bluuebunny/crossref_metadata_2025 huggingface dataset:
The Synergy of Legal and Medical Palliative Care: Challenges and Opportunities in Palliative MLP and the Yale Experience
Authors: Iannantuoni Rebecca , Rock Emily B. , Gluck Abbe R.
Published: March 2024

Palliative care and medical-legal partnership are complementary disciplines dedicated to integrating care to treat the whole patient and intervening before a legal or medical issue is at a crisis point. In this paper, we discuss the founding and operations of the Yale Palliative Medical Legal Partnership, give examples of typical cases, explain special considerations in this area of law, and propose areas for further research.
Conditions of Participation: Incorporating the History of Hospital Desegregation
Authors: Sanford Sallie Thieme
Published: March 2024

Our students ought to know about the history of formal hospital segregation and desegregation. To that end, this article urges those who teach foundational health law and policy courses to do three things. First, to teach the Simkins case. Second, to swap out the usual Medicare signing ceremony picture for one that includes W. Montague Cobb, M.D., Ph.D. Third, to highlight how the implementation of that program for the elderly led, in a matter of months, to the desegregation of hospitals throughout the country.
Assessment of Resident Physician Comfort in Screening for Social Determinants of Health in a Specialty Clinic Population
Authors: Silverman Erika L. , Sandsmark Danielle K. , Field Robert I.
Published: March 2024

Through qualitative surveys, a team of law students, law professors, physicians, and residents explored the perceptions of neurology residents towards referral to appropriate legal resources in an academic training program. Respondents reported feeling uncomfortable screening their patients for health-harming legal needs, which many attributed to a lack of training in this area. These findings indicate that neurology residents would benefit from training on screening for social factors that may be impacting their patients’ health.
Great Trees Require Strong Roots: Evaluating Data and Delegation Doctrine Underlying Proposed Reforms to FDA’s Accelerated Approval Program
Authors: Deshmukh Anjali D.
Published: March 2024

In “Missing the Forest for the Trees: Aduhelm, Accelerated Approvals & the Agency,” Dr. Matthew Herder argues that agency capture and politicized discretion drive delays in confirmatory trials of accelerated approval drugs amongst other concerns at US Food and Drug Administration (FDA). In highlighting this important problem and offering nuanced insight into agency workings based in part on interviews with twenty-three unnamed FDA officials and a three-drug case study, Dr. Herder suggests two innovative solutions. However, amidst broader debates balancing agency expertise, data, and delegation, these proposed policy solutions would benefit from more corroborative evidence and consideration of institutional advantages within constitutional limits.
Leveraging Academic-Medical Legal Partnerships to Advance Health Justice
Authors: Girard Vicki W. , Cannon Yael Z. , Perry Deborah F. , Moore Eileen S.
Published: March 2024

Unmet legal needs contribute to housing, income, and food insecurity, along with other conditions that harm health and drive health inequity. Addressing health injustice requires new tools for the next generations of lawyers, doctors, and other healthcare professionals. An interprofessional group of co-authors argue that law and medical schools and other university partners should develop and cultivate Academic Medical-Legal Partnerships (A-MLPs), which are uniquely positioned to leverage service, education, and research resources, to advance health justice.
What Can State Medical Boards Do to Effectively Address Serious Ethical Violations?
Authors: McIntosh Tristan , Pendo Elizabeth , Walsh Heidi A. , Baldwin Kari A. , King Patricia , Anderson Emily E. , Caldicott Catherine V. , Carter Jeffrey D. , Johnson Sandra H. , Mathews Katherine , Norcross William A. , Shaffer Dana C. , DuBois James M.
Published: March 2024

State Medical Boards (SMBs) can take severe disciplinary actions (e.g., license revocation or suspension) against physicians who commit egregious wrongdoing in order to protect the public. However, there is noteworthy variability in the extent to which SMBs impose severe disciplinary action. In this manuscript, we present and synthesize a subset of 11 recommendations based on findings from our team’s larger consensus-building project that identified a list of 56 policies and legal provisions SMBs can use to better protect patients from egregious wrongdoing by physicians.
Steering into the Curves: Using Diagnosis to Support the Dignity and Autonomy of Trans Youth
Authors: Boskey Elizabeth R. , Galarneau Charlene
Published: March 2024

This response to Kariyawasam and Rai affirms their critique of the pathologization of trans youth but forecasts a foreseeable negative outcome of their proposed elimination of diagnosis as a prerequisite to gender-affirming care (GAC) — the risk of removing GAC entirely from the medical sphere and compromising the wellbeing of those transgender individuals for whom GAC is deeply affirming. We suggest an ethical framework of GAC that expands past a focus on autonomy to incorporate a principle of respect for persons that affirms the dignity and diversity of trans youth — recognizing the need to facilitate both medical assistance and social change.
Epidemiology of tuberculosis among children in Beijing, China, 2012–2021
Authors: Zheng Huiwen , Xiao Jing , Yang Haiming , Li Feina , Guo Yajie , Wang Yonghong , Li Deze , Chen Hao , Wang Xiaotong , Li Huimin , Shen Chen
Published: March 2024

