bluuebunny/crossref_metadata_2025 huggingface dataset:
APOCALYPTIC ASCETICISM: COMPLETING THE EDITION OF ALEXANDER MINORITA'S EXPOSITIO IN APOCALYPSIM AS IT IS FOUND IN CAMBRIDGE, UNIVERSITY LIBRARY, MM.5.31
Authors: HAYTON MAGDA , SHAW ROBERT L. J.
Published: December 2023

The Expositio in Apocalypsim by Alexander Minorita (also known as Alexander of Bremen, d. 1271) is the earliest complete mendicant Apocalypse commentary. It has been noted for its highly chronological interpretation of the path toward the end times and its witness to the early spread of Joachimite texts into central Europe. Our knowledge of the transmission and, crucially, the use of this text has thus far not taken into account thirty-five folios of instruction on spiritual warfare found in one of the Expositio's eight manuscript witnesses: Cambridge, University Library, Mm.5.31 (c. 1270). The edition presented here of this unique addition, which was excluded from the modern critical edition of the Expositio, makes the complete Cambridge version of the Expositio available for the first time. While there has been some debate over the editorship of this version of the commentary — the Benedictine-turned-Franciscan Albert of Stade (d. c. 1260) and Alexander himself have both been suggested — we argue that a further possibility must be considered. Its author may have been a highly educated Benedictine writer, who adapted the commentary with his coreligionists (at least partly) in mind. His goal was not only to extol the importance within the apocalyptic timeline of Benedictine history, but also to promote ascetic values among his readers. Overall, the Cambridge Expositio provides further evidence of the intellectual conversations and cross-pollination of both practices of learning and structures of thought between mendicant, university, and cenobitic cultures in this period. Within this context, apocalyptic thought could find unexpected uses, including galvanizing monks in day-to-day religious practice and progress.
WODEN AND MAXIMS I
Authors: NEIDORF LEONARD
Published: December 2023

This paper reconsiders the passage in Maxims I in which Woden is said to have constructed wēos, a word that can be understood to mean “idols” or “pagan shrines.” It compares the passage to various euhemeristic narratives concerning Woden (or Óðinn) preserved by authors such as Ælfric, Æthelweard, Saxo Grammaticus, and Snorri Sturluson, and it argues that the Maxims I passage has more in common with ideas expressed in the later Scandinavian sources than in the earlier homiletic or insular historiographical sources. This exercise in comparative euhemerism suggests that the Woden passage in Maxims I is indebted to a narrative that resembled either the story of Óðinn's misadventure with an idol (preserved in Gesta Danorum) or the story of Óðinn as the builder of temples and founder of pagan religion (preserved in Ynglinga saga). In either case, it appears that a euhemeristic narrative of the sort preserved by Snorri and Saxo circulated centuries earlier in England. Toponymic evidence lends support to this conclusion, as place-names such as Wōdnes dīc and Grīmes dīc bear witness to the early circulation of otherwise unrecorded ideas about Woden as a supernatural builder. Finally, the presence of the Woden passage in Maxims I is viewed as a manifestation of the poem's indebtedness to the tradition of the wisdom contest, a genre associated with Óðinn in Old Norse sapiential literature.
Lockdown and Mental Health in Alzheimer’s Disease
Authors: El Haj Mohamad , Boutoleau-Bretonnière Claire , Chapelet Guillaume , Kapogiannis Dimitrios , Ndobo André
Published: December 2023

Abstract: We asked 44 French and 42 Lebanese participants with Alzheimer’s disease (AD) who lived in their own homes to rate their depression and anxiety during the late fall/early winter 2020 lockdown and compared their responses. We also asked caregivers to quantify the frequency of visits that participants received from family members during the lockdown. We found higher levels of depression and anxiety in French than in Lebanese participants as well as lower frequency of visits to French than Lebanese participants. Interestingly, we observed negative correlations between depression/anxiety levels and frequency of visits in the two populations. The higher depression and anxiety levels in French than in Lebanese participants may result from fewer opportunities for communication with family members.
Oceanic Redox State During the Early Cambrian: Insights From Mo‐S Isotopes and Geochemistry of Himalayan Shales
Authors: Venugopal Achyuth , Tripathy Gyana Ranjan , Goswami Vineet , Ghosh Sumit K. , Singh Deependra
Published: December 2023

