bluuebunny/crossref_metadata_2025 huggingface dataset:
Reconstruction of Zonal Precipitation From Sparse Historical Observations Using Climate Model Information and Statistical Learning
Authors: Egli Marius , Sippel Sebastian , Pendergrass Angeline G. , de Vries Iris , Knutti Reto
Published: December 2022

Future projected changes in precipitation substantially impact societies worldwide. However, large uncertainties remain due to sparse historical observational coverage, large internal climate variability, and climate model disagreement. Here, we present a novel reconstruction of seasonally averaged zonal precipitation metrics from sparse rain‐gauge data using regularized regression techniques that are trained across climate model simulations. Subsequently, we test the reconstruction on independent satellite data and reanalyzed precipitation, and find a large fraction of historical zonal mean precipitation (ZMP) variability is recovered, in particular over the Northern hemisphere and in parts of the tropics. Finally, we demonstrate that the reconstructed ZMP trends are outside the variability of pre‐industrial control simulations, and are largely consistent with the range of historical simulations driven by external forcing. Overall, we illustrate a novel way of estimating seasonally averaged zonal precipitation from gauge data, and trends therein that show a signal very likely caused by human influence.
High‐Rate Fluid Injection Reduces the Nucleation Length of Laboratory Earthquakes on Critically Stressed Faults in Granite
Authors: Ji Yinlin , Wang Lei , Hofmann Hannes , Kwiatek Grzegorz , Dresen Georg
Published: December 2022

We conducted fluid injection experiments on cylindrical low‐permeability granite samples with a critically stressed sawcut fault at local injection rates of 0.2 and 0.8 mL/min and confining pressures of 31 and 61 MPa. A local array of six strain gauges attached close to the faults allows us to estimate the nucleation length of each injection‐induced dynamic slip event (i.e., laboratory earthquake). We find nucleation lengths decrease from approximately 90% to <15% of the fault length with higher injection rate and increased effective normal stress. Injection‐induced laboratory earthquakes with smaller nucleation lengths show generally higher peak slip rates and larger fault slip displacements, signifying an intensified seismic hazard. Our results also indicate that initially stable fault patches may be reactivated to slip seismically by increasing injection rates. This study systematically demonstrates that higher injection rates constitute dynamic loading, which increase the seismic hazard by shrinking the earthquake nucleation length.
Monitoring Seasonal Shear Wave Velocity Changes in the Top 6 m at Garner Valley in Southern California With Borehole Data
Authors: Qin Lei , Steidl Jamison H. , Qiu Hongrui , Nakata Nori , Ben‐Zion Yehuda
Published: December 2022

Subsurface structures play important roles in seismic ground motion, crustal hydrology, stability of the built environment, and more. Constraining temporal changes of subsurface shear wave velocity (VS) can provide useful information to all these topics and the growing field of hydrological monitoring with seismic velocity. Using borehole records at Garner Valley, CA, we estimate seasonal subsurface VS variations from impulse response functions (IRFs) of earthquake data (2005–2018) along with IRFs and cross‐correlation of cross‐hole experiment data (2015–2018). The inferred VS variations are up to ∼25% in the top 6 m and ∼10% at 2–5 m in depth. The VS variations correlate strongly with the water table depth changes, suggesting that the changes are mostly due to fluctuations of pore pressure in the shallow material. The shallow velocity changes alter the near‐surface conditions, can affect seismic hazard estimation, and may be improperly attributed to deeper processes without careful analysis.
Transition From Slow to Fast Injection‐Induced Slip of an Experimental Fault in Granite Promoted by Elevated Temperature
Authors: Ji Yinlin , Hofmann Hannes , Rutter Ernest H. , Zang Arno
Published: December 2022

The influence of elevated temperature on injection‐induced fault slip is poorly constrained. In this study, at steady‐state elevated temperatures, triaxial shear‐flow experiments on a sawcut fault in granite were conducted to simulate injection‐induced slip of a critically stressed fault. Our results suggest that an elevated temperature favors a more uniform fluid pressure distribution over the fault surface mainly by reducing water viscosity. At temperatures above ambient, a larger perturbation force from the injected fluid is required to reactivate the fault primarily because of the enhanced thermally activated fault healing processes, resulting in a faster fault slip rate upon failure. This study may partially explain the causal link between higher reservoir temperature and higher maximum magnitude of injection‐induced earthquakes in geothermal systems, and the observation that larger magnitude seismic events concentrate near the deeper part of the reservoir, where temperature is higher.
Efficient single-component white light emitting diodes enabled by lanthanide ions doped lead halide perovskites via controlling Förster energy transfer and specific defect clearance
Authors: Sun Rui , Zhou Donglei , Ding Yujiao , Wang Yue , Wang Yuqi , Zhuang Xinmeng , Liu Shuainan , Ding Nan , Wang Tianyuan , Xu Wen , Song Hongwei
Published: December 2022