Data on epidemiology trends of paediatric tuberculosis (TB) are limited in China. So, we investigated the clinical and epidemiological profiles in diagnosed TB disease and TB infection patients at Beijing Children’s Hospital. Of 3 193 patients, 51.05% had pulmonary TB (PTB) and 15.16% had extrapulmonary TB (EPTB). The most frequent forms of EPTB were TB meningitis (39.05%), pleural TB (29.75%), and disseminated TB (10.33%). PTB patients were significantly younger and associated with higher hospitalization frequency. Children aged 1–4 years exhibited higher risk of PTB and TB meningitis, and children aged 5–12 years had higher risk of EPTB. The proportion of PTB patients increased slightly from 40.9% in 2012 to 65% in 2019, and then decreased to 17.8% in 2021. The percentage of EPTB cases decreased from 18.3% in 2012 to 15.2% in 2019, but increased to 16.4% in 2021. Among EPTB cases, the largest increase was seen in TB meningitis. In conclusion, female and young children had higher risk of PTB in children. TB meningitis was the most frequent forms of EPTB among children, and young children were at high risk of TB meningitis. The distribution of different types of EPTB differed by age.
Collapses, Maxima, Multi‐Year Modulation and Trends of the Zapiola Anticyclonic Circulation: Insights From Mercator Reanalysis
Authors: Poli Lea , Artana Camila , Provost Christine , Sirven Jérôme , Le Blanc‐Pressenda Ruben
Published: March 2024

The Argentine Basin hosts a unique oceanic feature: the Zapiola Anticyclonic Circulation (ZAC) located above a sedimentary deposit. Taking advantage of a high‐resolution (1/12°) global ocean reanalysis (GLORYS12) we examine the ZAC over 27 years (1993–2019). The mean ZAC is bottom‐intensified with bottom currents reaching 0.10 ms−1. The ZAC volume transport ranges from −18.5 to 268 Sv with a mean of 122 Sv. The strong negative peaks correspond to occasional ZAC collapses. During large transport events (>195.4 Sv) the ZAC shows a well defined coherent gyre. Strong transport events are associated with high eddy kinetic energy (EKE) at the periphery of the ZAC (especially to the west and south). In contrast, during weak transport events (<49.8 Sv), EKE increases at the center of the ZAC and decreases at the ZAC periphery. A weak ZAC is more permeable to external mesoscale structures. Each weak event features a cyclonic eddy at the center of the ZAC carrying subantarctic cold and fresh waters. The ZAC exhibits a multi‐year modulation, with periods of 4–5 years (1993–1997, 1998–2003 and 2004–2009) of low salinity corresponding to low transport, and high salinity to high transport. Over the last 27 years, transport time series exhibit a significant negative trend of −15 Sv.decade−1 associated with a negative trend in EKE (−0.015 (m/s)2.decade−1) to the north west of the ZAC. Waters in the Zapiola region become warmer and saltier in the first 2,000 m of the water column because of the southward migration of the subtropical front.
Spatiotemporal Variations of the Effects of Aerosols on Clouds and Precipitation in an Extreme‐Rain‐Producing MCS in South China
Authors: Yun Yuxing , Zhang Da‐Lin , Gao Wenhua , Yin Jinfang , Zhao Chun , Li Jiawei , Guo Jianping , Liu Hongli
Published: March 2024

Previous studies focus mostly on the storm‐scale‐averaged precipitation responses to aerosols. Yet, the spatiotemporal variations of the aerosol effects can lead to localized and short‐duration precipitation changes that are more relevant for improving rainfall forecasts. Here, we investigate the cloud and precipitation responses to aerosols during different life stages and in subregions with various cloud top heights of an extreme‐rain‐producing mesoscale convective system (MCS) in South China using the coupled WRF‐Chem model. Results show mostly similar MCS‐averaged precipitation responses between the polluted and clean conditions due to compensations among the subregions. However, the spatiotemporally discretized changes are divergent. Specifically, during the developing stage, aerosols increase precipitation in all subregions through generating larger precipitating hydrometers produced from the accretion of more cloud droplets. The most prominent precipitation enhancement occurs in the subregion with the strongest clean‐condition rainfall. In the mature stage, the CCN activation abates, and so does the aerosol‐induced precipitation increase. In the mixed‐phase (−40°C < Ttop < 0°C) and cold (Ttop ≤ −40°C) cloud top subregions, aerosols also reduce the melting of the ice‐phase precipitating hydrometers, which process becomes more important to precipitation formation during the mature stage. Therefore, the drop of rainfall rate is more significant in these ice‐phase‐involved subregions, bringing the polluted precipitation to be less than that in the clean condition during the mature stage. The substantial spatiotemporal variations of the aerosol effects and the early intensification of heavy precipitation suggest the importance of incorporating aerosols in the modeling and prediction of regional heavy rainfall events.
Dysregulated CREB3 cleavage at the nuclear membrane induces karyoptosis-mediated cell death
Authors: Lee Ga-Eun , Bang Geul , Byun Jiin , Lee Cheol-Jung , Chen Weidong , Jeung Dohyun , An Hyun-Jung , Kang Han Chang , Lee Joo Young , Lee Hye Suk , Hong Young-Soo , Kim Dae Joon , Keniry Megan , Kim Jin Young , Choi Jin-Sung , Fanto Manolis , Cho Sung-Jun , Kim Kwang-Dong , Cho Yong-Yeon
Published: March 2024

