bluuebunny/crossref_metadata_2025 huggingface dataset:
FROM “TIRED MUSCLES” TO “MIGHT-HAVE-BEENS”: A DEBATE ON THE NATURE OF COSTS IN THE LATE NINETEENTH CENTURY
Authors: Barbieri Fabio , Lourenço Filho Marcelo
Published: August 2023

This article explores a debate on the theory of cost that occurred in the 1890s between economist Silas MacVane and Austrian economists. MacVane defended the idea of objective “real cost” and the Austrians argued for subjective opportunity cost. Although this debate is rarely mentioned, it represents a noteworthy episode of active contrast between ideas on value and on cost, with implications that are relevant for contemporary economists. By highlighting the incompatibility of the objective and subjective conceptions of cost, this debate sheds light on the evolution of economic theory. The contributions of relatively unknown authors, such as MacVane and David Green, are also discussed. We interpret the debate in terms of the contrast between research programs based on wealth and on exchange, and note that the gradual shift in the period regarding the fundamental problem that informs economic theory is key to understanding the modern concept of cost.
Natural Denudation Versus Anthropogenically Accelerated Erosion in Central Brazil: A Confrontation of Time and Space Scales
Authors: Siame Lionel L. , Espíndola Rosa Lucas , Soares Cherem Luis Felipe , Guilherme de Oliveira José , Evrard Olivier , Barhoumi Houda , Leanni Laëtitia , Duvivier Adrien , Blard Pierre‐Henri , Bourlès Didier L. , Team ASTER , Cornu Sophie
Published: August 2023

Land degradation resulting from increased continental surface erosion is a worldwide and systemic phenomenon due to unsustainable human activities. Already fragile, the intertropical zone is likely to be further affected by climate change like increased aridity, an aggravating factor of soil erosion and land degradation. A major challenge is thus to provide the necessary knowledge to not only deepen our understanding of the Earth's system and its critical thresholds but also to help achieving sustainability. Understanding the factors that control the properties and processes of the critical zone, and especially what will be its responses to ongoing climate and land use changes, requires multidisciplinary efforts to tackle time scales that are compatible with morphogenesis and soil development as well as environmental disturbances of anthropogenic origin. Due to its prominent ecological importance, the Brazilian Cerrado biome is an ideal natural laboratory were to gauge the consequences of recent and intense agricultural activities on continental surface erosion. We focused on the region of Brasília where our approach allows confronting the temporal scales of long‐lived and stable cosmogenic nuclides with that of short‐lived radioactive isotopes, through a comparison of natural and anthropogenically disturbed land surfaces. Our results indicate that long‐term, background denudation rates are lower than 10 mm Kyr−1 whereas recent erosion rates due to human activities may reach rates at least 160 times higher, exceeding by far the sustainability of the soil resource.
Evaluating Habitat Suitability and Tidal Wetland Restoration Actions With ECOSTRESS
Authors: Gustine Rebecca N. , Nickles Cassandra L. , Lee Christine M. , Crawford Brian A. , Hestir Erin L. , Khanna Shruti
Published: August 2023

As temperatures rise, it is increasingly important to monitor changes in habitat conditions for aquatic species and mitigate emerging stressors. The ECOsystem Spaceborne Thermal Radiometer Experiment on Space Station (ECOSTRESS) instrument provides temperature products at a spatial and temporal scale not previously available. Here, we utilize ECOSTRESS temperature products to assess fluctuations in thermal habitat suitability for an endangered fish species and we also demonstrate the utility of the data set to assess water surface and bulk temperature changes following completion of two tidal wetland restoration efforts in the San Francisco Estuary and Sacramento–San Joaquin River Delta (Bay Delta). During all hours of the day throughout the 2018–2022 study period, key Delta Smelt habitat areas including Honker Bay, West Suisun Bay, and Mid Suisun Bay had greater than 75% of their areas suitable; there were several instances during which less than 25% of the area was thermally suitable generally coinciding with heatwave events. Overall, midday hours are less frequently suitable than morning and evening hours. Early evidence from ECOSTRESS indicates that there may be a decrease in surface water temperature of up to several degrees in tidal restoration areas, but more data is needed to show statistically significant outcomes. The ECOSTRESS record began in summer of 2018, and a longer record is needed to fully capture temperature changes associated with wetland processes and restoration efforts. Future applications of ECOSTRESS products can the capacity to help further understand ecosystem conditions and how restoration efforts affect water temperature, informing decisions that benefit Delta Smelt and other at‐risk aquatic species.
Verifying Methane Inventories and Trends With Atmospheric Methane Data
Authors: Worden John R. , Pandey Sudhanshu , Zhang Yuzhong , Cusworth Daniel H. , Qu Zhen , Bloom A. Anthony , Ma Shuang , Maasakkers Joannes D. , Byrne Brendan , Duren Riley , Crisp David , Gordon Deborah , Jacob Daniel J.
Published: August 2023

