bluuebunny/crossref_metadata_2025 huggingface dataset:
Australia in World Affairs 1971–1975
Authors: Hudson W. J.
Published: March 2024

The Australia in World Affairs series commenced in 1950 and provides a continuous, researched scholarly account of Australia's foreign policy. This fifth volume, Australia in World Affairs 1971–1976, includes the final years of the Coalition's post-1949 time in government, and describes and evaluates the foreign policy and diplomacy of the Whitlam Labor Government. Gough Whitlam not only led his party to its first taste of power in almost a quarter of a century, but also dominated his government's dealings with the world outside. Where for so long Australia's external relations had been based on what were seen as 'natural' alignments – especially with Britain and the United States – the nation now faced the much more difficult problems involved in forging and maintaining alignments of convenience with states with whom she lacked ethnic, cultural or historical bonds, and from whom she could not expect any special consideration or tolerance.
Ecosystem Water‐Saving Timescale Varies Spatially With Typical Drydown Length
Authors: Holtzman Natan , Sloan Brandon , Potkay Aaron , Katul Gabriel , Feng Xue , Konings Alexandra G.
Published: March 2024

Stomatal optimization theory is a commonly used framework for modeling how plants regulate transpiration in response to the environment. Most stomatal optimization models assume that plants instantaneously optimize a reward function such as carbon gain. However, plants are expected to optimize over longer timescales given the rapid environmental variability they encounter. There are currently no observational constraints on these timescales. Here, a new stomatal model is developed and is used to analyze the timescales over which stomatal closure is optimized. The proposed model assumes plants maximize carbon gain subject to the constraint that they cannot draw down soil moisture below a critical value. The reward is integrated over time, after being weighted by a discount factor that represents the timescale (τ) that a plant considers when optimizing stomatal conductance to save water. The model is simple enough to be analytically solvable, which allows the value of τ to be inferred from observations of stomatal behavior under known environmental conditions. The model is fitted to eddy covariance data in a range of ecosystems, finding the value of τ that best predicts the dynamics of evapotranspiration at each site. Across 82 sites, the climate metrics with the strongest correlation to τ are measures of the average number of dry days between rainfall events. Values of τ are similar in magnitude to the longest such dry period encountered in an average year. The results here shed light on which climate characteristics shape spatial variations in ecosystem‐level water use strategy.
Fault Orientation Trumps Fault Maturity in Controlling Coseismic Rupture Characteristics of the 2021 Maduo Earthquake
Authors: Liu‐Zeng Jing , Liu Zhijun , Liu Xiaoli , Milliner Chris , Rodriguez Padilla Alba M. , Xu Shiqing , Avouac Jean‐Philippe , Yao Wenqian , Klinger Yann , Han Longfei , Shao Yanxiu , Yan Xiaodong , Aati Saif , Shao Zhigang
Published: March 2024

Fault maturity has been proposed to exert a first order control on earthquake rupture, yet direct observations linking individual rupture to long‐term fault growth are rare. The 2021 Mw 7.4 Maduo earthquake ruptured the east‐growing end of the slow‐moving (∼1 mm/yr) Jiangcuo fault in north Tibet, providing an opportunity to examine the relation between rupture characteristics and fault structure. Here we combine field and multiple remote sensing techniques to map the surface rupture at cm‐resolution and document comprehensively on‐fault offsets and off‐fault deformation. The 158 km‐long surface rupture consists of misoriented structurally inherited N110°‐striking segments and younger optimally oriented N093°‐striking segments, relative to the regional stress field. Despite being comparatively newly formed, the ∼N093°‐striking fault segments accommodate more localized strain, with up to 3 m on‐fault left‐lateral slip and 25%–50% off‐fault deformation, and possibly faster rupture speed. These results are in contrast with previous findings showing more localized strain and faster rupture speed on more mature fault segments; instead, our observations suggest that fault orientation with respect to the regional stress can exert a more important control than fault maturity on coseismic rupture behavior when both factors are at play.
ROTATE: A Coordinate System for Analyzing Atmospheric Rivers
Authors: Asharaf S. , Guan B. , Waliser D. E.
Published: March 2024

This study introduces the ROTated Atmospheric river coordinaTE (ROTATE) system — a novel storm‐centric coordinate system designed specifically for analyzing atmospheric rivers (ARs). It effectively preserves key AR signals in the time mean that may be lost or obscured in simple averaging due to diverse AR orientations and shapes. By applying the ROTATE system, we compared climatological characteristics for northern hemisphere ARs. Composites of four key meteorological variables, integrated vapor transport, integrated water vapor, precipitation, and windspeed, indicate distinct and clearer patterns of ARs compared to the conventional non‐rotated AR centroid‐based compositing approach. Moreover, the ROTATE system improves precipitation rates, particularly around the AR center and its head and tail regions, providing more distinct delineations of the precipitation signals between landfalling and oceanic ARs. Overall, the ROTATE system has the potential to serve as a valuable tool for better comparing and understanding the characteristics, processes, and impacts of ARs across different regions.
Lunar South Polar Water Cycle and Water Resources: Diurnal and Spatial Variations in Surficial Hydration From Repeated Moon Mineralogy Mapper Observations
Authors: Lu Yu , Wang Wenwen , Jiao Hengyue , Xu Tianyi , Chen Xuejiao , Wu Yunzhao
Published: March 2024