Cancer cells often exhibit resistance to apoptotic cell death, but they may be vulnerable to other types of cell death. Elucidating additional mechanisms that govern cancer cell death is crucial for developing new therapies. Our research identified cyclic AMP-responsive element-binding protein 3 (CREB3) as a crucial regulator and initiator of a unique cell death mechanism known as karyoptosis. This process is characterized by nuclear shrinkage, deformation, and the loss of nuclear components following nuclear membrane rupture. We found that the N-terminal domain (aa 1-230) of full-length CREB3 (CREB3-FL), which is anchored to the nuclear inner membrane (INM), interacts with lamins and chromatin DNA. This interaction maintains a balance between the outward force exerted by tightly packed DNA and the inward constraining force, thereby preserving INM integrity. Under endoplasmic reticulum (ER) stress, aberrant cleavage of CREB3-FL at the INM leads to abnormal accumulation of the cleaved form of CREB3 (CREB3-CF). This accumulation disrupts the attachment of CREB3-FL to the INM, resulting in sudden rupture of the nuclear membrane and the onset of karyoptosis. Proteomic studies revealed that CREB3-CF overexpression induces a DNA damage response akin to that caused by UVB irradiation, which is associated with cellular senescence in cancer cells. These findings demonstrated that the dysregulation of CREB3-FL cleavage is a key factor in karyoptotic cell death. Consequently, these findings suggest new therapeutic strategies in cancer treatment that exploit the process of karyoptosis.
A Wnt10a-Notch signaling axis controls Hertwig’s epithelial root sheath cell behaviors during root furcation patterning
Authors: Sun Kai , Yu Miao , Wang Jiayu , Zhao Hu , Liu Haochen , Feng Hailan , Liu Yang , Han Dong
Published: March 2024

Human with bi-allelic WNT10A mutations and epithelial Wnt10a knockout mice present enlarged pulp chamber and apical displacement of the root furcation of multi-rooted teeth, known as taurodontism; thus, indicating the critical role of Wnt10a in tooth root morphogenesis. However, the endogenous mechanism by which epithelial Wnt10a regulates Hertwig’s epithelial root sheath (HERS) cellular behaviors and contributes to root furcation patterning remains unclear. In this study, we found that HERS in the presumptive root furcating region failed to elongate at an appropriate horizontal level in K14-Cre;Wnt10afl/fl mice from post-natal day 0.5 (PN0.5) to PN4.5. EdU assays and immunofluorescent staining of cyclin D1 revealed significantly decreased proliferation activity of inner enamel epithelial (IEE) cells of HERS in K14-Cre;Wnt10afl/fl mice at PN2.5 and PN3.5. Immunofluorescent staining of E-Cadherin and acetyl-α-Tubulin demonstrated that the IEE cells of HERS tended to divide perpendicularly to the horizontal plane, which impaired the horizontal extension of HERS in the presumptive root furcating region of K14-Cre;Wnt10afl/fl mice. RNA-seq and immunofluorescence showed that the expressions of Jag1 and Notch2 were downregulated in IEE cells of HERS in K14-Cre;Wnt10afl/fl mice. Furthermore, after activation of Notch signaling in K14-Cre;Wnt10afl/fl molars by Notch2 adenovirus and kidney capsule grafts, the root furcation defect was partially rescued. Taken together, our study demonstrates that an epithelial Wnt10a-Notch signaling axis is crucial for modulating HERS cell proper proliferation and horizontal-oriented division during tooth root furcation morphogenesis.
Single-cell RNA-seq reveals keratinocyte and fibroblast heterogeneity and their crosstalk via epithelial-mesenchymal transition in psoriasis
Authors: Guo Dianhao , Li Xiaokang , Wang Jing , Liu Xin , Wang Yibo , Huang Shuhong , Dang Ningning
Published: March 2024

The pathogenesis of psoriasis, a chronic inflammatory autoimmune skin disease with a high global prevalence, remains unclear. We performed a high-resolution single-cell RNA sequencing analysis of 94,759 cells from 13 samples, including those from psoriasis model mice and wild-type mice. We presented a single-cell atlas of the skin of imiquimod-induced mice with psoriasis and WT mice, especially the heterogeneity of keratinocytes and fibroblasts. More interestingly, we discovered that special keratinocyte subtypes and fibroblast subtypes could interact with each other through epithelial–mesenchymal transition and validated the results with drug verification. Moreover, we conducted a tentative exploration of the potential pathways involved and revealed that the IL-17 signalling pathway may be the most relevant pathway. Collectively, we revealed the full-cycle landscape of key cells associated with psoriasis and provided a more comprehensive understanding of the pathogenesis of psoriasis.
RNF166 promotes colorectal cancer progression by recognizing and destabilizing poly-ADP-ribosylated angiomotins
Authors: Li Yun , Zhang Xiangqian , Liu Na , Liu Ruijie , Zhang Wuming , Chen Lin , Chen Yongheng
Published: March 2024

Activation of the Hippo pathway by angiomotins to limit colorectal cancer progression is prevalent, whereas the regulation of angiomotins remains elusive. In this study, we uncover the involvement of an upregulated E3 ubiquitin ligase called RNF166, which destabilizes angiomotins, activates YAP, and is associated with a poor prognosis in colorectal cancer patients. Mechanistically, RNF166 specifically recognizes PARsylated angiomotin, a modification mediated by tankyrase at specific amino acid residues (D506, E513, E516, and E528). The tankyrase inhibitor XAV939, effectively prevents RNF166-dependent destabilization of angiomotins and subsequent activation of YAP. Additionally, YAP-5SA, a constitutively active form of YAP, rescues colorectal cancer progression following knockdown of RNF166. Importantly, the C-terminus of RNF66, particularly the Di19-ZF domain, is the crucial region responsible for recognizing ADP-ribosylated angiomotins. Together, this work not only sheds light on the regulation of the Hippo pathway in colorectal cancer but also uncovers a novel poly(ADP-ribose)-binding domain, which may serve as a potential therapeutic target for intervention.
Theileria parasites sequester host eIF5A to escape elimination by host-mediated autophagy
Authors: Villares Marie , Lourenço Nelly , Ktorza Ivan , Berthelet Jérémy , Panagiotou Aristeidis , Richard Aurélie , Amo Angélique , Koziy Yulianna , Medjkane Souhila , Valente Sergio , Fioravanti Rossella , Pioche-Durieu Catherine , Lignière Laurent , Chevreux Guillaume , Mai Antonello , Weitzman Jonathan B.
Published: March 2024

