bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoxia-induced immortalization of primary cells depends on Tfcp2L1 expression
Authors: Otero-Albiol D. , Santos-Pereira J. M. , Lucena-Cacace A. , Clemente-González C. , Muñoz-Galvan S. , Yoshida Y. , Carnero A.
Published: February 2024

Cellular senescence is a stress response mechanism that induces proliferative arrest. Hypoxia can bypass senescence and extend the lifespan of primary cells, mainly by decreasing oxidative damage. However, how hypoxia promotes these effects prior to malignant transformation is unknown. Here we observed that the lifespan of mouse embryonic fibroblasts (MEFs) is increased when they are cultured in hypoxia by reducing the expression of p16INK4a, p15INK4b and p21Cip1. We found that proliferating MEFs in hypoxia overexpress Tfcp2l1, which is a main regulator of pluripotency and self-renewal in embryonic stem cells, as well as stemness genes including Oct3/4, Sox2 and Nanog. Tfcp2l1 expression is lost during culture in normoxia, and its expression in hypoxia is regulated by Hif1α. Consistently, its overexpression in hypoxic levels increases the lifespan of MEFs and promotes the overexpression of stemness genes. ATAC-seq and Chip-seq experiments showed that Tfcp2l1 regulates genes that control proliferation and stemness such as Sox2, Sox9, Jarid2 and Ezh2. Additionally, Tfcp2l1 can replicate the hypoxic effect of increasing cellular reprogramming. Altogether, our data suggest that the activation of Tfcp2l1 by hypoxia contributes to immortalization prior to malignant transformation, facilitating tumorigenesis and dedifferentiation by regulating Sox2, Sox9, and Jarid2.
Marine protected areas promote stability of reef fish communities under climate warming
Authors: Benedetti-Cecchi Lisandro , Bates Amanda E. , Strona Giovanni , Bulleri Fabio , Horta e Costa Barbara , Edgar Graham J. , Hereu Bernat , Reed Dan C. , Stuart-Smith Rick D. , Barrett Neville S. , Kushner David J. , Emslie Michael J. , García-Charton Jose Antonio , Gonçalves Emanuel J. , Aspillaga Eneko
Published: February 2024

Protection from direct human impacts can safeguard marine life, yet ocean warming crosses marine protected area boundaries. Here, we test whether protection offers resilience to marine heatwaves from local to network scales. We examine 71,269 timeseries of population abundances for 2269 reef fish species surveyed in 357 protected versus 747 open sites worldwide. We quantify the stability of reef fish abundance from populations to metacommunities, considering responses of species and functional diversity including thermal affinity of different trophic groups. Overall, protection mitigates adverse effects of marine heatwaves on fish abundance, community stability, asynchronous fluctuations and functional richness. We find that local stability is positively related to distance from centers of high human density only in protected areas. We provide evidence that networks of protected areas have persistent reef fish communities in warming oceans by maintaining large populations and promoting stability at different levels of biological organization.
Understanding activity-stability tradeoffs in biocatalysts by enzyme proximity sequencing
Authors: Vanella Rosario , Küng Christoph , Schoepfer Alexandre A. , Doffini Vanni , Ren Jin , Nash Michael A.
Published: February 2024

Understanding the complex relationships between enzyme sequence, folding stability and catalytic activity is crucial for applications in industry and biomedicine. However, current enzyme assay technologies are limited by an inability to simultaneously resolve both stability and activity phenotypes and to couple these to gene sequences at large scale. Here we present the development of enzyme proximity sequencing, a deep mutational scanning method that leverages peroxidase-mediated radical labeling with single cell fidelity to dissect the effects of thousands of mutations on stability and catalytic activity of oxidoreductase enzymes in a single experiment. We use enzyme proximity sequencing to analyze how 6399 missense mutations influence folding stability and catalytic activity in a D-amino acid oxidase from Rhodotorula gracilis. The resulting datasets demonstrate activity-based constraints that limit folding stability during natural evolution, and identify hotspots distant from the active site as candidates for mutations that improve catalytic activity without sacrificing stability. Enzyme proximity sequencing can be extended to other enzyme classes and provides valuable insights into biophysical principles governing enzyme structure and function.
Zirconium and hafnium catalyzed C–C single bond hydroboration
Authors: Li Sida , Jiao Haijun , Shu Xing-Zhong , Wu Lipeng
Published: February 2024

Selective cleavage and subsequent functionalization of C−C single bonds present a fundamental challenge in synthetic organic chemistry. Traditionally, the activation of C−C single bonds has been achieved using stoichiometric transition-metal complexes. Recently, examples of catalytic processes were developed in which use is made of precious metals. However, the use of inexpensive and Earth-abundant group IV metals for catalytic C−C single-bond cleavage is largely underdeveloped. Herein, the zirconium-catalyzed C−C single-bond cleavage and subsequent hydroboration reactions is realized using Cp2ZrCl2 as a catalytic system. A series of structures of various γ-boronated amines are readily obtained, which are otherwise difficult to obtain. Mechanistic studies disclose the formation of a N–ZrIV species, and then a β-carbon elimination route is responsible for C–C single bond activation. Besides zirconium, hafnium exhibits a similar performance for this transformation.
Synthetic microbe-to-plant communication channels
Authors: Boo Alice , Toth Tyler , Yu Qiguo , Pfotenhauer Alexander , Fields Brandon D. , Lenaghan Scott C. , Stewart C. Neal , Voigt Christopher A.
Published: February 2024

