bluuebunny/crossref_metadata_2025 huggingface dataset:
Fragility Score: a REMS-based indicator for the prediction of incident fragility fractures at 5 years
Authors: Pisani Paola , Conversano Francesco , Muratore Maurizio , Adami Giovanni , Brandi Maria Luisa , Caffarelli Carla , Casciaro Ernesto , Di Paola Marco , Franchini Roberto , Gatti Davide , Gonnelli Stefano , Guglielmi Giuseppe , Lombardi Fiorella Anna , Natale Alessandra , Testini Valentina , Casciaro Sergio
Published: February 2023

Background

Accurate estimation of the imminent fragility fracture risk currently represents a challenging task. The novel Fragility Score (FS) parameter, obtained during a Radiofrequency Echographic Multi Spectrometry (REMS) scan of lumbar or femoral regions, has been developed for the non-ionizing estimation of skeletal fragility.

Aims

The aim of this study was to assess the performance of FS in the early identification of patients at risk for incident fragility fractures with respect to bone mineral density (BMD) measurements.

Methods

Data from 1989 Caucasians of both genders were analysed and the incidence of fractures was assessed during a follow-up period up to 5 years. The diagnostic performance of FS to discriminate between patients with and without incident fragility fracture in comparison to that of the BMD T-scores measured by both Dual X-ray Absorptiometry (DXA) and REMS was assessed through ROC analysis.

Results

Concerning the prediction of generic osteoporotic fractures, FS provided AUC = 0.811 for women and AUC = 0.780 for men, which resulted in AUC = 0.715 and AUC = 0.758, respectively, when adjusted for age and body mass index (BMI). For the prediction of hip fractures, the corresponding values were AUC = 0.780 for women and AUC = 0.809 for men, which became AUC = 0.735 and AUC = 0.758, respectively, after age- and BMI-adjustment. Overall, FS showed the highest prediction ability for any considered fracture type in both genders, resulting always being significantly higher than either T-scores, whose AUC values were in the range 0.472–0.709.

Conclusion

FS displayed a superior performance in fracture prediction, representing a valuable diagnostic tool to accurately detect a short-term fracture risk.
Reduction in Social Media Usage Produces Improvements in Physical Health and Wellbeing: An RCT
Authors: Reed Phil , Fowkes Tegan , Khela Mariam
Published: February 2023

Social media usage has increased over recent years and has been associated with negative effects on health and wellbeing. This study explored whether reducing smartphone screentime would improve health and wellbeing. Fifty students completed a battery of questionnaires regarding their health, immune function, loneliness, sleep, anxiety, and depression. They were allocated randomly to groups either using smartphones as normal (No Change), reducing usage by 15 min per day (Reduce), or reducing use by 15 min and substituting another activity during this time (Reduce + Activity). After 3 months, they completed the same questionnaires again. There was unexpectedly low compliance with the Reduce + Activity (leisure substitution) intervention. In contrast, there was a significant reduction in screentime for the Reduce group compared to the other two groups. There was a significant improvement in the Reduce group in general health, immune function, loneliness, and depression compared to the other groups. These findings extend previous results from similar studies and suggest limiting screentime may be beneficial to health and wellbeing.
Disseminated Invasive Mucormycosis Infection Following Autologous Stem Cell Transplantation for Diffuse Large B-Cell Lymphoma
Authors: Cliff Edward R. Scheffer , Reynolds Gemma , Grigg Andrew
Published: February 2023

Invasive fungal infections (IFI) are challenging to predict, diagnose and treat, and are associated with a particularly high mortality among patients with hematological malignancies. They are relatively uncommon in patients with lymphoma, compared with those with acute leukemia or undergoing allogeneic transplantation. We present a patient, autografted for recurrent lymphoma, with fever and refractory diarrhea persisting post engraftment, eventually attributable to disseminated mucor infection. This case illustrates the challenge of timely diagnosis and initiation of treatment for IFI in lymphoma patients, who do not routinely receive antifungal prophylaxis, and the importance of aggressive investigation and symptom-directed tissue sampling for evidence of IFI in febrile immunocompromised hosts not responding to broad-spectrum antibiotics.
A dual risk model with additive and proportional gains: ruin probability and dividends
Authors: Boxma Onno , Frostig Esther , Palmowski Zbigniew
Published: February 2023

We consider a dual risk model with constant expense rate and i.i.d. exponentially distributed gains
$C_i$
(
$i=1,2,\dots$
) that arrive according to a renewal process with general interarrival times. We add to this classical dual risk model the proportional gain feature; that is, if the surplus process just before the ith arrival is at level u, then for
$a>0$
the capital jumps up to the level
$(1+a)u+C_i$
. The ruin probability and the distribution of the time to ruin are determined. We furthermore identify the value of discounted cumulative dividend payments, for the case of a Poisson arrival process of proportional gains. In the dividend calculations, we also consider a random perturbation of our basic risk process modeled by an independent Brownian motion with drift.
Adaptation of a bidirectional crisis and emergency risk communication framework by community-engaged research partnerships in rural Mississippi during the COVID-19 pandemic
Authors: Washington Rodney , Weis Jennifer A. , Monger Mauda , Burse Nakeitra , Melvin Sandra Carr , Omondi Angela A. , Lohr Abby M. , Njeru Jane W. , Compretta Caroline E. , Sia Irene G. , Wieland Mark L.
Published: February 2023

