometry to determine the lymphocyte profile. CD4+ lymphocyte gene expression was evaluated by real-time polymerase chain reaction. We observed that in the Ganoderma lucidum group, concanavalin A stimulation increased lymphocyte proliferation. Further, we observed an increase in expression of Forkhead box P3, transforming growth factor-beta, IL-10, IL-6, retinoic acid receptor-related orphan receptor gamma, GATA-binding protein 3 and interferon gamma genes in the Ganoderma lucidum group. Furthermore, in the Ganoderma lucidum group, ionomycin and phorbol 12-myristate 13-acetate stimulation led to decrease in Th17+ cells and increase in Th2+ cells. Thus, in older women, Ganoderma lucidum regulates T lymphocyte function leading to a predominant anti-inflammatory action but does not induce T lymphocyte proliferation through CD28 signalling pathway.
MATRILINEAL SUCCESSION IN GREEK MYTH
Authors: Hawes Greta , Selth Rosemary
Published: May 2024

This article presents a systematic examination of matrilineal succession in Greek myth. It uses MANTO, a digital database of Greek myth, to identify kings who succeed their fathers-in-law, maternal grandfathers, step-fathers, or wives’ previous husbands. Analysis of the fifty-four instances identified shows that the prominence of the ‘succession via widow’ motif in archaic epic is not typical of the broader tradition. Rather, civic mythmaking more commonly relies on succession by sons-in-law and maternal grandsons to craft connections between cities and lineages, and to claim panhellenic prestige. We show that matrilineal successors are not treated as necessarily illegitimate or inferior within the overwhelmingly patrilineal conventions of Greek myth. In fact, matrilineal calculations afford certain advantages, like the ability to integrate heroes from elsewhere, or to champion local kings with divine fathers. Matrilineal succession reveals the gendered dynamics inherent to Greek myth; we argue that, although in these instances regnal power is transferred through female relatives, the heroines involved are typically treated simply as nodes for this power and their roles in these stories do not necessarily correlate to a greater visibility or autonomy.
Effect of double-premilking teat disinfection protocols on bacterial counts on teat skin of cows and milker gloves in a free-stall-housed dairy herd
Authors: Niero Thiago Resin , Kappes Roberto , Scheid Angelica Leticia , Ramos Andreina Ferreira , Ribeiro Eduardo Becker , Cardozo Leonardo Leite , Ferraz Sandra Maria , Thaler Neto André
Published: May 2024

This research communication addresses the hypothesis that double premilking teat disinfection (DD) is more effective in reducing soiling and bacterial count on the cows' teat skin and milkers' gloves than conventional disinfection (CONV). The design was a 3 × 3 Latin square (three groups of cows and three treatments) with conventional teat disinfection (CONV, lactic acid application after forestripping), double teat disinfection using the same disinfectant (DD1D, lactic acid application before and after forestripping), and double teat disinfection using two different disinfectants (DD2D, application of lactic acid before and chlorine-based disinfectant after forestripping). All groups were assigned for six days for each treatment, and the evaluations and samples were collected on the last day, before and after treatment. We evaluated the teat cleanliness score (TCS), count of Gram-negative bacteria (coliforms and noncoliforms), Staphylococcus spp., Streptococcus spp., and total bacterial count (TBC) on the cows' teats and TBC on the milkers' gloves. TCS after premilking was lower in DD than CONV treatment. The reduction of Staphylococcus spp. count was greater in the DD treatment and tended to be higher in the DD2D. The TBC reduction on the cows' teats was greater in the DD treatments. The TBC on the milkers' gloves was lower for DD before and after premilking. In conclusion, DD can be an alternative for reducing some bacterial populations on cow teats and preventing the transmission of microorganisms between cows via the milkers' hands.
Biocontrol potential of six Heterorhabditis bacteriophora strains isolated in the Azores Archipelago
Authors: Beltrí R. , Monteiro H.R. , Toubarro D. , Simões N. , Garriga A.
Published: May 2024

Entomopathogenic nematodes (EPNs) are closely associated with Popillia japonica and potentially used as their biological control agents, although field results proved inconsistent and evoked a continual pursuit of native EPNs more adapted to the environment. Therefore, we surveyed the Azorean Archipelago to isolate new strains of Heterorhabditis bacteriophora and to evaluate their virulence against the model organism Galleria mellonella under laboratory conditions. Six strains were obtained from pasture and coastal environments and both nematode and symbiont bacteria were molecularly identified. The bioassays revealed that Az172, Az186, and Az171 presented high virulence across the determination of a lethal dose (LD50) and short exposure time experiments with a comparable performance to Az29. After 72 hours, these virulent strains presented a mean determination of a lethal dose of 11 infective juveniles cm-2, a lethal time (LT50) of 34 hours, and achieved 40% mortality after an initial exposure time of only 60 minutes. Az170 exhibited an intermediate performance, whereas Az179 and Az180 were classified as low virulent strains. However, both strains presented the highest reproductive potential with means of 1700 infective juveniles/mg of larvae. The bioassays of the native EPNs obtained revealed that these strains hold the potential to be used in biological control initiatives targeting P. japonica because of their high virulence and locally adapted to environmental conditions.
Shared familial risk for type 2 diabetes mellitus and psychiatric disorders: a nationwide multigenerational genetics study
Authors: Wimberley Theresa , Brikell Isabell , Astrup Aske , Larsen Janne T. , Petersen Liselotte V. , Albiñana Clara , Vilhjálmsson Bjarni J. , Bulik Cynthia M. , Chang Zheng , Fanelli Giuseppe , Bralten Janita , Mota Nina R. , Salas-Salvadó Jordi , Fernandez-Aranda Fernando , Bulló Monica , Franke Barbara , Børglum Anders , Mortensen Preben B. , Horsdal Henriette T. , Dalsgaard Søren
Published: May 2024