The diurnal variation and distribution of lunar surficial hydration (OH/H2O) is of great significance for understanding the solar wind implantation and water cycle on the Moon. Lunar south pole is an ideal place to study the diurnal variation of surficial hydration due to the large number of repeat observations of the same region, which is very limited in mid‐ or low‐latitudes. Here we showed clear 0.5‐hr interval diurnal variation of surficial hydration at lunar south pole. The variation of hydration band depth with local time is exactly the opposite to the variation of temperature, indicating that lunar surficial hydration changes sufficiently with temperature. This relationship indicates that both the diurnal variation and hydration content are latitude dependent. Our observations support the hypothesis that the diurnal variation of hydration on the Moon is due to the formation of metastable hydroxyl.
Unveiling the Hidden Threat: Drought‐Induced Inelastic Subsidence in Expansive Soils
Authors: Welch Jennifer , Wang Guoquan , Bao Yan , Zhang Shuangcheng , Huang Guanwen , Hu Xie
Published: March 2024

Expansive soils pose a significant challenge in geotechnical engineering, especially in coastal areas. While research has mainly focused on their elastic properties, this study explores the overlooked aspect of inelastic subsidence during prolonged droughts, utilizing decade‐long GPS datasets from the University of Houston Coastal Center. Our findings reveal substantial subsidence, approximately one to two dm, during the summer droughts of 2018, 2020, 2022, and 2023, due to compaction within the upper 4 m of expansive soils. Inelastic subsidence constitutes roughly 10% of the total subsidence, resulting in step‐like permanent land elevation loss over time. Notably, drought‐induced subsidence is prominent in open‐field areas with expansive soils but is minor in built‐up areas or in non‐expansive soil regions. The occurrence of inelastic subsidence challenges traditional assessments of relative sea‐level rise and coastal flooding, emphasizing the need to consider it in coastal infrastructure planning for enhanced resilience against climate uncertainties.
Deformation, Strength and Tectonic Evolution of Basal Ice in Taylor Glacier, Antarctica
Authors: Fitzsimons Sean , Samyn Denis , Lorrain Regi
Published: March 2024

Observation and measurements of ice structure and deformation made in tunnels excavated into the margin of Taylor Glacier, a polythermal glacier in the McMurdo Dry Valleys of Antarctica, reveal a complex, rapidly deforming basal ice sequence. Displacement measurements in the basal ice, which is at a temperature of −18°C, together with the occurrence of cavities and slickenslides, suggest that sliding or rapid deformation in thin zones of high shear occurs at structural discontinuities within the basal zone. Strain measurements show that the highest strain rates occur in ice with average debris concentrations of 26% followed by ice with debris concentrations of around 12%. The lowest strain rates occur in clean bubbly ice that has very low debris concentrations (<0.02%). Deformation within the basal ice sequence is dominated by simple shear but disrupted by folding which results in shortening of the debris‐bearing ice followed by attenuation of the folds due to progressive simple shear which generates predominantly laminar basal ice structures. About 60% of glacier surface velocity can be attributed to deformation within the 4.5 m thick sequence of basal ice that was monitored for this study, and 15% of motion can be attributed to sliding or very localized shear. The combination of high debris concentrations and high strain rates in the debris‐bearing ice results in high rates of abrasion and the production of striated and facetted clasts typical of temperate glaciers, even though the basal ice is at a temperature of −18°C.
Geoelectric Field Estimations During Geomagnetic Storm in North China From SinoProbe Magnetotelluric Impedances
Authors: Shao Qihe , Liu Ying , Luo Yinhe , Heinson Graham , Xu Yixian , Du Jinsong , Chen Chao
Published: March 2024

Evaluating the impact of geomagnetic disturbances on power grid infrastructure is critical to mitigate the risk posed by geomagnetically induced currents (GICs). In this paper, the geoelectric field and induced voltage distribution in North China were estimated from the SinoProbe magnetotelluric (MT) impedance data together with the geomagnetic observatory data of six INTERMAGNET stations recorded during the significant geomagnetic storm of 17th March 2015. The measured impedances from 119 SinoProbe MT sites were convolved with geomagnetic observatory data to account for the Earth's complex three‐dimensional electrical resistivity structure. The resultant geoelectric field was then used to model the induced voltage distribution across the regional power transmission network in North China. Due to the large inter‐site distances of the SinoProbe MT program, the derived geoelectric field is mostly homogeneous, except in the Ordos Basin that displays a polarization of the geoelectric field, and with higher magnitudes in the orogenic belts. The estimated geoelectric fields in Taihang‐Lvliang, Yanshan, and Luxi orogenic belts of North China were large (>1 V/km) during the storm, due to high‐resistivity lithosphere resulting in large voltage gradients in the Earth. However, in relation to locations of major power transmission lines, only the central part of North China experienced induced voltages exceeding 100 V.
Age, Kinematic and Thermal Constraints of Syn‐Orogenic Low‐Temperature Deformation Events: Insights From Thermochronology and Structural Data of the Nekézseny Thrust (Alpine‐Carpathian‐Dinaric Area)
Authors: Oravecz Éva , Benkó Zsolt , Arató Róbert , Dunkl István , Héja Gábor , Kövér Szilvia , Németh Tibor , Fodor László
Published: March 2024