Currently, a major challenge for metal-halide perovskite light emitting diodes (LEDs) is to achieve stable and efficient white light emission due to halide ion segregation. Herein, we report a promising method to fabricate white perovskite LEDs using lanthanide (Ln3+) ions doped CsPbCl3 perovskite nanocrystals (PeNCs). First, K+ ions are doped into the lattice to tune the perovskite bandgap by partially substituting Cs+ ions, which are well matched to the transition energy of some Ln3+ ions from the ground state to the excited state, thereby greatly improving the Förster energy transfer efficiency from excitons to Ln3+ ions. Then, creatine phosphate (CP), a phospholipid widely found in organisms, serves as a tightly binding surface-capping multi-functional ligand which regulates the film formation and enhances the optical and electrical properties of PeNC film. Consequently, the Eu3+ doped PeNCs based-white LEDs show a peak luminance of 1678 cd m-2 and a maximum external quantum efficiency (EQE) of 5.4%, demonstrating excellent performance among existing white PeNC LEDs from a single chip. Furthermore, the method of bandgap modulation and the defect passivation were generalized to other Ln3+ ions doped perovskite LEDs and successfully obtained improved electroluminescence (EL). This work demonstrates the comprehensive and universal strategies in the realization of highly efficient and stable white LEDs via single-component Ln3+ ions doped PeNCs, which provides an optimal solution for the development of low-cost and simple white perovskite LEDs.
Soft metamaterial with programmable ferromagnetism
Authors: Kaya Kerem , Iseri Emre , van der Wijngaart Wouter
Published: December 2022

Magnetopolymers are of interest in smart material applications; however, changing their magnetic properties post synthesis is complicated. In this study, we introduce easily programmable polymer magnetic composites comprising 2D lattices of droplets of solid-liquid phase change material, with each droplet containing a single magnetic dipole particle. These composites are ferromagnetic with a Curie temperature defined by the rotational freedom of the particles above the droplet melting point. We demonstrate magnetopolymers combining high remanence characteristics with Curie temperatures below the composite degradation temperature. We easily reprogram the material between four states: (1) a superparamagnetic state above the melting point which, in the absence of an external magnetic field, spontaneously collapses to; (2) an artificial spin ice state, which after cooling forms either; (3) a spin glass state with low bulk remanence, or; (4) a ferromagnetic state with high bulk remanence when cooled in the presence of an external magnetic field. We observe the spontaneous emergence of 2D magnetic vortices in the spin ice and elucidate the correlation of these vortex structures with the external bulk remanence. We also demonstrate the easy programming of magnetically latching structures.
Aberrant ventral dentate gyrus structure and function in trauma susceptible mice
Authors: Dirven Bart C. J. , van der Geugten Dewi , Temporão Carolina , van Bodegom Miranda , Madder Leonie , van Agen Laura , Homberg Judith R. , Kozicz Tamas , Henckens Marloes J.A.G.
Published: December 2022

Post-traumatic stress disorder (PTSD) is a psychiatric disorder vulnerable individuals can develop following a traumatic event, whereas others are resilient. Enhanced insight into the mechanistic underpinnings contributing to these inter-individual differences in trauma susceptibility is key to improved treatment and prevention. Aberrant function of the hippocampal dentate gyrus (DG) may contribute to its psychopathology, with the dorsal DG potentially encoding trauma memory generalization and the ventral DG anxiety. Using a mouse model, we hypothesized that susceptibility to develop PTSD-like symptoms following trauma will be underpinned by aberrant DG structure and function. Mice were exposed to a traumatic event (unpredictable, inescapable foot shocks) and tested for PTSD-like symptomatology following recovery. In four independent experiments, DG neuronal morphology, synaptic protein gene and protein expression, and neuronal activity during trauma encoding and recall were assessed. Behaviorally, trauma-susceptible animals displayed increased anxiety-like behavior already prior to trauma, increased novelty-induced freezing, but no clear differences in remote trauma memory recall. Comparison of the ventral DG of trauma susceptible vs resilient mice revealed lower spine density, reduced expression of the postsynaptic protein homer1b/c gene and protein, a larger population of neurons active during trauma encoding, and a greater presence of somatostatin neurons. In contrast, the dorsal DG of trauma-susceptible animals did not differ in terms of spine density or gene expression but displayed more active neurons during trauma encoding and a lower amount of somatostatin neurons. Collectively, we here report on specific structural and functional changes in the ventral DG in trauma susceptible male mice.
Second- and third-line treatment strategies in multiple myeloma: a referral-center experience
Authors: Goldman-Mazur Sarah , Visram Alissa , Rajkumar S. Vincent , Kapoor Prashant , Dispenzieri Angela , Lacy Martha Q. , Gertz Morie A. , Buadi Francis K. , Hayman Suzanne R. , Dingli David , Kourelis Taxiarchis , Gonsalves Wilson , Warsame Rahma , Muchtar Eli , Leung Nelson , Kyle Robert A. , Kumar Shaji K.
Published: December 2022

The treatment landscape for relapsed multiple myeloma (MM) has increased. In this study, we aimed to characterize 2nd (n = 1439) and 3rd (n = 1104) line regimens and compare the results between subgroups based on the year of treatment initiation (2nd line: 2003–2008, 2009–2015, 2016–2021; 3rd line: 2004–2009, 2010–2015, and 2016–2021). In both the second- and third- lines, we observed increasing use of novel agents (from 78 to 95% and from 77 to 95%, respectively) and triplet regimens (from 15 to 69% and from 21 to 71%, respectively). The most frequently used regimens in the last studied periods included lenalidomide-dexamethasone (RD; 14%), carfilzomib-RD (12%), and daratumumab-RD (10%) for the second-line, and daratumumab-pomalidomide-dexamethasone (11%) and daratumumab-RD (10%) for the third-line. The median time to the next treatment from second-line therapy has improved from 10.4 months (95% CI: 8.4–12.4) to 16.6 months (95% CI: 13.3–20.3; p < 0.001). The median overall survival from the first relapse increased from 30.9 months (95% CI: 26.8–183.0) to 65.8 months (95% CI: 50.7–72.8; p < 0.001). Over the last two decades, more patients were treated with newer agents and triplets for relapsed MM. The landscape of regimens has become more diverse, and survival after the first relapse is continually improving.
RBCK1 regulates the progression of ER-positive breast cancer through the HIF1α signaling
Authors: Niu Zhiguo , Fan Jianing , Chen Fengzhe , Yang Huijie , Li Xin , Zhuang Ting , Guo Chunlei , Cao Qi , Zhu Jian , Wang Hui , Huang Qingsong
Published: December 2022