Background

Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM.

Methods

We linked 659 906 individuals born in Denmark 1990–2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981–2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders.

Results

Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35–1.42; grandparents: 1.14, 1.13–1.15; and aunts/uncles: 1.19, 1.16–1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08–1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa.

Conclusions

Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.
Jacques Copeau's “The Spirit in the Little Theatre”: Contexts and Texts
Authors: Gainor J. Ellen , Un John
Published: May 2024

The story of influential French stage director Jacques Copeau's 1917–19 residency in New York City was documented at the time by Copeau himself and subsequently analyzed by Copeau scholars.1 Copeau (1879–1949) is remembered today for his innovative, experimental theatre work in the early twentieth century; he developed core practices that became foundational for modernist stage artistry, including mime and physical theatre as well as devised theatre techniques.2 In 1913, he established his Théâtre du Vieux-Colombier in Paris, breaking away from traditional ornate design practices and envisioning an ensemble of actors trained in methods comparable to those used by Konstantin Stanislavsky, although Copeau knew comparatively little of his techniques at this time.3 Copeau's “‘attempt at dramatic renovation’”4 included staging plays to be performed in repertory and maintaining modest budgets and ticket prices to secure financial stability. In these and other regards, his vision paralleled those of other modernist colleagues not only in Europe, but also in the United States, where the Little Theatre movement was already underway,5 although Copeau similarly had little knowledge of US theatre at this early moment.
Dynamic simultaneous localization and mapping based on object tracking in occluded environment
Authors: Ding Weili , Pei Ziqi , Yang Tao , Chen Taiyu
Published: May 2024

In practical applications, many robots equipped with embedded devices have limited computing capabilities. These limitations often hinder the performance of existing dynamic SLAM algorithms, especially when faced with occlusions or processor constraints. Such challenges lead to subpar positioning accuracy and efficiency. This paper introduces a novel lightweight dynamic SLAM algorithm designed primarily to mitigate the interference caused by moving object occlusions. Our proposed approach combines a deep learning object detection algorithm with a Kalman filter. This combination offers prior information about dynamic objects for each SLAM algorithm frame. Leveraging geometric techniques like RANSAC and the epipolar constraint, our method filters out dynamic feature points, focuses on static feature points for pose determination, and enhances the SLAM algorithm’s robustness in dynamic environments. We conducted experimental validations on the TUM public dataset, which demonstrated that our approach elevates positioning accuracy by approximately 54% and boosts the running speed by 75.47% in dynamic scenes.
The Beneficial, Formative Role of Lifetime Exposures across Cognitive Domains in Barbados Using Data from the SABE Study
Authors: Steffener Jason , Nicholls Joanne , Farghal Shireen , Franklin Dylan
Published: May 2024

This study tested the hypothesis that within older Barbadian adults, sex, education, and occupation type lessen age-related cognitive decline. The analyses used a cross-sectional data set from 1325 people collected in the 2006 SABE Study (Health, Well-being, and Aging). Cognition was assessed as scores in each subdomain of the Mini-Mental State Exam. The loss of a single point in each subdomain was predicted by sex, years of education, job type, and their interactions with age. Results demonstrated that age and protective factors affect each cognitive domain differently. High education combined with mentally complex employment helped maintain cognitive performance in later life. Beneficial lifetime exposures are additive, providing combined benefits. Findings provide insight into public policy aiming to minimize the number of adults with cognitive decline and dementia in Barbados and the Caribbean.
Powder X-ray diffraction of acalabrutinib dihydrate Form III, C26H23N7O2(H2O)2
Authors: Kaduk James A. , Rost Megan M. , Dosen Anja , Blanton Thomas N.
Published: May 2024

The crystal structure of acalabrutinib dihydrate Form III has been refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Acalabrutinib dihydrate Form III crystallizes in space group P21 (#4) with a = 8.38117(5), b = 21.16085(14), c = 14.12494(16) Å, β = 94.5343(6)°, V = 2497.256(20) Å3, and Z = 4 (Z′ = 2) at 295 K. The crystal structure consists of herringbone layers parallel to the ac-plane. Hydrogen bonds between the acalabrutinib and water molecules generate a three-dimensional framework. Each water molecule acts as a donor in two hydrogen bonds and as an acceptor in at least one hydrogen bond. Amino groups and pyridine N atoms link the acalabrutinib molecules into dimers. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®).
Crystal structure of ribociclib hydrogen succinate, (C23H31N8O)(HC4H4O4)
Authors: Kaduk James A. , Dosen Anja , Blanton Thomas N.
Published: May 2024