Community engagement is important for reaching populations at risk for health inequities in the coronavirus disease 2019 (COVID-19) pandemic. A community-engaged risk communication intervention implemented by a community-engaged research partnership in Southeast Minnesota to address COVID-19 prevention, testing, and socioeconomic impacts has demonstrated high acceptability, feasibility, perceived efficacy, and sustainability. In this study, we describe the adaptation of the intervention by a community-academic partnership with rural African American populations in three Mississippi counties with high COVID-19 disparities. Intervention reach was assessed by the number of messages delivered by Communication Leaders to members of their social networks. Perceived scalability of the intervention was assessed by the Intervention Scalability Assessment Tool. Bidirectional communication between Communication Leaders and community members within their social networks was used by the partnership to refine messages, meet resource needs, and advise statewide decision-makers. In the first 3 months, more than 8482 individuals were reached in the three counties. The intervention was deemed to be highly scalable by partnership members. Adaptation of a community-engaged pandemic CERC intervention is feasible and scalable, and it has the potential to reduce COVID-19 inequities across heterogeneous populations. This approach may be incorporated into current and future pandemic preparedness policies for community engagement.
Cultivating Villa Economies: Archaeobotanical and Isotopic Evidence for Iron Age to Roman Agricultural Practices on the Chalk Downlands of Southern Britain
Authors: Lodwick Lisa
Published: February 2023

Agricultural practices are key for understanding socio-economic change, community organization, and relationships with landscape and the environment. Under the Roman Empire, cereals were vital for supplying urban and military populations, yet cereal husbandry practices within villa landscapes remain underexplored. In this article, the author applies new methods to analyse a large assemblage of charred plant remains from an area of chalk downland in central-southern England in order to evaluate changes in cereal production strategies over the Middle Iron Age to late Roman periods. Archaeobotany, carbon and nitrogen isotope analysis, and functional weed ecology are combined to reconstruct crop husbandry practices, in order to establish the cereal production system of Roman villas and the preceding Iron Age settlements, and to consider the environmental and socio-economic impact of cereal production systems.
Real-world evaluation of a two-step testing algorithm for Clostridioides difficile infection
Authors: Hecker Michelle T. , Son Andrea H. , Zuccaro Patricia , Conti Jennifer , Donskey Curtis J.
Published: February 2023

During the 4 years after implementation of the 2-step Clostridioides difficile infection (CDI) testing algorithm, 70% to 78% of patients with suspected CDI and a positive nucleic acid amplification test but a negative toxin test (NAAT+/TOX−) received CDI treatment. Overall, 73% of NAAT+/TOX− patients were classified as having probable or possible CDI.
Data science approaches provide a roadmap to understanding the role of abscisic acid in defence
Authors: Stevens Katie , Johnston Iain G. , Luna Estrella
Published: February 2023

Abscisic acid (ABA) is a plant hormone well known to regulate abiotic stress responses. ABA is also recognised for its role in biotic defence, but there is currently a lack of consensus on whether it plays a positive or negative role. Here, we used supervised machine learning to analyse experimental observations on the defensive role of ABA to identify the most influential factors determining disease phenotypes. ABA concentration, plant age and pathogen lifestyle were identified as important modulators of defence behaviour in our computational predictions. We explored these predictions with new experiments in tomato, demonstrating that phenotypes after ABA treatment were indeed highly dependent on plant age and pathogen lifestyle. Integration of these new results into the statistical analysis refined the quantitative model of ABA influence, suggesting a framework for proposing and exploiting further research to make more progress on this complex question. Our approach provides a unifying road map to guide future studies involving the role of ABA in defence.
Achieving health through diet: a joint event of the Sabri Ülker Foundation and The Nutrition Society of UK and Ireland, May 2022
Authors: Evans Charlotte Elizabeth Louise , Besler Halit Tanju , Dinç Özge , Lean Michael E. J. , Lovegrove Julie Anne , Lowe Nicola M. , Mathers John , Mutuş Begum , Satman Ilhan , Tanriover Mine D. , Tedstone Alison , Theobald Claire , Unal Serhat , Vartiainen Erkki , Wall Rachel , Yardim Nazan , Stowell Julian D.
Published: February 2023

Optimum nutrition plays a major role in the achievement and maintenance of good health. The Nutrition Society of the UK and Ireland and the Sabri Ülker Foundation, a charity based in Türkiye and focused on improving public health, combined forces to highlight this important subject. A hybrid conference was held in Istanbul, with over 4000 delegates from sixty-two countries joining the proceedings live online in addition to those attending in person. The primary purpose was to inspire healthcare professionals and nutrition policy makers to better consider the role of nutrition in their interactions with patients and the public at large to reduce the prevalence of non-communicable diseases such as obesity and type 2 diabetes. The event provided an opportunity to share and learn from different approaches in the UK, Türkiye and Finland, highlighting initiatives to strengthen research in the nutritional sciences and translation of that research into nutrition policy. The presenters provided evidence of the links between nutrition and disease risk and emphasised the importance of minimising risk and implementing early treatment of diet-related disease. Suggestions were made including improving health literacy and strengthening policies to improve the quality of food production and dietary behaviour. A multidisciplinary approach is needed whereby Governments, the food industry, non-governmental groups and consumer groups collaborate to develop evidence-based recommendations and appropriate joined-up policies that do not widen inequalities. This summary of the proceedings will serve as a gateway for those seeking to access additional information on nutrition and health across the globe.
The Unsung Activists: UK Shareholder Investigation Committees, 1888–1940
Authors: Rutterford Janette , Hannah Leslie
Published: February 2023