Breast cancer is the most common malignancy in women on a global scale. It can generally be divided into four main categories, of which estrogen receptor ER-positive breast cancer accounts for most breast cancer cases. RBCK1 protein is an E3 ubiquitin ligase containing the UBL, NZF, and RBR domains. It is well known to exhibit abnormal expression in breast tumors, making it a valuable diagnostic marker and drug target. Additionally, studies have confirmed that in breast cancer, about 25 to 40% of tumors appear as visible hypoxic regions, while in hypoxia, tumor cells can activate the hypoxia-inducing factor HIF1 pathway and widely activate the expression of downstream genes. Previous studies have confirmed that in the hypoxic environment of tumors, HIF1α promotes the remodeling of extracellular matrix, induces the recruitment of tumor-associated macrophages (TAM) and immunosuppression of allogeneic tumors, thereby influencing tumor recurrence and metastasis. This research aims to identify RBCK1 as an important regulator of HIF1α signaling pathway. Targeted therapy with RBCK1 could be a promising treatment strategy for ER-positive breast cancer.
Natural product preferentially targets redox and metabolic adaptations and aberrantly active STAT3 to inhibit breast tumor growth in vivo
Authors: Zhu Yinsong , Yue Peibin , Dickinson Cody F. , Yang Justin K. , Datanagan Kyrstin , Zhai Ning , Zhang Yi , Miklossy Gabriella , Lopez-Tapia Francisco , Tius Marcus A. , Turkson James
Published: December 2022

Dysregulated gene expression programs and redox and metabolic adaptations allow cancer cells to survive under high oxidative burden. These mechanisms also represent therapeutic vulnerabilities. Using triple-negative breast cancer (TNBC) as a model, we show that compared to normal human breast epithelial cells, the TNBC cells, MDA-MB-231 and MDA-MB-468 that harbor constitutively active STAT3 also express higher glucose-6-phosphate dehydrogenase (G6PD), thioredoxin reductase (TrxR)1, NADPH, and GSH levels for survival. Present studies discover that the natural product, R001, targets these adaptation mechanisms. Treatment of TNBC cells with R001 inhibited constitutively active STAT3, STAT3-regulated gene expression, and the functions of G6PD and TrxR1. Consequently, in the TNBC, but not normal cells, R001 suppressed GSH levels, but raised NADPH levels, reflective of a loss of mitochondrial respiration and which led to reactive oxygen species (ROS) induction, all of which led to loss of viable cells and inhibition of anchorage-dependent and independent growth. R001 treatment further led to early pyroptosis and late DNA damage, cell cycle arrest, and apoptosis only in the TNBC cells. Oral administration of 5 mg/kg R001 inhibited MDA-MB-468 xenografts growth in mice, with reduced pY705-STAT3, G6PD, TrxR1, and GSH levels. R001 serves as a therapeutic entity that targets the vulnerabilities of TNBC cells to inhibit tumor growth in vivo.
Bacterial protein MakA causes suppression of tumour cell proliferation via inhibition of PIP5K1α/Akt signalling
Authors: Toh Eric , Baryalai Palwasha , Nadeem Aftab , Aung Kyaw Min , Chen Sa , Persson Karina , Persson Jenny L. , Uhlin Bernt Eric , Wai Sun Nyunt
Published: December 2022

Recently, we demonstrated that a novel bacterial cytotoxin, the protein MakA which is released by Vibrio cholerae, is a virulence factor, causing killing of Caenorhabditis elegans when the worms are grazing on the bacteria. Studies with mammalian cell cultures in vitro indicated that MakA could affect eukaryotic cell signalling pathways involved in lipid biosynthesis. MakA treatment of colon cancer cells in vitro caused inhibition of growth and loss of cell viability. These findings prompted us to investigate possible signalling pathways that could be targets of the MakA-mediated inhibition of tumour cell proliferation. Initial in vivo studies with MakA producing V. cholerae and C. elegans suggested that the MakA protein might target the PIP5K1α phospholipid-signalling pathway in the worms. Intriguingly, MakA was then found to inhibit the PIP5K1α lipid-signalling pathway in cancer cells, resulting in a decrease in PIP5K1α and pAkt expression. Further analyses revealed that MakA inhibited cyclin-dependent kinase 1 (CDK1) and induced p27 expression, resulting in G2/M cell cycle arrest. Moreover, MakA induced downregulation of Ki67 and cyclin D1, which led to inhibition of cell proliferation. This is the first report about a bacterial protein that may target signalling involving the cancer cell lipid modulator PIP5K1α in colon cancer cells, implying an anti-cancer effect.
The chromatin remodeler CHD6 promotes colorectal cancer development by regulating TMEM65-mediated mitochondrial dynamics via EGF and Wnt signaling
Authors: Zhang Boyu , Liu Qingxin , Wen Weijie , Gao Han , Wei Wenxia , Tang Aiwen , Qin Baifu , Lyu Haiwen , Meng Xiangqi , Li Kai , Jin Huilin , Yu Fenghai , Pan Qihao , Lin Junzhong , Lee Mong-Hong
Published: December 2022