Unraveling the age and kinematics of low temperature deformation events is crucial in understanding the late‐stage evolution of orogens. However, accurate age constraints can often be challenging to obtain due to unideal outcrop conditions, large sedimentary hiatuses or the lack of well‐defined thermal events. In this study, we show on the example of the Nekézseny Thrust, a poorly exposed late orogenic thrust in the southern Western Carpathians, that a combined approach of structural analysis and multi‐method thermochronology can provide the necessary temporal, kinematic and thermal constraints for a detailed reconstruction of the deformation history. While structural mapping revealed that the Late Cretaceous Uppony Gosau Basin in the footwall of the Nekézseny Thrust underwent a significant post‐Campanian and pre‐Miocene shortening, K/Ar dating of fault gouge samples from the main fault zone constrained the primary thrusting event to the Maastrichtian. Based on the acquired apatite fission‐track and (U‐Th)/He ages, subsequent heating of the Upper Cretaceous sediments due to tectonic burial was limited to 75–100°C, followed by deformation‐related and gradual cooling between the Eocene and Early Miocene. Considering the reconstructed deformation history, as well as the large‐scale tectonic affinity of the displaced units in its footwall and hanging wall, the Nekézseny Thrust is a far‐traveled (ca. 600 km) segment of the Late Cretaceous Alps‐Dinarides contact zone, whose development was linked to the switch from lower plate to upper plate position with respect to the Sava Zone and Alpine Tethys sutures, respectively.
The two sides of chromosomal instability: drivers and brakes in cancer
Authors: Hosea Rendy , Hillary Sharon , Naqvi Sumera , Wu Shourong , Kasim Vivi
Published: March 2024

Chromosomal instability (CIN) is a hallmark of cancer and is associated with tumor cell malignancy. CIN triggers a chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes in chromosomes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to the formation of cells with abnormal number and/or structure of chromosomes. Errors in DNA replication result from abnormal replication licensing as well as replication stress, such as double-strand breaks and stalled replication forks; meanwhile, errors in chromosome segregation stem from defects in chromosome segregation machinery, including centrosome amplification, erroneous microtubule–kinetochore attachments, spindle assembly checkpoint, or defective sister chromatids cohesion. In normal cells, CIN is deleterious and is associated with DNA damage, proteotoxic stress, metabolic alteration, cell cycle arrest, and senescence. Paradoxically, despite these negative consequences, CIN is one of the hallmarks of cancer found in over 90% of solid tumors and in blood cancers. Furthermore, CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity, thereby facilitating adaptive resistance to therapies; however, excessive CIN could induce tumor cells death, leading to the “just-right” model for CIN in tumors. Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments. This review provides an overview of causes and consequences of CIN, as well as the paradox of CIN, a phenomenon that continues to perplex researchers. Finally, this review explores the potential of CIN-based anti-tumor therapy.
Trajectories in depressive symptoms and midlife brain health
Authors: Dintica Christina S. , Habes Mohamad , Schreiner Pamela J. , Launer Lenore J. , Yaffe Kristine
Published: March 2024

Depressive symptoms may either be a risk factor or prodromal to dementia. Investigating this association in midlife may help clarify the role of depression in cognitive aging. We aimed to identify trajectories in depressive symptoms in early to mid-life and related cognitive and brain outcomes in midlife. This study includes 3944 Black and White participants (ages 26−45 years at baseline) from the Coronary Artery Risk Development in Young Adults (CARDIA) study with 20 years of follow-up. Depressive symptoms were assessed using the Center for Epidemiological Studies Depression scale at five time points over 20 years. Growth mixture modeling (GMM) was used to identify depressive symptom trajectories. Participants completed a neuropsychological battery 20 years after baseline, including the Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop Test, Montreal Cognitive Assessment (MoCA), and category and letter fluency tests. A sub-sample of participants (n = 662) underwent brain magnetic resonance imaging (MRI) to characterize gray matter volumes and white matter hyperintensities (WMHs). We identified four classes of depressive symptom trajectories: a “declining” class (n = 286, 7.3%) with initially high symptoms and subsequent decline, a class with consistently high symptoms (“steady high”; n = 264, 6.7%), a class with late increases in symptoms (“increasing”; n = 277, 7%), and a class with consistently low symptoms (“steady low”; n = 3117, 79.0%). The steady high and the increasing classes had poorer performance on all cognitive tests, while the declining class had poorer performance on the DSST, verbal fluency, and MoCA. Compared to the steady low symptom class, the steady high class had lower volumes in the entorhinal cortex (β: −180.80, 95% CI: −336.69 to −24.91) and the amygdala (β: −40.97, 95% CI: −74.09 to −7.85), the increasing class had more WMHs (β: 0.55, 95% CI: 0.22 to 0.89), and the declining class was not significantly different in any brain measures. Trajectories in depressive symptoms in young to mid-adulthood show distinct cognitive and brain phenotypes in midlife. Steady high depressive symptoms may represent a group that is at risk for dementia, whereas increasing symptoms in midlife may be associated with white matter damage.
Identification of MYCN non-amplified neuroblastoma subgroups points towards molecular signatures for precision prognosis and therapy stratification
Authors: Hu Xiaoxiao , Zhou Yilu , Hill Charlotte , Chen Kai , Cheng Cheng , Liu Xiaowei , Duan Peiwen , Gu Yaoyao , Wu Yeming , Ewing Rob M. , Li Zhongrong , Wu Zhixiang , Wang Yihua
Published: March 2024

Background

Despite the extensive study of MYCN-amplified neuroblastomas, there is a significant unmet clinical need in MYCN non-amplified cases. In particular, the extent of heterogeneity within the MYCN non-amplified population is unknown.