The crystal structure of ribociclib hydrogen succinate (commonly referred to as ribociclib succinate) has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional theory techniques. Ribociclib hydrogen succinate crystallizes in space group P-1 (#2) with a = 6.52215(4), b = 12.67120(16), c = 18.16978(33) Å, α = 74.0855(8), β = 82.0814(4), γ = 88.6943(1)°, V = 1430.112(6) Å3, and Z = 2 at 295 K. The crystal structure consists of alternating layers of cations and anions parallel to the ab-plane. The protonated N in each ribociclib cation acts as a donor in two strong N–H⋯O hydrogen bonds to two different succinate anions. Strong O–H⋯O hydrogen bonds link the hydrogen succinate anions into chains parallel to the a-axis. N–H⋯N hydrogen bonds link the cations into dimers, with a graph set R2,2(8). The result is a three-dimensional hydrogen bond network. The powder pattern has been submitted to ICDD for inclusion in the Powder Diffraction File™ (PDF®)
Invoking the Goddess along the Southern Silk Roads: a transregional survey of Prajñāpāramitā protective texts
Authors: Bianchini Francesco
Published: May 2024

This article brings together various textual materials relating to the worship of Prajñāpāramitā in mediaeval Monsoon Asia. In particular, it covers sources from South Asia, mainland Southeast Asia (Angkor), maritime Southeast Asia (Java and Bali), and Southern China (Yunnan). The aims of this critical survey are twofold. On the one hand, the article argues for the importance of ritual language within wider discussions on cultural and linguistic cosmopolitanism within and beyond the so-called ‘Sanskrit Cosmopolis’. These discussions have too often focused on royal epigraphic eulogies, neglecting religious literature. On the other hand, it highlights the key role of Prajñāpāramitā as a protective deity, and the transregional heritage of her invocatory texts. These texts strike one for their traditional choice of imagery and associations, thus reminding of the importance of exoteric traditions within the history of Southeast Asian Buddhism.
Exploitation of genetics for improvement of morphological traits in segregating population of underutilized ornamental herb (Catharanthus roseus (L.) G. Don)
Authors: Ravikumar Bolagam , Dhatt Kiranjit Kaur
Published: May 2024

Periwinkle (Catharanthus roseus (L.) G. Don) is a vital summer season perennial semi-shrub and multipurpose drought-resilient flower crop of the tropical region of the Indian subcontinent. This industrially dominant crop is primarily used as border, bedding and pot culture in landscaping. There is a lack of information on the genetics of important traits and its correlation with quantitative characters like flower yield and understanding the co-segregation of these traits might be useful in crop improvement. Therefore, the present study was performed using 30 F2 segregating lines of Catharanthus developed from diallel crossing of six genetically dissimilar parents varied in many traits. Phenotyping of population was executed for 12 morphological traits. Results indicated that a significant positive association between days to flowering and plant height (0.753**), and leaf area and number of branches (0.463**) was recorded. Flowers per plant exhibit significantly positive correlation with all attributes except flower diameter (−005). The path coefficient analysis reported solely two traits, such as number of seeds per follicle (0.357) and corolla tube length (0.308) exerted positively significant direct effects on flower yield per plant. The scrutiny of principal components showed that the first three components demonstrated a cumulative variability of 70.1%. The dissipating of F2 plants in bi-plot is impenitent to our prior reports that six inbred lines were genetically diverse and quite different for the characters under study. The current research might be useful in breeding programmes for selection and hybridization of periwinkle in future.
Clever lernen
Authors: Rietzler Stefanie , Grolimund Fabian
Published: May 2024

Mach dir deinen Schulalltag leichter!

Dieses Buch verrät dir, wie du mit weniger Aufwand bessere Noten schreibst und sogar Spaß beim Lernen hast. Möchtest du wissen, wie du

bei der Prüfungsvorbereitung Wichtiges von Unwichtigem unterscheidest und dadurch Zeit einsparst?
zum Fremdsprachen-Checker wirst?
das Mathe-Monster zähmst – auch wenn deine Lehrkraft überhaupt nicht gut erklären kann?
dir den Inhalt von schwierigen Texten in Biologie, Geschichte, Geografie  &  Co. ratzfatz einprägst?
deine Motivation und Konzentration steigerst – sogar bei deinem Hassfach?
Referate meisterst und deine Nervosität in den Griff bekommst?
Prüfungsstress und Blackouts den Kampf ansagst?