The 2015 Paris Climate Agreement and Global Methane Pledge formalized agreement for countries to report and reduce methane emissions to mitigate near‐term climate change. Emission inventories generated through surface activity measurements are reported annually or bi‐annually, and evaluated periodically through a “Global Stocktake.” Emissions inverted from atmospheric data support evaluation of reported inventories, but their systematic use is stifled by spatially variable biases from prior errors combined with limited sensitivity of observations to emissions (also called smoothing error), as‐well‐as poorly characterized information content. Here, we demonstrate a Bayesian, optimal estimation (OE) algorithm for evaluating a state‐of‐the‐art inventory (EDGAR v6.0) using satellite‐based emissions from 2009 to 2018. The OE algorithm quantifies the information content (uncertainty reduction, sectoral attribution, spatial resolution) of the satellite‐based emissions and disentangles the effect of smoothing error when comparing to an inventory. We find robust differences between satellite and EDGAR for total livestock, rice, and coal emissions: 14 ± 9, 12 ± 8, −11 ± 6 Tg CH4/yr respectively. EDGAR and satellite agree that livestock emissions are increasing (0.25–1.3 Tg CH4/yr/yr), primarily in the Indo‐Pakistan region, sub‐tropical Africa, and the Southern Brazilian; East Asia rice emissions are also increasing, highlighting the importance of agriculture on the atmospheric methane growth rate. In contrast, low information content for the waste and fossil emission trends confounds comparison between EDGAR and satellite; increased sampling and spatial resolution of satellite observations are therefore needed to evaluate reported changes to emissions in these sectors.
Net Community Production in the Argentine Basin Estimated From Nitrate Drawdown Using Biogeochemical Argo Floats
Authors: Alkire Matthew B. , Riser Stephen
Published: August 2023

Net community production (NCP) was estimated from nitrate profiles measured via biogeochemical Argo floats drifting in the Argentine Basin. Two criteria were tested for defining hydrographic fronts used to separate the study area into five zones: potential density anomaly at 450 m and potential temperature at 100 m. The latter definition was preferred as it minimized overlapping among zones. Float profiles within each zone were used to construct monthly median profiles of nitrate. Monthly nitrate inventories were calculated for each zone by integrating the median profiles between the surface and a depth of 100 or 200 m. Three methods were utilized to estimate NCP from the nitrate drawdown. The resulting mean NCP estimates indicated a decline in NCP from 3 to 4 mol C m−2 yr−1 south of ∼40°S to ≤1 mol C m−2 yr−1 north of ∼40°S. The monthly median profiles suggested 20%–100% of drawdown occurred by the end of December; however, chlorophyll fluorescence indicated phytoplankton activity persisted through austral summer. We speculate that primary production during these summer months was supported by regenerated nitrogen sources (not nitrate), despite replete concentrations, likely due to the relative scarcity of bioavailable iron known to persist in the region. While a northward advective flux of nitrate was strongly suggested by meridional nitrate gradients over the upper 0–300 m, vertical mixing was apparently necessary to stimulate new production, indicating both processes are important for NCP in the Argentine Basin. This work highlights the potential for floats in studying biogeochemical cycles in hydrographically complex regions.
On Groundwater Recharge in Variably Saturated Subsurface Flow Models
Authors: Gong Chengcheng , Cook Peter G. , Therrien René , Wang Wenke , Brunner Philip
Published: August 2023

Groundwater models that simulate only saturated flow use groundwater recharge as an input parameter. In contrast, variably saturated subsurface flow models, including integrated surface and subsurface hydrologic models, can jointly simulate the movement of water in the saturated and unsaturated zones. Instead of recharge, they require climate data such as precipitation and potential evapotranspiration. Given that the latter models represent hydrological processes operating throughout the unsaturated zone and at the water table, one might expect that recharge can be readily extracted from them. In this paper, we demonstrate that it is not the case. When the commonly used definitions of groundwater recharge are implemented in variably saturated subsurface flow models, they do not yield meaningful results. Above all, the problems occur because of the storage dynamics in the capillary fringe above the water table. Despite this difficulty, variably saturated subsurface flow models can provide the information required for water resources management directly.
NPRC deletion mitigated atherosclerosis by inhibiting oxidative stress, inflammation and apoptosis in ApoE knockout mice
Authors: Cheng Cheng , Zhang Jie , Li Xiaodong , Xue Fei , Cao Lei , Meng Linlin , Sui Wenhai , Zhang Meng , Zhao Yuxia , Xi Bo , Yu Xiao , Xu Feng , Yang Jianmin , Zhang Yun , Zhang Cheng
Published: August 2023

Previous studies suggested a beneficial effect of natriuretic peptides in animal models of cardiovascular disease, but the role of natriuretic peptide receptor C (NPRC) in the pathogenesis of atherosclerosis (AS) remains unknown. This study was designed to test the hypothesis that NPRC may promote AS lesion formation and instability by enhancing oxidative stress, inflammation, and apoptosis via protein kinase A (PKA) signaling. ApoE−/− mice were fed chow or Western diet for 12 weeks and NPRC expression was significantly increased in the aortic tissues of Western diet-fed mice. Systemic NPRC knockout mice were crossed with ApoE−/− mice to generate ApoE−/−NPRC−/− mice, and NPRC deletion resulted in a significant decrease in the size and instability of aortic atherosclerotic lesions in ApoE−/−NPRC−/− versus ApoE−/− mice. In addition, endothelial cell-specific NPRC knockout attenuated atherosclerotic lesions in mice. In contrast, endothelial cell overexpression of NPRC aggravated the size and instability of atherosclerotic aortic lesions in mice. Experiments in vitro showed that NPRC knockdown in human aortic endothelial cells (HAECs) inhibited ROS production, pro-inflammatory cytokine expression and endothelial cell apoptosis, and increased eNOS expression. Furthermore, NPRC knockdown in HAECs suppressed macrophage migration, cytokine expression, and phagocytosis via its effects on endothelial cells. On the contrary, NPRC overexpression in endothelial cells resulted in opposite effects. Mechanistically, the anti-inflammation and anti-atherosclerosis effects of NPRC deletion involved activation of cAMP/PKA pathway, leading to downstream upregulated AKT1 pathway and downregulated NF-κB pathway. In conclusion, NPRC deletion reduced the size and instability of atherosclerotic lesions in ApoE−/− mice via attenuating inflammation and endothelial cell apoptosis and increasing eNOS expression by modulating cAMP/PKA-AKT1 and NF-κB pathways. Thus, targeting NPRC may provide a promising approach to the prevention and treatment of atherosclerosis.
Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy
Authors: Ferreri Christopher J. , Hildebrandt Michelle A. T. , Hashmi Hamza , Shune Leyla O. , McGuirk Joseph P. , Sborov Douglas W. , Wagner Charlotte B. , Kocoglu M. Hakan , Rapoport Aaron , Atrash Shebli , Voorhees Peter M. , Khouri Jack , Dima Danai , Afrough Aimaz , Kaur Gurbakhash , Anderson Larry D. , Simmons Gary , Davis James A. , Kalariya Nilesh , Peres Lauren C. , Lin Yi , Janakiram Murali , Nadeem Omar , Alsina Melissa , Locke Frederick L. , Sidana Surbhi , Hansen Doris K. , Patel Krina K. , Castaneda Puglianini Omar Alexis
Published: August 2023