Methods

A total of 1566 samples from 16 datasets were identified in Gene Expression Omnibus (GEO) and ArrayExpress. Characterisation of the subtypes was analysed by ConsensusClusterPlus. Independent predictors for subgrouping were constructed from the single sample predictor based on the multiclassPairs package. Findings were verified using immunohistochemistry and CIBERSORTx analysis.

Results

We demonstrate that MYCN non-amplified neuroblastomas are heterogeneous and can be classified into 3 subgroups based on their transcriptional signatures. Within these groups, subgroup_2 has the worst prognosis and this group shows a ‘MYCN’ signature that is potentially induced by the overexpression of Aurora Kinase A (AURKA); whilst subgroup_3 is characterised by an ‘inflamed’ gene signature. The clinical implications of this subtype classification are significant, as each subtype demonstrates a unique prognosis and vulnerability to investigational therapies. A total of 420 genes were identified as independent subgroup predictors with average balanced accuracy of 0.93 and 0.84 for train and test datasets, respectively.

Conclusion

We propose that transcriptional subtyping may enhance precision prognosis and therapy stratification for patients with MYCN non-amplified neuroblastomas.
Gemcitabine elaidate and ONC201 combination therapy for inhibiting pancreatic cancer in a KRAS mutated syngeneic mouse model
Authors: Kumar Virender , Sethi Bharti , Staller Dalton W. , Shrestha Prakash , Mahato Ram I.
Published: March 2024

Approximately 90% of pancreatic cancer (PC) contain KRAS mutations. Mutated KRAS activates the downstream oncogenic PI3K/AKT and MEK signaling pathways and induces drug resistance. However, targeting both pathways with different drugs can also lead to excessive toxicity. ONC201 is a dual PI3K/AKT and MEK pathway inhibitor with an excellent safety profile that targets death receptor 5 (DR5) to induce apoptosis. Gemcitabine (GEM) is a first-line chemotherapy in PC, but it is metabolically unstable and can be stabilized by a prodrug approach. In this study, phospho-Akt, phospho-mTOR, and phospho-ERK protein expressions were evaluated in patient PDAC-tissues (n = 10). We used lipid-gemcitabine (L_GEM) conjugate, which is more stable and enters the cells by passive diffusion. Further, we evaluated the efficacy of L_GEM and ONC201 in PC cells and “KrasLSL-G12D; p53LoxP; Pdx1-CreER (KPC) triple mutant xenograft tumor-bearing mice. PDAC patient tissues showed significantly higher levels of p-AKT (Ser473), p-ERK (T202/T204), and p-mTOR compared to surrounding non-cancerous tissues. ONC201 in combination with L_GEM, showed a superior inhibitory effect on the growth of MIA PaCa-2 cells. In our in-vivo study, we found that ONC201 and L_GEM combination prevented neoplastic proliferation via AKT/ERK blockade to overcome chemoresistance and increased T-cell tumor surveillance. Simultaneous inhibition of the PI3K/AKT and MEK pathways with ONC201 is an attractive approach to potentiate the effect of GEM. Our findings provide insight into rational-directed precision chemo and immunotherapy therapy in PDAC.
Bayesian optimization-driven enhancement of the thermoelectric properties of polycrystalline III-V semiconductor thin films
Authors: Ishiyama Takamitsu , Nozawa Koki , Nishida Takeshi , Suemasu Takashi , Toko Kaoru
Published: March 2024

Studying the properties of thermoelectric materials needs substantial effort owing to the interplay of the trade-off relationships among the influential parameters. In view of this issue, artificial intelligence has recently been used to investigate and optimize thermoelectric materials. Here, we used Bayesian optimization to improve the thermoelectric properties of multicomponent III–V materials; this domain warrants comprehensive investigation due to the need to simultaneously control multiple parameters. We designated the figure of merit ZT as the objective function to improve and search for a five-dimensional space comprising the composition of InGaAsSb thin films, dopant concentration, and film-deposition temperatures. After six Bayesian optimization cycles, ZT exhibited an approximately threefold improvement compared to its values obtained in the random initial experimental trials. Additional analysis employing Gaussian process regression elucidated that a high In composition and low substrate temperature were particularly effective at increasing ZT. The optimal substrate temperature (205 °C) demonstrated the potential for depositing InGaAsSb thermoelectric thin films onto plastic substrates. These findings not only promote the development of thermoelectric devices based on III–V semiconductors but also highlight the effectiveness of using Bayesian optimization for multicomponent materials.
Microinterfaces in biopolymer-based bicontinuous hydrogels guide rapid 3D cell migration
Authors: Xu Karen L. , Di Caprio Nikolas , Fallahi Hooman , Dehghany Mohammad , Davidson Matthew D. , Laforest Lorielle , Cheung Brian C. H. , Zhang Yuqi , Wu Mingming , Shenoy Vivek , Han Lin , Mauck Robert L. , Burdick Jason A.
Published: March 2024

