bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical features and prognosis of transient global amnesia in Israel: 6 years’ single-center experience
Authors: Gindes Ido , Kimiagar Itzhak , Peretz Shlomi , Kenan Gilad
Published: December 2024

Background

Transient global amnesia (TGA) is a benign neurological syndrome of unknown etiology, causing sudden anterograde amnesia that lasts up to 24 h. During the episode of TGA, other cognitive functions are normal. This is the first study describing the characteristics of the disease in Israel.

Methods

A retrospective review of all patients with a confirmed diagnosis of TGA at Shamir Medical Center (SMC) between January 2016 and December 2021.

Results

One-hundred and four patients with confirmed TGA were identified, with an average age of 64 years (range: 39–87). The annual incidence of TGA was 2.52 per 100,000 and 6.96 per 100,000 among those over 50, with a slight female predominance. The recurrence rate was 11.5%. 61.5% of patients had one or more cerebrovascular risk factors. A precipitating factor was described in 30.8% of cases, with emotional stress, Valsalva maneuver and sexual intercourse being the most prevalent. Chronic ischemic changes were the most common imaging abnormality. Focal slowing was found in nine patients, and epileptic activity was found in four patients.

Conclusions

In this study, we showed that patient characteristics and clinical features of TGA patients in Israel were similar to those described in other reports worldwide. We were unable to demonstrate a specific risk factor or a causative agent. Interestingly, the annual incidence in Israel was lower than in other countries.
Lessons from Nature: Advances and Perspectives in Bionic Microwave Absorption Materials
Authors: Wang Dashuang , Ping Tuo , Du Zhilan , Liu Xiaoying , Zhang Yuxin
Published: December 2024

Inspired by the remarkable electromagnetic response capabilities of the complex morphologies and subtle microstructures evolved by natural organisms, this paper delves into the research advancements and future application potential of bionic microwave-absorbing materials (BMAMs). It outlines the significance of achieving high-performance microwave-absorbing materials through ingenious microstructural design and judicious composition selection, while emphasizing the innovative strategies offered by bionic manufacturing. Furthermore, this work meticulously analyzes how inspiration can be drawn from the intricate structures of marine organisms, plants, animals, and non-metallic minerals in nature to devise and develop BMAMs with superior electromagnetic wave absorption properties. Additionally, the paper provides an in-depth exploration of the theoretical underpinnings of BMAMs, particularly the latest breakthroughs in broadband absorption. By incorporating advanced methodologies such as simulation modeling and bionic gradient design, we unravel the scientific principles governing the microwave absorption mechanisms of BMAMs, thereby furnishing a solid theoretical foundation for understanding and optimizing their performance. Ultimately, this review aims to offer valuable insights and inspiration to researchers in related fields, fostering the collective advancement of research on BMAMs.
Web-based single session therapy training for mental health support providers: a mixed-methods evaluation study protocol
Authors: Joseph Jasmine , Rajan Santhosh Kareepadath , Sudhesh N. T. , Krishnan Uma
Published: December 2024

The growing mental health needs and constrained resources in low- and middle-income countries necessitate scalable solutions. Single Session Therapy (SST) is a global trend in brief and cost-effective options for mental health interventions. It involves a single planned session between mental health service provider and client. This study aims to present a protocol to develop and evaluate a culture specific web-based training program to equip mental health support providers with the skills and confidence to deliver SST. The study protocol uses a mixed-methods evaluation design through three phases—need assessment – where psychologists and social workers collaborate to identify training needs and co-create the program; development and expert validation of the web-based training program; and randomized control trial to evaluate the training, followed by in-depth discussions with participants. This study breaks new ground by empirically designing and evaluating a training program for SST. It uniquely co-designs and validates a culturally sensitive SST training program, leveraging the expertise of a renowned international panel. This protocol goes beyond a blueprint for replicating this study, it serves as a foundational guide for nations seeking to implement effective SST training for their mental health professionals, preventing duplication of efforts.
The Social Dimensions of Scientific Knowledge
Authors: Miller Boaz
Published: December 2024

This Element is about the social dimensions of scientific knowledge. The first section asks in what ways scientific knowledge is social. The second section develops a conception of scientific knowledge that accommodates the insights of the first section, and is consonant with mainstream thinking about knowledge in analytic epistemology. The third section asks under what conditions we can tell, in the real world, that a consensus in a scientific community amounts to shared scientific knowledge, as characterized in the second section, and how to deal with scientific dissent. The fourth section reviews the ways epistemic and social elements mutually interact to coproduce scientific knowledge. This Element engages with literature from philosophy of science and social epistemology, especially social epistemology of science, as well as Science, Technology, and Society (STS), and analytic epistemology. The Element focuses on themes and debates that date from the start of the second millennium.
Les sources du droit, source de la légende ?
Authors: Brunori Luisa , Halpérin Jean-Louis
Published: December 2024

La démonstration de Francesca Trivellato, dans Juifs et capitalisme, part du premier chapitre des Us et coustumes de la mer d’Étienne Cleirac (1647) consacré à l’assurance et à la lettre de change. Les difficultés à intégrer ces deux instruments du droit commercial au sein du système des sources de tradition romaniste conduisent Cleirac à en attribuer l’invention aux Juifs. Cette opération essentiellement technique d’ajustement de la systématique des sources du droit entre néanmoins en consonance avec une mentalité répandue parmi la société des époques moderne puis contemporaine. En montrant le rôle des juristes dans l’élaboration d’une légende antisémite, le livre de F. Trivellato suscite une réflexion sur les apports réciproques développés ces dernières années entre l’histoire des idées et l’histoire du droit.
Toutes les dettes ne se valent pas
Authors: Trivellato Francesca
Published: December 2024