Intracellular pathogens develop elaborate mechanisms to survive within the hostile environments of host cells. Theileria parasites infect bovine leukocytes and cause devastating diseases in cattle in developing countries. Theileria spp. have evolved sophisticated strategies to hijack host leukocytes, inducing proliferative and invasive phenotypes characteristic of cell transformation. Intracellular Theileria parasites secrete proteins into the host cell and recruit host proteins to induce oncogenic signaling for parasite survival. It is unknown how Theileria parasites evade host cell defense mechanisms, such as autophagy, to survive within host cells. Here, we show that Theileria annulata parasites sequester the host eIF5A protein to their surface to escape elimination by autophagic processes. We identified a small-molecule compound that reduces parasite load by inducing autophagic flux in host leukocytes, thereby uncoupling Theileria parasite survival from host cell survival. We took a chemical genetics approach to show that this compound induced host autophagy mechanisms and the formation of autophagic structures via AMPK activation and the release of the host protein eIF5A which is sequestered at the parasite surface. The sequestration of host eIF5A to the parasite surface offers a strategy to escape elimination by autophagic mechanisms. These results show how intracellular pathogens can avoid host defense mechanisms and identify a new anti-Theileria drug that induces autophagy to target parasite removal.
Single-atom Mo-tailored high-entropy-alloy ultrathin nanosheets with intrinsic tensile strain enhance electrocatalysis
Authors: He Lin , Li Menggang , Qiu Longyu , Geng Shuo , Liu Yequn , Tian Fenyang , Luo Mingchuan , Liu Hu , Yu Yongsheng , Yang Weiwei , Guo Shaojun
Published: March 2024

The precise structural integration of single-atom and high-entropy-alloy features for energy electrocatalysis is highly appealing for energy conversion, yet remains a grand challenge. Herein, we report a class of single-atom Mo-tailored PdPtNiCuZn high-entropy-alloy nanosheets with dilute Pt-Pt ensembles and intrinsic tensile strain (Mo1-PdPtNiCuZn) as efficient electrocatalysts for enhancing the methanol oxidation reaction catalysis. The as-made Mo1-PdPtNiCuZn delivers an extraordinary mass activity of 24.55 A mgPt−1 and 11.62 A mgPd+Pt−1, along with impressive long-term durability. The planted oxophilic Mo single atoms as promoters modify the electronic structure of isolated Pt sites in the high-entropy-alloy host, suppressing the formation of CO adsorbates and steering the reaction towards the formate pathway. Meanwhile, Mo promoters and tensile strain synergistically optimize the adsorption behaviour of intermediates to achieve a more energetically favourable pathway and minimize the methanol oxidation reaction barrier. This work advances the design of atomically precise catalytic sites by creating a new paradigm of single atom-tailored high-entropy alloys, opening an encouraging pathway to the design of CO-tolerance electrocatalysts.
Understanding quantum machine learning also requires rethinking generalization
Authors: Gil-Fuster Elies , Eisert Jens , Bravo-Prieto Carlos
Published: March 2024

Quantum machine learning models have shown successful generalization performance even when trained with few data. In this work, through systematic randomization experiments, we show that traditional approaches to understanding generalization fail to explain the behavior of such quantum models. Our experiments reveal that state-of-the-art quantum neural networks accurately fit random states and random labeling of training data. This ability to memorize random data defies current notions of small generalization error, problematizing approaches that build on complexity measures such as the VC dimension, the Rademacher complexity, and all their uniform relatives. We complement our empirical results with a theoretical construction showing that quantum neural networks can fit arbitrary labels to quantum states, hinting at their memorization ability. Our results do not preclude the possibility of good generalization with few training data but rather rule out any possible guarantees based only on the properties of the model family. These findings expose a fundamental challenge in the conventional understanding of generalization in quantum machine learning and highlight the need for a paradigm shift in the study of quantum models for machine learning tasks.
Charting cellular differentiation trajectories with Ricci flow
Authors: Baptista Anthony , MacArthur Ben D. , Banerji Christopher R. S.
Published: March 2024

Complex biological processes, such as cellular differentiation, require intricate rewiring of intra-cellular signalling networks. Previous characterisations revealed a raised network entropy underlies less differentiated and malignant cell states. A connection between entropy and Ricci curvature led to applications of discrete curvatures to biological networks. However, predicting dynamic biological network rewiring remains an open problem. Here we apply Ricci curvature and Ricci flow to biological network rewiring. By investigating the relationship between network entropy and Forman-Ricci curvature, theoretically and empirically on single-cell RNA-sequencing data, we demonstrate that the two measures do not always positively correlate, as previously suggested, and provide complementary rather than interchangeable information. We next employ Ricci flow to derive network rewiring trajectories from stem cells to differentiated cells, accurately predicting true intermediate time points in gene expression time courses. In summary, we present a differential geometry toolkit for understanding dynamic network rewiring during cellular differentiation and cancer.
Population exposure to multiple air pollutants and its compound episodes in Europe
Authors: Chen Zhao-Yue , Petetin Hervé , Méndez Turrubiates Raúl Fernando , Achebak Hicham , Pérez García-Pando Carlos , Ballester Joan
Published: March 2024