Cell migration is critical for tissue development and regeneration but requires extracellular environments that are conducive to motion. Cells may actively generate migratory routes in vivo by degrading or remodeling their environments or instead utilize existing extracellular matrix microstructures or microtracks as innate pathways for migration. While hydrogels in general are valuable tools for probing the extracellular regulators of 3-dimensional migration, few recapitulate these natural migration paths. Here, we develop a biopolymer-based bicontinuous hydrogel system that comprises a covalent hydrogel of enzymatically crosslinked gelatin and a physical hydrogel of guest and host moieties bonded to hyaluronic acid. Bicontinuous hydrogels form through controlled solution immiscibility, and their continuous subdomains and high micro-interfacial surface area enable rapid 3D migration, particularly when compared to homogeneous hydrogels. Migratory behavior is mesenchymal in nature and regulated by biochemical and biophysical signals from the hydrogel, which is shown across various cell types and physiologically relevant contexts (e.g., cell spheroids, ex vivo tissues, in vivo tissues). Our findings introduce a design that leverages important local interfaces to guide rapid cell migration.
Transient expression of the neuropeptide galanin modulates peripheral‑to‑central connectivity in the somatosensory thalamus during whisker development in mice
Authors: Hevesi Zsofia , Bakker Joanne , Tretiakov Evgenii O. , Adori Csaba , Raabgrund Anika , Barde Swapnali S. , Caramia Martino , Krausgruber Thomas , Ladstätter Sabrina , Bock Christoph , Hökfelt Tomas , Harkany Tibor
Published: March 2024

The significance of transient neuropeptide expression during postnatal brain development is unknown. Here, we show that galanin expression in the ventrobasal thalamus of infant mice coincides with whisker map development and modulates subcortical circuit wiring. Time-resolved neuroanatomy and single-nucleus RNA-seq identified complementary galanin (Gal) and galanin receptor 1 (Galr1) expression in the ventrobasal thalamus and the principal sensory nucleus of the trigeminal nerve (Pr5), respectively. Somatodendritic galanin release from the ventrobasal thalamus was time-locked to the first postnatal week, when Gal1R+ Pr5 afferents form glutamatergic (Slc17a6+) synapses for the topographical whisker map to emerge. RNAi-mediated silencing of galanin expression disrupted glutamatergic synaptogenesis, which manifested as impaired whisker-dependent exploratory behaviors in infant mice, with behavioral abnormalities enduring into adulthood. Pharmacological probing of receptor selectivity in vivo corroborated that target recognition and synaptogenesis in the thalamus, at least in part, are reliant on agonist-induced Gal1R activation in inbound excitatory axons. Overall, we suggest a neuropeptide-dependent developmental mechanism to contribute to the topographical specification of a fundamental sensory neurocircuit in mice.
Secondary bone marrow graft loss after third-party virus-specific T cell infusion: Case report of a rare complication
Authors: Keller Michael D. , Schattgen Stefan A. , Chandrakasan Shanmuganathan , Allen E. Kaitlynn , Jensen-Wachspress Mariah A. , Lazarski Christopher A. , Qayed Muna , Lang Haili , Hanley Patrick J. , Tanna Jay , Pai Sung-Yun , Parikh Suhag , Berger Seth I. , Gottschalk Stephen , Pulsipher Michael A. , Thomas Paul G. , Bollard Catherine M.
Published: March 2024

Virus-specific T cells (VST) from partially-HLA matched donors have been effective for treatment of refractory viral infections in immunocompromised patients in prior studies with a good safety profile, but rare adverse events have been described. Here we describe a unique and severe adverse event of VST therapy in an infant with severe combined immunodeficiency, who receives, as part of a clinical trial (NCT03475212), third party VSTs for treating cytomegalovirus viremia following bone marrow transplantation. At one-month post-VST infusion, rejection of graft and reversal of chimerism is observed, as is an expansion of T cells exclusively from the VST donor. Single-cell gene expression and T cell receptor profiling demonstrate a narrow repertoire of predominantly activated CD4+ T cells in the recipient at the time of rejection, with the repertoire overlapping more with that of peripheral blood from VST donor than the infused VST product. This case thus demonstrates a rare but serious side effect of VST therapy.
Gasdermin D promotes influenza virus-induced mortality through neutrophil amplification of inflammation
Authors: Speaks Samuel , McFadden Matthew I. , Zani Ashley , Solstad Abigail , Leumi Steve , Roettger Jack E. , Kenney Adam D. , Bone Hannah , Zhang Lizhi , Denz Parker J. , Eddy Adrian C. , Amer Amal O. , Robinson Richard T. , Cai Chuanxi , Ma Jianjie , Hemann Emily A. , Forero Adriana , Yount Jacob S.
Published: March 2024

Influenza virus activates cellular inflammasome pathways, which can be both beneficial and detrimental to infection outcomes. Here, we investigate the function of the inflammasome-activated, pore-forming protein gasdermin D (GSDMD) during infection. Ablation of GSDMD in knockout (KO) mice (Gsdmd−/−) significantly attenuates influenza virus-induced weight loss, lung dysfunction, lung histopathology, and mortality compared with wild type (WT) mice, despite similar viral loads. Infected Gsdmd−/− mice exhibit decreased inflammatory gene signatures shown by lung transcriptomics. Among these, diminished neutrophil gene activation signatures are corroborated by decreased detection of neutrophil elastase and myeloperoxidase in KO mouse lungs. Indeed, directly infected neutrophils are observed in vivo and infection of neutrophils in vitro induces release of DNA and tissue-damaging enzymes that is largely dependent on GSDMD. Neutrophil depletion in infected WT mice recapitulates the reductions in mortality, lung inflammation, and lung dysfunction observed in Gsdmd−/− animals, while depletion does not have additive protective effects in Gsdmd−/− mice. These findings implicate a function for GSDMD in promoting lung neutrophil responses that amplify influenza virus-induced inflammation and pathogenesis. Targeting the GSDMD/neutrophil axis may provide a therapeutic avenue for treating severe influenza.
Harnessing strong aromatic conjugation in low-dimensional perovskite heterojunctions for high-performance photovoltaic devices
Authors: Li Bo , Liu Qi , Gong Jianqiu , Li Shuai , Zhang Chunlei , Gao Danpeng , Chen Zhongwei , Li Zhen , Wu Xin , Zhao Dan , Yu Zexin , Li Xintong , Wang Yan , Lu Haipeng , Zeng Xiao Cheng , Zhu Zonglong
Published: March 2024