Cet article répond aux remarques formulées par Jean-François Chauvard, Luisa Brunori et Jean-Louis Halpérin, Pierre-Cyrille Hautcœur ainsi que Maurice Kriegel sur mon livre The Promise and Peril of Credit, traduit en français sous le titre Juifs et capitalisme. Le livre examine les significations culturelles attachées à la diffusion des instruments de crédit de la finance privée à partir du xviie siècle. Il s’intéresse tout particulièrement à décrire les multiples associations avec les Juifs et l’usure suscitées par ces instruments. Ma réponse s’appuie sur une installation conçue par l’artiste suisse Christoph Büchel, Monte di pietà, présentée à la Fondation Prada au même moment que la 60e Biennale d’Art de Venise en 2024 – une installation qui privilégie les associations libres à une contextualisation analytique ou historique. Par ses allusions ambiguës aux Juifs et à l’État d’Israël en lien avec son thème principal – le rôle de l’endettement dans la guerre et dans la dégradation et l’exploitation humaine –, l’installation renvoie à une question centrale de mon livre, à savoir la persistance et la malléabilité des stéréotypes. Je saisis donc cette occasion pour passer en revue les points saillants de ma recherche sur cette question épineuse et pour parler des formes de contextualisation complémentaires développées par les contributeurs de ce forum.
Curbing Agency Expertise Threatens Public Health: Braidwood and the Nondelegation Doctrine
Authors: Twinamatsiko Andrew J. , Gostin Lawrence O.
Published: December 2024

For almost a century, the Supreme Court has not invalidated a law using the nondelegation doctrine. Recognizing that Congress seldom has expertise to address the ever-increasing complexities of society, the Court has long held that Congress can legislate broadly and seek help from federal agencies to fill up the details. Accordingly, courts defer to Congress’s delegation choices, as long as it lays down an intelligible principle to guide the agencies entrusted with implementing legislation. Under that approach, the Court has upheld broad delegations of authority to federal agencies. This approach has been the bedrock of meaningful agency action, especially in health policy in which agencies must leverage their expertise to respond to highly technical issues, emergencies, advances in technology, and the need to address health disparities. While this deferential approach has guided the courts and Congress for decades, delegation is increasingly under attack. Braidwood Management, Inc. v. Becerra, which challenges the Affordable Care Act’s preventive services requirement, exemplifies nondelegation-based attacks on agency authority. With several members of the Supreme Court signaling interest in revisiting the current deferential delegation standard, Braidwood likely provides an opportunity for the Supreme Court to do so. Reinvigorating the nondelegation doctrine — coupled with the major questions doctrine and rolling back of Chevron deference — will hurt U.S. health policy. It will not only constrain how agencies work, but also aggrandize the courts and limit how Congress may achieve legislative goals.
Economic control of next generation aerospace fleets
Authors: Montana Felipe , Jacobs Will , Pontika Evangelia , Laskaridis Panagiotis , Griffiths Matthew , Beecroft Peter , Wall Derek , Kadirkamanathan Visakan , Mills Andrew R
Published: December 2024

Engineering machines are becoming increasingly complex and possess more control variables, increasing the complexity and versatility of the control systems. Different configurations of the control system, named a policy, can result in similar output behavior but with different resource or component life usage. There is therefore an opportunity to find optimal policies with respect to economic decisions. While many solutions have been proposed to find such economic policy decisions at the asset level, we consider this problem at the fleet level. In this case, the optimal operation of each asset is affected by the state of all other assets in the fleet. Challenges introduced by considering multiple assets include the construction of economic multi-objective optimization criteria, handling rare events such as failures, application of fleet-level constraints, and scalability. The proposed solution presents a framework for economic fleet optimization. The framework is demonstrated for economic criteria relating to resource usage, component lifing, and maintenance scheduling, but is generically extensible. Direct optimization of lifetime distributions is considered in order to avoid the computational burden of discrete event simulation of rare events. Results are provided for a real-world case study targeting the optimal economic operation of a fleet of aerospace gas turbine engines.
Observed Influences of Subpolar Front in the Japan/East Sea on Winter and Spring North Pacific Storm Track Activity
Authors: Yu Peilong , Chen Shiyao , Wang Huijun , Lin Xiaopei , Duan Mingkeng , Zhang Chao
Published: December 2024

This study investigated the response of the North Pacific storm track (NPST) activity to the meridional shift of the Japan/East Sea subpolar front during the cold season using a statistical method called generalized equilibrium feedback analysis. Results showed that the NPST response exhibits a basin‐wide anomaly in winter but a north‐south dipole in spring. Synoptic eddy temperature variance budget was employed to explore possible mechanisms from the perspective of eddy available potential energy (EAPE) generation. In winter, the baroclinic conversion directly induced by baroclinicity changes drives EAPE generation, and then, the positive eddy feedback reinforces this EAPE generation, giving rise to an intensified NPST. In spring, poleward‐shifted baroclinicity drives a displaced EAPE generation, leading to the poleward displacement of NPST. The shifted baroclinicity is caused by a basin‐scale warm air temperature anomaly, which is coherent with the anticyclone anomaly induced by the divergence of synoptic eddy heat and vorticity fluxes.
Present‐Day Shortening Accommodated by Folding, Thrusting and Strike‐Slip Faulting in the Enriquillo Basin of Southern Central Hispaniola: Implications for the Regional Seismic Hazard
Authors: Escuder‐Viruete J. , Fernández F. J. , Valera F. Pérez , Medialdea A. , Castillo‐Carrión M.
Published: December 2024

