bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical Fitness of Thoroughbred Horse Racing Jockeys
Authors: Legg Kylie A. , Cochrane Darryl J. , Gee Erica K. , Chin Yin Y. , Rogers Chris W.
Published: October 2023

Purpose

Thoroughbred racing jockeys compete at maximum physiological capacity in a sport with a high risk of falls and injury. A greater understanding of the physical capacities determining jockey performance may lead to minimum physical performance parameters and corrective interventions to improve jockey fitness and performance and reduce jockey and horse injury. The aim of this study was to develop appropriate physical testing procedures for jockeys and a physical fitness profile for different licence levels.

Methods

Fifty-eight jockeys (n = 24 females, n = 34 males), representing all apprentice jockeys licenced in New Zealand in 2021 (100%, n = 8 probationers and n = 39 apprentices) and eleven professional jockeys (14%) were assessed to determine baseline physiological and fitness data. Descriptive statistics and boxplots were used to compare aerobic fitness, abdominal (core), upper and lower body strength, muscular power, reaction time, flexibility and a novel ‘saddle’ test targeting lower body strength, balance, and endurance between licencing levels. Effect Size (ES) was used to determine magnitude of differences between groups.

Results

More experienced jockeys had greater relative lower body strength (ES = 0.2–0.7) and better balance (ES = 0.5–0.9) compared to the less experienced groups. Jockeys who were in the top 20 of the premiership table (jockey rankings) had faster reaction times (ES = 0.7) and greater core extensor strength (ES = 0.7) than other cohorts. Most tests showed little differentiation between jockey licence levels, however the ‘saddle test’ showed greater variability in the less experienced race riders. This test may be an effective measure of jockey baseline performance.

Conclusions

These data could be used to inform minimum jockey licencing requirements and future physical fitness training programmes to increase jockey physiological fitness, thereby minimising risk of falls or injury due to physiological deficits and performance.
Flexible Institution Building in the International Anti-corruption Regime: Proposing a Transnational Asset Recovery Mechanism
Authors: Helfer Laurence R. , Rose Cecily , Brewster Rachel
Published: October 2023

Asset recovery is a fundamental principle of anti-corruption law, without which the financial damage from corruption cannot be repaired. Yet recovering assets is notoriously difficult and time-consuming, and the United Nations Convention Against Corruption provides little technical or institutional support to facilitate such returns. To remedy this, we propose the creation of a transnational asset recovery mechanism that could provide myriad services to states upon request, including gathering and publishing information, providing technical assistance and capacity building, helping to conclude agreements on asset return, and monitoring returned funds. Theoretically, we introduce the concepts of customizability and selectability to explain why a flexible transnational asset recovery mechanism has advantages over more formal international institutions, such as an international anti-corruption court. These benefits include lower financial and political costs, enhanced adaptability, and a greater likelihood of enhancing interstate cooperation regarding asset returns.
Prefix monoids of groups and right units of special inverse monoids
Authors: Dolinka Igor , Gray Robert D.
Published: October 2023

A prefix monoid is a finitely generated submonoid of a finitely presented group generated by the prefixes of its defining relators. Important results of Guba (1997), and of Ivanov, Margolis and Meakin (2001), show how the word problem for certain one-relator monoids, and inverse monoids, can be reduced to solving the membership problem in prefix monoids of certain one-relator groups. Motivated by this, in this paper, we study the class of prefix monoids of finitely presented groups. We obtain a complete description of this class of monoids. All monoids in this family are finitely generated, recursively presented and group-embeddable. Our results show that not every finitely generated recursively presented group-embeddable monoid is a prefix monoid, but for every such monoid, if we take a free product with a suitably chosen free monoid of finite rank, then we do obtain a prefix monoid. Conversely, we prove that every prefix monoid arises in this way. Also, we show that the groups that arise as groups of units of prefix monoids are precisely the finitely generated recursively presented groups, whereas the groups that arise as Schützenberger groups of prefix monoids are exactly the recursively enumerable subgroups of finitely presented groups. We obtain an analogous result classifying the Schützenberger groups of monoids of right units of special inverse monoids. We also give some examples of right cancellative monoids arising as monoids of right units of finitely presented special inverse monoids, and we show that not all right cancellative recursively presented monoids belong to this class.
Modeling Denitrification: Can We Report What We Don't Know?
Authors: Grosz B. , Matson A. , Butterbach‐Bahl K. , Clough T. , Davidson E. A. , Dechow R. , DelGrosso S. , Diamantopoulos E. , Dörsch P. , Haas E. , He H. , Henri C. V. , Hui D. , Kleineidam K. , Kraus D. , Kuhnert M. , Léonard J. , Müller C. , Petersen S. O. , Sihi D. , Vogeler I. , Well R. , Yeluripati J. , Zhang J. , Scheer C.
Published: October 2023

Biogeochemical models simulate soil nitrogen (N) turnover and are often used to assess N losses through denitrification. Though models simulate a complete N budget, often only a subset of N pools/fluxes (i.e., N2O, , NH3, NOx) are published since the full budget cannot be validated with measured data. Field studies rarely include full N balances, especially N2 fluxes, which are difficult to quantify. Limiting publication of modeling results based on available field data represents a missed opportunity to improve the understanding of modeled processes. We propose that the modeler community support publication of all simulated N pools and processes in future studies.
Kinetic Modeling of Radiation Belt Electrons With Geant4 to Study Energetic Particle Precipitation in Earth's Atmosphere
Authors: Berland G. D. , Marshall R. A. , Capannolo L. , McCarthy M. P. , Zheng L.
Published: October 2023