As companies became larger and shareholders more numerous in nineteenth and early twentieth-century Britain, the conventional wisdom is that the free-rider problem inhibited active shareholder participation. Discontented shareholders could sell in the market, but it was long before the takeover bid mechanism facilitated the removal of underperforming incumbent boards. We show, using a sample of fifty cases in the period from 1888 to 1940, that UK shareholders overcame the free-rider problem by using committees of investigation on a sufficiently large scale to present a credible threat to board malfeasance. Although there was more to corporate performance than corporate governance, this aspect of good governance plausibly contributed to London's precocity in divorcing ownership from control in domestic companies up to World War II.
Methodological Openness in Business History Research: Looking Afresh at the British Interwar Management Movement
Authors: Maclean Mairi , Shaw Gareth , Harvey Charles , Stringer Gary
Published: February 2023

Much thought has been accorded to the evolving nature of business history. It is only relatively recently, however, that attempts have been made to articulate methodological issues in a more epistemologically explicit and reflexive fashion. This article contributes to this burgeoning agenda by examining the methodology underpinning an intensive archival study of the British interwar management movement (1918–1939), a major force in British management education between the wars. We explicate the methodology employed and question what this material tells us about the interwar management movement, in terms of its determination to modernize management, encourage openness between firms, and extend a new spirit of partnership. We show that the interwar management movement was characterized by organized cooperation and methodological openness. Our main contribution is to demonstrate that interpretations themselves can become entrenched and prone to inertia, inviting us to revisit these periodically and, if appropriate, recast them.
Cartilage grafts mimicking cholesteatoma recurrence on diffusion-weighted magnetic resonance imaging: a case series
Authors: Walters H , Lee-Warder L , Mentias Y , Arullendran P
Published: February 2023

Background

Cholesteatomas present a high risk for residual and recurrent disease, and the surveillance of post-operative patients can be challenging. Diffusion-weighted magnetic resonance imaging is becoming the preferred method for investigating recidivism; however, false positive imaging findings increase the risk of patients undergoing unnecessary second look surgery.

Case reports

This study reports two patients with false positive diffusion restriction associated with cartilage grafts that mimicked cholesteatoma and resulted in second look surgery with no disease found at operation. This study also discusses the related medical literature, including potential causes of abnormal diffusion restriction and methods to negate this.

Conclusion

Caution should be exercised when considering second look surgery in the presence of a cartilage graft and a high confidence of disease clearance. A multi-disciplinary approach is recommended for the operating surgeon to review the images with a radiologist.
Unlikely Expropriators: Why Right-Wing Parties Implemented Agrarian Reform in Democratic Brazil
Authors: López Matias
Published: February 2023

What motivated right-wing and conservative parties to endorse a policy of land expropriation and redistribution in Brazil? I argue that urban-dominated right-wing parties endorsed agrarian reform in order to: (i) reduce crime in wealthier metropolises by reversing rural–urban migration; and (ii) gain competitive advantage against left-wing challengers. To test this argument I conduct process tracing, analysing over 500 elite statements about agrarian reform, drawn from archival, interview and survey data. In addition, I model land expropriations at the municipal level and show how right-wing administrations disproportionately expropriated land in the states of origin of migrants and, within those, in localities where the Left was more competitive. My results portray how two externalities of inequality – crime and competition with the Left – motivated conservative support for agrarian reform in Brazil.
A time of need: Exploring the changing poverty risk facing larger families in the UK
Authors: Stewart Kitty , Patrick Ruth , Reeves Aaron
Published: February 2023

Despite its significance in determining poverty risk, family size has received little focus in recent social policy analysis. This paper provides a correction, focusing squarely on the changing poverty risk of larger families (those with three or more dependent children) in the UK over recent years. It argues that we need to pay much closer attention to how and why poverty risk differs according to family size. Our analysis of Family Resource Survey data reveals how far changes in child poverty rates since 1997 – both falling poverty risk to 2012/13 and increases since then – have been concentrated in larger families. Social security changes are identified as central: these have affected larger families most as they have greater need for support, due to both lower work intensity and higher household needs. By interrogating the way policy change has affected families of different sizes the paper seeks to increase understanding of the effects of different poverty reduction strategies, with implications for policy debates in the UK and beyond. In providing evidence about the socio-demographics of larger families and their changing poverty risk it also aims to inform contested debates about the state’s role in providing financial support for children.
Impact of glaucoma on the spatial frequency processing of scenes in central vision
Authors: Trouilloud Audrey , Ferry Elvia , Boucart Muriel , Kauffmann Louise , Warniez Aude , Rouland Jean-François , Peyrin Carole
Published: February 2023