Hispaniola accommodates a significant portion of the present‐day convergence between Caribbean and North American plates. Located in southern Hispaniola, the Neogene Enriquillo basin is bounded by the Neiba and Bahoruco mountain ranges. The role of active individual faults and fault systems in this basin is not well understood, particularly their geometry and kinematics, slip rates and seismic activity. Knowing this information is important to characterize the active deformation pattern in southern Hispaniola, but it is also crucial to estimate the regional seismic hazard. Here, we analyze GPS geodetic data and seismicity and present the results of fault mapping of the Enriquillo basin based on tectonic field observations, radiocarbon and luminescence dating, remote sensing and regional magnetic data. These observations indicate that WNW to NW‐trending thrust faults and associate large‐scale folds, as well as minor strike‐slip and normal faults, have been active both in the Tertiary rocks within the mountain ranges and in the basin margins along the Quaternary. Inversion of fault‐slip data establishes that a NE‐directed shortening has controlled the formation of these structures. We propose a regional kinematic model in which the present‐day kinematics of each main fault depend strongly on its orientation with respect to the regional stress tensor. Computed seismic hazard defines a map pattern for the peak ground acceleration elongated to the main seismotectonic fault zones. Regions around the southwest Sierra de Neiba, the western Enriquillo basin and the northwest Sierra de Bahoruco, where peak ground acceleration exceed 500 cm/s2, have a high seismic hazard.
Mitophagy in ischemic heart disease: molecular mechanisms and clinical management
Authors: Xu Shujuan , Wang Zihan , Guo Fan , Zhang Yehao , Peng Han , Zhang Huiyu , Liu Zixin , Cao Ce , Xin Gaojie , Chen Yuan Yuan , Fu Jianhua
Published: December 2024

The influence of the mitochondrial control system on ischemic heart disease has become a major focus of current research. Mitophagy, as a very crucial part of the mitochondrial control system, plays a special role in ischemic heart disease, unlike mitochondrial dynamics. The published reviews have not explored in detail the unique function of mitophagy in ischemic heart disease, therefore, the aim of this paper is to summarize how mitophagy regulates the progression of ischemic heart disease. We conclude that mitophagy affects ischemic heart disease by promoting cardiomyocyte hypertrophy and fibrosis, the progression of oxidative stress, the development of inflammation, and cardiomyocyte death, and that the specific mechanisms of mitophagy are worthy of further investigation.
Combining genomics and epidemiology to investigate a zoonotic outbreak of rabies in Romblon Province, Philippines
Authors: Yuson Mirava , Bautista Criselda T. , Rees Eleanor M. , Bogaardt Carlijn , Cruz Van Denn D. , Durrant Rowan , Formstone Anna , Manalo Daria L. , Manzanilla Duane R. , Kundergorski Mikolaj , Nacion Leilanie , Aloyon Hannaniah , Bolivar Jude Karlo , Bondoc Jeromir , Cobbold Christina , Panganiban Efraim , Telmo Shynie Vee. M. , Maestro Jobin , Miranda Mary Elizabeth G. , Chng Nai Rui , Brunker Kirstyn , Hampson Katie
Published: December 2024

Rabies is a viral zoonosis that kills thousands of people annually in low- and middle-income countries across Africa and Asia where domestic dogs are the reservoir. ‘Zero by 30’, the global strategy to end dog-mediated human rabies, promotes a One Health approach underpinned by mass dog vaccination, post-exposure vaccination of bite victims, robust surveillance and community engagement. Using Integrated Bite Case Management (IBCM) and whole genome sequencing (WGS), we enhanced rabies surveillance to detect an outbreak in a formerly rabies-free island province in the Philippines. We inferred that the outbreak was seeded by at least three independent human-mediated introductions that were identified as coming from neighbouring rabies-endemic provinces. Considerable local transmission went undetected, and two human deaths occurred within 6 months of outbreak detection. Suspension of routine dog vaccination due to COVID-19 restrictions likely facilitated rabies spread from these introductions. Emergency response, consisting of awareness measures, and ring vaccination, were performed, but swifter and more widespread implementation is needed to contain and eliminate the outbreak and to secure rabies freedom. We conclude that strengthened surveillance making use of new tools such as IBCM, WGS, and rapid diagnostic tests can support One Health in action and progress towards the ‘Zero by 30’ goal.
Antibodies to the RBD of SARS-CoV-2 spike mediate productive infection of primary human macrophages
Authors: Pickering Suzanne , Wilson Harry , Bravo Enrico , Perera Marianne R. , Seow Jeffrey , Graham Carl , Almeida Nathalia , Fotopoulos Lazaros , Williams Thomas , Moitra Atlanta , Winstone Helena , Nissen Tinne A. D. , Galão Rui Pedro , Snell Luke B. , Doores Katie J. , Malim Michael H. , Neil Stuart J. D.
Published: December 2024