We present a new model designed to simulate the process of energetic particle precipitation, a vital coupling mechanism from Earth's magnetosphere to its atmosphere. The atmospheric response, namely excess ionization in the upper and middle atmosphere, together with bremsstrahlung X‐ray production, is calculated with kinetic particle simulations using the Geant4 Monte Carlo framework. Mono‐energy and mono‐pitch angle electron beams are simulated and combined using a Green's function approach to represent realistic electron spectra and pitch angle distributions. Results from this model include more accurate ionization profiles than previous analytical models, deeper photon penetration into the atmosphere than previous Monte Carlo model predictions, and predictions of backscatter fractions of loss cone electrons up to 40%. The model results are verified by comparison with previous precipitation modeling results, and validated using balloon X‐ray measurements from the Balloon Array for RBSP Relativistic Electron Losses mission and backscattered electron energy and pitch angle measurements from the Electron Loss and Fields Investigation with a Spatio‐Temporal Ambiguity‐Resolving CubeSat mission. The model results and solution techniques are developed into a Python package for public use.
Decadal Variability in Subsurface Nutrient Availability on the Scotian Shelf Reflects Changes in the Northwest Atlantic Ocean
Authors: Lehmann N. , Reed D. C. , Buchwald C. , Lavoie D. , Yeats P. A. , Mei Z.‐P. , Wang Z. , Johnson C. L.
Published: October 2023

Subsurface nutrients on the Scotian Shelf, an ocean region at the convergence of the subpolar and subtropical western boundary currents (i.e., Labrador Current (LC) and Gulf Stream (GS)), are chiefly modulated by upstream shelf and slope waters. Yet little is known about long‐term fluctuations in the advective transport of nutrients to the shelf. Here, we synthesized nutrient and hydrographic data from 1975 to 2020 to characterize decadal changes in upper (60–150 m) and lower (150–200 m) subsurface nutrient availability across the shelf. Hydrographic and nutrient anomalies highlight a transition from a warm, saline, high‐nutrient GS‐dominated system in the 1980 to colder, fresher, lower‐nutrient LC‐dominated conditions in the late 1980 and early 1990. In the mid‐1990, an increase in excess silicate and phosphate (relative to nitrate) marks a shift in the LC contribution toward a strengthening of the inner shelf component relative to the outer shelf‐edge branch. Since 2010, rapid increases in subsurface temperature and salinity indicate the transition back to a GS‐dominated system, albeit with a distinct decline in dissolved nutrients relative to the previous warm period, which diverges from the nutrient increase generally associated with GS water. Declines in lower subsurface nutrient concentrations since 2010 are likely driven by a density‐related shift in the GS source water toward a less dense, lower‐nutrient GS contribution. This shift is evidenced by a decrease in excess phosphate amidst minor declines in excess silicate, reflecting the characteristic density‐related patterns of excess nutrients in GS waters.
Design and Assessment of a Novel Approach for Ecosystem Warming Experiments in High‐Energy Tidal Wetlands
Authors: Rich Roy L. , Mueller Peter , Fuß Miriam , Gonçalves Salomé , Ostertag Eva , Reents Svenja , Tang Hao , Tashjian Allegra , Thomsen Simon , Kutzbach Lars , Jensen Kai , Nolte Stefanie
Published: October 2023

Coastal salt marshes have an important role in climate change adaptation and mitigation. Direct and indirect responses to warming are expected to vary along the marsh elevation gradient, making ecosystem responses to warming at this marine‐terrestrial ecotone uncertain. The Marsh Ecosystem Response to Increased Temperatures (MERIT) experiment was established in 2018 on the North Sea coast of Germany. Experimental plots are evenly distributed over three elevational marsh zones (pioneer, low marsh, and high marsh) and include three temperature treatments (ambient, +1.5°C, +3.0°C). MERIT's novel design combines active warming (horizontal surface warming cables and vertical soil warming pins) with passive, partially covered domes. For performance assessment, temperature deltas between ambient and warmed plots were calculated and evaluated at seasonal, daily, and diurnal timescales. We used Linear Mixed Models with Residual Maximum Likelihood for evaluating warming treatment effects and constraining environmental factors. MERIT was effective at ecosystem warming in this high‐energy environment both above‐ and belowground. Mixed models show that warming treatment dominates temperature differences belowground and at the soil surface, along with factors such as wind speed, flooding duration, and solar radiation. Aboveground warming was lower than belowground warming, but the dome design minimized issues seen in other open‐top chamber experiments. The combination of passive aboveground warming with feedback‐controlled active surface and belowground heating provides a setup for understanding warming effects on tidal ecosystems without altering the natural impacts of wind, radiation, and tidal inundations at high‐energy coastlines. Our design creates opportunities to expand future warming experiments to remote locations and technically challenging environments.
Small Reservoirs as Nitrogen Transformers: Accounting for Seasonal Variability in Inorganic and Organic Nitrogen Processing
Authors: Whitney Christopher T. , Wollheim Wilfred M. , Gold Arthur J. , Buonpane Joshua M.
Published: October 2023