Air pollution remains as a substantial health problem, particularly regarding the combined health risks arising from simultaneous exposure to multiple air pollutants. However, understanding these combined exposure events over long periods has been hindered by sparse and temporally inconsistent monitoring data. Here we analyze daily ambient PM2.5, PM10, NO2 and O3 concentrations at a 0.1-degree resolution during 2003–2019 across 1426 contiguous regions in 35 European countries, representing 543 million people. We find that PM10 levels decline by 2.72% annually, followed by NO2 (2.45%) and PM2.5 (1.72%). In contrast, O3 increase by 0.58% in southern Europe, leading to a surge in unclean air days. Despite air quality advances, 86.3% of Europeans experience at least one compound event day per year, especially for PM2.5-NO2 and PM2.5-O3. We highlight the improvements in air quality control but emphasize the need for targeted measures addressing specific pollutants and their compound events, particularly amidst rising temperatures.
Enantioselective functionalization of unactivated C(sp3)–H bonds through copper-catalyzed diyne cyclization by kinetic resolution
Authors: Chen Yang-Bo , Liu Li-Gao , Wang Zhe-Qi , Chang Rong , Lu Xin , Zhou Bo , Ye Long-Wu
Published: March 2024

Site- and stereoselective C–H functionalization is highly challenging in the synthetic chemistry community. Although the chemistry of vinyl cations has been vigorously studied in C(sp3)–H functionalization reactions, the catalytic enantioselective C(sp3)–H functionalization based on vinyl cations, especially for an unactivated C(sp3)–H bond, has scarcely explored. Here, we report an asymmetric copper-catalyzed tandem diyne cyclization/unactivated C(sp3)–H insertion reaction via a kinetic resolution, affording both chiral polycyclic pyrroles and diynes with generally excellent enantioselectivities and excellent selectivity factors (up to 750). Importantly, this reaction demonstrates a metal-catalyzed enantioselective unactivated C(sp3)–H functionalization via vinyl cation and constitutes a kinetic resolution reaction based on diyne cyclization. Theoretical calculations further support the mechanism of vinyl cation-involved C(sp3)–H insertion reaction and elucidate the origin of enantioselectivity.
Divergent dynamics of sexual and habitat isolation at the transition between stick insect populations and species
Authors: Nosil Patrik , Gompert Zachariah , Funk Daniel J.
Published: March 2024

Speciation is often viewed as a continuum along which populations diverge until they become reproductively-isolated species. However, such divergence may be heterogeneous, proceeding in fits and bursts, rather than being uniform and gradual. We show in Timema stick insects that one component of reproductive isolation evolves non-uniformly across this continuum, whereas another does not. Specifically, we use thousands of host-preference and mating trials to study habitat and sexual isolation among 42 pairs of taxa spanning a range of genomic differentiation and divergence time. We find that habitat isolation is uncoupled from genomic differentiation within species, but accumulates linearly with it between species. In contrast, sexual isolation accumulates linearly across the speciation continuum, and thus exhibits similar dynamics to morphological traits not implicated in reproductive isolation. The results show different evolutionary dynamics for different components of reproductive isolation and highlight a special relevance for species status in the process of speciation.
NME3 is a gatekeeper for DRP1-dependent mitophagy in hypoxia
Authors: Chen Chih-Wei , Su Chi , Huang Chang-Yu , Huang Xuan-Rong , Cuili Xiaojing , Chao Tung , Fan Chun-Hsiang , Ting Cheng-Wei , Tsai Yi-Wei , Yang Kai-Chien , Yeh Ti-Yen , Hsieh Sung-Tsang , Chen Yi-Ju , Feng Yuxi , Hunter Tony , Chang Zee-Fen
Published: March 2024

NME3 is a member of the nucleoside diphosphate kinase (NDPK) family localized on the mitochondrial outer membrane (MOM). Here, we report a role of NME3 in hypoxia-induced mitophagy dependent on its active site phosphohistidine but not the NDPK function. Mice carrying a knock-in mutation in the Nme3 gene disrupting NME3 active site histidine phosphorylation are vulnerable to ischemia/reperfusion-induced infarction and develop abnormalities in cerebellar function. Our mechanistic analysis reveals that hypoxia-induced phosphatidic acid (PA) on mitochondria is essential for mitophagy and the interaction of DRP1 with NME3. The PA binding function of MOM-localized NME3 is required for hypoxia-induced mitophagy. Further investigation demonstrates that the interaction with active NME3 prevents DRP1 susceptibility to MUL1-mediated ubiquitination, thereby allowing a sufficient amount of active DRP1 to mediate mitophagy. Furthermore, MUL1 overexpression suppresses hypoxia-induced mitophagy, which is reversed by co-expression of ubiquitin-resistant DRP1 mutant or histidine phosphorylatable NME3. Thus, the site-specific interaction with active NME3 provides DRP1 a microenvironment for stabilization to proceed the segregation process in mitophagy.
Electrostatic potentials of atomic nanostructures at metal surfaces quantified by scanning quantum dot microscopy
Authors: Bolat Rustem , Guevara Jose M. , Leinen Philipp , Knol Marvin , Arefi Hadi H. , Maiworm Michael , Findeisen Rolf , Temirov Ruslan , Hofmann Oliver T. , Maurer Reinhard J. , Tautz F. Stefan , Wagner Christian
Published: March 2024