The role of myeloid cells in the pathogenesis of SARS-CoV-2 is well established, in particular as drivers of cytokine production and systemic inflammation characteristic of severe COVID-19. However, the potential for myeloid cells to act as bona fide targets of productive SARS-CoV-2 infection, and the specifics of entry, remain unclear. Using a panel of anti-SARS-CoV-2 monoclonal antibodies (mAbs) we performed a detailed assessment of antibody-mediated infection of monocytes/macrophages. mAbs with the most consistent potential to mediate infection were those targeting a conserved region of the receptor binding domain (RBD; group 1/class 4). Infection was closely related to the neutralising concentration of the mAbs, with peak infection occurring below the IC50, while pre-treating cells with remdesivir or FcγRI-blocking antibodies inhibited infection. Studies performed in primary macrophages demonstrated high-level and productive infection, with infected macrophages appearing multinucleated and syncytial. Infection was not seen in the absence of antibody with the same quantity of virus. Addition of ruxolitinib significantly increased infection, indicating restraint of infection through innate immune mechanisms rather than entry. High-level production of pro-inflammatory cytokines directly correlated with macrophage infection levels. We hypothesise that infection via antibody-FcR interactions could contribute to pathogenesis in primary infection, systemic virus spread or persistent infection.
NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression
Authors: Reddy Tejaswini , Puri Akshjot , Guzman-Rojas Liliana , Thomas Christoforos , Qian Wei , Zhou Jianying , Zhao Hong , Mahboubi Bijan , Oo Adrian , Cho Young-Jae , Kim Baek , Thaiparambil Jose , Rosato Roberto , Martinez Karina Ortega , Chervo Maria Florencia , Ayerbe Camila , Giese Noah , Wink David , Lockett Stephen , Wong Stephen , Chang Jeffrey , Krishnamurthy Savitri , Yam Clinton , Moulder Stacy , Piwnica-Worms Helen , Meric-Bernstam Funda , Chang Jenny
Published: December 2024

Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH2-terminal kinase (JNK)/c-Jun complex to repress its transcriptional output, leading to enhanced tumor differentiation and associated chemosensitivity. As a result, combined NOS and PI3K inhibition with taxane targets MpBC stem cells and improves survival in patient-derived xenograft models relative to single-/dual-agent therapy. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed a post-treatment reversal of epithelial-to-mesenchymal transition and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a unique strategy to decrease chemoresistance and improve clinical outcomes in MpBC.
Rapid nongenomic estrogen signaling controls alcohol drinking behavior in mice
Authors: Zallar Lia J. , Rivera-Irizarry Jean K. , Hamor Peter U. , Pigulevskiy Irena , Rico Rozo Ana-Sofia , Mehanna Hajar , Liu Dezhi , Welday Jacqueline P. , Bender Rebecca , Asfouri Joseph J. , Levine Olivia B. , Skelly Mary Jane , Hadley Colleen K. , Fecteau Kristopher M. , Nelson Scottie , Miller John , Ghazal Pasha , Bellotti Peter , Singh Ashna , Hollmer Lauren V. , Erikson David W. , Geri Jacob , Pleil Kristen E.
Published: December 2024

Ovarian-derived estrogen can signal non-canonically at membrane-associated receptors in the brain to rapidly regulate neuronal function. Early alcohol drinking confers greater risk for alcohol use disorder in women than men, and binge alcohol drinking is correlated with high estrogen levels, but a causal role for estrogen in driving alcohol drinking has not been established. We found that female mice displayed greater binge alcohol drinking and reduced avoidance when estrogen was high during the estrous cycle than when it was low. The pro-drinking, but not anxiolytic, effect of high endogenous estrogen occurred via rapid signaling at membrane-associated estrogen receptor alpha in the bed nucleus of the stria terminalis, which promoted synaptic excitation of corticotropin-releasing factor neurons and facilitated their activity during alcohol drinking. Thus, this study demonstrates a rapid, nongenomic signaling mechanism for ovarian-derived estrogen in the brain controlling behavior in gonadally intact females.
Reconstitution of pluripotency from mouse fibroblast through Sall4 overexpression
Authors: Xiao Lizhan , Huang Zifen , Wu Zixuan , Yang Yongzheng , Zhang Zhen , Kumar Manish , Wu Haokaifeng , Mao Huiping , Lin Lihui , Lin Runxia , Long Jingxian , Zeng Lihua , Guo Jing , Luo Rongping , Li Yi , Zhu Ping , Liao Baojian , Wang Luqin , Liu Jing
Published: December 2024

Somatic cells can be reprogrammed into pluripotent stem cells (iPSCs) by overexpressing defined transcription factors. Specifically, overexpression of OCT4 alone has been demonstrated to reprogram mouse fibroblasts into iPSCs. However, it remains unclear whether any other single factor can induce iPSCs formation. Here, we report that SALL4 alone, under an optimized reprogramming medium iCD4, is capable of reprogramming mouse fibroblasts into iPSCs. Mechanistically, SALL4 facilitates reprogramming by inhibiting somatic genes and activating pluripotent genes, such as Esrrb and Tfap2c. Furthermore, we demonstrate that co-overexpressing SALL4 and OCT4 synergistically enhances reprogramming efficiency. Specifically, the activation of Rsk1/Esrrb/Tfap2c by SALL4, alongside OCT4’s activation of Sox2 and the suppression of Mndal by SALL4 and Sbsn by OCT4, cooperate to facilitate SALL4+OCT4-mediated reprogramming. Overall, our study not only establishes an efficient method for iPSCs induction using the SALL4 single factor but also provides insights into the synergistic effects of SALL4 and OCT4 in reprogramming.
Minimal presynaptic protein machinery governing diverse kinetics of calcium-evoked neurotransmitter release
Authors: Bose Dipayan , Bera Manindra , Norman Christopher A. , Timofeeva Yulia , Volynski Kirill E. , Krishnakumar Shyam S.
Published: December 2024