Anthropogenic nitrogen (N) inputs to the landscape have serious consequences for inland and coastal waters. Reservoirs are effective at mitigating downstream N fluxes but measurements have generally focused on large reservoirs and have not considered seasonal variability or all N forms. In this study, we conducted an N mass balance in eight small reservoirs (surface area <0.55 km2) in coastal New England over annual time periods, including both inorganic and organic forms of N. We found that small reservoirs have high capacity for dissolved inorganic N (DIN) retention during low and moderate discharge, but are roughly in balance for DIN at higher discharge. Because proportional DIN retention occurred when N inputs were at their lowest, their effect on downstream N fluxes is small over annual time frames. Further, dissolved organic N (DON) was also evident during low flow late in the warm season. Accounting for DON production, the net effect of reservoirs on total dissolved N (TDN) fluxes was limited. These transformations between inorganic and organic N should be considered when evaluating the effect of small reservoirs on TDN fluxes over seasonal and annual timescales. With dam removal becoming a common solution to aging, unsafe dams, their ability to retain or produce N must be scrutinized at longer time scales while accounting for the complete N pool to better comprehend the effect their reservoirs have on downstream waters.
Diachronous Quaternary Development of the Jiayuguan Fault and Implications for Strain Compartmentalization and Modern Earthquake Hazards in the NW Hexi Corridor, China
Authors: Yang Haibo , Li An , Cunningham Dickson , Zhan Yan , Luo Jiahong , Yang Xiaoping , Chen Zhidan , Zuo Yuqi , Hu Zongkai , Tang Ruoni
Published: October 2023

The NNW‐trending Jiayuguan Fault (JYGF) is an actively developing thrust fault that delimits the SW margin of Jiayuguan, a major industrial city in the northwestern Hexi Corridor, China. In this study, we document the geometry, kinematics, and slip rates of the JYGF based on analysis of satellite imagery, low‐altitude photogrammetry, field observations, paleo‐seismic trenching, and Quaternary dating. The JYGF hanging‐wall contains a NE‐vergent asymmetric anticline of Cretaceous redbeds unconformably overlain by faulted, tilted and folded alluvial fan and fluvial terrace surfaces. Subsidiary fault scarps are associated with anticlinal flexure and contractional strain. The vertical uplift and crustal shortening rates are both ∼0.1 mm/a since ∼420 ka and geomorphic markers and dated landforms indicate southeastward fault propagation and hanging‐wall uplift from the Heishan toward the modern Beida River channel. The NW end of the fault appears to connect with the Altyn‐Tagh‐Heishan‐Jinta'Nanshan sinistral strike‐slip fault array suggesting that the JYGF is one of several parallel, splay faults that transfer strike‐slip motion to active folding and thrusting in the region. We relocate the 1992 Ms 5.4 earthquake epicenter using the NonLinLoc method and suggest that the JYGF may link southeastward with Quaternary‐active faults and folds in the Wenshushan. A seismic rupture along the total fault length of 25–40 km for the JYGF‐Wenshushan deforming belt corresponds to a potential earthquake magnitude in the 6.6–7.0 range. Compartmentalized faulting and folding in the NW–most Hexi Corridor defines a triangular block of active deformation where NE‐directed contractional deformation of the Qilian Shan foreland interacts with E‐W left‐lateral displacement along the Altyn‐Tagh‐Heishan‐Jinta'Nanshan sinistral strike‐slip system.
Concentrations and Yields of Mercury, Methylmercury, and Dissolved Organic Carbon From Contrasting Catchments in the Discontinuous Permafrost Region, Western Canada
Authors: Thompson L. M. , Low M. , Shewan R. , Schulze C. , Simba M. , Sonnentag O. , Tank S. E. , Olefeldt D.
Published: October 2023

Climate change and permafrost thaw may impact the mobilization of terrestrial dissolved organic carbon (DOC), mercury (Hg), and neurotoxic methylmercury (MeHg) into aquatic ecosystems; thus, understanding processes that control analyte export in northern catchments is needed. We monitored water chemistry for 3 years (2019–2021) at a peatland catchment (Scotty Creek) and a mixed catchment (Smith Creek) in the Dehcho (Northwest Territories), within the discontinuous permafrost zone of boreal western Canada. The peatland catchment had higher DOC and dissolved MeHg, but lower total Hg concentrations (mean ± standard deviation; 19 ± 2.6 mg DOC L−1; 0.08 ± 0.04 ng DMeHg L−1; 1.1 ± 0.3 ng THg L−1) than the mixed catchment (12 ± 4.4 mg DOC L−1; 0.05 ± 0.01 ng DMeHg L−1; 3.1 ± 2.2 ng THg L−1). Analyte concentrations increased with discharge at the mixed catchment, suggesting transport limitation and the flushing of near‐surface, organic‐rich flow paths during wet periods. In contrast, analyte concentrations in the peatland catchment were not primarily associated with discharge. MeHg concentrations, MeHg:THg, and MeHg:DOC increased with water temperature, suggesting enhanced Hg methylation during warmer periods. Mean open water season DOC and total MeHg yields were greater and more variable from the peatland than the mixed catchment (1.1–6.6 vs. 1.4–2.4 g DOC m−2; 5.2–36 vs. 6.1–10 ng MeHg m−2). Crucial storage thresholds controlling runoff generation likely drove greater inter‐annual variability in analyte yields from the peatland catchment. Our results suggest climate change may influence the production and transport of MeHg from boreal‐Arctic catchments as temperatures increase, peatlands thaw, and runoff generation is altered.
Automatic Time Step Control to Resolve Hydromechanically Driven Fault Reactivation, Spontaneous Nucleation, and Seismic Arrest
Authors: Han Zheng , Ren Guotong , Younis Rami M.
Published: October 2023