The discrete and charge-separated nature of matter — electrons and nuclei — results in local electrostatic fields that are ubiquitous in nanoscale structures and relevant in catalysis, nanoelectronics and quantum nanoscience. Surface-averaging techniques provide only limited experimental access to these potentials, which are determined by the shape, material, and environment of the nanostructure. Here, we image the potential over adatoms, chains, and clusters of Ag and Au atoms assembled on Ag(111) and quantify their surface dipole moments. By focusing on the total charge density, these data establish a benchmark for theory. Our density functional theory calculations show a very good agreement with experiment and allow a deeper analysis of the dipole formation mechanisms, their dependence on fundamental atomic properties and on the shape of the nanostructures. We formulate an intuitive picture of the basic mechanisms behind dipole formation, allowing better design choices for future nanoscale systems such as single-atom catalysts.
Nanobubble-actuated ultrasound neuromodulation for selectively shaping behavior in mice
Authors: Hou Xuandi , Jing Jianing , Jiang Yizhou , Huang Xiaohui , Xian Quanxiang , Lei Ting , Zhu Jiejun , Wong Kin Fung , Zhao Xinyi , Su Min , Li Danni , Liu Langzhou , Qiu Zhihai , Sun Lei
Published: March 2024

Ultrasound is an acoustic wave which can noninvasively penetrate the skull to deep brain regions, enabling neuromodulation. However, conventional ultrasound’s spatial resolution is diffraction-limited and low-precision. Here, we report acoustic nanobubble-mediated ultrasound stimulation capable of localizing ultrasound’s effects to only the desired brain region in male mice. By varying the delivery site of nanobubbles, ultrasound could activate specific regions of the mouse motor cortex, evoking EMG signaling and limb movement, and could also, separately, activate one of two nearby deep brain regions to elicit distinct behaviors (freezing or rotation). Sonicated neurons displayed reversible, low-latency calcium responses and increased c-Fos expression in the sub-millimeter-scale region with nanobubbles present. Ultrasound stimulation of the relevant region also modified depression-like behavior in a mouse model. We also provide evidence of a role for mechanosensitive ion channels. Altogether, our treatment scheme allows spatially-targetable, repeatable and temporally-precise activation of deep brain circuits for neuromodulation without needing genetic modification.
Single-cell division tracing and transcriptomics reveal cell types and differentiation paths in the regenerating lung
Authors: Martins Leila R. , Sieverling Lina , Michelhans Michelle , Schiller Chiara , Erkut Cihan , Grünewald Thomas G. P. , Triana Sergio , Fröhling Stefan , Velten Lars , Glimm Hanno , Scholl Claudia
Published: March 2024

Understanding the molecular and cellular processes involved in lung epithelial regeneration may fuel the development of therapeutic approaches for lung diseases. We combine mouse models allowing diphtheria toxin-mediated damage of specific epithelial cell types and parallel GFP-labeling of functionally dividing cells with single-cell transcriptomics to characterize the regeneration of the distal lung. We uncover cell types, including Krt13+ basal and Krt15+ club cells, detect an intermediate cell state between basal and goblet cells, reveal goblet cells as actively dividing progenitor cells, and provide evidence that adventitial fibroblasts act as supporting cells in epithelial regeneration. We also show that diphtheria toxin-expressing cells can persist in the lung, express specific inflammatory factors, and transcriptionally resemble a previously undescribed population in the lungs of COVID-19 patients. Our study provides a comprehensive single-cell atlas of the distal lung that characterizes early transcriptional and cellular responses to concise epithelial injury, encompassing proliferation, differentiation, and cell-to-cell interactions.
PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer
Authors: Lin Chang-Ching , Chang Tsung-Cheng , Wang Yunguan , Guo Lei , Gao Yunpeng , Bikorimana Emmanuel , Lemoff Andrew , Fang Yisheng V. , Zhang He , Zhang Yanfeng , Ye Dan , Soria-Bretones Isabel , Servetto Alberto , Lee Kyung-min , Luo Xuemei , Otto Joseph J. , Akamatsu Hiroaki , Napolitano Fabiana , Mani Ram , Cescon David W. , Xu Lin , Xie Yang , Mendell Joshua T. , Hanker Ariella B. , Arteaga Carlos L.
Published: March 2024

CDK4/6 inhibitors (CDK4/6i) have improved survival of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug resistance and progress. RB1 loss-of-function alterations confer resistance to CDK4/6i, but the optimal therapy for these patients is unclear. Through a genome-wide CRISPR screen, we identify protein arginine methyltransferase 5 (PRMT5) as a molecular vulnerability in ER+/RB1-knockout breast cancer cells. Inhibition of PRMT5 blocks the G1-to-S transition in the cell cycle independent of RB, leading to growth arrest in RB1-knockout cells. Proteomics analysis uncovers fused in sarcoma (FUS) as a downstream effector of PRMT5. Inhibition of PRMT5 results in dissociation of FUS from RNA polymerase II, leading to hyperphosphorylation of serine 2 in RNA polymerase II, intron retention, and subsequent downregulation of proteins involved in DNA synthesis. Furthermore, treatment with the PRMT5 inhibitor pemrametostat and a selective ER degrader fulvestrant synergistically inhibits growth of ER+/RB-deficient cell-derived and patient-derived xenografts. These findings highlight dual ER and PRMT5 blockade as a potential therapeutic strategy to overcome resistance to CDK4/6i in ER+/RB-deficient breast cancer.
Interfacial ice sprouting during salty water droplet freezing
Authors: Chu Fuqiang , Li Shuxin , Zhao Canjun , Feng Yanhui , Lin Yukai , Wu Xiaomin , Yan Xiao , Miljkovic Nenad
Published: March 2024