Most patients with multiple myeloma experience disease relapse after treatment with a B-cell maturation antigen-targeted therapy (BCMA-TT), and data describing outcomes for patients treated with sequential BCMA-TT are limited. We analyzed clinical outcomes for patients infused with standard-of-care idecabtagene vicleucel, an anti-BCMA chimeric antigen receptor (CAR) T-cell therapy, at 11 US medical centers. A total of 50 patients with prior BCMA-TT exposure (38 antibody-drug conjugate, 7 bispecific, 5 CAR T) and 153 patients with no prior BCMA-TT were infused with ide-cel, with a median follow-up duration of 4.5 and 6.0 months, respectively. Safety outcomes between cohorts were comparable. The prior BCMA-TT cohort had a lower overall response rate (74% versus 88%; p = 0.021), median duration of response (7.4 versus 9.6 months; p = 0.03), and median progression-free survival (3.2 months versus 9.0 months; p = 0.0002) compared to the cohort without prior BCMA-TT. All five patients who received a prior anti-BCMA CAR T responded to ide-cel, and survival outcomes were best for this subgroup. In conclusion, treatment with ide-cel yielded meaningful clinical responses in real-world patients exposed to a prior BCMA-TT, though response rates and durability were suboptimal compared to those not treated with a prior BCMA-TT.
Infant body composition at 6 and 24 months: what are the driving factors?
Authors: Santos Ina S. , Costa Caroline S. , Hills Andrew P. , Ariff Shabina , Wickramasinghe V. Pujitha , Norris Shane , Murphy-Alford Alexia J. , Slater Christine , Lucas Nishani , Nyati Lukhanyo H. , Kurpad Anura V. , Ahuja Kiran D. K. , Kuriyan Rebecca ,   Multi-center Infant Body Composition Reference Study- MIBCRS, Nyati Lukhanyo , Ahmad Tanvir , Beckett Jeffrey M. , Bielemann Renata M. , Byrne Nuala M. , Charania Laila , Christian Michele P. , Divya Priscilla J. , Hanley Anne , Herath Manoja P. , Ismail Leila C. , Jayasinghe Sisitha , Lanerolle Pulani , Loechl Cornelia , Moktar Najat , Senerath Upul , Soofi Sajid , Street Steven J. , Valle Neiva C. J. , Yameen Ayesha
Published: August 2023

Background/Objective

Available evidence on infant body composition is limited. This study aimed to investigate factors associated with body composition at 6 and 24 months.

Subjects/Methods

Multicenter study with data from a 0 to 6-mo cohort (Australia, India and South Africa) and a 3 to 24-mo cohort (Brazil, Pakistan, South Africa, and Sri Lanka). For the 0–6-mo cohort, body composition was assessed by air-displacement plethysmography (ADP) and for the 3–24-month cohort by the deuterium dilution (DD) technique. Fat mass (FM), fat-free mass (FFM), FM index (FMI), and FFM index (FFMI) were calculated. Independent variables comprised the Gini index of the country, maternal and infant characteristics, and breastfeeding pattern at 3 months. For the 3–24-mo cohort, breastfeeding, and minimum dietary diversity (MDD) at 12 months were also included. Crude and adjusted analyses stratified by sex were conducted by multilevel modelling using mixed models.

Results

At 6 months, every 1 kg increase in birth weight was associated with an increase of 0.716 kg in FFM and 0.582 kg/m2 in FFMI in girls, whereas in boys, the increase was of 0.277 kg in FFM. At 24 months, compared to those weaned before 12 months, girls still breastfed at 12 months presented a decrease of 0.225 kg in FM, 0.645 kg in FFM and 0.459 kg/m2 in FFMI, and in boys the decreases were of 0.467 kg in FM, 0.603 kg in FFM and 0.628 kg/m2 in FFMI.

Conclusion

Birth weight and breastfeeding are independent predictors of body composition in early life, irrespective of sex.
High-throughput characterization of HLA-E-presented CD94/NKG2x ligands reveals peptides which modulate NK cell activation
Authors: Huisman Brooke D. , Guan Ning , Rückert Timo , Garner Lee , Singh Nishant K. , McMichael Andrew J. , Gillespie Geraldine M. , Romagnani Chiara , Birnbaum Michael E.
Published: August 2023