Plants and microbes communicate to collaborate to stop pests, scavenge nutrients, and react to environmental change. Microbiota consisting of thousands of species interact with each other and plants using a large chemical language that is interpreted by complex regulatory networks. In this work, we develop modular interkingdom communication channels, enabling bacteria to convey environmental stimuli to plants. We introduce a “sender device” in Pseudomonas putida and Klebsiella pneumoniae, that produces the small molecule p-coumaroyl-homoserine lactone (pC-HSL) when the output of a sensor or circuit turns on. This molecule triggers a “receiver device” in the plant to activate gene expression. We validate this system in Arabidopsis thaliana and Solanum tuberosum (potato) grown hydroponically and in soil, demonstrating its modularity by swapping bacteria that process different stimuli, including IPTG, aTc and arsenic. Programmable communication channels between bacteria and plants will enable microbial sentinels to transmit information to crops and provide the building blocks for designing artificial consortia.
Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies
Authors: Wang Bofei , Reville Patrick K. , Yassouf Mhd Yousuf , Jelloul Fatima Z. , Ly Christopher , Desai Poonam N. , Wang Zhe , Borges Pamella , Veletic Ivo , Dasdemir Enes , Burks Jared K. , Tang Guilin , Guo Shengnan , Garza Araceli Isabella , Nasnas Cedric , Vaughn Nicole R. , Baran Natalia , Deng Qing , Matthews Jairo , Gunaratne Preethi H. , Antunes Dinler A. , Ekmekcioglu Suhendan , Sasaki Koji , Garcia Miriam B. , Cuglievan Branko , Hao Dapeng , Daver Naval , Green Michael R. , Konopleva Marina , Futreal Andrew , Post Sean M. , Abbas Hussein A.
Published: February 2024

Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.
A framework for evaluating clinical artificial intelligence systems without ground-truth annotations
Authors: Kiyasseh Dani , Cohen Aaron , Jiang Chengsheng , Altieri Nicholas
Published: February 2024

A clinical artificial intelligence (AI) system is often validated on data withheld during its development. This provides an estimate of its performance upon future deployment on data in the wild; those currently unseen but are expected to be encountered in a clinical setting. However, estimating performance on data in the wild is complicated by distribution shift between data in the wild and withheld data and the absence of ground-truth annotations. Here, we introduce SUDO, a framework for evaluating AI systems on data in the wild. Through experiments on AI systems developed for dermatology images, histopathology patches, and clinical notes, we show that SUDO can identify unreliable predictions, inform the selection of models, and allow for the previously out-of-reach assessment of algorithmic bias for data in the wild without ground-truth annotations. These capabilities can contribute to the deployment of trustworthy and ethical AI systems in medicine.
Cellular reprogramming as a tool to model human aging in a dish
Authors: Pitrez Patricia R. , Monteiro Luis M. , Borgogno Oliver , Nissan Xavier , Mertens Jerome , Ferreira Lino
Published: February 2024

The design of human model systems is highly relevant to unveil the underlying mechanisms of aging and to provide insights on potential interventions to extend human health and life span. In this perspective, we explore the potential of 2D or 3D culture models comprising human induced pluripotent stem cells and transdifferentiated cells obtained from aged or age-related disorder-affected donors to enhance our understanding of human aging and to catalyze the discovery of anti-aging interventions.
A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE
Authors: Tan Lavinia , Brown Chris , Mersiades Antony , Lee Chee Khoon , John Thomas , Kao Steven , Newnham Genni , O’Byrne Kenneth , Parakh Sagun , Bray Victoria , Jasas Kevin , Yip Sonia , Wong Stephen Q. , Ftouni Sarah , Guinto Jerick , Chandrashekar Sushma , Clarke Stephen , Pavlakis Nick , Stockler Martin R. , Dawson Sarah-Jane , Solomon Benjamin J.
Published: February 2024

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5–55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.
Rational molecular and device design enables organic solar cells approaching 20% efficiency
Authors: Fu Jiehao , Yang Qianguang , Huang Peihao , Chung Sein , Cho Kilwon , Kan Zhipeng , Liu Heng , Lu Xinhui , Lang Yongwen , Lai Hanjian , He Feng , Fong Patrick W. K. , Lu Shirong , Yang Yang , Xiao Zeyun , Li Gang
Published: February 2024