Icing of seawater droplets is capable of causing catastrophic damage to vessels, buildings, and human life, yet it also holds great potential for enhancing applications such as droplet-based freeze desalination and anti-icing of sea sprays. While large-scale sea ice growth has been investigated for decades, the icing features of small salty droplets remain poorly understood. Here, we demonstrate that salty droplet icing is governed by salt rejection-accompanied ice crystal growth, resulting in freezing dynamics different from pure water. Aided by the observation of brine films emerging on top of frozen salty droplets, we propose a universal definition of freezing duration to quantify the icing rate of droplets having varying salt concentrations. Furthermore, we show that the morphology of frozen salty droplets is governed by ice crystals that sprout from the bottom of the brine film. These crystals grow until they pierce the free interface, which we term ice sprouting. We reveal that ice sprouting is controlled by condensation at the brine film free interface, a mechanism validated through molecular dynamics simulations. Our findings shed light on the distinct physics that govern salty droplet icing, knowledge that is essential for the development of related technologies.
Broadband angular spectrum differentiation using dielectric metasurfaces
Authors: Deng Ming , Cotrufo Michele , Wang Jian , Dong Jianji , Ruan Zhichao , Alù Andrea , Chen Lin
Published: March 2024

Signal processing is of critical importance for various science and technology fields. Analog optical processing can provide an effective solution to perform large-scale and real-time data processing, superior to its digital counterparts, which have the disadvantages of low operation speed and large energy consumption. As an important branch of modern optics, Fourier optics exhibits great potential for analog optical image processing, for instance for edge detection. While these operations have been commonly explored to manipulate the spatial content of an image, mathematical operations that act directly over the angular spectrum of an image have not been pursued. Here, we demonstrate manipulation of the angular spectrum of an image, and in particular its differentiation, using dielectric metasurfaces operating across the whole visible spectrum. We experimentally show that this technique can be used to enhance desired portions of the angular spectrum of an image. Our approach can be extended to develop more general angular spectrum analog meta-processors, and may open opportunities for optical analog data processing and biological imaging.
Cost-effectiveness uncertainty may bias the decision of coal power transitions in China
Authors: Yan Xizhe , Tong Dan , Zheng Yixuan , Liu Yang , Chen Shaoqing , Qin Xinying , Chen Chuchu , Xu Ruochong , Cheng Jing , Shi Qinren , Zheng Dongsheng , He Kebin , Zhang Qiang , Lei Yu
Published: March 2024

A transition away from coal power always maintains a high level of complexity as there are several overlapping considerations such as technical feasibility, economic costs, and environmental and health impacts. Here, we explore the cost-effectiveness uncertainty brought by policy implementation disturbances of different coal power phaseout and new-built strategies (i.e., the disruption of phaseout priority) in China based on a developed unit-level uncertainty assessment framework. We reveal the opportunity and risk of coal transition decisions by employing preference analysis. We find that, the uncertainty of a policy implementation might lead to potential delays in yielding the initial positive annual net benefits. For example, a delay of six years might occur when implementing the prior phaseout practice. A certain level of risk remains in the implementation of the phaseout policy, as not all strategies can guarantee the cumulative positive net benefits from 2018–2060. Since the unit-level heterogeneities shape diverse orientation of the phaseout, the decision-making preferences would remarkably alter the selection of a coal power transition strategy. More strikingly, the cost-effectiveness uncertainty might lead to missed opportunities in identifying an optimal strategy. Our results highlight the importance of minimizing the policy implementation disturbance, which helps mitigate the risk of negative benefits and strengthen the practicality of phaseout decisions.
Bacteriophage DNA induces an interrupted immune response during phage therapy in a chicken model
Authors: Podlacha Magdalena , Gaffke Lidia , Grabowski Łukasz , Mantej Jagoda , Grabski Michał , Pierzchalska Małgorzata , Pierzynowska Karolina , Węgrzyn Grzegorz , Węgrzyn Alicja
Published: March 2024

One of the hopes for overcoming the antibiotic resistance crisis is the use of bacteriophages to combat bacterial infections, the so-called phage therapy. This therapeutic approach is generally believed to be safe for humans and animals as phages should infect only prokaryotic cells. Nevertheless, recent studies suggested that bacteriophages might be recognized by eukaryotic cells, inducing specific cellular responses. Here we show that in chickens infected with Salmonella enterica and treated with a phage cocktail, bacteriophages are initially recognized by animal cells as viruses, however, the cGAS-STING pathway (one of two major pathways of the innate antiviral response) is blocked at the stage of the IRF3 transcription factor phosphorylation. This inhibition is due to the inability of RNA polymerase III to recognize phage DNA and to produce dsRNA molecules which are necessary to stimulate a large protein complex indispensable for IRF3 phosphorylation, indicating the mechanism of the antiviral response impairment.
Natural variation in OsMYB8 confers diurnal floret opening time divergence between indica and japonica subspecies
Authors: Gou Yajun , Heng Yueqin , Ding Wenyan , Xu Canhong , Tan Qiushuang , Li Yajing , Fang Yudong , Li Xiaoqing , Zhou Degui , Zhu Xinyu , Zhang Mingyue , Ye Rongjian , Wang Haiyang , Shen Rongxin
Published: March 2024