Chromodomain helicase DNA binding protein (CHD) family plays critical roles in regulating gene transcription. The family is linked to cancer disease, but the family member’s role in tumorigenesis remains largely unknown. Here, we report that CHD6 is highly expressed in colorectal cancer (CRC). CHD6 knockdown inhibited cancer cell proliferation, migration, invasion, and tumorigenesis. Consistently, Villin-specific Chd6 knockout in mice attenuates cancer formation in AOM/DSS model. We found that aberrant EGF signals promoted the stability of CHD6 by diminishing ubiquitin-mediated degradation. EGF signal inhibits GSK3β activity, which in turn prevents phosphodegron formation of CHD6, thereby hindering E3 ligase FBXW7-mediated CHD6 ubiquitination and degradation. CHD6’s chromatin remodeler activity engages in binding Wnt signaling transcription factor TCF4 to facilitate the transcriptional expression of TMEM65, a mitochondrial inner membrane protein involved in ATP production and mitochondrial dynamics. In addition, Wnt signaling is also an upstream regulator of CHD6. CHD6 promoter contains TCF4 and β-catenin binding site, and CHD6 can be transcriptionally activated by Wnt ligand to facilitate TMEM65 transcription. Thus CHD6-TMEM65 axis can be regulated by both EGF and Wnt signaling pathways through two different mechanisms. We further illustrate that CHD6-TMEM65 axis is deregulated in cancer and that co-administration of Wnt inhibitor LGK974 and the anti-EGFR monoclonal antibody cetuximab largely restricted the growth of patient-derived xenografts of CRC. Targeting CHD6-TMEM65 axis may be effective for cancer intervention.
Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing
Authors: Hocking Lynne J. , Andrews Claire , Armstrong Christine , Ansari Morad , Baty David , Berg Jonathan , Bradley Therese , Clark Caroline , Diamond Austin , Doherty Jill , Lampe Anne , McGowan Ruth , Moore David J. , O’Sullivan Dawn , Purvis Andrew , Santoyo-Lopez Javier , Westwood Paul , Abbott Michael , Williams Nicola ,   Scottish Genomes Partnership, Aitman Timothy J. , Biankin Andrew V. , Cooke Susanna L. , Humphrey Wendy Inglis , Martin Sancha , Meynert Alison , Murphy Fiona , Nourse Craig , Semple Colin A. , Williams Nicola , Dean John , Foley Patricia , Robertson Lisa , Ross Alison , Williamson Karen , Berg Jonathan , Goudie David , McWilliam Catherine , Fitzpatrick David , Fletcher Elaine , Jackson Andrew , Lam Wayne , Porteous Mary , Barr Kate , Bradshaw Nicola , Davidson Rosemarie , Gardiner Carol , Gorrie Jennifer , Hague Rosie , Hamilton Mark , Joss Shelagh , Kinning Esther , Longman Cheryl , Martin Neil , McGowan Ruth , Paterson Jenny , Pilz Daniela , Snadden Lesley , Tobias Edward , Wedderburn Sarah , Whiteford Margo , Aitman Timothy J. , Miedzybrodzka Zosia
Published: December 2022

NHS genetics centres in Scotland sought to investigate the Genomics England 100,000 Genomes Project diagnostic utility to evaluate genome sequencing for in rare, inherited conditions. Four regional services recruited 999 individuals from 394 families in 200 rare phenotype categories, with negative historic genetic testing. Genome sequencing was performed at Edinburgh Genomics, and phenotype and sequence data were transferred to Genomics England for variant calling, gene-based filtering and variant prioritisation. NHS Scotland genetics laboratories performed interpretation, validation and reporting. New diagnoses were made in 23% cases – 19% in genes implicated in disease at the time of variant prioritisation, and 4% from later review of additional genes. Diagnostic yield varied considerably between phenotype categories and was minimal in cases with prior exome testing. Genome sequencing with gene panel filtering and reporting achieved improved diagnostic yield over previous historic testing but not over now routine trio-exome sequence tests. Re-interpretation of genomic data with updated gene panels modestly improved diagnostic yield at minimal cost. However, to justify the additional costs of genome vs exome sequencing, efficient methods for analysis of structural variation will be required and / or cost of genome analysis and storage will need to decrease.
New globally distributed bacterial phyla within the FCB superphylum
Authors: Gong Xianzhe , del Río Álvaro Rodríguez , Xu Le , Chen Zhiyi , Langwig Marguerite V. , Su Lei , Sun Mingxue , Huerta-Cepas Jaime , De Anda Valerie , Baker Brett J.
Published: December 2022