HLA-E is a non-classical class I MHC protein involved in innate and adaptive immune recognition. While recent studies have shown HLA-E can present diverse peptides to NK cells and T cells, the HLA-E repertoire recognized by CD94/NKG2x has remained poorly defined, with only a limited number of peptide ligands identified. Here we screen a yeast-displayed peptide library in the context of HLA-E to identify 500 high-confidence unique peptides that bind both HLA-E and CD94/NKG2A or CD94/NKG2C. Utilizing the sequences identified via yeast display selections, we train prediction algorithms and identify human and cytomegalovirus (CMV) proteome-derived, HLA-E-presented peptides capable of binding and signaling through both CD94/NKG2A and CD94/NKG2C. In addition, we identify peptides which selectively activate NKG2C+ NK cells. Taken together, characterization of the HLA-E-binding peptide repertoire and identification of NK activity-modulating peptides present opportunities for studies of NK cell regulation in health and disease, in addition to vaccine and therapeutic design.
A machine-learning approach to human ex vivo lung perfusion predicts transplantation outcomes and promotes organ utilization
Authors: Sage Andrew T. , Donahoe Laura L. , Shamandy Alaa A. , Mousavi S. Hossein , Chao Bonnie T. , Zhou Xuanzi , Valero Jerome , Balachandran Sharaniyaa , Ali Aadil , Martinu Tereza , Tomlinson George , Del Sorbo Lorenzo , Yeung Jonathan C. , Liu Mingyao , Cypel Marcelo , Wang Bo , Keshavjee Shaf
Published: August 2023

Ex vivo lung perfusion (EVLP) is a data-intensive platform used for the assessment of isolated lungs outside the body for transplantation; however, the integration of artificial intelligence to rapidly interpret the large constellation of clinical data generated during ex vivo assessment remains an unmet need. We developed a machine-learning model, termed InsighTx, to predict post-transplant outcomes using n = 725 EVLP cases. InsighTx model AUROC (area under the receiver operating characteristic curve) was 79 ± 3%, 75 ± 4%, and 85 ± 3% in training and independent test datasets, respectively. Excellent performance was observed in predicting unsuitable lungs for transplantation (AUROC: 90 ± 4%) and transplants with good outcomes (AUROC: 80 ± 4%). In a retrospective and blinded implementation study by EVLP specialists at our institution, InsighTx increased the likelihood of transplanting suitable donor lungs [odds ratio=13; 95% CI:4-45] and decreased the likelihood of transplanting unsuitable donor lungs [odds ratio=0.4; 95%CI:0.16–0.98]. Herein, we provide strong rationale for the adoption of machine-learning algorithms to optimize EVLP assessments and show that InsighTx could potentially lead to a safe increase in transplantation rates.
Hybridization of short-range and long-range charge transfer excited states in multiple resonance emitter
Authors: Lee Ha Lim , Kang Jihoon , Lim Junseop , Kim Seung Chan , Jeon Soon Ok , Lee Jun Yeob
Published: August 2023

Multiple resonance (MR) thermally activated delayed fluorescence emitters have been actively studied as pure blue dopants for organic light-emitting diodes (OLEDs) because of excellent color purity and high efficiency. However, the reported MR emitter, 2,5,13,16-tetra-tert-butylindolo[3,2,1-jk]indolo[1′,2′,3′:1,7]indolo[2,3-b]carbazole (tDIDCz) based on bis-fused indolocarbazole framework could not demonstrate efficient triplet-to-singlet spin crossover. In this work, we report two isomeric MR emitters designed to promote triplet exciton harvesting by reconstructing the electronic structure of tDIDCz. To manage excited states, strong electron donors were introduced at the 2,5-/1,6-position of tDIDCz. As a result, 2,5-positions managed tDIDCz shows long-range charge transfer characteristics while preserving the MR nature. Quantum chemical calculation demonstrates direct spin-orbit coupling by long-range charge transfer and spin-vibronic coupling assisted reverse intersystem crossing by short-range charge transfer simultaneously contribute to triplet-to-singlet spin crossover. Consequently, high performance blue OLED recorded a high external quantum efficiency of 30.8% at a color coordinate of (0.13, 0.13).
Over-coupled resonator for broadband surface enhanced infrared absorption (SEIRA)
Authors: Paggi Laura , Fabas Alice , El Ouazzani Hasnaa , Hugonin Jean-Paul , Fayard Nikos , Bardou Nathalie , Dupuis Christophe , Greffet Jean-Jacques , Bouchon Patrick
Published: August 2023

Detection of molecules is a key issue for many applications. Surface enhanced infrared absorption (SEIRA) uses arrays of resonant nanoantennas with good quality factors which can be used to locally enhance the illumination of molecules. The technique has proved to be an effective tool to detect small amount of material. However, nanoresonators can detect molecules on a narrow bandwidth so that a set of resonators is necessary to identify a molecule fingerprint. Here, we introduce an alternative paradigm and use low quality factor resonators with large radiative losses (over-coupled resonators). The bandwidth enables to detect all absorption lines between 5 and 10 μm, reproducing the molecular absorption spectrum. Counterintuitively, despite a lower quality factor, the system sensitivity is improved and we report a reflectivity variation as large as one percent per nanometer of molecular layer of PMMA. This paves the way to specific identification of molecules. We illustrate the potential of the technique with the detection of the explosive precursor 2,4-dinitrotoluene (DNT). There is a fair agreement with electromagnetic simulations and we also introduce an analytic model of the SEIRA signal obtained in the over-coupling regime.
Origin and arrangement of actin filaments for gliding motility in apicomplexan parasites revealed by cryo-electron tomography
Authors: Martinez Matthew , Mageswaran Shrawan Kumar , Guérin Amandine , Chen William David , Thompson Cameron Parker , Chavin Sabine , Soldati-Favre Dominique , Striepen Boris , Chang Yi-Wei
Published: August 2023