Glaucoma is an eye disease characterized by a progressive vision loss usually starting in peripheral vision. However, a deficit for scene categorization is observed even in the preserved central vision of patients with glaucoma. We assessed the processing and integration of spatial frequencies in the central vision of patients with glaucoma during scene categorization, considering the severity of the disease, in comparison to age-matched controls. In the first session, participants had to categorize scenes filtered in low-spatial frequencies (LSFs) and high-spatial frequencies (HSFs) as a natural or an artificial scene. Results showed that the processing of spatial frequencies was impaired only for patients with severe glaucoma, in particular for HFS scenes. In the light of proactive models of visual perception, we investigated how LSF could guide the processing of HSF in a second session. We presented hybrid scenes (combining LSF and HSF from two scenes belonging to the same or different semantic category). Participants had to categorize the scene filtered in HSF while ignoring the scene filtered in LSF. Surprisingly, results showed that the semantic influence of LSF on HSF was greater for patients with early glaucoma than controls, and then disappeared for the severe cases. This study shows that a progressive destruction of retinal ganglion cells affects the spatial frequency processing in central vision. This deficit may, however, be compensated by increased reliance on predictive mechanisms at early stages of the disease which would however decline in more severe cases.
Handel as Miscellany
Authors: DeSimone Alison
Published: February 2023

During the early eighteenth century, music composed by George Frideric Handel began to circulate in miscellaneous publications of songs and arias. His music appeared in various forms. Some publications, such as four notable pocket collections published in the mid-1720s, preserve the music largely unchanged, although within a new sonic context. Other publications completely transform arias and even overtures into vocal works with new texts, creating layers of musical associations and meanings. Unauthorized appearances of Handel's music in songbook miscellanies and single-sided prints show alternative ways in which consumers may have heard and experienced the composer outside of the opera house or a concert setting. Examining these alternative sources for Handel's music allows for an enriched assessment of which works of the composer were critically and commercially appreciated during the early eighteenth century. Analysing appearances of Handel's music in songbook anthologies also offers insight into how musical miscellanies became ubiquitous forms of the production and reception of his works in the early eighteenth century.
Depressive Störungen in der Adoleszenz: Aktuelle Studienlage zur Mikrobiota-Darm-Hirn-Achse
Authors: Kandsperger Stephanie , Brunner Romuald , Rupprecht Rainer , Baghai Thomas C.
Published: February 2023

Zusammenfassung. Im Verlauf der Adoleszenz nehmen depressive Störungen zu und führen oft trotz Behandlung zu deutlichen Einschränkungen bei den Betroffenen. Aktuelle Forschungsbemühungen haben sich zum Ziel gesetzt, die Pathophysiologie der Depression vor dem Hintergrund des Einflusses der Darmmikrobiota auf die Darm-Hirn-Achse näher zu untersuchen. Im Rahmen dieser narrativen Übersichtsarbeit zur aktuellen Studienlage der Mikrobiota-Darm-Hirn-Achse bei depressiven Störungen in der Adoleszenz werden die direkten und indirekten Wechselwirkungen erläutert und ein besonderer Fokus auf den Zeitraum der Adoleszenz gelegt. Neben vielversprechenden Ergebnissen aus tierexperimentellen Studien wächst die Studienlage bei depressiven Erwachsenen zur Mikrobiota-Darm-Hirn-Achse stetig. Bei depressiven Adoleszenten ist die Studienlage allerdings noch marginal, sodass nach aktuellem Forschungsstand noch keine Empfehlung für die Supplementation von Probiotika und Präbiotika bei depressiven Kindern und Jugendlichen ausgesprochen werden kann. Aufgrund der sehr begrenzten Studienlage bei Adoleszenten mit depressiven Störungen sollte auf die interaktive Rolle der Mikrobiota-Darm-Hirn-Achse in der adoleszenten Entwicklung bei zukünftigen Forschungsvorhaben ein besonderer Fokus gelegt werden.
Heat Transport by Mesoscale Eddies in the Norwegian and Greenland Seas
Authors: Bashmachnikov I. L. , Raj R. P. , Golubkin P. , Kozlov I. E.
Published: February 2023

Ocean vortices are an important regional agent of water transport and cross‐frontal exchange. This study is a first attempt to compare statistics of 3D properties of mesoscale eddies over the Norwegian and Greenland Seas. Results suggest that eddies in the central Greenland Sea are less intense, have smaller vertical extent and much smaller heat anomalies in their cores compared to eddies in the Lofoten Basin of the Norwegian Sea. In addition, these results suggest a relatively small inter‐basin eddy exchange. The large‐scale pattern of eddy translations shows that eddies cyclonically skirt the Norwegian‐Greenland region. There is also a regional cyclonic pattern in the Lofoten Basin with a consistent signature of eddy merger in the northern part of the basin. We confirm that eddies generated from the Norwegian Atlantic Slope Current (NwASC) have a significant effect on the amount of heat the NwASC brings to the Arctic. The heat lost from the NwASC between the Svinoy and Sorkapp sections associated with the westward eddy heat transport translates to 70 ± 23 TW, 90% of which occurs in the Lofoten Basin. This accounts to 35% of the heat advected by the NwASC across the Svinoy section and is comparable with the heat loss in the Barents Sea. Interannual variability of the heat flux due to a change in the number of generated eddies is relatively small (∼10 TW). Nevertheless, our estimates suggest that, by varying temperature of their cores, the generated eddies can effectively damp temperature anomalies that propagate north along the NwASC.
The Coexistence of Gravity Waves From Diverse Sources During a SOUTHTRAC Flight
Authors: Alexander P. , de la Torre A. , Llamedo P. , Hierro R. , Marcos T. , Kaifler B. , Kaifler N. , Geldenhuys M. , Preusse P. , Giez A. , Rapp M. , Hormaechea J. L.
Published: February 2023