A physical understanding of the progression from flow‐driven (quasi‐static) poromechanical deformation to dynamic fault rupture is critical to the resilient operations of several engineering systems. These processes are bridged by a progression from fault reactivation to the spontaneous nucleation of unstable sliding. Toward addressing this challenge, novel automatic time step size control methods are developed to enable accurate and efficient simulation of these dynamics and transitions from the first principles. The controllers combine local models for discretization error and Coulomb failure conditions to automatically adjust the time step size across several orders of magnitude. The methods do not require additional empirical or theoretical input and can resolve the pre‐rupture, interseismic, and seismic periods to the allowed accuracy. The computational results reveal that the proposed methods automatically capture the onset of reactivation and nucleation for homogeneous and heterogeneous fields. Hydrodynamic and structural heterogeneity lead to disparate critical nucleation sizes compared to those predicted by theory. The results highlight its potential in predicting induced seismicity in realistic subsurface engineering systems and at practical scales.
Dimensionless Thermal Efficiency Analysis for Aquifer Thermal Energy Storage
Authors: Tang Darrell W. S. , Rijnaarts Huub H. M.
Published: October 2023

Seasonal warm and cold water storage in groundwater aquifers is a cost‐effective renewable energy technology for indoor heating and cooling. Simple dimensionless analytical solutions for the thermal recovery efficiency of Aquifer Thermal Energy Storage (ATES) systems are derived, subject to heat losses caused by thermal diffusion and mechanical dispersion. The analytical solutions pertain to transient pumping rates and storage durations, and multiple cycles of operation, and are applicable to various well configurations and thermal plume geometries. Heat losses to confining layers, its implications for optimizing plume geometries and aspect ratios, and heat spreading due to free convection are also discussed. This provides a general tool for broad and rapid assessment of aquifers and ATES systems. We show that if heat exchange with the confining layers is negligible, the thermal recovery efficiency of thermal plumes with cylindrical geometry is independent of the aquifer porosity and heat capacity C0. Therefore, if mechanical dispersion is negligible as is often the case, the only aquifer property that affects the recovery efficiency is the aquifer thermal conductivity. The field‐scale aquifer thermal conductivity λ can therefore be inferred from the recovery efficiency of a push‐pull heat recovery test. Remarkably, an increase in C0 could either increase, decrease, or not affect the recovery efficiency, depending on the thermal plume geometry. Hence, the analytical solutions reveal that the recovery efficiency is affected by complex interactions between the thermal plume geometry and aquifer properties. Approximate analytical solutions for subsurface temperature profiles over an entire ATES cycle are also derived.
The microprotein encoded by exosomal lncAKR1C2 promotes gastric cancer lymph node metastasis by regulating fatty acid metabolism
Authors: Zhu Ke-Gan , Yang Jiayu , Zhu Yuehong , Zhu Qihang , Pan Wen , Deng Siyu , He Yi , Zuo Duo , Wang Peiyun , Han Yueting , Zhang Hai-Yang
Published: October 2023

Lymph node metastasis (LNM) is the prominent route of gastric cancer dissemination, and usually leads to tumor progression and a dismal prognosis of gastric cancer. Although exosomal lncRNAs have been reported to be involved in tumor development, whether secreted lncRNAs can encode peptides in recipient cells remains unknown. Here, we identified an exosomal lncRNA (lncAKR1C2) that was clinically correlated with lymph node metastasis in gastric cancer in a VEGFC-independent manner. Exo-lncAKR1C2 secreted from gastric cancer cells was demonstrated to enhance tube formation and migration of lymphatic endothelial cells, and facilitate lymphangiogenesis and lymphatic metastasis in vivo. By comparing the metabolic characteristics of LN metastases and primary focuses, we found that LN metastases of gastric cancer displayed higher lipid metabolic activity. Moreover, exo-lncAKR1C2 encodes a microprotein (pep-AKR1C2) in lymphatic endothelial cells and promotes CPT1A expression by regulating YAP phosphorylation, leading to enhanced fatty acid oxidation (FAO) and ATP production. These findings highlight a novel mechanism of LNM and suggest that the microprotein encoded by exosomal lncAKR1C2 serves as a therapeutic target for advanced gastric cancer.
AMPK-induced novel phosphorylation of RUNX1 inhibits STAT3 activation and overcome imatinib resistance in chronic myelogenous leukemia (CML) subjects
Authors: Gayatri Meher Bolisetti , Kancha Rama Krishna , Behera Abhayananda , Patchva Dorababu , Velugonda Nagaraj , Gundeti Sadasivudu , Reddy Aramati Bindu Madhava
Published: October 2023