For organic solar cells to be competitive, the light-absorbing molecules should simultaneously satisfy multiple key requirements, including weak-absorption charge transfer state, high dielectric constant, suitable surface energy, proper crystallinity, etc. However, the systematic design rule in molecules to achieve the abovementioned goals is rarely studied. In this work, guided by theoretical calculation, we present a rational design of non-fullerene acceptor o-BTP-eC9, with distinct photoelectric properties compared to benchmark BTP-eC9. o-BTP-eC9 based device has uplifted charge transfer state, therefore significantly reducing the energy loss by 41 meV and showing excellent power conversion efficiency of 18.7%. Moreover, the new guest acceptor o-BTP-eC9 has excellent miscibility, crystallinity, and energy level compatibility with BTP-eC9, which enables an efficiency of 19.9% (19.5% certified) in PM6:BTP-C9:o-BTP-eC9 based ternary system with enhanced operational stability.
Functional regulation of aquaporin dynamics by lipid bilayer composition
Authors: Nguyen Anh T. P. , Weigle Austin T. , Shukla Diwakar
Published: February 2024

With the diversity of lipid-protein interactions, any observed membrane protein dynamics or functions directly depend on the lipid bilayer selection. However, the implications of lipid bilayer choice are seldom considered unless characteristic lipid-protein interactions have been previously reported. Using molecular dynamics simulation, we characterize the effects of membrane embedding on plant aquaporin SoPIP2;1, which has no reported high-affinity lipid interactions. The regulatory impacts of a realistic lipid bilayer, and nine different homogeneous bilayers, on varying SoPIP2;1 dynamics are examined. We demonstrate that SoPIP2;1’s structure, thermodynamics, kinetics, and water transport are altered as a function of each membrane construct’s ensemble properties. Notably, the realistic bilayer provides stabilization of non-functional SoPIP2;1 metastable states. Hydrophobic mismatch and lipid order parameter calculations further explain how lipid ensemble properties manipulate SoPIP2;1 behavior. Our results illustrate the importance of careful bilayer selection when studying membrane proteins. To this end, we advise cautionary measures when performing membrane protein molecular dynamics simulations.
Mode-multiplexing deep-strong light-matter coupling
Authors: Mornhinweg Joshua , Diebel Laura Katharina , Halbhuber Maike , Prager Michael , Riepl Josef , Inzenhofer Tobias , Bougeard Dominique , Huber Rupert , Lange Christoph
Published: February 2024

Dressing electronic quantum states with virtual photons creates exotic effects ranging from vacuum-field modified transport to polaritonic chemistry, and squeezing or entanglement of modes. The established paradigm of cavity quantum electrodynamics maximizes the light-matter coupling strength $${\varOmega }_{{{{{{\rm{R}}}}}}}/{\omega }_{{{{{{\rm{c}}}}}}}$$

Ω

R

/

ω

c

, defined as the ratio of the vacuum Rabi frequency and the frequency of light, by resonant interactions. Yet, the finite oscillator strength of a single electronic excitation sets a natural limit to $${\varOmega }_{{{{{{\rm{R}}}}}}}/{\omega }_{{{{{{\rm{c}}}}}}}$$

Ω

R

/

ω

c

. Here, we enter a regime of record-strong light-matter interaction which exploits the cooperative dipole moments of multiple, highly non-resonant magnetoplasmon modes tailored by our metasurface. This creates an ultrabroadband spectrum of 20 polaritons spanning 6 optical octaves, calculated vacuum ground state populations exceeding 1 virtual excitation quantum, and coupling strengths equivalent to $${\varOmega }_{{{{{{\rm{R}}}}}}}/{\omega }_{{{{{{\rm{c}}}}}}}=3.19$$

Ω

R

/

ω

c

=
3.19
. The extreme interaction drives strongly subcycle energy exchange between multiple bosonic vacuum modes akin to high-order nonlinearities, and entangles previously orthogonal electronic excitations solely via vacuum fluctuations.
BTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion
Authors: Yu Xueping , Yang Feifei , Shen Zhongliang , Zhang Yao , Sun Jian , Qiu Chao , Zheng Yijuan , Zhao Weidong , Yuan Songhua , Zeng Dawu , Zhang Shenyan , Long Jianfei , Zhu Mengqi , Zhang Xueyun , Wu Jingwen , Ma Zhenxuan , Zhu Haoxiang , Su Milong , Xu Jianqing , Li Bin , Mao Richeng , Su Zhijun , Zhang Jiming
Published: February 2024

B- and T-lymphocyte attenuator (BTLA) levels are increased in patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This condition is characterized by susceptibility to infection and T-cell immune exhaustion. However, whether BTLA can induce T-cell immune exhaustion and increase the risk of infection remains unclear. Here, we report that BTLA levels are significantly increased in the circulating and intrahepatic CD4+ T cells from patients with HBV-ACLF, and are positively correlated with disease severity, prognosis, and infection complications. BTLA levels were upregulated by the IL-6 and TNF signaling pathways. Antibody crosslinking of BTLA activated the PI3K-Akt pathway to inhibit the activation, proliferation, and cytokine production of CD4+ T cells while promoting their apoptosis. In contrast, BTLA knockdown promoted their activation and proliferation. BTLA-/- ACLF mice exhibited increased cytokine secretion, and reduced mortality and bacterial burden. The administration of a neutralizing anti-BTLA antibody reduced Klebsiella pneumoniae load and mortality in mice with ACLF. These data may help elucidate HBV-ACLF pathogenesis and aid in identifying novel drug targets.
Myriad Mapping of nanoscale minerals reveals calcium carbonate hemihydrate in forming nacre and coral biominerals
Authors: Schmidt Connor A. , Tambutté Eric , Venn Alexander A. , Zou Zhaoyong , Castillo Alvarez Cristina , Devriendt Laurent S. , Bechtel Hans A. , Stifler Cayla A. , Anglemyer Samantha , Breit Carolyn P. , Foust Connor L. , Hopanchuk Andrii , Klaus Connor N. , Kohler Isaac J. , LeCloux Isabelle M. , Mezera Jaiden , Patton Madeline R. , Purisch Annie , Quach Virginia , Sengkhammee Jaden S. , Sristy Tarak , Vattem Shreya , Walch Evan J. , Albéric Marie , Politi Yael , Fratzl Peter , Tambutté Sylvie , Gilbert Pupa U.P.A.
Published: February 2024