We use observations from one of the SOUTHTRAC (Southern Hemisphere Transport, Dynamics, and Chemistry) Campaign flights in Patagonia and the Antarctic Peninsula during September 2019 to analyze possible sources of gravity waves (GW) in this hotspot during austral late winter and early spring. Data from two of the instruments onboard the German High Altitude and Long Range Research Aircraft (HALO) are employed: the Airborne Lidar for Middle Atmosphere research (ALIMA) and the Basic HALO Measurement and Sensor System (BAHAMAS). The former provides vertical temperature profiles along the trajectory, while the latter gives the three components of velocity, pressure, and temperature at the flight position. GW‐induced perturbations are obtained from these observations. We include numerical simulations from the Weather Research and Forecast (WRF) model to place a four‐dimensional context for the GW observed during the flight and to present possible interpretations of the measurements, for example, the orientation or eventual propagation sense of the waves may not be inferred using only data obtained onboard. We first evaluate agreements and discrepancies between the model outcomes and the observations. This allowed us an assessment of the WRF performance in the generation, propagation, and eventual dissipation of diverse types of GW through the troposphere, stratosphere, and lower mesosphere. We then analyze the coexistence and interplay of mountain waves (MW) and non‐orographic (NO) GW. The MW dominate above topographic areas and in the direction of the so‐called GW belt, whereas the latter waves are mainly relevant above oceanic zones. WRF simulates NOGW as mainly upward propagating entities above the lower stratosphere. Model runs show that deep vertical propagation conditions are in general favorable during this flight but also that in the upper stratosphere and lower mesosphere and mainly above topography there is some potential for wave breaking. The numerical simulations evaluate the GW drag for the whole flight area and find that the strongest effect is located in the zonal component around the stratopause. The general behavior against height resembles that obtained with a local fixed lidar data. According to WRF results, up to 100 km horizontal wavelength MW account for about half of the force opposing the circulation of the atmosphere.
Distributions and Trends of the Aerosol Direct Radiative Effect in the 21st Century: Aerosol and Environmental Contributions
Authors: Yu Qiurun , Huang Yi
Published: February 2023

The aerosol direct radiative effect (ADRE) is controlled by both aerosol distributions and environmental factors, making it interesting and important to quantitatively assess their effects on the ADRE inhomogeneity and climate trends. By analyzing the ADRE in the 21st century from a global reanalysis data set, we find that the spatial variability of the ADRE and its trends can be well explained by a linear regression model. In this model, scattering and absorbing aerosol optical depths (AODs) are used, along with critical environmental variables such as surface albedo and cloud radiative effect, as predictors. Based on this model, we find that approximately 70% of the ADRE inhomogeneity is due to the AOD distributions and the remainder is attributable to environmental factors. This study also shows that a stronger cooling effect of the scattering aerosols in the Northern Hemisphere drives northward cross‐equator meridional energy transport, although this transport exhibits a declining trend over the last two decades. The changes in surface albedo and cloud radiative effect strongly influence the trends in the regional ADRE and the meridional energy transport driven by them. In particular, the reduction of surface albedo (sea ice) is primarily responsible for the enhancement of the cooling ADRE, as well as an associated trend in meridional energy transport, in the Arctic.
Late Cretaceous‐Early Paleogene Extensional Ancestry of the Harcuvar and Buckskin‐Rawhide Metamorphic Core Complexes, Western Arizona
Authors: Wong Martin S. , Singleton John S. , Seymour Nikki M. , Gans Phillip B. , Wrobel Alexander J.
Published: February 2023