Neurotransmitters are released from synaptic vesicles with remarkable precision in response to presynaptic calcium influx but exhibit significant heterogeneity in exocytosis timing and efficacy based on the recent history of activity. This heterogeneity is critical for information transfer in the brain, yet its molecular basis remains poorly understood. Here, we employ a biochemically-defined fusion assay under physiologically relevant conditions to delineate the minimal protein machinery sufficient to account for various modes of calcium-triggered vesicle fusion dynamics. We find that Synaptotagmin-1, Synaptotagmin-7, and Complexin synergistically restrain SNARE complex assembly, thus preserving vesicles in a stably docked state at rest. Upon calcium activation, Synaptotagmin-1 induces rapid vesicle fusion, while Synaptotagmin-7 mediates delayed fusion. Competitive binding of Synaptotagmin-1 and Synaptotagmin-7 to the same SNAREs, coupled with differential rates of calcium-triggered fusion clamp reversal, govern the overall kinetics of vesicular fusion. Under conditions mimicking sustained neuronal activity, the Synaptotagmin-7 fusion clamp is destabilized by the elevated basal calcium concentration, thereby enhancing the synchronous component of fusion. These findings provide a direct demonstration that a small set of proteins is sufficient to account for how nerve terminals adapt and regulate the calcium-evoked neurotransmitter exocytosis process to support their specialized functions in the nervous system.
Anti-CTLA4 treatment reduces lymphedema risk potentially through a systemic expansion of the FOXP3+ Treg population
Authors: Wolf Stefan , Madanchi Matiar , Turko Patrick , Hollmén Maija , Tugues Sonia , von Atzigen Julia , Giovanoli Pietro , Dummer Reinhard , Lindenblatt Nicole , Halin Cornelia , Detmar Michael , Levesque Mitchell , Gousopoulos Epameinondas
Published: December 2024

Secondary lymphedema is a common sequel of oncologic surgery and presents a global health burden still lacking pharmacological treatment. The infiltration of the lymphedematous extremities with CD4+T cells influences lymphedema onset and emerges as a promising therapy target. Here, we show that the modulation of CD4+FOXP3+CD25+regulatory T (Treg) cells upon anti-CTLA4 treatment protects against lymphedema development in patients with melanoma and in a mouse lymphedema model. A retrospective evaluation of a melanoma patient registry reveals that anti-CTLA4 reduces lymphedema risk; in parallel, anti-CTLA4 reduces edema and improves lymphatic function in a mouse-tail lymphedema model. This protective effect of anti-CTLA4 correlates with a systemic expansion of Tregs, both in the animal model and in patients with melanoma. Our data thus show that anti-CTLA4 with its lymphedema-protective and anti-tumor properties is a promising candidate for more diverse application in the clinics.
Integrative determination of atomic structure of mutant huntingtin exon 1 fibrils implicated in Huntington disease
Authors: Bagherpoor Helabad Mahdi , Matlahov Irina , Kumar Raj , Daldrop Jan O. , Jain Greeshma , Weingarth Markus , van der Wel Patrick C. A. , Miettinen Markus S.
Published: December 2024

Neurodegeneration in Huntington’s disease (HD) is accompanied by the aggregation of fragments of the mutant huntingtin protein, a biomarker of disease progression. A particular pathogenic role has been attributed to the aggregation-prone huntingtin exon 1 (HTTex1), generated by aberrant splicing or proteolysis, and containing the expanded polyglutamine (polyQ) segment. Unlike amyloid fibrils from Parkinson’s and Alzheimer’s diseases, the atomic-level structure of HTTex1 fibrils has remained unknown, limiting diagnostic and treatment efforts. We present and analyze the structure of fibrils formed by polyQ peptides and polyQ-expanded HTTex1 in vitro. Atomic-resolution perspectives are enabled by an integrative analysis and unrestrained all-atom molecular dynamics (MD) simulations incorporating experimental data from electron microscopy (EM), solid-state NMR, and other techniques. Alongside the use of prior data, we report magic angle spinning NMR studies of glutamine residues of the polyQ fibril core and surface, distinguished via hydrogen-deuterium exchange (HDX). Our study provides a molecular understanding of the structure of the core as well as surface of aggregated HTTex1, including the fuzzy coat and polyQ–water interface. The obtained data are discussed in context of their implications for understanding the detection of such aggregates (diagnostics) as well as known biological properties of the fibrils.
Laser scribed proton exchange membranes for enhanced fuel cell performance and stability
Authors: Chen Jianuo , Lu Xuekun , Wang Lingtao , Du Wenjia , Guo Hengyi , Rimmer Max , Zhai Heng , Liu Yuhan , Shearing Paul R. , Haigh Sarah J. , Holmes Stuart M. , Miller Thomas S.
Published: December 2024