Calcium carbonate (CaCO3) is abundant on Earth, is a major component of marine biominerals and thus of sedimentary and metamorphic rocks and it plays a major role in the global carbon cycle by storing atmospheric CO2 into solid biominerals. Six crystalline polymorphs of CaCO3 are known—3 anhydrous: calcite, aragonite, vaterite, and 3 hydrated: ikaite (CaCO3·6H2O), monohydrocalcite (CaCO3·1H2O, MHC), and calcium carbonate hemihydrate (CaCO3·½H2O, CCHH). CCHH was recently discovered and characterized, but exclusively as a synthetic material, not as a naturally occurring mineral. Here, analyzing 200 million spectra with Myriad Mapping (MM) of nanoscale mineral phases, we find CCHH and MHC, along with amorphous precursors, on freshly deposited coral skeleton and nacre surfaces, but not on sea urchin spines. Thus, biomineralization pathways are more complex and diverse than previously understood, opening new questions on isotopes and climate. Crystalline precursors are more accessible than amorphous ones to other spectroscopies and diffraction, in natural and bio-inspired materials.
Coordinated inflammatory responses dictate Marburg virus control by reservoir bats
Authors: Guito Jonathan C. , Kirejczyk Shannon G. M. , Schuh Amy J. , Amman Brian R. , Sealy Tara K. , Graziano James , Spengler Jessica R. , Harmon Jessica R. , Wozniak David M. , Prescott Joseph B. , Towner Jonathan S.
Published: February 2024

Bats are increasingly recognized as reservoirs of emerging zoonotic pathogens. Egyptian rousette bats (ERBs) are the known reservoir of Marburg virus (MARV), a filovirus that causes deadly Marburg virus disease (MVD) in humans. However, ERBs harbor MARV asymptomatically, likely due to a coadapted and specific host immunity-pathogen relationship. Recently, we measured transcriptional responses in MARV-infected ERB whole tissues, showing that these bats possess a disease tolerant strategy that limits pro-inflammatory gene induction, presumably averting MVD-linked immunopathology. However, the host resistant strategy by which ERBs actively limit MARV burden remains elusive, which we hypothesize requires localized inflammatory responses unresolvable at bulk-tissue scale. Here, we use dexamethasone to attenuate ERB pro-inflammatory responses and assess MARV replication, shedding and disease. We show that MARV-infected ERBs naturally mount coordinated pro-inflammatory responses at liver foci of infection, comprised of recruited mononuclear phagocytes and T cells, the latter of which proliferate with likely MARV-specificity. When pro-inflammatory responses are diminished, ERBs display heightened MARV replication, oral/rectal shedding and severe MVD-like liver pathology, demonstrating that ERBs balance immunoprotective tolerance with discreet MARV-resistant pro-inflammatory responses. These data further suggest that natural ERB immunomodulatory stressors like food scarcity and habitat disruption may potentiate viral shedding, transmission and therefore outbreak risk.
Variational quantum algorithm for experimental photonic multiparameter estimation
Authors: Cimini Valeria , Valeri Mauro , Piacentini Simone , Ceccarelli Francesco , Corrielli Giacomo , Osellame Roberto , Spagnolo Nicolò , Sciarrino Fabio
Published: February 2024

Variational quantum metrology represents a powerful tool to optimize estimation strategies, resulting particularly beneficial for multiparameter estimation problems that often suffer from limitations due to the curse of dimensionality and computational complexity. To overcome these challenges, we develop a variational approach able to efficiently optimize a quantum multiphase sensor. Leveraging the reconfigurability of an integrated photonic device, we implement a hybrid quantum-classical feedback loop able to enhance the estimation performances. The quantum circuit evaluations are used to compute the system partial derivatives by applying the parameter-shift rule, and thus reconstruct experimentally the Fisher information matrix. This in turn is adopted as the cost function of a classical learning algorithm run to optimize the measurement settings. Our experimental results showcase significant improvements in estimation accuracy and noise robustness, highlighting the potential of variational techniques for practical applications in quantum sensing and more generally in quantum information processing using photonic circuits.
Durable and efficient gene silencing in vivo by hit-and-run epigenome editing
Authors: Cappelluti Martino Alfredo , Mollica Poeta Valeria , Valsoni Sara , Quarato Piergiuseppe , Merlin Simone , Merelli Ivan , Lombardo Angelo
Published: February 2024