Dann ist dieses Buch genau das Richtige für dich.
Association between high-altitude polycythemia and hypertension: a cross-sectional study in adults at Tibetan ultrahigh altitudes
Authors: Yin Rong , Wu Yunhong , Li Man , Liu Chunrong , Pu Xue , Yi Wen
Published: May 2024

The study aimed to evaluate the association between high-altitude polycythemia and hypertension in adults residing on Anduo County’s plateau, which is located 4700 meters above sea level. A total of 387 individuals participated in the cross-sectional survey conducted between April and May of 2021. Interviews, physical inspections, and laboratory tests were employed to gather information about all of the subjects. The association between high-altitude polycythemia and hypertension was assessed using multivariable logistic regression models. The average age of the 387 participants was 32.6 ± 6.3 years. Of these participants, 260 (67%) were male. The overall prevalence of hypertension was 27.1% (57/380). When stratified by gender, the prevalence was 12.6% (16/127) in females and 34.2% (89/260) in males. The overall prevalence of high-altitude polycythemia was 19.6% (76/387). When stratified by gender, the prevalence was 26.2% (68/260) in males and 6.3% (8/127) in females. During logistic regression analysis, we found that participants with elevated hemoglobin per 10 g/L had a 26% greater risk of hypertension (adjusting for odds ratio [OR], 1.26; 95% confidence interval [CI], 1.11–1.44). Additionally, high-altitude polycythemia greatly increased the risk of hypertension in comparison to non-high-altitude polycythemia (OR, 3.01; 95% CI, 1.66–5.44, P < 0.001). The consistency of the results was further demonstrated by stratified and interaction analyses, showing that Hans individuals had a higher risk of hypertension. High-altitude polycythemia is positively associated with hypertension in adults residing at Tibetan ultrahigh altitudes. The results of the investigation may aid in the planning of future research and guide the development of targeted healthcare practices for high-altitude populations, particularly among Han Chinese residents of the Tibetan Plateau.
Artificial intelligence model system for bone age assessment of preschool children
Authors: Gao Chengcheng , Hu Chunfeng , Qian Qi , Li Yangsheng , Xing Xiaowei , Gong Ping , Lin Min , Ding Zhongxiang
Published: May 2024

Backgroud

Our study aimed to assess the impact of inter- and intra-observer variations when utilizing an artificial intelligence (AI) system for bone age assessment (BAA) of preschool children.

Methods

A retrospective study was conducted involving a total sample of 53 female individuals and 41 male individuals aged 3–6 years in China. Radiographs were assessed by four mid-level radiology reviewers using the TW3 and RUS–CHN methods. Bone age (BA) was analyzed in two separate situations, with/without the assistance of AI. Following a 4-week wash-out period, radiographs were reevaluated in the same manner. Accuracy metrics, the correlation coefficient (ICC)and Bland-Altman plots were employed.

Results

The accuracy of BAA by the reviewers was significantly improved with AI. The results of RMSE and MAE decreased in both methods (p < 0.001). When comparing inter-observer agreement in both methods and intra-observer reproducibility in two interpretations, the ICC results were improved with AI. The ICC values increased in both two interpretations for both methods and exceeded 0.99 with AI.

Conclusion

In the assessment of BA for preschool children, AI was found to be capable of reducing inter-observer variability and enhancing intra-observer reproducibility, which can be considered an important tool for clinical work by radiologists.

Impact

The RUS-CHN method is a special bone age method devised to be suitable for Chinese children.

The preschool stage is a critical phase for children, marked by a high degree of variability that renders BA prediction challenging.

The accuracy of BAA by the reviewers can be significantly improved with the aid of an AI model system.

This study is the first to assess the impact of inter- and intra-observer variations when utilizing an AI model system for BAA of preschool children using both the TW3 and RUS-CHN methods.
APF2: an improved ensemble method for pharmacogenomic variant effect prediction
Authors: Zhou Yitian , Pirmann Sebastian , Lauschke Volker M.
Published: May 2024

Lack of efficacy or adverse drug response are common phenomena in pharmacological therapy causing considerable morbidity and mortality. It is estimated that 20–30% of this variability in drug response stems from variations in genes encoding drug targets or factors involved in drug disposition. Leveraging such pharmacogenomic information for the preemptive identification of patients who would benefit from dose adjustments or alternative medications thus constitutes an important frontier of precision medicine. Computational methods can be used to predict the functional effects of variant of unknown significance. However, their performance on pharmacogenomic variant data has been lackluster. To overcome this limitation, we previously developed an ensemble classifier, termed APF, specifically designed for pharmacogenomic variant prediction. Here, we aimed to further improve predictions by leveraging recent key advances in the prediction of protein folding based on deep neural networks. Benchmarking of 28 variant effect predictors on 530 pharmacogenetic missense variants revealed that structural predictions using AlphaMissense were most specific, whereas APF exhibited the most balanced performance. We then developed a new tool, APF2, by optimizing algorithm parametrization of the top performing algorithms for pharmacogenomic variations and aggregating their predictions into a unified ensemble score. Importantly, APF2 provides quantitative variant effect estimates that correlate well with experimental results (R2 = 0.91, p = 0.003) and predicts the functional impact of pharmacogenomic variants with higher accuracy than previous methods, particularly for clinically relevant variations with actionable pharmacogenomic guidelines. We furthermore demonstrate better performance (92% accuracy) on an independent test set of 146 variants across 61 pharmacogenes not used for model training or validation. Application of APF2 to population-scale sequencing data from over 800,000 individuals revealed drastic ethnogeographic differences with important implications for pharmacotherapy. We thus think that APF2 holds the potential to improve the translation of genetic information into pharmacogenetic recommendations, thereby facilitating the use of Next-Generation Sequencing data for stratified medicine.
Outdoor air pollution and risk of incident adult haematologic cancer subtypes in a large US prospective cohort
Authors: Diver W. Ryan , Teras Lauren R. , Deubler Emily L. , Turner Michelle C.
Published: May 2024