High-temperature proton exchange membrane fuel cells (HT-PEMFCs) offer solutions to challenges intrinsic to low-temperature PEMFCs, such as complex water management, fuel inflexibility, and thermal integration. However, they are hindered by phosphoric acid (PA) leaching and catalyst migration, which destabilize the critical three-phase interface within the membrane electrode assembly (MEA). This study presents an innovative approach to enhance HT-PEMFC performance through membrane modification using picosecond laser scribing, which optimises the three-phase interface by forming a graphene-like structure that mitigates PA leaching. Our results demonstrate that laser-induced modification of PA-doped membranes, particularly on the cathode side, significantly enhances the performance and durability of HT-PEMFCs, achieving a peak power density of 817.2 mW cm⁻² after accelerated stress testing, representing a notable 58.2% increase compared to untreated membranes. Furthermore, a comprehensive three-dimensional multi-physics model, based on X-ray micro-computed tomography data, was employed to visualise and quantify the impact of this laser treatment on the dynamic electrochemical processes within the MEA. Hence, this work provides both a scalable methodology to stabilise an important future membrane technology, and a clear mechanistic understanding of how this targeted laser modification acts to optimise the three-phase interface of HT-PEMFCs, which can have impact across a wide array of applications.
Genome sequencing of Plasmodium malariae identifies continental segregation and mutations associated with reduced pyrimethamine susceptibility
Authors: Ibrahim Amy , Mohring Franziska , Manko Emilia , van Schalkwyk Donelly A. , Phelan Jody E. , Nolder Debbie , Borrmann Steffen , Adegnika Ayola A. , Di Santi Silvia Maria , Alam Mohammad Shafiul , Mondal Dinesh , Nosten Francois , Sutherland Colin J. , Moon Robert W. , Clark Taane G. , Campino Susana
Published: December 2024

Plasmodium malariae parasites are widely observed across the tropics and sub-tropics. This slow-growing species, known to maintain chronic asymptomatic infections, has been associated with reduced antimalarial susceptibility. We analyse 251 P. malariae genomes from 28 countries, and leveraging 131,601 high-quality SNPs, demonstrate segregation of African and Asian isolates. Signals of recent evolutionary selection were identified in genes encoding putative surface proteins (pmmsp1) and putative erythrocyte invasion proteins (pmdpap3, pmrbp2, pmnif4). Amino acid substitutions were identified in orthologs of genes associated with antimalarial susceptibility including 2 amino acid substitutions in pmdhfr aligning with pyrimethamine resistance mutations in P. falciparum. Additionally, we characterise pmdhfr mutation F57L and demonstrate its involvement in reduced susceptibility to pyrimethamine in an in vitro parasite assay. We validate CRISPR-Cas9 mediated ortholog replacement in P. knowlesi parasites to determine the function of pmdhfr mutations and demonstrate that circulating pmdhfr genotypes are less susceptible to pyrimethamine.
Strained two-dimensional tungsten diselenide for mechanically tunable exciton transport
Authors: Kim Jin Myung , Jeong Kwang-Yong , Kwon Soyeong , So Jae-Pil , Wang Michael Cai , Snapp Peter , Park Hong-Gyu , Nam SungWoo
Published: December 2024

Tightly bound electron-hole pairs (excitons) hosted in atomically-thin semiconductors have emerged as prospective elements in optoelectronic devices for ultrafast and secured information transfer. The controlled exciton transport in such excitonic devices requires manipulating potential energy gradient of charge-neutral excitons, while electrical gating or nanoscale straining have shown limited efficiency of exciton transport at room temperature. Here, we report strain gradient induced exciton transport in monolayer tungsten diselenide (WSe2) across microns at room temperature via steady-state pump-probe measurement. Wrinkle architecture enabled optically-resolvable local strain (2.4%) and energy gradient (49 meV/μm) to WSe2. We observed strain gradient induced flux of high-energy excitons and emission of funneled, low-energy excitons at the 2.5 μm-away pump point with nearly 45% of relative emission intensity compared to that of excited excitons. Our results strongly support the strain-driven manipulation of exciton funneling in two-dimensional semiconductors at room temperature, opening up future opportunities of 2D straintronic exciton devices.
Deep neural networks and humans both benefit from compositional language structure
Authors: Galke Lukas , Ram Yoav , Raviv Limor
Published: December 2024

Deep neural networks drive the success of natural language processing. A fundamental property of language is its compositional structure, allowing humans to systematically produce forms for new meanings. For humans, languages with more compositional and transparent structures are typically easier to learn than those with opaque and irregular structures. However, this learnability advantage has not yet been shown for deep neural networks, limiting their use as models for human language learning. Here, we directly test how neural networks compare to humans in learning and generalizing different languages that vary in their degree of compositional structure. We evaluate the memorization and generalization capabilities of a large language model and recurrent neural networks, and show that both deep neural networks exhibit a learnability advantage for more structured linguistic input: neural networks exposed to more compositional languages show more systematic generalization, greater agreement between different agents, and greater similarity to human learners.
MaizeCODE reveals bi-directionally expressed enhancers that harbor molecular signatures of maize domestication
Authors: Cahn Jonathan , Regulski Michael , Lynn Jason , Ernst Evan , de Santis Alves Cristiane , Ramakrishnan Srividya , Chougule Kapeel , Wei Sharon , Lu Zhenyuan , Xu Xiaosa , Ramu Umamaheswari , Drenkow Jorg , Kramer Melissa , Seetharam Arun , Hufford Matthew B. , McCombie W. Richard , Ware Doreen , Jackson David , Schatz Michael C. , Gingeras Thomas R. , Martienssen Robert A.
Published: December 2024