Permanent epigenetic silencing using programmable editors equipped with transcriptional repressors holds great promise for the treatment of human diseases1–3. However, to unlock its full therapeutic potential, an experimental confirmation of durable epigenetic silencing after the delivery of transient delivery of editors in vivo is needed. To this end, here we targeted Pcsk9, a gene expressed in hepatocytes that is involved in cholesterol homeostasis. In vitro screening of different editor designs indicated that zinc-finger proteins were the best-performing DNA-binding platform for efficient silencing of mouse Pcsk9. A single administration of lipid nanoparticles loaded with the editors’ mRNAs almost halved the circulating levels of PCSK9 for nearly one year in mice. Notably, Pcsk9 silencing and accompanying epigenetic repressive marks also persisted after forced liver regeneration, further corroborating the heritability of the newly installed epigenetic state. Improvements in construct design resulted in the development of an all-in-one configuration that we term evolved engineered transcriptional repressor (EvoETR). This design, which is characterized by a high specificity profile, further reduced the circulating levels of PCSK9 in mice with an efficiency comparable with that obtained through conventional gene editing, but without causing DNA breaks. Our study lays the foundation for the development of in vivo therapeutics that are based on epigenetic silencing.
On the genetic basis of tail-loss evolution in humans and apes
Authors: Xia Bo , Zhang Weimin , Zhao Guisheng , Zhang Xinru , Bai Jiangshan , Brosh Ran , Wudzinska Aleksandra , Huang Emily , Ashe Hannah , Ellis Gwen , Pour Maayan , Zhao Yu , Coelho Camila , Zhu Yinan , Miller Alexander , Dasen Jeremy S. , Maurano Matthew T. , Kim Sang Y. , Boeke Jef D. , Yanai Itai
Published: February 2024

The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the ‘anthropomorphous apes’1–3, with a proposed role in contributing to human bipedalism4–6. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element—inserted into an intron of the TBXT gene7–9—pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans10. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.
Mutualisms weaken the latitudinal diversity gradient among oceanic islands
Authors: Delavaux Camille S. , Crowther Thomas W. , Bever James D. , Weigelt Patrick , Gora Evan M.
Published: February 2024

The latitudinal diversity gradient (LDG) dominates global patterns of diversity1,2, but the factors that underlie the LDG remain elusive. Here we use a unique global dataset3 to show that vascular plants on oceanic islands exhibit a weakened LDG and explore potential mechanisms for this effect. Our results show that traditional physical drivers of island biogeography4—namely area and isolation—contribute to the difference between island and mainland diversity at a given latitude (that is, the island species deficit), as smaller and more distant islands experience reduced colonization. However, plant species with mutualists are underrepresented on islands, and we find that this plant mutualism filter explains more variation in the island species deficit than abiotic factors. In particular, plant species that require animal pollinators or microbial mutualists such as arbuscular mycorrhizal fungi contribute disproportionately to the island species deficit near the Equator, with contributions decreasing with distance from the Equator. Plant mutualist filters on species richness are particularly strong at low absolute latitudes where mainland richness is highest, weakening the LDG of oceanic islands. These results provide empirical evidence that mutualisms, habitat heterogeneity and dispersal are key to the maintenance of high tropical plant diversity and mediate the biogeographic patterns of plant diversity on Earth.
The CRL5–SPSB3 ubiquitin ligase targets nuclear cGAS for degradation
Authors: Xu Pengbiao , Liu Ying , Liu Chong , Guey Baptiste , Li Lingyun , Melenec Pauline , Ricci Jonathan , Ablasser Andrea
Published: February 2024