Metamorphic core complexes in the western North American Cordillera are commonly interpreted as the result of a single phase of large‐magnitude extension during the middle to late Cenozoic. We present evidence that mylonitic shear zones in the Harcuvar and Buckskin‐Rawhide core complexes in west‐central Arizona also accommodated an earlier phase of extension during the Late Cretaceous to early Paleocene. Microstructural data indicate substantial top‐NE mylonitization occurred at amphibolite‐facies, and40Ar/39Ar thermochronology documents post‐tectonic footwall cooling to <500°C by the Paleocene to mid‐Eocene. Amphibolite‐facies mylonites are spatially associated with voluminous and variably deformed footwall leucogranites that were emplaced from ca. 74–64 Ma, and a late kinematic ca. 63 Ma dike indicates this phase of mylonitization had waned by the early Paleocene. Reconstruction of the footwall architecture indicates that this latest Cretaceous—early Paleocene deformation occurred within a NE‐dipping extensional shear zone. The leucogranites were likely the result of crustal melting due to orogenic thickening, consistent with a model whereby crustal heating triggered gravitational collapse of overthickened crust. Other tectonic processes, such as the Laramide underplating of Orocopia Schist or mantle delamination, may have also contributed to this episode of orogenic extension. Miocene large‐magnitude extension was superimposed on this older shear zone and had similar kinematics, suggesting that the location and geometry of Miocene extension was strongly influenced by tectonic inheritance. We speculate that other Cordilleran core complexes also experienced a more complex and polyphase extensional history than previously recognized, but in many cases the evidence may be obscured by later Miocene overprinting.
Transarterial chemoembolization with PD-(L)1 inhibitors plus molecular targeted therapies for hepatocellular carcinoma (CHANCE001)
Authors: Zhu Hai-Dong , Li Hai-Liang , Huang Ming-Sheng , Yang Wei-Zhu , Yin Guo-Wen , Zhong Bin-Yan , Sun Jun-Hui , Jin Zhi-Cheng , Chen Jian-Jian , Ge Nai-Jian , Ding Wen-Bin , Li Wen-Hui , Huang Jin-Hua , Mu Wei , Gu Shan-Zhi , Li Jia-Ping , Zhao Hui , Wen Shu-Wei , Lei Yan-Ming , Song Yu-Sheng , Yuan Chun-Wang , Wang Wei-Dong , Huang Ming , Zhao Wei , Wu Jian-Bing , Wang Song , Zhu Xu , Han Jian-Jun , Ren Wei-Xin , Lu Zai-Ming , Xing Wen-Ge , Fan Yong , Lin Hai-Lan , Zhang Zi-Shu , Xu Guo-Hui , Hu Wen-Hao , Tu Qiang , Su Hong-Ying , Zheng Chuan-Sheng , Chen Yong , Zhao Xu-Ya , Fang Zhu-Ting , Wang Qi , Zhao Jin-Wei , Xu Ai-Bing , Xu Jian , Wu Qing-Hua , Niu Huan-Zhang , Wang Jian , Dai Feng , Feng Dui-Ping , Li Qing-Dong , Shi Rong-Shu , Li Jia-Rui , Yang Guang , Shi Hai-Bin , Ji Jian-Song , Liu Yu-E , Cai Zheng , Yang Po , Zhao Yang , Zhu Xiao-Li , Lu Li-Gong , Teng Gao-Jun ,   for the CHANCE001 Investigators
Published: February 2023

There is considerable potential for integrating transarterial chemoembolization (TACE), programmed death-(ligand)1 (PD-[L]1) inhibitors, and molecular targeted treatments (MTT) in hepatocellular carcinoma (HCC). It is necessary to investigate the therapeutic efficacy and safety of TACE combined with PD-(L)1 inhibitors and MTT in real-world situations. In this nationwide, retrospective, cohort study, 826 HCC patients receiving either TACE plus PD-(L)1 blockades and MTT (combination group, n = 376) or TACE monotherapy (monotherapy group, n = 450) were included from January 2018 to May 2021. The primary endpoint was progression-free survival (PFS) according to modified RECIST. The secondary outcomes included overall survival (OS), objective response rate (ORR), and safety. We performed propensity score matching approaches to reduce bias between two groups. After matching, 228 pairs were included with a predominantly advanced disease population. Median PFS in combination group was 9.5 months (95% confidence interval [CI], 8.4–11.0) versus 8.0 months (95% CI, 6.6–9.5) (adjusted hazard ratio [HR], 0.70, P = 0.002). OS and ORR were also significantly higher in combination group (median OS, 19.2 [16.1–27.3] vs. 15.7 months [13.0–20.2]; adjusted HR, 0.63, P = 0.001; ORR, 60.1% vs. 32.0%; P < 0.001). Grade 3/4 adverse events were observed at a rate of 15.8% and 7.5% in combination and monotherapy groups, respectively. Our results suggest that TACE plus PD-(L)1 blockades and MTT could significantly improve PFS, OS, and ORR versus TACE monotherapy for Chinese patients with predominantly advanced HCC in real-world practice, with an acceptable safety profile.
Aryl hydrocarbon receptor dependent anti-inflammation and neuroprotective effects of tryptophan metabolites on retinal ischemia/reperfusion injury
Authors: Yang Yijie , Wang Ning , Xu Li , Liu Yixin , Huang Lulu , Gu Mengyang , Wu Yue , Guo Wenyi , Sun Hao
Published: February 2023

Glaucoma is the major cause of irreversible blindness in the world characterized by progressive retinal neurodegeneration, in which local inflammation in retina is involved in persistent loss of retinal ganglion cells (RGCs). In order to explore whether aryl hydrocarbon receptor (AhR) and its agonists tryptophan metabolites are involved in the development of glaucoma, we collected serum and retinas from non-glaucoma controls and patients with glaucoma. Results showed altered serum tryptophan metabolism and reduced retinal AhR expression in glaucoma patients. We also showed intraperitoneally injection of tryptophan metabolite 2-(1′H-indole-3′-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) down-regulated retinal local inflammation and protected RGC apoptosis from retinal ischemia/reperfusion (IR) injury via AhR activation. We further revealed that ITE could inhibit inflammation in BV2 microglia and alleviate the neurotoxicity of microglial conditioned medium to RGCs under IR. Finally, we illustrated the possible mechanism that ITE limited ERK and NFκB dependent microglial inflammation. In summary, these findings suggest the critical role of tryptophan metabolism and retinal AhR signaling in modulating local inflammation mediated by microglia in glaucoma, and provide a novel avenue to targeting the intrinsically altered AhR signaling resulted from disturbed tryptophan metabolism for glaucoma treatment.
Gasdermin D inhibition ameliorates neutrophil mediated brain damage in acute ischemic stroke
Authors: Hu Ruiyao , Liang Jing , Ding Lan , Zhang Wan , Wang Yuying , Zhang Yige , Zhang Ding , Pei Lulu , Liu Xinjing , Xia Zongping , Xu Yuming , Song Bo
Published: February 2023