Modern maize (Zea mays ssp. mays) was domesticated from Teosinte parviglumis (Zea mays ssp. parviglumis), with subsequent introgressions from Teosinte mexicana (Zea mays ssp. mexicana), yielding increased kernel row number, loss of the hard fruit case and dissociation from the cob upon maturity, as well as fewer tillers. Molecular approaches have identified transcription factors controlling these traits, yet revealed that a complex regulatory network is at play. MaizeCODE deploys ENCODE strategies to catalog regulatory regions in the maize genome, generating histone modification and transcription factor ChIP-seq in parallel with transcriptomics datasets in 5 tissues of 3 inbred lines which span the phenotypic diversity of maize, as well as the teosinte inbred TIL11. Transcriptomic analysis reveals that pollen grains share features with endosperm, and express dozens of “proto-miRNAs” potential vestiges of gene drive and hybrid incompatibility. Integrated analysis with chromatin modifications results in the identification of a comprehensive set of regulatory regions in each tissue of each inbred, and notably of distal enhancers expressing non-coding enhancer RNAs bi-directionally, reminiscent of “super enhancers” in animal genomes. Furthermore, the morphological traits selected during domestication are recapitulated, both in gene expression and within regulatory regions containing enhancer RNAs, while highlighting the conflict between enhancer activity and silencing of the neighboring transposable elements.
Distinguishing local isomorphism classes in quasicrystals by high-order harmonic spectroscopy
Authors: Liu Jia-Qi , Bian Xue-Bin
Published: December 2024

Electron diffraction spectroscopy is a fundamental tool for investigating quasicrystal structures, which unveils the quasiperiodic long-range order. Nevertheless, it falls short in effectively distinguishing separate local isomorphism classes. This is a long outstanding problem. Here, we study the high-order harmonic generation in two-dimensional generalized Penrose quasicrystals to optically resolve different local isomorphism classes. The results reveal that: (i) harmonic spectra from different parts of a quasicrystal are identical, even though their atomic arrangements vary significantly. (ii) The harmonic yields of diverse local isomorphism classes exhibit variations, providing a way to distinguish local isomorphism classes. (iii) The rotational symmetry of harmonic yield can serve as a characteristic of quasicrystal harmonics and is consistent with the orientation order. Our results not only pave the way for confirming the experimental reproducibility of quasicrystal harmonics and identifying quasicrystal local isomorphism classes, but also shed light on comprehending electron dynamics influenced by the vertex environments.
Ampere-level reduction of pure nitrate by electron-deficient Ru with K+ ions repelling effect
Authors: Zhang Shi-Nan , Gao Peng , Liu Qian-Yu , Zhang Zhao , Leng Bing-Liang , Chen Jie-Sheng , Li Xin-Hao
Published: December 2024

Electrochemical nitrate reduction reaction offers a sustainable and efficient pathway for ammonia synthesis. Maintaining satisfactory Faradaic efficiency for long-term nitrate reduction under ampere-level current density remains challenging due to the inevitable hydrogen evolution, particularly in pure nitrate solutions. Herein, we present the application of electron deficiency of Ru metals to boost the repelling effect of counter K+ ions via the electric-field-dependent synergy of interfacial water and cations, and thus largely promote nitrate reduction reaction with a high yield and well-maintained Faradaic efficiency under ampere-level current density. The pronounced electron deficiency of Ru metals boosts the repelling effect on hydrated K+ ions, as indicated by the distance of K+ ions to catalyst surface, which can loosen the water layer to depress hydrogen evolution and accelerate nitrate conversion. Consequently, the optimized electrode loaded with electron-deficient Ru atomic layers can directly produce 0.26 M ammonia solution in pure nitrate solution in 6 h, providing a high yield (74.8 mg mgcat–1 h–1) and well-maintained the Faradaic efficiency for over 120 h under ampere-level reduction.
Bayesian modeling of HFC production pipeline suggests growth in unreported CFC by-product and feedstock production
Authors: Bourguet Stephen , Lickley Megan
Published: December 2024

Observationally-derived emissions of ozone depleting substances must be scrutinized to maintain the progress made by the Montreal Protocol in protecting the stratospheric ozone layer. Recent observations of three chlorofluorocarbons (CFCs), CFC-113, CFC-114, and CFC-115, suggest that emissions of these compounds have not decreased as expected given global reporting of their production. These emissions have been associated with hydrofluorocarbon (HFC) production, which can require CFCs as feedstocks or generate CFCs as by-products, yet emissions from these pathways have not been rigorously quantified. Here, we develop a Bayesian framework to jointly infer emissions of CFC-113, CFC-114, and CFC-115 during HFC-134a and HFC-125 production. We estimate that feedstock emissions from HFC-134a production accounted for 90% (82–94%) and 65% (47–77%) of CFC-113 and CFC-114 emissions, respectively, from 2015–2019, while by-product emissions during HFC-125 production accounted for 81% (68–92%) of CFC-115 emissions. Our results suggest that unreported feedstock production in low- to middle-income countries may explain the unexpected emissions of CFC-113 and CFC-114, although uncertainties within chemical manufacturing processes call for further investigation and industry transparency. This work motivates tightened feedstock regulations and adds a reduction in CFC emissions to the benefits of the HFC phasedowns scheduled by the Kigali Amendment.
Unsupervised inter-domain transformation for virtually stained high-resolution mid-infrared photoacoustic microscopy using explainable deep learning
Authors: Park Eunwoo , Misra Sampa , Hwang Dong Gyu , Yoon Chiho , Ahn Joongho , Kim Donggyu , Jang Jinah , Kim Chulhong
Published: December 2024