Imatinib resistance remains an unresolved problem in CML disease. Activation of JAK2/STAT3 pathway and increased expression of RUNX1 have become one reason for development of imatinib resistance in CML subjects. Metformin has gained attention as an antileukemic drug in recent times. However, the molecular mechanism remains elusive. The present study shows that RUNX1 is a novel substrate of AMP-activated kinase (AMPK), where AMPK phosphorylates RUNX1 at Ser 94 position. Activation of AMPK by metformin could lead to increased cytoplasmic retention of RUNX1 due to Ser 94 phosphorylation. RUNX1 Ser 94 phosphorylation resulted in increased interaction with STAT3, which was reflected in reduced transcriptional activity of both RUNX1 and STAT3 due to their cytoplasmic retention. The reduced transcriptional activity of STAT3 and RUNX1 resulted in the down-regulation of their signaling targets involved in proliferation and anti-apoptosis. Our cell proliferation assays using in vitro resistant cell line models and PBMCs isolated from CML clinical patients and normal subjects demonstrate that metformin treatment resulted in reduced growth and improved imatinib sensitivity of resistant subjects.
GWAS of lipids in Greenlanders finds association signals shared with Europeans and reveals an independent PCSK9 association signal
Authors: Senftleber Ninna Karsbæk , Andersen Mette K. , Jørsboe Emil , Stæger Frederik Filip , Nøhr Anne Krogh , Garcia-Erill Genis , Meisner Jonas , Santander Cindy G. , Balboa Renzo F. , Gilly Arthur , Bjerregaard Peter , Larsen Christina Viskum Lytken , Grarup Niels , Jørgensen Marit Eika , Zeggini Eleftheria , Moltke Ida , Hansen Torben , Albrechtsen Anders
Published: October 2023

Perturbation of lipid homoeostasis is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. We aimed to identify genetic variants affecting lipid levels, and thereby risk of CVD, in Greenlanders. Genome-wide association studies (GWAS) of six blood lipids, triglycerides, LDL-cholesterol, HDL-cholesterol, total cholesterol, as well as apolipoproteins A1 and B, were performed in up to 4473 Greenlanders. For genome-wide significant variants, we also tested for associations with additional traits, including CVD events. We identified 11 genome-wide significant loci associated with lipid traits. Most of these loci were already known in Europeans, however, we found a potential causal variant near PCSK9 (rs12117661), which was independent of the known PCSK9 loss-of-function variant (rs11491147). rs12117661 was associated with lower LDL-cholesterol (βSD(SE) = −0.22 (0.03), p = 6.5 × 10−12) and total cholesterol (−0.17 (0.03), p = 1.1 × 10−8) in the Greenlandic study population. Similar associations were observed in Europeans from the UK Biobank, where the variant was also associated with a lower risk of CVD outcomes. Moreover, rs12117661 was a top eQTL for PCSK9 across tissues in European data from the GTEx portal, and was located in a predicted regulatory element, supporting a possible causal impact on PCSK9 expression. Combined, the 11 GWAS signals explained up to 16.3% of the variance of the lipid traits. This suggests that the genetic architecture of lipid levels in Greenlanders is different from Europeans, with fewer variants explaining the variance.
An apical Phe-His pair defines the Orai1-coupling site and its occlusion within STIM1
Authors: Zhou Yandong , Jennette Michelle R. , Ma Guolin , Kazzaz Sarah A. , Baraniak James H. , Nwokonko Robert M. , Groff Mallary L. , Velasquez-Reynel Marcela , Huang Yun , Wang Youjun , Gill Donald L.
Published: October 2023

Ca2+ signal-generation through inter-membrane junctional coupling between endoplasmic reticulum (ER) STIM proteins and plasma membrane (PM) Orai channels, remains a vital but undefined mechanism. We identify two unusual overlapping Phe-His aromatic pairs within the STIM1 apical helix, one of which (F394-H398) mediates important control over Orai1-STIM1 coupling. In resting STIM1, this locus is deeply clamped within the folded STIM1-CC1 helices, likely near to the ER surface. The clamped environment in holo-STIM1 is critical—positive charge replacing Phe-394 constitutively unclamps STIM1, mimicking store-depletion, negative charge irreversibly locks the clamped-state. In store-activated, unclamped STIM1, Phe-394 mediates binding to the Orai1 channel, but His-398 is indispensable for transducing STIM1-binding into Orai1 channel-gating, and is spatially aligned with Phe-394 in the exposed Sα2 helical apex. Thus, the Phe-His locus traverses between ER and PM surfaces and is decisive in the two critical STIM1 functions—unclamping to activate STIM1, and conformational-coupling to gate the Orai1 channel.
A tautomerized ligand enabled meta selective C–H borylation of phenol
Authors: Guria Saikat , Hassan Mirja Md Mahamudul , Ma Jiawei , Dey Sayan , Liang Yong , Chattopadhyay Buddhadeb
Published: October 2023

Remote meta selective C–H functionalization of aromatic compounds remains a challenging problem in chemical synthesis. Here, we report an iridium catalyst bearing a bidentate pyridine-pyridone (PY-PYRI) ligand framework that efficiently catalyzes this meta selective borylation reaction. We demonstrate that the developed concept can be employed to introduce a boron functionality at the remote meta position of phenols, phenol containing bioactive and drug molecules, which was an extraordinary challenge. Moreover, we have demonstrated that the method can also be applied for the remote C6 borylation of indole derivatives including tryptophan that was the key synthetic precursor for the total synthesis of Verruculogen and Fumitremorgin A alkaloids. The inspiration of this catalytic concept was started from the O–Si secondary interaction, which by means of several more detailed control experiments and detailed computational investigations revealed that an unprecedented Bpin shift occurs during the transformation of iridium bis(boryl) complex to iridium tris(boryl) complex, which eventually control the remote meta selectivity by means of the dispersion between the designed ligand and steering silane group.
Nanobody-based VSR7 tracing shows clathrin-dependent TGN to Golgi recycling
Authors: Shao Xiaoyu , Xu Hao , Pimpl Peter
Published: October 2023