Microbes in marine sediments play crucial roles in global carbon and nutrient cycling. However, our understanding of microbial diversity and physiology on the ocean floor is limited. Here, we use phylogenomic analyses of thousands of metagenome-assembled genomes (MAGs) from coastal and deep-sea sediments to identify 55 MAGs that are phylogenetically distinct from previously described bacterial phyla. We propose that these MAGs belong to 4 novel bacterial phyla (Blakebacterota, Orphanbacterota, Arandabacterota, and Joyebacterota) and a previously proposed phylum (AABM5-125-24), all of them within the FCB superphylum. Comparison of their rRNA genes with public databases reveals that these phyla are globally distributed in different habitats, including marine, freshwater, and terrestrial environments. Genomic analyses suggest these organisms are capable of mediating key steps in sedimentary biogeochemistry, including anaerobic degradation of polysaccharides and proteins, and respiration of sulfur and nitrogen. Interestingly, these genomes code for an unusually high proportion (~9% on average, up to 20% per genome) of protein families lacking representatives in public databases. Genes encoding hundreds of these protein families colocalize with genes predicted to be involved in sulfur reduction, nitrogen cycling, energy conservation, and degradation of organic compounds. Our findings advance our understanding of bacterial diversity, the ecological roles of these bacteria, and potential links between novel gene families and metabolic processes in the oceans.
Ruminant inner ear shape records 35 million years of neutral evolution
Authors: Mennecart Bastien , Dziomber Laura , Aiglstorfer Manuela , Bibi Faysal , DeMiguel Daniel , Fujita Masaki , Kubo Mugino O. , Laurens Flavie , Meng Jin , Métais Grégoire , Müller Bert , Ríos María , Rössner Gertrud E. , Sánchez Israel M. , Schulz Georg , Wang Shiqi , Costeur Loïc
Published: December 2022

Extrinsic and intrinsic factors impact diversity. On deep-time scales, the extrinsic impact of climate and geology are crucial, but poorly understood. Here, we use the inner ear morphology of ruminant artiodactyls to test for a deep-time correlation between a low adaptive anatomical structure and both extrinsic and intrinsic variables. We apply geometric morphometric analyses in a phylogenetic frame to X-ray computed tomographic data from 191 ruminant species. Contrasting results across ruminant clades show that neutral evolutionary processes over time may strongly influence the evolution of inner ear morphology. Extant, ecologically diversified clades increase their evolutionary rate with decreasing Cenozoic global temperatures. Evolutionary rate peaks with the colonization of new continents. Simultaneously, ecologically restricted clades show declining or unchanged rates. These results suggest that both climate and paleogeography produced heterogeneous environments, which likely facilitated Cervidae and Bovidae diversification and exemplifies the effect of extrinsic and intrinsic factors on evolution in ruminants.
Spin-defect qubits in two-dimensional transition metal dichalcogenides operating at telecom wavelengths
Authors: Lee Yeonghun , Hu Yaoqiao , Lang Xiuyao , Kim Dongwook , Li Kejun , Ping Yuan , Fu Kai-Mei C. , Cho Kyeongjae
Published: December 2022

Solid state quantum defects are promising candidates for scalable quantum information systems which can be seamlessly integrated with the conventional semiconductor electronic devices within the 3D monolithically integrated hybrid classical-quantum devices. Diamond nitrogen-vacancy (NV) center defects are the representative examples, but the controlled positioning of an NV center within bulk diamond is an outstanding challenge. Furthermore, quantum defect properties may not be easily tuned for bulk crystalline quantum defects. In comparison, 2D semiconductors, such as transition metal dichalcogenides (TMDs), are promising solid platform to host a quantum defect with tunable properties and a possibility of position control. Here, we computationally discover a promising defect family for spin qubit realization in 2D TMDs. The defects consist of transition metal atoms substituted at chalcogen sites with desirable spin-triplet ground state, zero-field splitting in the tens of GHz, and strong zero-phonon coupling to optical transitions in the highly desirable telecom band.
Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma
Authors: Kameda-Smith Michelle M. , Zhu Helen , Luo En-Ching , Suk Yujin , Xella Agata , Yee Brian , Chokshi Chirayu , Xing Sansi , Tan Frederick , Fox Raymond G. , Adile Ashley A. , Bakhshinyan David , Brown Kevin , Gwynne William D. , Subapanditha Minomi , Miletic Petar , Picard Daniel , Burns Ian , Moffat Jason , Paruch Kamil , Fleming Adam , Hope Kristin , Provias John P. , Remke Marc , Lu Yu , Reya Tannishtha , Venugopal Chitra , Reimand Jüri , Wechsler-Reya Robert J. , Yeo Gene W. , Singh Sheila K.
Published: December 2022

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.
A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes
Authors: Alharthi Jawaher , Bayoumi Ali , Thabet Khaled , Pan Ziyan , Gloss Brian S. , Latchoumanin Olivier , Lundberg Mischa , Twine Natalie A. , McLeod Duncan , Alenizi Shafi , Adams Leon A. , Weltman Martin , Berg Thomas , Liddle Christopher , George Jacob , Eslam Mohammed
Published: December 2022