Cyclic GMP-AMP synthase (cGAS) senses aberrant DNA during infection, cancer and inflammatory disease, and initiates potent innate immune responses through the synthesis of 2′3′-cyclic GMP-AMP (cGAMP)1–7. The indiscriminate activity of cGAS towards DNA demands tight regulatory mechanisms that are necessary to maintain cell and tissue homeostasis under normal conditions. Inside the cell nucleus, anchoring to nucleosomes and competition with chromatin architectural proteins jointly prohibit cGAS activation by genomic DNA8–15. However, the fate of nuclear cGAS and its role in cell physiology remains unclear. Here we show that the ubiquitin proteasomal system (UPS) degrades nuclear cGAS in cycling cells. We identify SPSB3 as the cGAS-targeting substrate receptor that associates with the cullin–RING ubiquitin ligase 5 (CRL5) complex to ligate ubiquitin onto nuclear cGAS. A cryo-electron microscopy structure of nucleosome-bound cGAS in a complex with SPSB3 reveals a highly conserved Asn-Asn (NN) minimal degron motif at the C terminus of cGAS that directs SPSB3 recruitment, ubiquitylation and cGAS protein stability. Interference with SPSB3-regulated nuclear cGAS degradation primes cells for type I interferon signalling, conferring heightened protection against infection by DNA viruses. Our research defines protein degradation as a determinant of cGAS regulation in the nucleus and provides structural insights into an element of cGAS that is amenable to therapeutic exploitation.
Latitudinal patterns in stabilizing density dependence of forest communities
Authors: Hülsmann Lisa , Chisholm Ryan A. , Comita Liza , Visser Marco D. , de Souza Leite Melina , Aguilar Salomon , Anderson-Teixeira Kristina J. , Bourg Norman A. , Brockelman Warren Y. , Bunyavejchewin Sarayudh , Castaño Nicolas , Chang-Yang Chia-Hao , Chuyong George B. , Clay Keith , Davies Stuart J. , Duque Alvaro , Ediriweera Sisira , Ewango Corneille , Gilbert Gregory S. , Holík Jan , Howe Robert W. , Hubbell Stephen P. , Itoh Akira , Johnson Daniel J. , Kenfack David , Král Kamil , Larson Andrew J. , Lutz James A. , Makana Jean-Remy , Malhi Yadvinder , McMahon Sean M. , McShea William J. , Mohamad Mohizah , Nasardin Musalmah , Nathalang Anuttara , Norden Natalia , Oliveira Alexandre A. , Parmigiani Renan , Perez Rolando , Phillips Richard P. , Pongpattananurak Nantachai , Sun I-Fang , Swanson Mark E. , Tan Sylvester , Thomas Duncan , Thompson Jill , Uriarte Maria , Wolf Amy T. , Yao Tze Leong , Zimmerman Jess K. , Zuleta Daniel , Hartig Florian
Published: February 2024

Numerous studies have shown reduced performance in plants that are surrounded by neighbours of the same species1,2, a phenomenon known as conspecific negative density dependence (CNDD)3. A long-held ecological hypothesis posits that CNDD is more pronounced in tropical than in temperate forests4,5, which increases community stabilization, species coexistence and the diversity of local tree species6,7. Previous analyses supporting such a latitudinal gradient in CNDD8,9 have suffered from methodological limitations related to the use of static data10–12. Here we present a comprehensive assessment of latitudinal CNDD patterns using dynamic mortality data to estimate species-site-specific CNDD across 23 sites. Averaged across species, we found that stabilizing CNDD was present at all except one site, but that average stabilizing CNDD was not stronger toward the tropics. However, in tropical tree communities, rare and intermediate abundant species experienced stronger stabilizing CNDD than did common species. This pattern was absent in temperate forests, which suggests that CNDD influences species abundances more strongly in tropical forests than it does in temperate ones13. We also found that interspecific variation in CNDD, which might attenuate its stabilizing effect on species diversity14,15, was high but not significantly different across latitudes. Although the consequences of these patterns for latitudinal diversity gradients are difficult to evaluate, we speculate that a more effective regulation of population abundances could translate into greater stabilization of tropical tree communities and thus contribute to the high local diversity of tropical forests.
Crym-positive striatal astrocytes gate perseverative behaviour
Authors: Ollivier Matthias , Soto Joselyn S. , Linker Kay E. , Moye Stefanie L. , Jami-Alahmadi Yasaman , Jones Anthony E. , Divakaruni Ajit S. , Kawaguchi Riki , Wohlschlegel James A. , Khakh Baljit S.
Published: February 2024

Astrocytes are heterogeneous glial cells of the central nervous system1–3. However, the physiological relevance of astrocyte diversity for neural circuits and behaviour remains unclear. Here we show that a specific population of astrocytes in the central striatum expresses μ-crystallin (encoded by Crym in mice and CRYM in humans) that is associated with several human diseases, including neuropsychiatric disorders4–7. In adult mice, reducing the levels of μ-crystallin in striatal astrocytes through CRISPR–Cas9-mediated knockout of Crym resulted in perseverative behaviours, increased fast synaptic excitation in medium spiny neurons and dysfunctional excitatory–inhibitory synaptic balance. Increased perseveration stemmed from the loss of astrocyte-gated control of neurotransmitter release from presynaptic terminals of orbitofrontal cortex–striatum projections. We found that perseveration could be remedied using presynaptic inhibitory chemogenetics8, and that this treatment also corrected the synaptic deficits. Together, our findings reveal converging molecular, synaptic, circuit and behavioural mechanisms by which a molecularly defined and allocated population of striatal astrocytes gates perseveration phenotypes that accompany neuropsychiatric disorders9–12. Our data show that Crym-positive striatal astrocytes have key biological functions within the central nervous system, and uncover astrocyte–neuron interaction mechanisms that could be targeted in treatments for perseveration.
Study on heat transfer performance of cold plate with grid channel
Authors: Zhang Kaihua , Ye Xiaojiang , Hou Zhijian , Ren Yahui , Shi Qiuyi
Published: February 2024