Background

Outdoor air pollution and particulate matter (PM) are classified as Group 1 human carcinogens for lung cancer. Pollutant associations with haematologic cancers are suggestive, but these cancers are aetiologically heterogeneous and sub-type examinations are lacking.

Methods

The American Cancer Society Cancer Prevention Study-II Nutrition Cohort was used to examine associations of outdoor air pollutants with adult haematologic cancers. Census block group level annual predictions of particulate matter (PM2.5, PM10, PM10-2.5), nitrogen dioxide (NO2), ozone (O3), sulfur dioxide (SO2), and carbon monoxide (CO) were assigned with residential addresses. Hazard ratios (HR) and 95% confidence intervals (CI) between time-varying pollutants and haematologic subtypes were estimated.

Results

Among 108,002 participants, 2659 incident haematologic cancers were identified from 1992–2017. Higher PM10-2.5 concentrations were associated with mantle cell lymphoma (HR per 4.1 μg/m3 = 1.43, 95% CI 1.08–1.90). NO2 was associated with Hodgkin lymphoma (HR per 7.2 ppb = 1.39; 95% CI 1.01–1.92) and marginal zone lymphoma (HR per 7.2 ppb = 1.30; 95% CI 1.01–1.67). CO was associated with marginal zone (HR per 0.21 ppm = 1.30; 95% CI 1.04–1.62) and T-cell (HR per 0.21 ppm = 1.27; 95% CI 1.00–1.61) lymphomas.

Conclusions

The role of air pollutants on haematologic cancers may have been underestimated previously because of sub-type heterogeneity.
PKA inhibition kills l-asparaginase-resistant leukemic cells from relapsed acute lymphoblastic leukemia patients
Authors: Lee Jung Kwon , Wang Xidi , Wang Jinghua , Rosales Jesusa L. , Lee Ki-Young
Published: May 2024

Despite the success in treating newly diagnosed pediatric acute lymphoblastic leukemia (aLL), the long-term cure rate for the 20% of children who relapse is poor, making relapsed aLL the primary cause of cancer death in children. By unbiased genome-wide retroviral RNAi screening and knockdown studies, we previously discovered opioid receptor mu 1 (OPRM1) as a new aLL cell resistance biomarker for the aLL chemotherapeutic drug, l-asparaginase, i.e., OPRM1 loss triggers l-asparaginase resistance. Indeed, aLL cell OPRM1 level is inversely proportional to l-asparaginase IC50: the lower the OPRM1 level, the higher the l-asparaginase IC50, indicating that aLL cells expressing reduced OPRM1 levels show resistance to l-asparaginase. In the current study, we utilized OPRM1-expressing and -knockdown aLL cells as well as relapsed patient aLL cells to identify candidate targeted therapy for l-asparaginase-resistant aLL. In OPRM1-expressing cells, l-asparaginase induces apoptosis via a cascade of events that include OPRM1-mediated decline in [cAMP]i, downregulation of PKA-mediated BAD S118 phosphorylation that can be reversed by 8-CPT-cAMP, cyt C release from the mitochondria, and subsequent caspase activation and PARP1 cleavage. The critical role of PKA inhibition due to a decrease in [cAMP]i in this apoptotic process is evident in the killing of OPRM1-knockdown and low OPRM1-expressing relapsed patient aLL cells by the PKA inhibitors, H89 and 14–22 amide. These findings demonstrate for the first time that PKA can be targeted to kill aLL cells resistant to l-asparaginase due to OPRM1 loss, and that H89 and 14–22 amide may be utilized to destroy l-asparaginase-resistant patient aLL cells.
Characteristics, aetiology and implications for management of multiple primary renal tumours: a systematic review
Authors: Zhang Huairen , Andreou Avgi , Bhatt Rupesh , Whitworth James , Yngvadottir Bryndis , Maher Eamonn R.
Published: May 2024