Receptor-mediated transport of soluble proteins is nature’s key to empowering eukaryotic cells to access a plethora of macromolecules, either by direct accumulation or as products from resulting biochemical pathways. The transport efficiency of these mechanisms results from the receptor’s capability to capture, transport, and release ligands on the one hand and the cycling ability that allows for performing multiple rounds of ligand transport on the other. However, the plant VACUOLAR SORTING RECEPTOR (VSR) protein family is diverse, and their ligand-specificity and bidirectional trafficking routes and transport mechanisms remain highly controversial. Here we employ nanobody-epitope interaction-based molecular tools to assess the function of the VSR 7 in vivo. We demonstrate the specificity of the VSR7 for sequence-specific vacuolar sorting signals, and we trace its anterograde transport and retrograde recycling route. VSR7 localizes at the cis-Golgi apparatus at steady state conditions and transports ligands downstream to release them in the trans-Golgi network/early endosome (TGN/EE) before undergoing clathrin-dependent recycling from the TGN/EE back to the cis-Golgi.
Large interlayer Dzyaloshinskii-Moriya interactions across Ag-layers
Authors: Arregi Jon Ander , Riego Patricia , Berger Andreas , Vedmedenko Elena Y.
Published: October 2023

Seeking to enhance the strength of the interlayer Dzyaloshinskii-Moriya interaction (IL-DMI) through a combination of atomic and Rashba type spin-orbit coupling (SOC) we studied the strength and the thickness evolution of effective interlayer coupling in Co/Ag/Co trilayers by means of surface sensitive magneto-optical measurements that take advantage of the light penetration depth. Here, we report the observation of oscillatory, thickness-dependent chiral interaction between ferromagnetic layers. Despite the weakness of the Ag atomic SOC, the IL-DMI in our trilayers is orders of magnitude larger than that of known systems using heavy metals as a spacer except of recently reported −0.15 mJ/m2 in Co/Pt/Ru(t)/Pt/Co and varies between ≈ ±0.2 mJ/m2. In contrast to known multilayers Co/Ag/Co promotes in-plane chirality between magnetic layers. The strength of IL-DMI opens up new routes for design of three-dimensional chiral spin structures combining intra- and interlayer DMI and paves the way for enhancements of the DMI strength.
Increasing atmospheric dryness reduces boreal forest tree growth
Authors: Mirabel Ariane , Girardin Martin P. , Metsaranta Juha , Way Danielle , Reich Peter B.
Published: October 2023

Rising atmospheric vapour pressure deficit (VPD) associated with climate change affects boreal forest growth via stomatal closure and soil dryness. However, the relationship between VPD and forest growth depends on the climatic context. Here we assess Canadian boreal forest responses to VPD changes from 1951-2018 using a well-replicated tree-growth increment network with approximately 5,000 species-site combinations. Of the 3,559 successful growth models, we observed a relationship between growth and concurrent summer VPD in one-third of the species-site combinations, and between growth and prior summer VPD in almost half of those combinations. The relationship between previous year VPD and current year growth was almost exclusively negative, while current year VPD also tended to reduce growth. Tree species, age, annual temperature, and soil moisture primarily determined tree VPD responses. Younger trees and species like white spruce and Douglas fir exhibited higher VPD sensitivity, as did areas with high annual temperature and low soil moisture. Since 1951, summer VPD increases in Canada have paralleled tree growth decreases, particularly in spruce species. Accelerating atmospheric dryness in the decades ahead will impair carbon storage and societal-economic services.
DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress
Authors: Yepuri Gautham , Ramirez Lisa M. , Theophall Gregory G. , Reverdatto Sergei V. , Quadri Nosirudeen , Hasan Syed Nurul , Bu Lei , Thiagarajan Devi , Wilson Robin , Díez Raquel López , Gugger Paul F. , Mangar Kaamashri , Narula Navneet , Katz Stuart D. , Zhou Boyan , Li Huilin , Stotland Aleksandr B. , Gottlieb Roberta A. , Schmidt Ann Marie , Shekhtman Alexander , Ramasamy Ravichandran
Published: October 2023

Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits ofDIAPH1silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.
A canonical trajectory of executive function maturation from adolescence to adulthood
Authors: Tervo-Clemmens Brenden , Calabro Finnegan J. , Parr Ashley C. , Fedor Jennifer , Foran William , Luna Beatriz
Published: October 2023

Theories of human neurobehavioral development suggest executive functions mature from childhood through adolescence, underlying adolescent risk-taking and the emergence of psychopathology. Investigations with relatively small datasets or narrow subsets of measures have identified general executive function development, but the specific maturational timing and independence of potential executive function subcomponents remain unknown. Integrating four independent datasets (N = 10,766; 8–35 years old) with twenty-three measures from seventeen tasks, we provide a precise charting, multi-assessment investigation, and replication of executive function development from adolescence to adulthood. Across assessments and datasets, executive functions follow a canonical non-linear trajectory, with rapid and statistically significant development in late childhood to mid-adolescence (10–15 years old), before stabilizing to adult-levels in late adolescence (18–20 years old). Age effects are well captured by domain-general processes that generate reproducible developmental templates across assessments and datasets. Results provide a canonical trajectory of executive function maturation that demarcates the boundaries of adolescence and can be integrated into future studies.
Isoform-resolved transcriptome of the human preimplantation embryo
Authors: Torre Denis , Francoeur Nancy J. , Kalma Yael , Gross Carmel Ilana , Melo Betsaida S. , Deikus Gintaras , Allette Kimaada , Flohr Ron , Fridrikh Maya , Vlachos Konstantinos , Madrid Kent , Shah Hardik , Wang Ying-Chih , Sridhar Shwetha H. , Smith Melissa L. , Eliyahu Efrat , Azem Foad , Amir Hadar , Mayshar Yoav , Marazzi Ivan , Guccione Ernesto , Schadt Eric , Ben-Yosef Dalit , Sebra Robert
Published: October 2023