Acute ischemic stroke (AIS) induces high level of neutrophils, which correlates inversely with patient survival. Pyroptosis induced by gasdermin D (GSDMD) has been shown to have an important role in the pathophysiology of several inflammatory disorders. The role of GSDMD in the high level of neutrophils after AIS is unknown. Using a middle cerebral artery occlusion (MCAO) mouse model, we identified activation of pyroptosis signal, including expression of caspase-1/11, GSDMD, and interleukin-1β/18 (IL-1β/18), in the brain and spleen at early ischemic injury. Knockout of GSDMD in mice reduced infarct size, improved neurological function, and increased survival after MCAO. GSDMD deficiency decreased the overall degree of inflammation and the proportion of neutrophils in the brain after MCAO. Quantitative studies of neutrophils at several time intervals and organs demonstrated that early inflammatory leucocyte production and supplement (1 day after MCAO) was GSDMD-dependent. A series of bone marrow transplantation experiments, neutrophil depletion experiments, and RNA sequencing results demonstrated that neutrophil specific GSDMD is essential for the production and supply of neutrophil in bone marrow to blood. Moreover, pharmacological suppression of GSDMD decreased pathological abnormalities, infarct volume, and ameliorated neurological function. These results provided a new viewpoint on the immunological modulation of neutrophils after MCAO and suggest that suppression of GSDMD may relieve the neuroinflammatory load, thereby providing a potential treatment strategy for stroke.
Higher consumption of ultra-processed foods and increased likelihood of central nervous system demyelination in a case-control study of Australian adults
Authors: Mannino Adriana , Daly Alison , Dunlop Eleanor , Probst Yasmine , Ponsonby Anne-Louise , van der Mei Ingrid A. F. ,   the Ausimmune Investigator Group, Chapman Caron , Coulthard Alan , Dear Keith , Dwyer Terry , Kilpatrick Trevor , Lucas Robyn , McMichael Tony , Ponsonby Anne-Louise , Taylor Bruce , Valery Patricia , van der Mei Ingrid A. F. , Williams David , Black Lucinda J.
Published: February 2023

Background

Consumption of ultra-processed foods (UPFs) has been linked to risk of chronic diseases, with scant evidence in relation to multiple sclerosis (MS).

Methods

We tested associations between UPF consumption and likelihood of a first clinical diagnosis of central nervous system demyelination (FCD) (267 cases, 508 controls), a common precursor to MS. We used data from the 2003–2006 Ausimmune Study and logistic regression with full propensity score matching for age, sex, region of residence, education, smoking history, body mass index, physical activity, history of infectious mononucleosis, dietary misreporting, and total energy intake.

Results

Higher UPF consumption was statistically significantly associated with an increased likelihood of FCD (adjusted odds ratio = 1.08; 95% confidence interval = 1.0,1.15; p = 0.039), representing an 8% increase in likelihood of FCD per one energy-adjusted serving/day of UPFs.

Conclusion

Higher intakes of UPF were associated with increased likelihood of FCD in this Australian cohort. Nutrition education and awareness of healthy eating patterns may benefit those at high risk of FCD.
Design and implementation of a hybrid cloud system for large-scale human genomic research
Authors: Nagasaki Masao , Sekiya Yayoi , Asakura Akihiro , Teraoka Ryo , Otokozawa Ryoko , Hashimoto Hiroki , Kawaguchi Takahisa , Fukazawa Keiichiro , Inadomi Yuichi , Murata Ken T. , Ohkawa Yasuyuki , Yamaguchi Izumi , Mizuhara Takamichi , Tokunaga Katsushi , Sekiya Yuji , Hanawa Toshihiro , Yamada Ryo , Matsuda Fumihiko
Published: February 2023

In the field of genomic medical research, the amount of large-scale information continues to increase due to advances in measurement technologies, such as high-performance sequencing and spatial omics, as well as the progress made in genomic cohort studies involving more than one million individuals. Therefore, researchers require more computational resources to analyze this information. Here, we introduce a hybrid cloud system consisting of an on-premise supercomputer, science cloud, and public cloud at the Kyoto University Center for Genomic Medicine in Japan as a solution. This system can flexibly handle various heterogeneous computational resource-demanding bioinformatics tools while scaling the computational capacity. In the hybrid cloud system, we demonstrate the way to properly perform joint genotyping of whole-genome sequencing data for a large population of 11,238, which can be a bottleneck in sequencing data analysis. This system can be one of the reference implementations when dealing with large amounts of genomic medical data in research centers and organizations.
CryoET reveals organelle phenotypes in huntington disease patient iPSC-derived and mouse primary neurons
Authors: Wu Gong-Her , Smith-Geater Charlene , Galaz-Montoya Jesús G. , Gu Yingli , Gupte Sanket R. , Aviner Ranen , Mitchell Patrick G. , Hsu Joy , Miramontes Ricardo , Wang Keona Q. , Geller Nicolette R. , Hou Cathy , Danita Cristina , Joubert Lydia-Marie , Schmid Michael F. , Yeung Serena , Frydman Judith , Mobley William , Wu Chengbiao , Thompson Leslie M. , Chiu Wah
Published: February 2023