In a subset of patients with renal tumours, multiple primary lesions may occur. Predisposition to multiple primary renal tumours (MPRT) is a well-recognised feature of some inherited renal cancer syndromes. The diagnosis of MPRT should therefore provoke a thorough assessment for clinical and genetic evidence of disorders associated with predisposition to renal tumourigenesis. To better define the clinical and genetic characteristics of MPRT, a systematic literature review was performed for publications up to 3 April 2024. A total of 7689 patients from 467 articles were identified with MPRT. Compared to all patients with renal cell carcinoma (RCC), patients with MPRT were more likely to be male (71.8% versus 63%) and have an earlier age at diagnosis (<46 years, 32.4% versus 19%). In 61.1% of cases MPRT were synchronous. The proportion of cases with similar histology and the proportion of cases with multiple papillary renal cell carcinoma (RCC) (16.1%) were higher than expected. In total, 14.9% of patients with MPRT had a family history of cancer or were diagnosed with a hereditary RCC associated syndrome with von Hippel-Lindau (VHL) disease being the most common one (69.7%), followed by Birt-Hogg-Dubé (BHD) syndrome (14.2%). Individuals with a known or likely genetic cause were, on average, younger (43.9 years versus 57.1 years). In rare cases intrarenal metastatic RCC can phenocopy MPRT. We review potential genetic causes of MPRT and their implications for management, suggest an approach to genetic testing for individuals presenting with MPRT and considerations in cases in which routine germline genetic testing does not provide a diagnosis.
Refining clinically relevant parameters for mis-splicing risk in shortened introns with donor-to-branchpoint space constraint
Authors: Zhang Katharine Y. , Joshi Himanshu , Marchant Rhett G. , Bryen Samantha J. , Dawes Ruebena , Yuen Michaela , Cooper Sandra T. , Evesson Frances J.
Published: May 2024

Intronic deletions that critically shorten donor-to-branchpoint (D-BP) distance of a precursor mRNA impose biophysical space constraint on assembly of the U1/U2 spliceosomal complex, leading to canonical splicing failure. Here we use a series of β-globin (HBB) gene constructs with intron 1 deletions to define D-BP lengths that present low/no risk of mis-splicing and lengths which are critically short and likely elicit clinically relevant mis-splicing. We extend our previous observation in EMD intron 5 of 46 nt as the minimal productive D-BP length, demonstrating spliceosome assembly constraint persists at D-BP lengths of 47-56 nt. We exploit the common HBB exon 1 β-thalassemia variant that strengthens a cryptic donor (NM_000518.5(HBB):c.79G > A) to provide a simple barometer for the earliest signs of space constraint, via cryptic donor activation. For clinical evaluation of intronic deletions, we assert D-BP lengths > 60 nt present low mis-splicing risk while space constraint increases exponentially with D-BP lengths < 55 nt, with critical risk and profound splicing abnormalities with D-BP lengths < 50 nt.
Pushing the envelope: the feasibility of using a mailed contrast sensitivity test to prioritise cataract waiting lists
Authors: Bianchi Eleonora , Reddingius Peter F. , Rathore Mehal , Lindfield Dan , Crabb David P. , Jones Pete R.
Published: May 2024

Background

Cataract waiting lists are growing globally. Pragmatic, cost-effective methods are required to prioritise the most urgent cases. Here we investigate the feasibility of using a third-party pen-and-paper contrast sensitivity, CS, test (SpotChecksTM), delivered by mail, and performed by patients at home unsupervised, to flag eyes requiring surgery.

Methods

Pen-and-paper CS tests were mailed to 233 people waiting for a cataract assessment, along with a prepaid return envelope (cross-sectional study). Response rates were tabulated (stratified by age, sex and socioeconomic status), and test scores analysed to see how well the home tests predicted which eyes were listed subsequently for surgery. A subset of patients (N = 39) also underwent in-person follow-up testing, to confirm the accuracy of the home data.

Results

Forty-six percent of patients responded (216 eyes). No gross differences were observed between respondents and non-respondents, either in terms of age, sex, socioeconomic status, or geographic location (all P > 0.05). The home-test CS scores predicted which eyes were subsequently listed for surgery, with an AUROC {±CI95%} of 0.69 {0.61–0.76}. Predictive performance was further-improved when machine learning was used to combine CS scores with letter acuity, extracted from patients’ medical records (AUROC {±CI95%} = 0.77 {0.70–0.83}). Among 39 patients who underwent follow-up testing, home CS scores were correlated with various measures made in clinic: biometry signal-to-noise (P = 0.032), LogMAR acuity, Pelli-Robson CS and SpotChecks CS (all P < 0.001).