The breakdown of toll-like receptor (TLR) tolerance results in tissue damage, and hyperactivation of the TLRs and subsequent inflammatory consequences have been implicated as risk factors for more severe forms of disease and poor outcomes from various diseases including COVID-19 and metabolic (dysfunction) associated fatty liver disease (MAFLD). Here we provide evidence that membrane bound O-acyltransferase domain containing 7 (MBOAT7) is a negative regulator of TLR signalling. MBOAT7 deficiency in macrophages as observed in patients with MAFLD and in COVID-19, alters membrane phospholipid composition. We demonstrate that this is associated with a redistribution of arachidonic acid toward proinflammatory eicosanoids, induction of endoplasmic reticulum stress, mitochondrial dysfunction, and remodelling of the accessible inflammatory-related chromatin landscape culminating in macrophage inflammatory responses to TLRs. Activation of MBOAT7 reverses these effects. These outcomes are further modulated by the MBOAT7 rs8736 (T) MAFLD risk variant. Our findings suggest that MBOAT7 can potentially be explored as a therapeutic target for diseases associated with dysregulation of the TLR signalling cascade.
The dynamic clustering of insulin receptor underlies its signaling and is disrupted in insulin resistance
Authors: Dall’Agnese Alessandra , Platt Jesse M. , Zheng Ming M. , Friesen Max , Dall’Agnese Giuseppe , Blaise Alyssa M. , Spinelli Jessica B. , Henninger Jonathan E. , Tevonian Erin N. , Hannett Nancy M. , Lazaris Charalampos , Drescher Hannah K. , Bartsch Lea M. , Kilgore Henry R. , Jaenisch Rudolf , Griffith Linda G. , Cisse Ibrahim I. , Jeppesen Jacob F. , Lee Tong I. , Young Richard A.
Published: December 2022

Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches.
Liquid water on cold exo-Earths via basal melting of ice sheets
Authors: Ojha Lujendra , Troncone Bryce , Buffo Jacob , Journaux Baptiste , McDonald George
Published: December 2022

Liquid water is a critical component of habitability. However, the production and stability of surficial liquid water can be challenging on planets outside the Habitable Zone and devoid of adequate greenhouse warming. On such cold, icy exo-Earths, basal melting of regional/global ice sheets by geothermal heat provides an alternative means of forming liquid water. Here, we model the thermophysical evolution of ice sheets to ascertain the geophysical conditions that allow liquid water to be produced and maintained at temperatures above the pressure-controlled freezing point of water ice on exo-Earths. We show that even with a modest, Moon-like geothermal heat flow, subglacial oceans of liquid water can form at the base of and within the ice sheets on exo-Earths. Furthermore, subglacial oceans may persist on exo-Earths for a prolonged period due to the billion-year half-lives of heat-producing elements responsible for geothermal heat. These subglacial oceans, often in contact with the planet’s crust and shielded from the high energy radiation of their parent star by thick ice layers, may provide habitable conditions for an extended period.
Next generation genetically encoded fluorescent sensors for serotonin
Authors: Kubitschke Martin , Müller Monika , Wallhorn Lutz , Pulin Mauro , Mittag Manuel , Pollok Stefan , Ziebarth Tim , Bremshey Svenja , Gerdey Jill , Claussen Kristin Carolin , Renken Kim , Groß Juliana , Gneiße Pascal , Meyer Niklas , Wiegert J. Simon , Reiner Andreas , Fuhrmann Martin , Masseck Olivia Andrea
Published: December 2022

We developed a family of genetically encoded serotonin (5-HT) sensors (sDarken) on the basis of the native 5-HT1A receptor and circularly permuted GFP. sDarken 5-HT sensors are bright in the unbound state and diminish their fluorescence upon binding of 5-HT. Sensor variants with different affinities for serotonin were engineered to increase the versatility in imaging of serotonin dynamics. Experiments in vitro and in vivo showed the feasibility of imaging serotonin dynamics with high temporal and spatial resolution. As demonstrated here, the designed sensors show excellent membrane expression, have high specificity and a superior signal-to-noise ratio, detect the endogenous release of serotonin and are suitable for two-photon in vivo imaging.
25-year retrospective longitudinal study on seasonal allergic rhinitis associations with air temperature in general practice
Authors: Schreurs Wendy , Schermer Tjard Ronald Jacob , Akkermans Reinier Peter , Bischoff Erik Wiely Maria Anton , Luijks Hilde Dymphna
Published: December 2022

Due to climate change, air temperature in the Netherlands has gradually increased. Higher temperatures lead to longer pollen seasons. Possible relations between air temperature and increased impact of seasonal allergic rhinitis (SAR) in general practice have not been investigated yet. We explored trends in timing of frequent seasonal allergic rhinitis presentation to general practitioners (GPs) over 25 years and explored associations with air temperature. We performed a retrospective exploratory longitudinal study with data from our Family Medicine Network (1995–2019), including all SAR patients and their GP-encounters per week. We determined patients’ GP-consultation frequency. Every year we identified seasonal periods with substantial increase in SAR related encounters: peak-periods. We determined start date and duration of the peak-period and assessed associations with air temperature in the beginning and throughout the year, respectively. The peak-period duration increased by a mean of 1.3 days (95% CI 0.23–2.45, P = 0.02) per year throughout the study period. Air temperature between February and July showed a statistically significant association with peak-period duration. We could not observe direct effects of warmer years on the start of peak-periods within distinct years (P = 0.06). SAR patients’ contact frequency slightly increased by 0.01 contacts per year (95% CI 0.002–0.017, P = 0.015). These longitudinal findings may help to facilitate further research on the impact of climate change, and raise awareness of the tangible impact of climate change in general practice.
Validation of grip strength as a measure of frailty in rheumatoid arthritis
Authors: Sobue Yasumori , Suzuki Mochihito , Ohashi Yoshifumi , Koshima Hiroshi , Okui Nobuyuki , Funahashi Koji , Ishikawa Hisato , Inoue Hidenori , Kojima Masayo , Asai Shuji , Terabe Kenya , Kishimoto Kenji , Maeda Masataka , Kihira Daisuke , Imagama Shiro , Kojima Toshihisa
Published: December 2022