Huntington’s disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. While experiments with patient-derived induced pluripotent stem cells (iPSCs) can help understand disease, defining pathological biomarkers remains challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered sheet aggregates in double membrane-bound organelles, and mitochondria with distorted cristae and enlarged granules, likely mitochondrial RNA granules. We used artificial intelligence to quantify mitochondrial granules, and proteomics experiments reveal differential protein content in isolated HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC- and BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.
Engineering the lymph node environment promotes antigen-specific efficacy in type 1 diabetes and islet transplantation
Authors: Gammon Joshua M. , Carey Sean T. , Saxena Vikas , Eppler Haleigh B. , Tsai Shannon J. , Paluskievicz Christina , Xiong Yanbao , Li Lushen , Ackun-Farmmer Marian , Tostanoski Lisa H. , Gosselin Emily A. , Yanes Alexis A. , Zeng Xiangbin , Oakes Robert S. , Bromberg Jonathan S. , Jewell Christopher M.
Published: February 2023

Antigen-specific tolerance is a key goal of experimental immunotherapies for autoimmune disease and allograft rejection. This outcome could selectively inhibit detrimental inflammatory immune responses without compromising functional protective immunity. A major challenge facing antigen-specific immunotherapies is ineffective control over immune signal targeting and integration, limiting efficacy and causing systemic non-specific suppression. Here we use intra-lymph node injection of diffusion-limited degradable microparticles that encapsulate self-antigens with the immunomodulatory small molecule, rapamycin. We show this strategy potently inhibits disease during pre-clinical type 1 diabetes and allogenic islet transplantation. Antigen and rapamycin are required for maximal efficacy, and tolerance is accompanied by expansion of antigen-specific regulatory T cells in treated and untreated lymph nodes. The antigen-specific tolerance in type 1 diabetes is systemic but avoids non-specific immune suppression. Further, microparticle treatment results in the development of tolerogenic structural microdomains in lymph nodes. Finally, these local structural and functional changes in lymph nodes promote memory markers among antigen-specific regulatory T cells, and tolerance that is durable. This work supports intra-lymph node injection of tolerogenic microparticles as a powerful platform to promote antigen-dependent efficacy in type 1 diabetes and allogenic islet transplantation.
MORF and MOZ acetyltransferases target unmethylated CpG islands through the winged helix domain
Authors: Becht Dustin C. , Klein Brianna J. , Kanai Akinori , Jang Suk Min , Cox Khan L. , Zhou Bing-Rui , Phanor Sabrina K. , Zhang Yi , Chen Ruo-Wen , Ebmeier Christopher C. , Lachance Catherine , Galloy Maxime , Fradet-Turcotte Amelie , Bulyk Martha L. , Bai Yawen , Poirier Michael G. , Côté Jacques , Yokoyama Akihiko , Kutateladze Tatiana G.
Published: February 2023

Human acetyltransferases MOZ and MORF are implicated in chromosomal translocations associated with aggressive leukemias. Oncogenic translocations involve the far amino terminus of MOZ/MORF, the function of which remains unclear. Here, we identified and characterized two structured winged helix (WH) domains, WH1 and WH2, in MORF and MOZ. WHs bind DNA in a cooperative manner, with WH1 specifically recognizing unmethylated CpG sequences. Structural and genomic analyses show that the DNA binding function of WHs targets MORF/MOZ to gene promoters, stimulating transcription and H3K23 acetylation, and WH1 recruits oncogenic fusions to HOXA genes that trigger leukemogenesis. Cryo-EM, NMR, mass spectrometry and mutagenesis studies provide mechanistic insight into the DNA-binding mechanism, which includes the association of WH1 with the CpG-containing linker DNA and binding of WH2 to the dyad of the nucleosome. The discovery of WHs in MORF and MOZ and their DNA binding functions could open an avenue in developing therapeutics to treat diseases associated with aberrant MOZ/MORF acetyltransferase activities.
Weak CO binding sites induced by Cu–Ag interfaces promote CO electroreduction to multi-carbon liquid products
Authors: Li Jing , Xiong Haocheng , Liu Xiaozhi , Wu Donghuan , Su Dong , Xu Bingjun , Lu Qi
Published: February 2023

Electrochemical reduction of carbon monoxide to high-value multi-carbon (C2+) products offers an appealing route to store sustainable energy and make use of the chief greenhouse gas leading to climate change, i.e., CO2. Among potential products, C2+liquid products such as ethanol are of particular interest owing to their high energy density and industrial relevance. In this work, we demonstrate that Ag-modified oxide-derive Cu catalysts prepared via high-energy ball milling exhibit near 80% Faradaic efficiencies for C2+liquid products at commercially relevant current densities (>100 mA cm−2) in the CO electroreduction in a microfluidic flow cell. Such performance is retained in an over 100-hour electrolysis in a 100 cm2membrane electrode assembly (MEA) electrolyzer. A method based on surface-enhanced infrared absorption spectroscopy is developed to characterize the CO binding strength on the catalyst surface. The lower C and O affinities of the Cu–Ag interfacial sites in the prepared catalysts are proposed to be responsible for the enhanced selectivity for C2+oxygenates, which is the experimental verification of recent computational predictions.