The phylum Apicomplexa comprises important eukaryotic parasites that invade host tissues and cells using a unique mechanism of gliding motility. Gliding is powered by actomyosin motors that translocate host-attached surface adhesins along the parasite cell body. Actin filaments (F-actin) generated by Formin1 play a central role in this critical parasitic activity. However, their subcellular origin, path and ultrastructural arrangement are poorly understood. Here we used cryo-electron tomography to image motile Cryptosporidium parvum sporozoites and reveal the cellular architecture of F-actin at nanometer-scale resolution. We demonstrate that F-actin nucleates at the apically positioned preconoidal rings and is channeled into the pellicular space between the parasite plasma membrane and the inner membrane complex in a conoid extrusion-dependent manner. Within the pellicular space, filaments on the inner membrane complex surface appear to guide the apico-basal flux of F-actin. F-actin concordantly accumulates at the basal end of the parasite. Finally, analyzing a Formin1-depleted Toxoplasma gondii mutant pinpoints the upper preconoidal ring as the conserved nucleation hub for F-actin in Cryptosporidium and Toxoplasma. Together, we provide an ultrastructural model for the life cycle of F-actin for apicomplexan gliding motility.
Orbital-symmetry effects on magnetic exchange in open-shell nanographenes
Authors: Du Qingyang , Su Xuelei , Liu Yufeng , Jiang Yashi , Li Can , Yan KaKing , Ortiz Ricardo , Frederiksen Thomas , Wang Shiyong , Yu Ping
Published: August 2023

Open-shell nanographenes appear as promising candidates for future applications in spintronics and quantum technologies. A critical aspect to realize this potential is to design and control the magnetic exchange. Here, we reveal the effects of frontier orbital symmetries on the magnetic coupling in diradical nanographenes through scanning probe microscope measurements and different levels of theoretical calculations. In these open-shell nanographenes, the exchange energy exhibits a remarkable variation between 20 and 160 meV. Theoretical calculations reveal that frontier orbital symmetries play a key role in affecting the magnetic coupling on such a large scale. Moreover, a triradical nanographene is demonstrated for investigating the magnetic interaction among three unpaired electrons with unequal magnetic exchange, in agreement with Heisenberg spin model calculations. Our results provide insights into both theoretical design and experimental realization of nanographene materials with different exchange interactions through tuning the orbital symmetry, potentially useful for realizing magnetically operable graphene-based nanomaterials.
Bone marrow adiposity modulation after long duration spaceflight in astronauts
Authors: Liu Tammy , Melkus Gerd , Ramsay Tim , Sheikh Adnan , Laneuville Odette , Trudel Guy
Published: August 2023

Space travel requires metabolic adaptations from multiple systems. While vital to bone and blood production, human bone marrow adipose (BMA) tissue modulation in space is unknown. Here we show significant downregulation of the lumbar vertebrae BMA in 14 astronauts, 41 days after landing from six months’ missions on the International Space Station. Spectral analyses indicated depletion of marrow adipose reserves. We then demonstrate enhanced erythropoiesis temporally related to low BMA. Next, we demonstrated systemic and then, local lumbar vertebrae bone anabolism temporally related to low BMA. These support the hypothesis that BMA is a preferential local energy source supplying the hypermetabolic bone marrow postflight, leading to its downregulation. A late postflight upregulation abolished the lower BMA of female astronauts and BMA modulation amplitude was higher in younger astronauts. The study design in the extreme environment of space can limit these conclusions. BMA modulation in astronauts can help explain observations on Earth.
Searching for ductile superconducting Heusler X2YZ compounds
Authors: Hoffmann Noah , Cerqueira Tiago F. T. , Borlido Pedro , Sanna Antonio , Schmidt Jonathan , Marques Miguel A. L.
Published: August 2023

Heusler compounds attract a great deal of attention from researchers thanks to a wealth of interesting properties, among which is superconductivity. Here we perform an extensive study of the superconducting and elastic properties of the cubic (full-)Heusler family using a mixture of ab initio methods, as well as interpretable and predictive machine-learning models. By analyzing the statistical distributions of these properties and comparing them to anti-perovskites, we recognize universal behaviors that should be common to all conventional superconductors while others turn out to be specific to the material family. In total, we discover a total of eight hypothetical materials with critical temperatures above 10 K to be compared with the current record of Tc = 4.7 K in this family. Furthermore, we expect most of these materials to be highly ductile, making them potential candidates for the manufacture of wires and tapes for superconducting magnets.
Design of refractory multi-principal-element alloys for high-temperature applications
Authors: Ouyang Gaoyuan , Singh Prashant , Su Ranran , Johnson Duane D. , Kramer Matthew J. , Perepezko John H. , Senkov Oleg N. , Miracle Daniel , Cui Jun
Published: August 2023

Refractory multi-principal-element alloys (RMPEAs) exhibit high specific strength at elevated temperatures (T). However, current RMPEAs lack a balance of room-temperature (RT) ductility, high-T strength, and high-T creep resistance. Using density-functional theory methods, we scanned composition space using four criteria: (1) formation energies for operational stability: $$-150\le {E}_{{\rm {f}}}$$

−
150
≤

E

f

 ≤ +70 meV per atom; (2) higher strength found via interstitial electron density with Young’s moduli E > 250 GPa; (3) inverse Pugh ratio for ductility: G/B < 0.57; and (4) high melting points: Tm > 2500 °C. Using rapid bulk alloy synthesis and characterization, we validated theory and down-selected promising alloy compositions and discovered Mo72.3W12.8Ta10.0Ti2.5Zr2.5 having well-balanced RT and high-T mechanical properties. This alloy has comparable high-T compressive strength to well-known MoNbTaW but is more ductile and more creep resistant. It is also superior to a commercial Mo-based refractory alloy and a nickel-based superalloy (Haynes-282) with improved high-T tensile strength and creep resistance.
Predicting corrosion inhibition efficiencies of small organic molecules using data-driven techniques
Authors: Li Xuejiao , Vaghefinazari Bahram , Würger Tim , Lamaka Sviatlana V. , Zheludkevich Mikhail L. , Feiler Christian
Published: August 2023