Human preimplantation development involves extensive remodeling of RNA expression and splicing. However, its transcriptome has been compiled using short-read sequencing data, which fails to capture most full-length mRNAs. Here, we generate an isoform-resolved transcriptome of early human development by performing long- and short-read RNA sequencing on 73 embryos spanning the zygote to blastocyst stages. We identify 110,212 unannotated isoforms transcribed from known genes, including highly conserved protein-coding loci and key developmental regulators. We further identify 17,964 isoforms from 5,239 unannotated genes, which are largely non-coding, primate-specific, and highly associated with transposable elements. These isoforms are widely supported by the integration of published multi-omics datasets, including single-cell 8CLC and blastoid studies. Alternative splicing and gene co-expression network analyses further reveal that embryonic genome activation is associated with splicing disruption and transient upregulation of gene modules. Together, these findings show that the human embryo transcriptome is far more complex than currently known, and will act as a valuable resource to empower future studies exploring development.
eQTL mapping in fetal-like pancreatic progenitor cells reveals early developmental insights into diabetes risk
Authors: Nguyen Jennifer P. , Arthur Timothy D. , Fujita Kyohei , Salgado Bianca M. , Donovan Margaret K. R. ,   iPSCORE Consortium, Aguiar Lana Ribeiro , Arias Angelo D. , Benaglio Paola , Berggren W. Travis , Belmonte Juan Carlos Izpisua , Borja Victor , Cook Megan , DeBoever Christopher , Diffenderfer Kenneth E. , Farnam KathyJean , Garcia Melvin , Harismendy Olivier , Henson Benjamin A. , Jakubosky David , Jepsen Kristen , Li He , Nariai Naoki , O’Connor Daniel T. , Okubo Jonathan , Panopoulos Athanasia D. , Rao Fengwen , Reyna Joaquin , Silva Nayara , Smith Erin N. , Sohmer Josh , Yost Shawn , Young Greenwald William. W. , Matsui Hiroko , Kim Ji Hyun , D’Antonio-Chronowska Agnieszka , D’Antonio Matteo , Frazer Kelly A.
Published: October 2023

The impact of genetic regulatory variation active in early pancreatic development on adult pancreatic disease and traits is not well understood. Here, we generate a panel of 107 fetal-like iPSC-derived pancreatic progenitor cells (iPSC-PPCs) from whole genome-sequenced individuals and identify 4065 genes and 4016 isoforms whose expression and/or alternative splicing are affected by regulatory variation. We integrate eQTLs identified in adult islets and whole pancreas samples, which reveal 1805 eQTL associations that are unique to the fetal-like iPSC-PPCs and 1043 eQTLs that exhibit regulatory plasticity across the fetal-like and adult pancreas tissues. Colocalization with GWAS risk loci for pancreatic diseases and traits show that some putative causal regulatory variants are active only in the fetal-like iPSC-PPCs and likely influence disease by modulating expression of disease-associated genes in early development, while others with regulatory plasticity likely exert their effects in both the fetal and adult pancreas by modulating expression of different disease genes in the two developmental stages.
RNA N6-methyladenosine modification-based biomarkers for absorbed ionizing radiation dose estimation
Authors: Chen Hongxia , Zhao Xi , Yang Wei , Zhang Qi , Hao Rongjiao , Jiang Siao , Han Huihui , Yu Zuyin , Xing Shuang , Feng Changjiang , Wang Qianqian , Lu Hao , Li Yuanfeng , Quan Cheng , Lu Yiming , Zhou Gangqiao
Published: October 2023

Radiation triage and biological dosimetry are critical for the medical management of massive potentially exposed individuals following radiological accidents. Here, we performed a genome-wide screening of radiation-responding mRNAs, whose N6-methyladenosine (m6A) levels showed significant alteration after acute irradiation. The m6A levels of three genes, Ncoa4, Ate1 and Fgf22, in peripheral blood mononuclear cells (PBMCs) of mice showed excellent dose-response relationships and could serve as biomarkers of radiation exposure. Especially, the RNA m6A of Ncoa4 maintained a high level as long as 28 days after irradiation. We demonstrated its responsive specificity to radiation, conservation across the mice, monkeys and humans, and the dose-response relationship in PBMCs from cancer patients receiving radiation therapy. Finally, NOCA4 m6A-based biodosimetric models were constructed for estimating absorbed radiation doses in mice or humans. Collectively, this study demonstrated the potential feasibility of RNA m6A in radiation accidents management and clinical applications.
Origin of fungal hybrids with pathogenic potential from warm seawater environments
Authors: del Olmo Valentina , Mixão Verónica , Fotedar Rashmi , Saus Ester , Al Malki Amina , Księżopolska Ewa , Nunez-Rodriguez Juan Carlos , Boekhout Teun , Gabaldón Toni
Published: October 2023