The inter-subspecific indica-japonica hybrid rice confer potential higher yield than the widely used indica-indica intra-subspecific hybrid rice. Nevertheless, the utilization of this strong heterosis is currently hindered by asynchronous diurnal floret opening time (DFOT) of indica and japonica parental lines. Here, we identify OsMYB8 as a key regulator of rice DFOT. OsMYB8 induces the transcription of JA-Ile synthetase OsJAR1, thereby regulating the expression of genes related to cell osmolality and cell wall remodeling in lodicules to promote floret opening. Natural variations of OsMYB8 promoter contribute to its differential expression, thus differential transcription of OsJAR1 and accumulation of JA-Ile in lodicules of indica and japonica subspecies. Furthermore, introgression of the indica haplotype of OsMYB8 into japonica effectively promotes DFOT in japonica. Our findings reveal an OsMYB8-OsJAR1 module that regulates differential DFOT in indica and japonica, and provide a strategy for breeding early DFOT japonica to facilitate breeding of indica-japonica hybrids.
The decline of the 2022 Italian mpox epidemic: Role of behavior changes and control strategies
Authors: Guzzetta Giorgio , Marziano Valentina , Mammone Alessia , Siddu Andrea , Ferraro Federica , Caraglia Anna , Maraglino Francesco , Rezza Giovanni , Vespignani Alessandro , Longini Ira , Ajelli Marco , Merler Stefano
Published: March 2024

In 2022, a global outbreak of mpox occurred, predominantly impacting men who have sex with men (MSM). The rapid decline of this epidemic is yet to be fully understood. We investigated the Italian outbreak by means of an individual-based mathematical model calibrated to surveillance data. The model accounts for transmission within the MSM sexual contact network, in recreational and sex clubs attended by MSM, and in households. We indicate a strong spontaneous reduction in sexual transmission (61-87%) in affected MSM communities as the possible driving factor for the rapid decline in cases. The MSM sexual contact network was the main responsible for transmission (about 80%), with clubs and households contributing residually. Contact tracing prevented about half of the potential cases, and a higher success rate in tracing contacts could significantly amplify its effectiveness. Notably, immunizing the 23% of MSM with the highest sexual activity (10 or more partners per year) could completely prevent new mpox resurgences. This research underscores the importance of augmenting contact tracing, targeted immunization campaigns of high-risk groups, and fostering reactive behavioral changes as key strategies to manage and prevent the spread of emerging sexually transmitted pathogens like mpox within the MSM community.
Predicting multiple observations in complex systems through low-dimensional embeddings
Authors: Wu Tao , Gao Xiangyun , An Feng , Sun Xiaotian , An Haizhong , Su Zhen , Gupta Shraddha , Gao Jianxi , Kurths Jürgen
Published: March 2024

Forecasting all components in complex systems is an open and challenging task, possibly due to high dimensionality and undesirable predictors. We bridge this gap by proposing a data-driven and model-free framework, namely, feature-and-reconstructed manifold mapping (FRMM), which is a combination of feature embedding and delay embedding. For a high-dimensional dynamical system, FRMM finds its topologically equivalent manifolds with low dimensions from feature embedding and delay embedding and then sets the low-dimensional feature manifold as a generalized predictor to achieve predictions of all components. The substantial potential of FRMM is shown for both representative models and real-world data involving Indian monsoon, electroencephalogram (EEG) signals, foreign exchange market, and traffic speed in Los Angeles Country. FRMM overcomes the curse of dimensionality and finds a generalized predictor, and thus has potential for applications in many other real-world systems.
High-performance bifacial perovskite solar cells enabled by single-walled carbon nanotubes
Authors: Zhang Jing , Hu Xian-Gang , Ji Kangyu , Zhao Songru , Liu Dongtao , Li Bowei , Hou Peng-Xiang , Liu Chang , Liu Lirong , Stranks Samuel D. , Cheng Hui-Ming , Silva S. Ravi P. , Zhang Wei
Published: March 2024

Bifacial perovskite solar cells have shown great promise for increasing power output by capturing light from both sides. However, the suboptimal optical transmittance of back metal electrodes together with the complex fabrication process associated with front transparent conducting oxides have hindered the development of efficient bifacial PSCs. Here, we present a novel approach for bifacial perovskite devices using single-walled carbon nanotubes as both front and back electrodes. single-walled carbon nanotubes offer high transparency, conductivity, and stability, enabling bifacial PSCs with a bifaciality factor of over 98% and a power generation density of over 36%. We also fabricate flexible, all-carbon-electrode-based devices with a high power-per-weight value of 73.75 W g−1 and excellent mechanical durability. Furthermore, we show that our bifacial devices have a much lower material cost than conventional monofacial PSCs. Our work demonstrates the potential of SWCNT electrodes for efficient, stable, and low-cost bifacial perovskite photovoltaics.
Cryo-EM structures of Banna virus in multiple states reveal stepwise detachment of viral spikes
Authors: Li Zhiqiang , Xia Han , Rao Guibo , Fu Yan , Chong Tingting , Tian Kexing , Yuan Zhiming , Cao Sheng
Published: March 2024

Banna virus (BAV) is the prototype Seadornavirus, a class of reoviruses for which there has been little structural study. Here, we report atomic cryo-EM structures of three states of BAV virions—surrounded by 120 spikes (full virions), 60 spikes (partial virions), or no spikes (cores). BAV cores are double-layered particles similar to the cores of other non-turreted reoviruses, except for an additional protein component in the outer capsid shell, VP10. VP10 was identified to be a cementing protein that plays a pivotal role in the assembly of BAV virions by directly interacting with VP2 (inner capsid), VP8 (outer capsid), and VP4 (spike). Viral spikes (VP4/VP9 heterohexamers) are situated on top of VP10 molecules in full or partial virions. Asymmetrical electrostatic interactions between VP10 monomers and VP4 trimers are disrupted by high pH treatment, which is thus a simple way to produce BAV cores. Low pH treatment of BAV virions removes only the flexible receptor binding protein VP9 and triggers significant conformational changes in the membrane penetration protein VP4. BAV virions adopt distinct spatial organization of their surface proteins compared with other well-studied reoviruses, suggesting that BAV may have a unique mechanism of penetration of cellular endomembranes.