The utilization of cold plate radiators as a prevalent method for indirect liquid cooling has been extensively investigated and implemented in server cooling systems. However, there is a lack of comprehensive study on the application of this technology at the chip size, indicating a need for more development and exploration in this area. A proposal was made for a grid-channel chip cold plate heat sink to facilitate the dissipation of heat from a chip. tests were conducted to investigate the impact of the flow rate of the cold plate and the layout of the inlet and outlet on various thermal parameters, including the average temperature, maximum temperature, thermal resistance, and uniformity coefficient of the cold plate. The tests were specifically conducted under a chip power of 150W, and the accuracy of the simulation was confirmed through the use of FLUENT. The findings indicate that the cold plate effectively regulates the temperature of the chip, ensuring it remains below 85 °C throughout all experimental groups. In contrast to the single in single out configuration, the single-in multiple-out layout exhibits a higher degree of temperature uniformity within the cold plate. Nevertheless, it is important to note that augmenting the quantity of exits does not guarantee an improvement in heat transfer efficiency. This outcome is contingent upon the presence of a longitudinal flow channel shared by the outlet and intake, as well as the dispersion characteristics of the outlet. Enhancing the dispersion of the exit can significantly enhance the thermal transfer efficiency of the cold plate. Furthermore, a strategy for adjusting the aperture of the orifice is proposed as a solution to address the challenges related to flow uniformity and the issue of high pressure drop in the cold plate.
NEDD4-2 and the CLC-2 channel regulate neuronal excitability in the pathogenesis of mesial temporal lobe epilepsy
Authors: Liu Yuting , Yang Haiyan , Zeng Rongrong , He Lu , Xiao Ting , Peng Xiaomei , Kuang Zhuo , Wu Liwen
Published: February 2024

An increasing number of studies have focused on the role of NEDD4-2 in regulating neuronal excitability and the mechanism of epilepsy. However, the exact mechanism has not yet been elucidated. Here, we explored the roles of NEDD4-2 and the CLC-2 channel in regulating neuronal excitability and mesial temporal lobe epilepsy (MTLE) pathogenesis. First, chronic MTLE models were induced by lithium-pilocarpine in developmental rats. Coimmunoprecipitation analysis revealed that the interaction between CLC-2 and NEDD4-2. Western blot analyses indicated that NEDD4-2 expression was downregulated, while phosphorylated (P-) NEDD4-2 and CLC-2 expression was upregulated in adult MTLE rats. Then, the primary hippocampal neuronal cells were isolated and cultured, and the NEDD4-2 was knocked down by shRNA vector, resulting in decreased protein levels of CLC-2. While CLC-2 absence caused increased NEDD4-2 in cells. Next, in an epileptic cell model induced by a Mg2+-free culture, whole-cell current-clamp recording demonstrated that NEDD4-2 deficiency inhibited the spontaneous action potentials of cells, and CLC-2 absence caused more significant decrease in the spontaneous action potentials of cells. In conclusion, we herein revealed that NEDD4-2 regulates the expression of CLC-2, which is involved in neuronal excitability, and participates in the pathogenesis of MTLE.
On thermal characterization method of integrated magnetic components
Authors: Basma Bechir Mahamat , Piétroy David , Boukhari Mahamat Issa , Chahbi Zacharia , Blanchet Thomas , Chatelon Jean Pierre , Capraro Stéphane , Rousseau Jean Jacques
Published: February 2024

The operating temperature of integrated magnetic components can be critical. Excessively high temperature can significantly modify the properties of components, especially those of magnetic material, such as saturation magnetization and magnetic permeability. This article introduces an experimental characterization method using two different sensors. We compare the results obtained from these sensors. Initially, the method is validated using a “meander component, and subsequently, it is applied to planar spiral inductors, both with and without magnetic material.
Association of the trajectory of plasma aldosterone concentration with the risk of cardiovascular disease in patients with hypertension: a cohort study
Authors: Cai Xintian , Song Shuaiwei , Hu Junli , Zhu Qing , Shen Di , Yang Wenbo , Ma Huimin , Luo Qin , Hong Jing , Zhang Delian , Li Nanfang
Published: February 2024

The purpose of this study was to determine the long-term pattern of plasma aldosterone concentration (PAC) trajectories and to explore the relationship between PAC trajectory patterns and cardiovascular disease (CVD) risk in patients with hypertension. Participants were surveyed three times between 2010 and 2016, and latent mixed modeling was employed to determine the trajectory of PAC over the exposure period (2010–2016). A Cox regression analysis was used to examine the association between PAC trajectory patterns and the risk of CVD (stroke and myocardial infarction). Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were calculated and reported. During a median follow-up of 4.10 (3.37–4.50) years, 82 incident CVD cases (33 myocardial infarction cases and 49 stroke cases) were identified. Among all three PAC models, the high-stability PAC pattern exhibited the highest risk of CVD. After full adjustment for all covariables, HRs were 2.19 (95% CI 1.59–3.01) for the moderate-stable pattern and 2.56 (95% CI 1.68–3.91) for the high-stable pattern in comparison to the low-stable pattern. Subgroup and sensitivity analyses verified this association. The presence of a high-stable PAC trajectory pattern is associated with an elevated risk of CVD in hypertensive patients. Nevertheless, more studies are warranted to confirm these findings.
Measures of type 2 diabetes burden in Italy assessed using the AMD dataset over a twelve year span across the Great Recession
Authors: Abbafati Cristiana , Nieddu Luciano , Monasta Lorenzo
Published: February 2024