Selecting effective corrosion inhibitors from the vast chemical space is not a trivial task, as it is essentially infinite. Fortunately, machine learning techniques have shown great potential in generating shortlists of inhibitor candidates prior to large-scale experimental testing. In this work, we used the corrosion responses of 58 small organic molecules on the magnesium alloy AZ91 and utilized molecular descriptors derived from their geometry and density functional theory calculations to encode their molecular information. Statistical methods were applied to select the most relevant features to the target property for support vector regression and kernel ridge regression models, respectively, to predict the behavior of untested compounds. The performance of the two supervised learning approaches were compared and the robustness of the data-driven models were assessed by experimental blind testing.
A Strep A vaccine global demand and return on investment forecast to inform industry research and development prioritization
Authors: Walkinshaw Donald R. , Wright Meghan E. E. , Williams Marni , Scarapicchia Tanya M. F. , Excler Jean-Louis , Wiley Ryan E. , Mullin Anne E.
Published: August 2023

Investment in Strep A vaccine R&D is disproportionately low relative to the large burden of Strep A diseases globally. This study presents a novel Strep A vaccine global demand and financial forecast model with estimates of potential global demand and associated revenue and profits for a hypothetical Strep A vaccine as well as a net present value (NPV) analysis of return on capital investments required to develop the vaccine. A positive NPV was calculated for a variety of developer scenarios and target populations, including the global rollout of the vaccine in private and public markets by a multinational pharmaceutical corporation and a staged rollout by a developing country vaccine manufacturer for both infant and child populations. The results suggest there is a viable commercial market for a Strep A vaccine. It is hoped that this study will help to inform industry decision-making and drive increased prioritization of, and investment in, Strep A vaccine research and development.
Malonyl-CoA is a conserved endogenous ATP-competitive mTORC1 inhibitor
Authors: Nicastro Raffaele , Brohée Laura , Alba Josephine , Nüchel Julian , Figlia Gianluca , Kipschull Stefanie , Gollwitzer Peter , Romero-Pozuelo Jesus , Fernandes Stephanie A. , Lamprakis Andreas , Vanni Stefano , Teleman Aurelio A. , De Virgilio Claudio , Demetriades Constantinos
Published: August 2023

Cell growth is regulated by the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which functions both as a nutrient sensor and a master controller of virtually all biosynthetic pathways. This ensures that cells are metabolically active only when conditions are optimal for growth. Notably, although mTORC1 is known to regulate fatty acid biosynthesis, how and whether the cellular lipid biosynthetic capacity signals back to fine-tune mTORC1 activity remains poorly understood. Here we show that mTORC1 senses the capacity of a cell to synthesise fatty acids by detecting the levels of malonyl-CoA, an intermediate of this biosynthetic pathway. We find that, in both yeast and mammalian cells, this regulation is direct, with malonyl-CoA binding to the mTOR catalytic pocket and acting as a specific ATP-competitive inhibitor. When fatty acid synthase (FASN) is downregulated/inhibited, elevated malonyl-CoA levels are channelled to proximal mTOR molecules that form direct protein–protein interactions with acetyl-CoA carboxylase 1 (ACC1) and FASN. Our findings represent a conserved and unique homeostatic mechanism whereby impaired fatty acid biogenesis leads to reduced mTORC1 activity to coordinately link this metabolic pathway to the overall cellular biosynthetic output. Moreover, they reveal the existence of a physiological metabolite that directly inhibits the activity of a signalling kinase in mammalian cells by competing with ATP for binding.
Superconductivity from a melted insulator in Josephson junction arrays
Authors: Mukhopadhyay S. , Senior J. , Saez-Mollejo J. , Puglia D. , Zemlicka M. , Fink J. M. , Higginbotham A. P.
Published: August 2023

Arrays of Josephson junctions are governed by a competition between superconductivity and repulsive Coulomb interactions, and are expected to exhibit diverging low-temperature resistance when interactions exceed a critical level. Here we report a study of the transport and microwave response of Josephson arrays with interactions exceeding this level. Contrary to expectations, we observe that the array resistance drops dramatically as the temperature is decreased—reminiscent of superconducting behaviour—and then saturates at low temperature. Applying a magnetic field, we eventually observe a transition to a highly resistive regime. These observations can be understood within a theoretical picture that accounts for the effect of thermal fluctuations on the insulating phase. On the basis of the agreement between experiment and theory, we suggest that apparent superconductivity in our Josephson arrays arises from melting the zero-temperature insulator.
Genome-wide prediction of disease variant effects with a deep protein language model
Authors: Brandes Nadav , Goldman Grant , Wang Charlotte H. , Ye Chun Jimmie , Ntranos Vasilis
Published: August 2023