Rheumatoid arthritis (RA) patients often exhibit finger/wrist joint symptoms and reduced grip strength. This study aimed to validate grip strength as a measure of frailty in RA patients. Subjects were 424 female RA patients (mean age ± standard deviation, 66.8 ± 14.5 years). Frailty was defined as a score of ≥ 8 points on the Kihon Checklist (KCL). Finger/wrist joint symptoms were defined based on tender or swollen joints. Associations between frailty and grip strength were determined using receiver operating characteristic (ROC) curve analysis and multivariable logistic regression analysis. There were 179 subjects with frailty (42.2%). Multivariable logistic regression analysis revealed that frailty was significantly associated with grip strength independently of finger/wrist joint symptoms. In ROC curves, cut-off scores of grip strength for frailty in subjects without and with finger/wrist joint symptoms were 17 kg (sensitivity, 62.1%; specificity, 69.0%) and 14 kg (sensitivity, 63.2%; specificity, 73.0%), respectively. The results of the present study suggest that grip strength in female RA patients is associated with frailty, with a cut-off score of 17 kg (equivalent to Cardiovascular Health Study criteria, < 18 kg) when RA patients have no finger/wrist joint symptoms. However, when RA patients have finger/wrist joint symptoms, it may be considered to reduce the cut-off score of grip strength.
Machine learning for exploring neurophysiological functionality in multiple sclerosis based on trigeminal and hand blink reflexes
Authors: Biggio Monica , Caligiore Daniele , D’Antoni Federico , Bove Marco , Merone Mario
Published: December 2022

Brainstem dysfunctions are very common in Multiple Sclerosis (MS) and are a critical predictive factor for future disability. Brainstem functionality can be explored with blink reflexes, subcortical responses consisting in a blink following a peripheral stimulation. Some reflexes are already employed in clinical practice, such as Trigeminal Blink Reflex (TBR). Here we propose for the first time in MS the exploration of Hand Blink Reflex (HBR), which size is modulated by the proximity of the stimulated hand to the face, reflecting the extension of the peripersonal space. The aim of this work is to test whether Machine Learning (ML) techniques could be used in combination with neurophysiological measurements such as TBR and HBR to improve their clinical information and potentially favour the early detection of brainstem dysfunctionality. HBR and TBR were recorded from a group of People with MS (PwMS) with Relapsing-Remitting form and from a healthy control group. Two AdaBoost classifiers were trained with TBR and HBR features each, for a binary classification task between PwMS and Controls. Both classifiers were able to identify PwMS with an accuracy comparable and even higher than clinicians. Our results indicate that ML techniques could represent a tool for clinicians for investigating brainstem functionality in MS. Also, HBR could be promising when applied in clinical practice, providing additional information about the integrity of brainstem circuits potentially favouring early diagnosis.
The transmembrane domains mediate oligomerization of the human ZIP4 transporter in vivo
Authors: Liu Yuting , Bafaro Elizabeth M. , Cowan Ann E. , Dempski Robert E.
Published: December 2022

The human (h) ZIP4 is a plasma membrane transporter that functions to increase cytosolic zinc levels. hZIP4 encodes eight transmembrane domains and a large extracellular domain (ECD). This ECD is cleaved from the holo-transporter when cells are zinc-deficient. At the same time, mutations in the ECD can result in the zinc-deficiency disease Acrodermatitis enteropathica. Previously, it was shown that hZIP4’s ECD is comprised of two structurally independent subdomains where contacts between the ECD monomeric units are centered at the PAL motif. These results lead to the hypothesis that ZIP4-ECD is essential to the dimerization of the holo-transporter. To test this hypothesis, we used Fluorescence Correlation Spectroscopy (FCS) to quantify the oligomeric state of full-length hZIP4 and hZIP4 lacking the ECD domain, each tagged with eGFP. Inspection of our experimental results demonstrate that both the full-length and truncated hZIP4 is a dimer when expressed in HEK293 cells. Parallel functional experiments demonstrate that the Km and Vmax for truncated and full-length hZIP4/eGFP are similar. Determining that truncated hZIP4/eGFP forms a dimer is a crucial step for understanding the function of the hZIP4-ECD, which provides more insight into how the diseases related to hZIP4 protein.
Statistical power for MACE and individual secondary endpoints in cardiovascular outcomes trials for type 2 diabetes: a systematic review
Authors: Birker Sebastian , Meier Juris J. , Nauck Michael A.
Published: December 2022