Conclusions

Mailing patients pen-and-paper CS tests may be a feasible, 'low-tech' way of prioritising patients on cataract waiting lists.
Safety outcomes following COVID-19 vaccination and infection in 5.1 million children in England
Authors: Copland Emma , Patone Martina , Saatci Defne , Handunnetthi Lahiru , Hirst Jennifer , Hunt David P. J. , Mills Nicholas L. , Moss Paul , Sheikh Aziz , Coupland Carol A. C. , Harnden Anthony , Robertson Chris , Hippisley-Cox Julia
Published: May 2024

The risk-benefit profile of COVID-19 vaccination in children remains uncertain. A self-controlled case-series study was conducted using linked data of 5.1 million children in England to compare risks of hospitalisation from vaccine safety outcomes after COVID-19 vaccination and infection. In 5-11-year-olds, we found no increased risks of adverse events 1–42 days following vaccination with BNT162b2, mRNA-1273 or ChAdOX1. In 12-17-year-olds, we estimated 3 (95%CI 0–5) and 5 (95%CI 3–6) additional cases of myocarditis per million following a first and second dose with BNT162b2, respectively. An additional 12 (95%CI 0–23) hospitalisations with epilepsy and 4 (95%CI 0–6) with demyelinating disease (in females only, mainly optic neuritis) were estimated per million following a second dose with BNT162b2. SARS-CoV-2 infection was associated with increased risks of hospitalisation from seven outcomes including multisystem inflammatory syndrome and myocarditis, but these risks were largely absent in those vaccinated prior to infection. We report a favourable safety profile of COVID-19 vaccination in under-18s.
Integrated photonic encoder for low power and high-speed image processing
Authors: Wang Xiao , Redding Brandon , Karl Nicholas , Long Christopher , Zhu Zheyuan , Skowronek James , Pang Shuo , Brady David , Sarma Raktim
Published: May 2024

Modern lens designs are capable of resolving greater than 10 gigapixels, while advances in camera frame-rate and hyperspectral imaging have made data acquisition rates of Terapixel/second a real possibility. The main bottlenecks preventing such high data-rate systems are power consumption and data storage. In this work, we show that analog photonic encoders could address this challenge, enabling high-speed image compression using orders-of-magnitude lower power than digital electronics. Our approach relies on a silicon-photonics front-end to compress raw image data, foregoing energy-intensive image conditioning and reducing data storage requirements. The compression scheme uses a passive disordered photonic structure to perform kernel-type random projections of the raw image data with minimal power consumption and low latency. A back-end neural network can then reconstruct the original images with structural similarity exceeding 90%. This scheme has the potential to process data streams exceeding Terapixel/second using less than 100 fJ/pixel, providing a path to ultra-high-resolution data and image acquisition systems.
Exposure to environmental pollutants selects for xenobiotic-degrading functions in the human gut microbiome
Authors: De Filippis Francesca , Valentino Vincenzo , Sequino Giuseppina , Borriello Giorgia , Riccardi Marita Georgia , Pierri Biancamaria , Cerino Pellegrino , Pizzolante Antonio , Pasolli Edoardo , Esposito Mauro , Limone Antonio , Ercolini Danilo
Published: May 2024

Environmental pollutants from different chemical families may reach the gut microbiome, where they can be metabolized and transformed. However, how our gut symbionts respond to the exposure to environmental pollution is still underexplored. In this observational, cohort study, we aim to investigate the influence of environmental pollution on the gut microbiome composition and potential activity by shotgun metagenomics. We select as a case study a population living in a highly polluted area in Campania region (Southern Italy), proposed as an ideal field for exposomic studies and we compare the fecal microbiome of 359 subjects living in areas with high, medium and low environmental pollution. We highlight changes in gut microbiome composition and functionality that were driven by pollution exposure. Subjects from highly polluted areas show higher blood concentrations of dioxin and heavy metals, as well as an increase in microbial genes related to degradation and/or resistance to these molecules. Here we demonstrate the dramatic effect that environmental xenobiotics have on gut microbial communities, shaping their composition and boosting the selection of strains with degrading capacity. The gut microbiome can be considered as a pivotal player in the environment-health interaction that may contribute to detoxifying toxic compounds and should be taken into account when developing risk assessment models. The study was registered at ClinicalTrials.gov with the identifier NCT05976126.
Proton-coupled transport mechanism of the efflux pump NorA
Authors: Li Jianping , Li Yan , Koide Akiko , Kuang Huihui , Torres Victor J. , Koide Shohei , Wang Da-Neng , Traaseth Nathaniel J.
Published: May 2024

Efflux pump antiporters confer drug resistance to bacteria by coupling proton import with the expulsion of antibiotics from the cytoplasm. Despite efforts there remains a lack of understanding as to how acid/base chemistry drives drug efflux. Here, we uncover the proton-coupling mechanism of the Staphylococcus aureus efflux pump NorA by elucidating structures in various protonation states of two essential acidic residues using cryo-EM. Protonation of Glu222 and Asp307 within the C-terminal domain stabilized the inward-occluded conformation by forming hydrogen bonds between the acidic residues and a single helix within the N-terminal domain responsible for occluding the substrate binding pocket. Remarkably, deprotonation of both Glu222 and Asp307 is needed to release interdomain tethering interactions, leading to opening of the pocket for antibiotic entry. Hence, the two acidic residues serve as a “belt and suspenders” protection mechanism to prevent simultaneous binding of protons and drug that enforce NorA coupling stoichiometry and confer antibiotic resistance.
Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2
Authors: Schiefer Samira , Hale Benjamin G.
Published: May 2024