Hybridisation is a common event in yeasts often leading to genomic variability and adaptation. The yeast Candida orthopsilosis is a human-associated opportunistic pathogen belonging to the Candida parapsilosis species complex. Most C. orthopsilosis clinical isolates are hybrids resulting from at least four independent crosses between two parental lineages, of which only one has been identified. The rare presence or total absence of parentals amongst clinical isolates is hypothesised to be a consequence of a reduced pathogenicity with respect to their hybrids. Here, we sequence and analyse the genomes of environmental C. orthopsilosis strains isolated from warm marine ecosystems. We find that a majority of environmental isolates are hybrids, phylogenetically closely related to hybrid clinical isolates. Furthermore, we identify the missing parental lineage, thus providing a more complete overview of the genomic evolution of this species. Additionally, we discover phenotypic differences between the two parental lineages, as well as between parents and hybrids, under conditions relevant for pathogenesis. Our results suggest a marine origin of C. orthopsilosis hybrids, with intrinsic pathogenic potential, and pave the way to identify pre-existing environmental adaptations that rendered hybrids more prone than parental lineages to colonise and infect the mammalian host.
Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis
Authors: Åkesson Julia , Hojjati Sara , Hellberg Sandra , Raffetseder Johanna , Khademi Mohsen , Rynkowski Robert , Kockum Ingrid , Altafini Claudio , Lubovac-Pilav Zelmina , Mellergård Johan , Jenmalm Maria C. , Piehl Fredrik , Olsson Tomas , Ernerudh Jan , Gustafsson Mika
Published: October 2023

Sensitive and reliable protein biomarkers are needed to predict disease trajectory and personalize treatment strategies for multiple sclerosis (MS). Here, we use the highly sensitive proximity-extension assay combined with next-generation sequencing (Olink Explore) to quantify 1463 proteins in cerebrospinal fluid (CSF) and plasma from 143 people with early-stage MS and 43 healthy controls. With longitudinally followed discovery and replication cohorts, we identify CSF proteins that consistently predicted both short- and long-term disease progression. Lower levels of neurofilament light chain (NfL) in CSF is superior in predicting the absence of disease activity two years after sampling (replication AUC = 0.77) compared to all other tested proteins. Importantly, we also identify a combination of 11 CSF proteins (CXCL13, LTA, FCN2, ICAM3, LY9, SLAMF7, TYMP, CHI3L1, FYB1, TNFRSF1B and NfL) that predict the severity of disability worsening according to the normalized age-related MS severity score (replication AUC = 0.90). The identification of these proteins may help elucidate pathogenetic processes and might aid decisions on treatment strategies for persons with MS.
A marine cryptochrome with an inverse photo-oligomerization mechanism
Authors: Vu Hong Ha , Behrmann Heide , Hanić Maja , Jeyasankar Gayathri , Krishnan Shruthi , Dannecker Dennis , Hammer Constantin , Gunkel Monika , Solov’yov Ilia A. , Wolf Eva , Behrmann Elmar
Published: October 2023

Cryptochromes (CRYs) are a structurally conserved but functionally diverse family of proteins that can confer unique sensory properties to organisms. In the marine bristle worm Platynereis dumerilii, its light receptive cryptochrome L-CRY (PdLCry) allows the animal to discriminate between sunlight and moonlight, an important requirement for synchronizing its lunar cycle-dependent mass spawning. Using cryo-electron microscopy, we show that in the dark, PdLCry adopts a dimer arrangement observed neither in plant nor insect CRYs. Intense illumination disassembles the dimer into monomers. Structural and functional data suggest a mechanistic coupling between the light-sensing flavin adenine dinucleotide chromophore, the dimer interface, and the C-terminal tail helix, with a likely involvement of the phosphate binding loop. Taken together, our work establishes PdLCry as a CRY protein with inverse photo-oligomerization with respect to plant CRYs, and provides molecular insights into how this protein might help discriminating the different light intensities associated with sunlight and moonlight.
Localization and interaction of interlayer excitons in MoSe2/WSe2 heterobilayers
Authors: Fang Hanlin , Lin Qiaoling , Zhang Yi , Thompson Joshua , Xiao Sanshui , Sun Zhipei , Malic Ermin , Dash Saroj P. , Wieczorek Witlef
Published: October 2023

Transition metal dichalcogenide (TMD) heterobilayers provide a versatile platform to explore unique excitonic physics via the properties of the constituent TMDs and external stimuli. Interlayer excitons (IXs) can form in TMD heterobilayers as delocalized or localized states. However, the localization of IX in different types of potential traps, the emergence of biexcitons in the high-excitation regime, and the impact of potential traps on biexciton formation have remained elusive. In our work, we observe two types of potential traps in a MoSe2/WSe2 heterobilayer, which result in significantly different emission behavior of IXs at different temperatures. We identify the origin of these traps as localized defect states and the moiré potential of the TMD heterobilayer. Furthermore, with strong excitation intensity, a superlinear emission behavior indicates the emergence of interlayer biexcitons, whose formation peaks at a specific temperature. Our work elucidates the different excitation and temperature regimes required for the formation of both localized and delocalized IX and biexcitons and, thus, contributes to a better understanding and application of the rich exciton physics in TMD heterostructures.