Predicting the effects of coding variants is a major challenge. While recent deep-learning models have improved variant effect prediction accuracy, they cannot analyze all coding variants due to dependency on close homologs or software limitations. Here we developed a workflow using ESM1b, a 650-million-parameter protein language model, to predict all ~450 million possible missense variant effects in the human genome, and made all predictions available on a web portal. ESM1b outperformed existing methods in classifying ~150,000 ClinVar/HGMD missense variants as pathogenic or benign and predicting measurements across 28 deep mutational scan datasets. We further annotated ~2 million variants as damaging only in specific protein isoforms, demonstrating the importance of considering all isoforms when predicting variant effects. Our approach also generalizes to more complex coding variants such as in-frame indels and stop-gains. Together, these results establish protein language models as an effective, accurate and general approach to predicting variant effects.
Genetics of circulating inflammatory proteins identifies drivers of immune-mediated disease risk and therapeutic targets
Authors: Zhao Jing Hua , Stacey David , Eriksson Niclas , Macdonald-Dunlop Erin , Hedman Åsa K. , Kalnapenkis Anette , Enroth Stefan , Cozzetto Domenico , Digby-Bell Jonathan , Marten Jonathan , Folkersen Lasse , Herder Christian , Jonsson Lina , Bergen Sarah E. , Gieger Christian , Needham Elise J. , Surendran Praveen ,   Estonian Biobank Research Team, Metspalu Andres , Milani Lili , Mägi Reedik , Nelis Mari , Hudjašov Georgi , Paul Dirk S. , Polasek Ozren , Thorand Barbara , Grallert Harald , Roden Michael , Võsa Urmo , Esko Tonu , Hayward Caroline , Johansson Åsa , Gyllensten Ulf , Powell Nick , Hansson Oskar , Mattsson-Carlgren Niklas , Joshi Peter K. , Danesh John , Padyukov Leonid , Klareskog Lars , Landén Mikael , Wilson James F. , Siegbahn Agneta , Wallentin Lars , Mälarstig Anders , Butterworth Adam S. , Peters James E.
Published: August 2023

Circulating proteins have important functions in inflammation and a broad range of diseases. To identify genetic influences on inflammation-related proteins, we conducted a genome-wide protein quantitative trait locus (pQTL) study of 91 plasma proteins measured using the Olink Target platform in 14,824 participants. We identified 180 pQTLs (59 cis, 121 trans). Integration of pQTL data with eQTL and disease genome-wide association studies provided insight into pathogenesis, implicating lymphotoxin-α in multiple sclerosis. Using Mendelian randomization (MR) to assess causality in disease etiology, we identified both shared and distinct effects of specific proteins across immune-mediated diseases, including directionally discordant effects of CD40 on risk of rheumatoid arthritis versus multiple sclerosis and inflammatory bowel disease. MR implicated CXCL5 in the etiology of ulcerative colitis (UC) and we show elevated gut CXCL5 transcript expression in patients with UC. These results identify targets of existing drugs and provide a powerful resource to facilitate future drug target prioritization.
Daratumumab monotherapy for refractory lupus nephritis
Authors: Roccatello Dario , Fenoglio Roberta , Caniggia Ilaria , Kamgaing Joelle , Naretto Carla , Cecchi Irene , Rubini Elena , Rossi Daniela , De Simone Emanuele , Del Vecchio Giulio , Cozzi Martina , Sciascia Savino
Published: August 2023

Treatment-refractory lupus nephritis (LN) has a high risk of a poor outcome and is often life-threatening. Here we report a case series of six patients (one male and five females) with a median age of 41.3 years (range, 20–61 years) with refractory LN who received renal biopsies and were subsequently treated with intravenous daratumumab, an anti-CD38 monoclonal antibody (weekly for 8 weeks, followed by eight biweekly infusions and up to eight monthly infusions). One patient did not show any improvement after 6 months of therapy, and daratumumab was discontinued. In five patients, the mean disease activity, as assessed by the Systemic Lupus Erythematosus Disease Activity 2000 index, decreased from 10.8 before treatment to 3.6 at 12 months after treatment. Mean proteinuria (5.6 g per 24 h to 0.8 g per 24 h) and mean serum creatinine (2.3 mg dl−1 to 1.5 mg dl−1) also decreased after 12 months. Improvement of clinical symptoms was accompanied by seroconversion of anti-double-stranded DNA antibodies; decreases in median interferon-gamma levels, B cell maturation antigen and soluble CD163 levels; and increases in C4 and interleukin-10 levels. These data suggest that daratumumab monotherapy warrants further exploration as a potential treatment for refractory LN.
Photosensitization of TiO2 microspheres by novel Quinazoline-derivative as visible-light-harvesting antenna for enhanced Rhodamine B photodegradation
Authors: Hamza Mahmoud Adel , Rizk Sameh A. , Ezz-Elregal Ezz-Elregal M. , El-Rahman Shaimaa A. Abd , Ramadan Sayed K. , Abou‑Gamra Zeinab M.
Published: August 2023

Water pollution is one of the global threats severely affecting our planet and human health. Organic textile dyes are one of the common organic water pollutants that are presentient to degradation by traditional physical methods. Semiconductor-assisted photocatalysis is considered a green, efficient, and sustainable technology for wastewater treatment. To maximize the efficient utilization of solar radiation, it is of pivotal significance to explore novel organic molecules to be employed as efficient dye sensitizers for wide-bandgap semiconductors to extend their performance to the Visible-light region. Hence, in this work, we are proposing the design and synthesis of novel structures of QAD molecule as a dye photosensitizer with extended visible light absorptivity due to the extended π–π/n–π conjugations, to promote the performance of TiO2 nanoparticles to the visible-light region and enhance the charge separation. The physicochemical characterizations confirmed the successful synthesis of QAD, TiO2, and QAD/TiO2 samples with the proposed structures. The anchoring of QAD molecules on the surface of TiO2 caused a substantial improvement in the optical characteristics of TiO2 as well as overcoming its common drawbacks by decreasing its bandgap energy to 2.6 eV, a remarkable reduction of PL intensity indicating reducing the e–h recombination and enhancing the charge separation, and creation of efficient visible light-harvesting antenna in the range of 400–600 nm. Besides, the QAD/TiO2 sample achieved a 3-fold enhancement in the observed rate constant of the photodegradation of Rhodamine B dye compared to the bare TiO2. The parameters affecting the photodegradation process were optimized and the sample displayed outstanding stability after 4 consecutive cycles. Finally, the effect of the scavengers was investigated and $${\mathrm{O}}_{2}^{\cdot -}$$