Deciphering the intricate dynamic events governing type I interferon (IFN) signaling is critical to unravel key regulatory mechanisms in host antiviral defense. Here, we leverage TurboID-based proximity labeling coupled with affinity purification-mass spectrometry to comprehensively map the proximal human proteomes of all seven canonical type I IFN signaling cascade members under basal and IFN-stimulated conditions. This uncovers a network of 103 high-confidence proteins in close proximity to the core members IFNAR1, IFNAR2, JAK1, TYK2, STAT1, STAT2, and IRF9, and validates several known constitutive protein assemblies, while also revealing novel stimulus-dependent and -independent associations between key signaling molecules. Functional screening further identifies PJA2 as a negative regulator of IFN signaling via its E3 ubiquitin ligase activity. Mechanistically, PJA2 interacts with TYK2 and JAK1, promotes their non-degradative ubiquitination, and limits the activating phosphorylation of TYK2 thereby restraining downstream STAT signaling. Our high-resolution proximal protein landscapes provide global insights into the type I IFN signaling network, and serve as a valuable resource for future exploration of its functional complexities.
A tipping point in stable isotope composition of Antarctic meteoric waters during Cenozoic glaciation
Authors: Dallai Luigi , Sharp Zachary D.
Published: May 2024

Triple oxygen isotopes of Cenozoic intrusive rocks emplaced along the Ross Sea coastline in Antarctica, reveal that meteoric-hydrothermal waters imprinted their stable isotope composition on mineral phases, leaving a clear record of oxygen and hydrogen isotope variations during the establishment of the polar cap. Calculated O- and H-isotope compositions of meteoric waters vary from −9 ± 2‰ and −92 ± 5‰ at 40 ± 0.6 Ma, to −30 and −234 ± 5‰ at 34 ± 1.9 Ma, and intersect the modern Global Meteoric Water Line. These isotopic variations likely depict the combined variations in temperature, humidity, and moisture source regions, resulting from rearrangement of oceanic currents and atmospheric cooling during the onset of continental ice cap. Here, we report a paleo-climatic proxy based on triple oxygen geochemistry of crystalline rocks that reveals changes in the hydrological cycle. We discuss the magnitude of temperature changes at high latitudes during the Eocene-Oligocene climatic transition.
Dynamic movement of the Golgi unit and its glycosylation enzyme zones
Authors: Harada Akihiro , Kunii Masataka , Kurokawa Kazuo , Sumi Takuya , Kanda Satoshi , Zhang Yu , Nadanaka Satomi , Hirosawa Koichiro M. , Tokunaga Kazuaki , Tojima Takuro , Taniguchi Manabu , Moriwaki Kenta , Yoshimura Shin-ichiro , Yamamoto-Hino Miki , Goto Satoshi , Katagiri Toyomasa , Kume Satoshi , Hayashi-Nishino Mitsuko , Nakano Miyako , Miyoshi Eiji , Suzuki Kenichi G. N. , Kitagawa Hiroshi , Nakano Akihiko
Published: May 2024

Knowledge on the distribution and dynamics of glycosylation enzymes in the Golgi is essential for better understanding this modification. Here, using a combination of CRISPR/Cas9 knockin technology and super-resolution microscopy, we show that the Golgi complex is assembled by a number of small ‘Golgi units’ that have 1-3 μm in diameter. Each Golgi unit contains small domains of glycosylation enzymes which we call ‘zones’. The zones of N- and O-glycosylation enzymes are colocalised. However, they are less colocalised with the zones of a glycosaminoglycan synthesizing enzyme. Golgi units change shapes dynamically and the zones of glycosylation enzymes rapidly move near the rim of the unit. Photobleaching analysis indicates that a glycosaminoglycan synthesizing enzyme moves between units. Depletion of giantin dissociates units and prevents the movement of glycosaminoglycan synthesizing enzymes, which leads to insufficient glycosaminoglycan synthesis. Thus, we show the structure-function relationship of the Golgi and its implications in human pathogenesis.
AI-enabled Lorentz microscopy for quantitative imaging of nanoscale magnetic spin textures
Authors: McCray Arthur R. C. , Zhou Tao , Kandel Saugat , Petford-Long Amanda , Cherukara Mathew J. , Phatak Charudatta
Published: May 2024

The manipulation and control of nanoscale magnetic spin textures are of rising interest as they are potential foundational units in next-generation computing paradigms. Achieving this requires a quantitative understanding of the spin texture behavior under external stimuli using in situ experiments. Lorentz transmission electron microscopy (LTEM) enables real-space imaging of spin textures at the nanoscale, but quantitative characterization of in situ data is extremely challenging. Here, we present an AI-enabled phase-retrieval method based on integrating a generative deep image prior with an image formation forward model for LTEM. Our approach uses a single out-of-focus image for phase retrieval and achieves significantly higher accuracy and robustness to noise compared to existing methods. Furthermore, our method is capable of isolating sample heterogeneities from magnetic contrast, as shown by application to simulated and experimental data. This approach allows quantitative phase reconstruction of in situ data and can also enable near real-time quantitative magnetic imaging.