Patients with Type 2 Diabetes Mellitus (T2DM) are rapidly increasing in Italy due to aging, preventable risk factors, and worsening socioeconomic context. T2DM and its sequelae take a heavy toll on healthcare systems and the economy, given costly management, difficulties in coping with everyday life, and decreasing patient/worker productivity. Considering long life expectancy in Italy and a decreasing mortality rate due to T2DM, this study aims to calculate the years lived with disability (YLDs) of T2DM and its sequelae grouped into three categories: Neuropathy, Chronic Kidney Disease and No Complications, taking into consideration sex, year, and geographical location. This is the first attempt to measure YLDs from data that do not rely on self-reported diabetes diagnoses. Data come from the Italian Diabetologists Association dataset, the most comprehensive longitudinal source of national outpatient data. YLDs are obtained by multiplying the number of individuals living with a specific health condition and a disability weight which represents the magnitude of health loss associated with that particular condition. Findings show increasing YLD age-standardized rates for T2DM and its sequelae, especially Neuropathy, with the trend being stronger in the central macro-region and among men, and that 2009 marks a structural change in YLD growth rate. Systematic data collection for measuring the burden of diseases is key, among other things, to policy-making and implementation.
Dickson polynomial-based secure group authentication scheme for Internet of Things
Authors: Syed Salman Ali , Manickam Selvakumar , Uddin Mueen , Alsufyani Hamed , Shorfuzzaman Mohammad , Selvarajan Shitharth , Mohammed Gouse Baig
Published: February 2024

Internet of Things (IoT) paves the way for the modern smart industrial applications and cities. Trusted Authority acts as a sole control in monitoring and maintaining the communications between the IoT devices and the infrastructure. The communication between the IoT devices happens from one trusted entity of an area to the other by way of generating security certificates. Establishing trust by way of generating security certificates for the IoT devices in a smart city application can be of high cost and expensive. In order to facilitate this, a secure group authentication scheme that creates trust amongst a group of IoT devices owned by several entities has been proposed. The majority of proposed authentication techniques are made for individual device authentication and are also utilized for group authentication; nevertheless, a unique solution for group authentication is the Dickson polynomial based secure group authentication scheme. The secret keys used in our proposed authentication technique are generated using the Dickson polynomial, which enables the group to authenticate without generating an excessive amount of network traffic overhead. IoT devices' group authentication has made use of the Dickson polynomial. Blockchain technology is employed to enable secure, efficient, and fast data transfer among the unique IoT devices of each group deployed at different places. Also, the proposed secure group authentication scheme developed based on Dickson polynomials is resistant to replay, man-in-the-middle, tampering, side channel and signature forgeries, impersonation, and ephemeral key secret leakage attacks. In order to accomplish this, we have implemented a hardware-based physically unclonable function. Implementation has been carried using python language and deployed and tested on Blockchain using Ethereum Goerli’s Testnet framework. Performance analysis has been carried out by choosing various benchmarks and found that the proposed framework outperforms its counterparts through various metrics. Different parameters are also utilized to assess the performance of the proposed blockchain framework and shows that it has better performance in terms of computation, communication, storage and latency.
Prevalence and predictors of postcholecystectomy syndrome in Nepalese patients after 1 week of laparoscopic cholecystectomy: a cross-sectional study
Authors: Shrestha Roshani , Chayaput Prangtip , Wongkongkam Kessiri , Chanruangvanich Wallada
Published: February 2024

Postcholecystectomy syndrome (PCS) is persistent distressing symptoms which develops following a laparoscopic cholecystectomy (LC); in cases when the condition is severe, readmission may be necessary. However, research on the prevalence of PCS and potential factors associated with PCS in Nepalese patients is still limited. An observational point-prevalence, correlational predictive cross-sectional study was conducted to determine the prevalence of PCS and examine what predicting factors including preoperative anxiety, preoperative dyspepsia, smoking, alcohol consumption, and duration of preoperative symptoms are associated with PCS. A total of 127 eligible Nepalese patients who came for follow-up after 1 week of LC at outpatient department of surgery in one single university hospital, Kathmandu, Nepal, were recruited. A set of questionnaires consisting participants' information record form, Hospital Anxiety and Depression Scale (HADS), Leeds Dyspepsia Questionnaires (LDQ), Fagerstrom Test for Nicotine Dependence (FTND), and Alcohol Use Disorder Identification Test (AUDIT) was administered for data collection. The associations between influential factors and PCS were analyzed using Binary logistic regression. 43.3% of participants reported PCS after 1 week of surgery. The findings from logistic regression analysis affirmed that the patients with preoperative anxiety (OR = 6.38, 95%CI = 2.07–19.67, p < 0.01) and moderate to severe dyspepsia (OR = 4.01, 95%CI = 1.34–12.02, p < 0.05) held the likelihood to report PCS 6.38 and 4.01 times, respectively, greater than others. The implications from study results are that screening of anxiety and patients’ tailored interventions to reduce anxiety should be implemented preoperatively. An appropriate health education about persistence of PCS and self-management should be provided to those postoperative patients.