O

2

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was proposed to be the most reactive species and the mechanism of the enhancement was suggested based on the electron injection from the QAD’s HOMO level to the TiO2’s CB. Finally, this work opens the door for various studies for the investigation of the proposed structures or similar structures in various photocatalytic/biomedical applications.
Assessment of nutritional status using anthropometric index among older adult and elderly population in India
Authors: Khan Junaid , Chattopadhyay Aparajita , Shaw Subhojit
Published: August 2023

Malnutrition poses a significant risk to the older population globally, highlighting the critical role of nutrition in healthy aging. In this study, the aim is to estimate the prevalence of malnutrition among older adults aged 45–59 years and the elderly population aged 60 years and above based on their socioeconomic and demographic characteristics. Furthermore, the study examines the risk factors within a multivariate framework. A sample of 59,073 individuals aged 45 years and above from the Longitudinal Aging Study in India (LASI), Wave 1 survey constitutes the study population. This study adopts a cross-sectional design. Bivariate cross-tabulation analysis and multivariate logistic regression analysis are employed to understand the prevalence and determinants of nutritional status. About 25% of males and 37% of females below the age of 60 years are overweight (including obese), while among those aged 60 years and above, 28% of males and 25% of females are underweight. The elderly male population carries a comparatively higher burden of underweight (28%) prevalence than the females (25%) in the same age group. Overall, the urban population is less likely to be underweight [AOR: 0.41, C.I 0.38–0.43] and more likely to be overweight [AOR: 2.41, C.I 2.32–2.52]. Older adults from low economic and social strata are more likely to be underweight. In terms of bio-physical factors, individuals aged 60 years and above with infections to endemic diseases [AOR: 1.24; p-value < 0.01] and those with edentulism [AOR: 1.29; p-value < 0.01] are more likely to be underweight. As evident from the study, nutritional status among older adults is a complicated manifestation of multiple risk factors and requires potential nutritional intervention. Initiating a routine screening program at the grassroots level can effectively identify older adults and the elderly in India, facilitating the provision of nutritional care.
Alpha cell receptor for advanced glycation end products associate with glucagon expression in type 1 diabetes
Authors: Leung Sherman S. , Lenchik Nataliya , Mathews Clayton , Pugliese Alberto , McCarthy Domenica A. , Le Bagge Selena , Ewing Adam , Harris Mark , Radford Kristen J. , Borg Danielle J. , Gerling Ivan , Forbes Josephine M.
Published: August 2023

Hypoglycemia in type 1 diabetes associates with changes in the pancreatic islet α cells, where the receptor for advanced glycation end products (RAGE) is highly expressed. This study compared islet RAGE expression in donors without diabetes, those at risk of, and those with type 1 diabetes. Laser-dissected islets were subject to RNA bioinformatics and adjacent pancreatic tissue were assessed by confocal microscopy. We found that islets from type 1 diabetes donors had differential expression of the RAGE gene (AGER) and its correlated genes, based on glucagon expression. Random forest machine learning revealed that AGER was the most important predictor for islet glucagon levels. Conversely, a generalized linear model identified that glucagon expression could be predicted by expression of RAGE signaling molecules, its ligands and enzymes that create or clear RAGE ligands. Confocal imaging co-localized RAGE, its ligands and signaling molecules to the α cells. Half of the type 1 diabetes cohort comprised of adolescents and a patient with history of hypoglycemia—all showed an inverse relationship between glucagon and RAGE. These data confirm an association between glucagon and islet RAGE, its ligands and signaling pathways in type 1 diabetes, which warrants functional investigation into a role for RAGE in hypoglycemia.
YWHAZ and TBP are potential reference gene candidates for qPCR analysis of response to radiation therapy in colorectal cancer
Authors: Kim Shin , Park Jee Young , Lee Hye Won , Bae Sung Uk , Kim Kyeong Eui , Byun Sang Jun , Seo Incheol
Published: August 2023

The expression profiles of conventional reference genes (RGs), including ACTB and GAPDH, used in quantitative real-time PCR (qPCR), vary depending on tissue types and environmental conditions. We searched for suitable RGs for qPCR to determine the response to radiotherapy in colorectal cancer (CRC) cell lines, organoids, and patient-derived tissues. Ten CRC cell lines (Caco-2, COLO 205, DLD-1, HCT116, HCT-15, HT-29, RKO, SW1116, SW480, and SW620) and organoids were selected and irradiated with 2, 10 or 21 grays (Gy) based on the previous related studies conducted over the last decade. The expression stability of 14 housekeeping genes (HKGs; ACTB, B2M, G6PD, GAPDH, GUSB, HMBS, HPRT1, IPO8, PGK1, PPIA, TBP, TFRC, UBC, and YWHAZ) after irradiation was evaluated using RefFinder using raw quantification cycle (Cq) values obtained from samples before and after irradiation. The expression stability of HKGs were also evaluated for paired fresh frozen tissues or formalin-fixed, paraffin-embedded samples obtained from CRC patients before and after chemoradiotherapy. The expression of YWHAZ and TBP encoding 14-3-3-zeta protein and TATA-binding protein were more stable than the other 12 HKGs in CRC cell lines, organoids, and patient-derived tissues after irradiation. The findings suggest that YWHAZ and TBP are potential RG candidates for normalizing qPCR results in CRC radiotherapy experiments.