Low-dimensional/three-dimensional perovskite heterojunctions have shown great potential for improving the performance of perovskite photovoltaics, but large organic cations in low-dimensional perovskites hinder charge transport and cause carrier mobility anisotropy at the heterojunction interface. Here, we report a low-dimensional/three-dimensional perovskite heterojunction that introduces strong aromatic conjugated low-dimensional perovskites in p-i-n devices to reduce the electron transport resistance crossing the perovskite/electron extraction interface. The strong aromatic conjugated π-conjugated network results in continuous energy orbits among [Pb2I6]2− frameworks, thereby effectively suppressing interfacial non-radiative recombination and boosting carrier extraction. Consequently, the devices achieved an improved efficiency to 25.66% (certified 25.20%), and maintained over 95% of the initial efficiency after 1200 hours and 1000 hours under ISOS-L-1I and ISOS-D-1 protocols, respectively. The chemical design of strong aromatic conjugated molecules in perovskite heterojunctions provides a promising avenue for developing efficient and stable perovskite photovoltaics.
Structural basis of Acinetobacter type IV pili targeting by an RNA virus
Authors: Meng Ran , Xing Zhongliang , Chang Jeng-Yih , Yu Zihao , Thongchol Jirapat , Xiao Wen , Wang Yuhang , Chamakura Karthik , Zeng Zhiqi , Wang Fengbin , Young Ry , Zeng Lanying , Zhang Junjie
Published: March 2024

Acinetobacters pose a significant threat to human health, especially those with weakened immune systems. Type IV pili of acinetobacters play crucial roles in virulence and antibiotic resistance. Single-stranded RNA bacteriophages target the bacterial retractile pili, including type IV. Our study delves into the interaction between Acinetobacter phage AP205 and type IV pili. Using cryo-electron microscopy, we solve structures of the AP205 virion with an asymmetric dimer of maturation proteins, the native Acinetobacter type IV pili bearing a distinct post-translational pilin cleavage, and the pili-bound AP205 showing its maturation proteins adapted to pilin modifications, allowing each phage to bind to one or two pili. Leveraging these results, we develop a 20-kilodalton AP205-derived protein scaffold targeting type IV pili in situ, with potential for research and diagnostics.
Automated mitotic spindle hotspot counts are highly associated with clinical outcomes in systemically untreated early-stage triple-negative breast cancer
Authors: Leon-Ferre Roberto A. , Carter Jodi M. , Zahrieh David , Sinnwell Jason P. , Salgado Roberto , Suman Vera J. , Hillman David W. , Boughey Judy C. , Kalari Krishna R. , Couch Fergus J. , Ingle James N. , Balkenhol Maschenka , Ciompi Francesco , van der Laak Jeroen , Goetz Matthew P.
Published: March 2024

Operable triple-negative breast cancer (TNBC) has a higher risk of recurrence and death compared to other subtypes. Tumor size and nodal status are the primary clinical factors used to guide systemic treatment, while biomarkers of proliferation have not demonstrated value. Recent studies suggest that subsets of TNBC have a favorable prognosis, even without systemic therapy. We evaluated the association of fully automated mitotic spindle hotspot (AMSH) counts with recurrence-free (RFS) and overall survival (OS) in two separate cohorts of patients with early-stage TNBC who did not receive systemic therapy. AMSH counts were obtained from areas with the highest mitotic density in digitized whole slide images processed with a convolutional neural network trained to detect mitoses. In 140 patients from the Mayo Clinic TNBC cohort, AMSH counts were significantly associated with RFS and OS in a multivariable model controlling for nodal status, tumor size, and tumor-infiltrating lymphocytes (TILs) (p < 0.0001). For every 10-point increase in AMSH counts, there was a 16% increase in the risk of an RFS event (HR 1.16, 95% CI 1.08–1.25), and a 7% increase in the risk of death (HR 1.07, 95% CI 1.00–1.14). We corroborated these findings in a separate cohort of systemically untreated TNBC patients from Radboud UMC in the Netherlands. Our findings suggest that AMSH counts offer valuable prognostic information in patients with early-stage TNBC who did not receive systemic therapy, independent of tumor size, nodal status, and TILs. If further validated, AMSH counts could help inform future systemic therapy de-escalation strategies.
Improving HIC resistance of pipe-steel by Ti/Mg treatment with insights into hydrogen migration
Authors: Peng Zhixian , Liu Jing , Hu Rongzhe , Zhang Shiqi , Huang Feng , Xue Zhengliang
Published: March 2024