Mid-infrared photoacoustic microscopy can capture biochemical information without staining. However, the long mid-infrared optical wavelengths make the spatial resolution of photoacoustic microscopy significantly poorer than that of conventional confocal fluorescence microscopy. Here, we demonstrate an explainable deep learning-based unsupervised inter-domain transformation of low-resolution unlabeled mid-infrared photoacoustic microscopy images into confocal-like virtually fluorescence-stained high-resolution images. The explainable deep learning-based framework is proposed for this transformation, wherein an unsupervised generative adversarial network is primarily employed and then a saliency constraint is added for better explainability. We validate the performance of explainable deep learning-based mid-infrared photoacoustic microscopy by identifying cell nuclei and filamentous actins in cultured human cardiac fibroblasts and matching them with the corresponding CFM images. The XDL ensures similar saliency between the two domains, making the transformation process more stable and more reliable than existing networks. Our XDL-MIR-PAM enables label-free high-resolution duplexed cellular imaging, which can significantly benefit many research avenues in cell biology.
Cerebellar-driven cortical dynamics can enable task acquisition, switching and consolidation
Authors: Pemberton Joseph , Chadderton Paul , Costa Rui Ponte
Published: December 2024

The brain must maintain a stable world model while rapidly adapting to the environment, but the underlying mechanisms are not known. Here, we posit that cortico-cerebellar loops play a key role in this process. We introduce a computational model of cerebellar networks that learn to drive cortical networks with task-outcome predictions. First, using sensorimotor tasks, we show that cerebellar feedback in the presence of stable cortical networks is sufficient for rapid task acquisition and switching. Next, we demonstrate that, when trained in working memory tasks, the cerebellum can also underlie the maintenance of cognitive-specific dynamics in the cortex, explaining a range of optogenetic and behavioural observations. Finally, using our model, we introduce a systems consolidation theory in which task information is gradually transferred from the cerebellum to the cortex. In summary, our findings suggest that cortico-cerebellar loops are an important component of task acquisition, switching, and consolidation in the brain.
Rapid optical determination of salivary cortisol responses in individuals undergoing physiological and psychological stress
Authors: Ahmed Tashfia , Powner Michael B. , Qassem Meha , Kyriacou Panayiotis A.
Published: December 2024

Traditional methods for management of mental illnesses in the post-pandemic setting can be inaccessible for many individuals due to a multitude of reasons, including financial stresses and anxieties surrounding face-to-face interventions. The use of a point-of-care tool for self-management of stress levels and mental health status is the natural trajectory towards creating solutions for one of the primary contributors to the global burden of disease. Notably, cortisol is the main stress hormone and a key logical indicator of hypothalamic-pituitary adrenal (HPA) axis activity that governs the activation of the human stress system. Therefore, the measurement of cortisol is imperative to lead the discussion of the relationship between psychological stress and mental health deterioration. The aim of the current study was to determine salivary cortisol concentrations of healthy individuals undergoing the MAST protocol for human stress activation, through optical-colorimetric techniques. The study demonstrates the use of the blue tetrazolium (BT) method as successful means of rapid measurement of cortisol in saliva, comparable to the gold-standard technique i.e., enzyme-linked immunoassays (ELISA) with a coefficient of determination (R2) of 0.997. The results support the future development of a point-of-care optical sensor-based device and mobile application for cortisol monitoring and stress profiling in adults.
Prognostic role of aetiological agent vs. clinical pattern in candidates to lead extraction for cardiac implantable electronic device infections
Authors: Massaro Giulia , Pascale Renato , Biffi Mauro , Martignani Cristian , Ziacchi Matteo , Simeone Andrea , Pittorru Raimondo , De Lazzari Manuel , Migliore Federico , Diemberger Igor
Published: December 2024

Cardiac implantable electronic devices infections (CIEDI) are associated with poor survival despite the improvement in transvenous lead extraction (TLE). Aetiology and systemic involvement are driving factors of clinical outcomes. The aim of this study was to explore their contribute on overall mortality. A prospective study was performed between 2011 and 2021, including all TLE candidates at our regional referral University hospital for CIEDI with microbiological confirmed aetiology. Considering significant predictors of mortality at multivariate Cox regression analyses, a 5-point BOP2D score was developed, and it was validated with a prospective cohort from the Padua University. 157 patients were enrolled (mean age 71.3 ± 12.3 years, 81.5% male). S. aureus was isolated in 32.5% of patients, and it was more associated with valvular heart disease, systemic infection, and chronic kidney disease. CIEDI pattern was associated with 1-year mortality, with a significantly worse outcome in patients with “cold closed pocket” (CCP). The developed BOP2D score presented a 0.807 AUC (95%CI 0.703–0.910, p < 0.001) and a good predictive value (OR 2.355, 95%CI 1.754–3.162; p < 0.001), and was associated with a progressive increase in mortality with a score > 2. The score validation with the registry from the Padua University (135 patients) retrieved a C-statistic of 0.746 (95%CI 0.613–0.879; p = 0.002). Both CCP and S. aureus were confirmed as risk factors for mortality in CIEDI patients. This study supports the hypothesis that the infectious process may occur through different mechanisms associated with different infection patterns, and high-risk patients should be considered for specific and aggressive approaches.