Cardiovascular outcomes trials (CVOTs) with novel drugs to treat type 2 diabetes have uniformly chosen the composite “major adverse cardiovascular events (MACE)” as their primary endpoint, but they also report hazard ratios for individual cardiovascular outcomes (myocardial infarction, stroke, cardiovascular death, all-cause death, hospitalization for heart failure). We wanted to scrutinize the power to identify significant differences with respect to individual as compared to composite outcomes. We estimated post hoc the statistical power to detect significant differences of 10–25% for published studies, comparing the proportions of patients with an event (two-sided log-rank tests). For MACE, the power to detect a 15% difference ranged from 82.3 to 100.0% for larger trials, but was only 69.1 and 50.5 for smaller, preliminary trials (SUSTAIN-6 and PIONEER-6). For individual endpoints, the power, as a rule, was substantially lower. In conclusion, cardiovascular outcomes trials had appropriate power to detect significant reductions in hazard ratios with respect to the primary endpoint, but not for individual cardiovascular outcomes. This was particularly the case for small, preliminary studies. Our results call for caution when comparing results regarding individual endpoints between CVOTs, if the aim is to identify heterogeneity within or between medication classes.
The effect of explantation on systemic disease symptoms and quality of life in patients with breast implant illness: a prospective cohort study
Authors: Bird G. R. , Niessen F. B.
Published: December 2022

Silicone breast implants (SBIs) have been subject to scientific scrutiny since the 1960’s because of their potential link with systemic disease symptoms. Breast implant illness (BII) is a cluster of over 56 (systemic) symptoms attributed by patients to their SBIs. BII remains an unofficial medical diagnosis, although its symptoms include but are not limited to the clinical manifestations of autoimmune/inflammatory syndrome induced by adjuvants (ASIA). The aim of this study was to prospectively analyse the effect of explantation on clinical manifestations of ASIA/BII symptoms, as well as to compare (breast-surgery specific) QoL in patients pre- and postoperatively while recording relevant perioperative/patient data. A prospective cohort study was conducted on 140 patients consulting a single surgeon for explantation of SBIs at a single clinic from 2019 to 2021 via their general practitioner, a medical specialist or self-referral. Of all patients, medical (implant) history, lifestyle factors and biometric data were obtained. Patients filled out a novel ASIA/BII symptom-survey termed the ASIA-scale, three domains of the SF-36 and the augmentation module of the BREAST-Q before and four months after the operation. A total of 109 patients completed both the pre- and postoperative survey with a mean follow-up duration of 205 days. There was a significant decrease in all individual symptom scores as well as ASIA-scale summary scores after explantation (p < .001). All SF-36 subdomains showed significant improvement postoperatively (p < .001). The BREAST-Q subdomain ‘satisfaction with breasts’ improved significantly after explantation (p = .036). No statistically significant association was found between any clinical parameters (such as age, capsulectomy, rupture etc.) and the recovery of symptom scores. This is the largest prospective cohort study on SBI explantation to date showing significant improvement of the most common systemic complaints in SBI patients as well as improvement of satisfaction with breasts and overall quality of life.
Optimization of magnetic nano-iron production by Aspergillus flavipes MN956655.1 using response surface methodology and evaluation of their dye decolorizing and antifungal activities
Authors: Abdullah Nashwa H.
Published: December 2022

Iron nanoparticles have been biosynthesized by a newAspergillus flavipesisolate. Size of biosynthesized iron nanoparticles was in a range of 32.7 and 47.6 nm, their surface charge was − 33.5 ± 5.3 and they showed semihard ferromagnetic behavior. Salt concentration, volume of added culture filtrate and pH have been optimized using response surface methodology. A significant effect for the added culture filtrate and a mutual interaction between this factor and the pH has been detected. Model validation results showed 3.3% deviation from the statistically predicted values which reflects the accuracy of the employed model. Optimization process has increased the quantity of iron in the prepared samples and the amount of produced iron nanoparticles to a fourfold. The optimized conditions have stimulated the formation of nanoparticles in a tetrahedron shape rather than the truncated tetrahedron shape without affecting their size or surface charge. The biosynthesized iron nanoparticles have recorded a good decolorization activity for methylene blue. They showed 57 ± 4.3 decolorization percent after 6 h when tested with only 0.1 mg/ml concentration. Moreover, 50 ppm concentration has exerted a detectable antifungal activity againstAlternaria solani. This study represents a new competitive green synthesis method for magnetic iron nanoparticle.
Synthesis and in vitro antibacterial, antifungal, anti-proliferative activities of novel adamantane-containing thiazole compounds
Authors: Warda Eman T. , El-Ashmawy Mahmoud B. , Habib El-Sayed E. , Abdelbaky Mohammed S. M. , Garcia-Granda Santiago , Thamotharan Subbiah , El-Emam Ali A.
Published: December 2022

A series of (Z)-N-(adamantan-1-yl)-3,4-diarylthiazol-2(3H)-imines (5a-r) was synthesized via condensation of 1-(adamantan-1-yl)-3-arylthioureas (3a-c) with various aryl bromomethyl ketones (4a-f). The structures of the synthesized compounds were characterized by 1H NMR, 13C NMR and by X-ray crystallography. The in vitro inhibitory activities of the synthesized compounds were assessed against a panel of Gram-positive and Gram-negative bacteria, and pathogenic fungi. Compounds 5c, 5g, 5l, 5m, and 5q displayed potent broad-spectrum antibacterial activity, while compounds 5a and 5o showed activity against the tested Gram-positive bacteria. Compounds 5b, 5l and 5q displayed potent antifungal activity against Candida albicans. In addition, the synthesized compounds were evaluated for anti-proliferative activity towards five human tumor cell lines. The optimal anti-proliferative activity was attained by compounds 5e and 5k which showed potent inhibitory activity against all the tested cell lines. Molecular docking analysis reveals that compounds 5e and 5k can occupy the positions of NAD cofactor and the histone deacetylase inhibitor EX527 at the active site of SIRT1 enzyme.