The presence of inclusions in steels is responsible for hydrogen-induced cracking (HIC), which necessitates control over their size and distribution. The aims of this study are to investigate the effects of different inclusion-modifying elements on steels, as well as reveal the impact of inclusions on hydrogen migration. Various methods, including HIC evaluation, electrochemical hydrogen permeation, silver microprint, and in-situ hydrogen escape observation, are utilized. The results indicate that steel with a Ti/Mg content ratio of 4:1 exhibits favorable comprehensive resistance against HIC. Moreover, the observation of in-situ hydrogen escape observations reveals that steels with a higher number of hydrogen bubbles and a higher ratio of bubbles related to the inclusions demonstrate better HIC resistance. The refined, dispersed, and multi-compounded inclusions facilitate the formation of more complex trapping sites, ultimately improving the dispersion and pinning of dissociative hydrogen atoms. Consequently, employing a multicomponent inclusion modification strategy holds promise for the development of hydrogen-resistant pipeline steel.
Genotype–phenotype correlation in PRKN-associated Parkinson’s disease
Authors: Menon Poornima Jayadev , Sambin Sara , Criniere-Boizet Baptiste , Courtin Thomas , Tesson Christelle , Casse Fanny , Ferrien Melanie , Mariani Louise-Laure , Carvalho Stephanie , Lejeune Francois-Xavier , Rebbah Sana , Martet Gaspard , Houot Marion , Lanore Aymeric , Mangone Graziella , Roze Emmanuel , Vidailhet Marie , Aasly Jan , Gan Or Ziv , Yu Eric , Dauvilliers Yves , Zimprich Alexander , Tomantschger Volker , Pirker Walter , Álvarez Ignacio , Pastor Pau , Di Fonzo Alessio , Bhatia Kailash P. , Magrinelli Francesca , Houlden Henry , Real Raquel , Quattrone Andrea , Limousin Patricia , Korlipara Prasad , Foltynie Thomas , Grosset Donald , Williams Nigel , Narendra Derek , Lin Hsin-Pin , Jovanovic Carna , Svetel Marina , Lynch Timothy , Gallagher Amy , Vandenberghe Wim , Gasser Thomas , Brockmann Kathrin , Morris Huw R. , Borsche Max , Klein Christine , Corti Olga , Brice Alexis , Lesage Suzanne , Corvol Jean Christophe ,   French Parkinson disease Genetics Study Group (PDG)
Published: March 2024

Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.
Electric polarization near vortices in the extended Kitaev model
Authors: Freitas Lucas R. D. , Bauer Tim , Egger Reinhold , Pereira Rodrigo G.
Published: March 2024

We formulate a Majorana mean-field theory for the extendedJKΓ Kitaev model in a magnetic Zeeman field of arbitrary direction, and apply it for studying spatially inhomogeneous states harboring vortices. This mean-field theory is exact in the pure Kitaev limit and captures the essential physics throughout the Kitaev spin liquid phase. We determine the charge profile around vortices and the corresponding quadrupole tensor. The quadrupole-quadrupole interaction between distant vortices is shown to be either repulsive or attractive, depending on parameters. We predict that electrically biased scanning probe tips enable the creation of vortices at preselected positions. Our results paves the way for the electric manipulation of Ising anyons in Kitaev spin liquids.
Cyclophilin A supports translation of intrinsically disordered proteins and affects haematopoietic stem cell ageing
Authors: Maneix Laure , Iakova Polina , Lee Charles G. , Moree Shannon E. , Lu Xuan , Datar Gandhar K. , Hill Cedric T. , Spooner Eric , King Jordon C. K. , Sykes David B. , Saez Borja , Di Stefano Bruno , Chen Xi , Krause Daniela S. , Sahin Ergun , Tsai Francis T. F. , Goodell Margaret A. , Berk Bradford C. , Scadden David T. , Catic André
Published: March 2024

Loss of protein function is a driving force of ageing. We have identified peptidyl-prolyl isomerase A (PPIA or cyclophilin A) as a dominant chaperone in haematopoietic stem and progenitor cells. Depletion of PPIA accelerates stem cell ageing. We found that proteins with intrinsically disordered regions (IDRs) are frequent PPIA substrates. IDRs facilitate interactions with other proteins or nucleic acids and can trigger liquid–liquid phase separation. Over 20% of PPIA substrates are involved in the formation of supramolecular membrane-less organelles. PPIA affects regulators of stress granules (PABPC1), P-bodies (DDX6) and nucleoli (NPM1) to promote phase separation and increase cellular stress resistance. Haematopoietic stem cell ageing is associated with a post-transcriptional decrease in PPIA expression and reduced translation of IDR-rich proteins. Here we link the chaperone PPIA to the synthesis of intrinsically disordered proteins, which indicates that impaired protein interaction networks and macromolecular condensation may be potential determinants of haematopoietic stem cell ageing.
Preclinical evaluation of the SARS-CoV-2 Mpro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir
Authors: Chen Xiaoxin , Huang Xiaodong , Ma Qinhai , Kuzmič Petr , Zhou Biao , Zhang Sai , Chen Jizheng , Xu Jinxin , Liu Bin , Jiang Haiming , Zhang Wenjie , Yang Chunguang , Wu Shiguan , Huang Jianzhou , Li Haijun , Long Chaofeng , Zhao Xin , Xu Hongrui , Sheng Yanan , Guo Yaoting , Niu Chuanying , Xue Lu , Xu Yong , Liu Jinsong , Zhang Tianyu , Spencer James , Zhu Zhenzhen , Deng Wenbin , Chen Xinwen , Chen Shu-Hui , Zhong Nanshan , Xiong Xiaoli , Yang Zifeng
Published: March 2024

Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (Mpro), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4 nM and suggests that it dissociates about 12 times slower from Mpro compared with nirmatrelvir. The crystal structure of the SARS-CoV-2 Mpro:RAY1216 complex shows that RAY1216 covalently binds to the catalytic Cys145 through the α-ketoamide group. In vitro and using human ACE2 transgenic mouse models, RAY1216 shows antiviral activities against SARS-CoV-2 variants comparable to those of nirmatrelvir. It also shows improved pharmacokinetics in mice and rats, suggesting that RAY1216 could be used without ritonavir, which is co-administered with nirmatrelvir. RAY1216 has been approved as a single-component drug named ‘leritrelvir’ for COVID-19 treatment in China.
Satellite-based time-series of sea-surface temperature since 1980 for climate applications
Authors: Embury Owen , Merchant Christopher J. , Good Simon A. , Rayner Nick A. , Høyer Jacob L. , Atkinson Chris , Block Thomas , Alerskans Emy , Pearson Kevin J. , Worsfold Mark , McCarroll Niall , Donlon Craig
Published: March 2024

A 42-year climate data record of global sea surface temperature (SST) covering 1980 to 2021 has been produced from satellite observations, with a high degree of independence from in situ measurements. Observations from twenty infrared and two microwave radiometers are used, and are adjusted for their differing times of day of measurement to avoid aliasing and ensure observational stability. A total of 1.5 × 1013 locations are processed, yielding 1.4 × 1012 SST observations deemed to be suitable for climate applications. The corresponding observation density varies from less than 1 km−2 yr−1 in 1980 to over 100 km−2 yr−1 after 2007. Data are provided at their native resolution, averaged on a global 0.05° latitude-longitude grid (single-sensor with gaps), and as a daily, merged, gap-free, SST analysis at 0.05°. The data include the satellite-based SSTs, the corresponding time-and-depth standardised estimates, their standard uncertainty and quality flags. Accuracy, spatial coverage and length of record are all improved relative to a previous version, and the timeseries is routinely extended in time using consistent methods.
Three years of weekly DEMs, aerial orthomosaics and surveyed shoreline positions at Waikīkī Beach, Hawai‘i
Authors: Mikkelsen Anna B. , McDonald Kristian K. , Kalksma Julianne , Tyrrell Zachary H. , Fletcher Charles H.
Published: March 2024

In this dataset, we present 128 coastal surveys conducted between 2018 and 2021 at Kahaloa Beach, also known as the Royal Hawaiian Beach, in Waikīkī, Hawai‘i. Surveys were conducted on a near-weekly basis, providing a 0.5 m digital elevation model, an orthorectified image mosaic with 0.03 m resolution, and shoreline vectors at MHHW and MSL, along with a surveyed shoreline position for each survey. We captured overlapping images using a small Unoccupied Aerial System (sUAS), processing the imagery with photogrammetric software to produce orthomosaics and Digital Terrain Models (DTM). Simultaneously, the shoreline position and reference points for sUAS-derived products were surveyed using total station and rod-mounted surveying prism. A quality assessment of 424 randomly sampled points across two surveys showed normally distributed errors of DTM elevations (µ1 = 0.0060 m; σ1 = 0.0998 m; µ2 = 0.0035 m; σ2 = 0.0680). Elevation uncertainties were quantified as 95% confidence intervals (±0.0130 m and ±0.0095 m). These data are intended to encourage research on reef-fringed beaches and provide a dataset for evaluating the accuracy of satellite-derived shorelines at reef-fringed beaches.
A bioinformatics approach to elucidate conserved genes and pathways in C. elegans as an animal model for cardiovascular research
Authors: Ray Ashwini Kumar , Priya Anjali , Malik Md. Zubbair , Thanaraj Thangavel Alphonse , Singh Alok Kumar , Mago Payal , Ghosh Chirashree , Shalimar  , Tandon Ravi , Chaturvedi Rupesh
Published: March 2024

Cardiovascular disease (CVD) is a collective term for disorders of the heart and blood vessels. The molecular events and biochemical pathways associated with CVD are difficult to study in clinical settings on patients and in vitro conditions. Animal models play a pivotal and indispensable role in CVD research. Caenorhabditis elegans, a nematode species, has emerged as a prominent experimental organism widely utilized in various biomedical research fields. However, the specific number of CVD-related genes and pathways within the C. elegans genome remains undisclosed to date, limiting its in-depth utilization for investigations. In the present study, we conducted a comprehensive analysis of genes and pathways related to CVD within the genomes of humans and C. elegans through a systematic bioinformatic approach. A total of 1113 genes in C. elegans orthologous to the most significant CVD-related genes in humans were identified, and the GO terms and pathways were compared to study the pathways that are conserved between the two species. In order to infer the functions of CVD-related orthologous genes in C. elegans, a PPI network was constructed. Orthologous gene PPI network analysis results reveal the hubs and important KRs: pmk-1, daf-21, gpb-1, crh-1, enpl-1,eef-1G, acdh-8, hif-1, pmk-2, and aha-1 in C. elegans. Modules were identified for determining the role of the orthologous genes at various levels in the created network. We also identified 9 commonly enriched pathways between humans and C. elegans linked with CVDs that include autophagy (animal), the ErbB signaling pathway, the FoxO signaling pathway, the MAPK signaling pathway, ABC transporters, the biosynthesis of unsaturated fatty acids, fatty acid metabolism, glutathione metabolism, and metabolic pathways. This study provides the first systematic genomic approach to explore the CVD-associated genes and pathways that are present in C. elegans, supporting the use of C. elegans as a prominent animal model organism for cardiovascular diseases.