The Precambrian‐Cambrian (Pc‐C) boundary marks significant biological, atmospheric, and oceanic changes. These changes include extinction of the Ediacaran fauna, initiation of complex lifeforms, and oxygenation of the atmosphere and oceans. In this contribution, elemental and Mo‐S isotopic compositions of organic‐rich shales overlying the Pc‐C boundary from the Tal Formation, Lesser Himalaya, have been investigated. These datasets are used to reconstruct past oceanic redox state and sulfate concentrations. The principal component analysis of the elemental dataset identifies six major factors, with factors associated with organic matter and sulfide phases accounting for about half of the total variance. Iron speciation and Mo/U data suggest that the shales were deposited in anoxic and ferruginous deep water conditions. The δ98Mo data (1.5 ± 0.2‰) and their mass balance calculations indicate that the areal extent of sulfidic waters and pyrite burial rates were about 2–4 times higher during the Pc‐C transition than in the modern ocean. The pyrite‐δ34S values (3.6–8.3‰) for the Tal shales are isotopically heavier compared to modern‐day sedimentary pyrites (∼−21‰). Calculations involving earlier‐reported δ34S values for early Cambrian seawater and our measured pyrite‐δ34S data estimate the seawater sulfate concentration (8 ± 3 mM) during their deposition. This sulfate value for the Tal basin is higher than that reported for the late Neoproterozoic ocean (<5 mM), attributable to increasing oxygen availability and continental supply during this time. The observed basinal conditions and high terrestrial input may have influenced metazoan diversification.
First‐Order Transition in Appalachian Orogenic Processes Revealed by Along‐Strike Variation of the Moho Geometry
Authors: Luo Yantao , Long Maureen D. , Karabinos Paul , Rondenay Stéphane , Masis Arce Roberto
Published: December 2023

Along‐strike variation of the Laurentian rifted margin and the Appalachian orogen has long been recognized in the geologic record. We investigated the manifestation of this along‐strike variation at depth by generating scattered wavefield migration profiles from four dense seismic arrays deployed across the Appalachian orogen at different latitudes. All profiles exhibit a similar crustal thickness decrease of 15–20 km from the Mesoproterozoic Grenville Province to the Paleozoic Appalachian accreted terranes, but the Moho architecture differs dramatically along strike. The profiles beneath the central and southern Appalachians show a smoothly varying Moho geometry; in contrast, there is an abrupt Moho depth offset beneath the New England Appalachians. This contrast in Moho geometry may result from variations in the Laurentian rifted margin architecture, changes in Taconic orogeny subduction polarity, and greater crustal shortening during the Acadian‐Neoacadian orogeny in southern New England and the Alleghanian orogeny in the central and southern Appalachians. A first‐order along‐strike transition in the behavior of Appalachian orogenic processes is located between the central and New England Appalachians.
Middle Miocene Onset of the Litang Fault System Records Kinematic Change in Eastern Tibet
Authors: Cao Kai , Zhang Di , Shen Xiaoming , Zhang Junfeng , Wang Dun , Xu Yadong , Wang Guocan
Published: December 2023

The ∼400‐km‐long Litang fault system (LTFS) is a major intracontinental strike‐slip fault inside the Chuandian block, eastern Tibet, but its evolution and role in accommodating the India‐Asia convergence remain poorly known. Structural analysis shows that the LTFS splits into 5 strands as a left‐lateral, right‐stepping en‐echelon pattern formed under NW‐directed compression, subsequently reactivated by transtensive faults under NNE‐directed extension. Displaced geological and morphological markers yield a cumulative left‐lateral offset of 28.9–42.8 km. Inverse thermal‐history modeling of thermochronological data of the faulted rocks reveal accelerated cooling at 38–35 Ma, 16–13 Ma, and 7–5 Ma. The late Eocene rapid cooling is ascribed to the reactivation of the Garze‐Litang suture. Rapid cooling events at 16–13 Ma and 7–5 Ma record the onset of transpression and transtension of the LTFS, respectively, yielding a geologic slip rate of 2.6 ± 0.7 mm/yr. Both bifurcated geometry and slow slip rate of the LTFS since 16–13 Ma indicate diffuse deformation inside the Chuandian block, contrasting with strain localized on fast‐slip strike‐slip faults on the block margins. This implies a significant kinematic transition in the middle Miocene, such that the extrusion of the segmented mega‐blocks has been accommodated by both localized and distributed deformation in eastern Tibet. This tectonic transition could be explained by a change in lithospheric rheology from an earlier rigid state to a viscous state underneath the Chuandian block due to thermal weakening of the lower crust. We thus reconcile the end‐member geodynamic models of block extrusion and lower crustal flow in late Cenozoic times.
Managing Sibling Referrals: Ethical Considerations for Integrated Pediatric Primary Care
Authors: Forcino Stacy S. , Grimes L. Michelle , Kuhn Brett R.
Published: December 2023

Objective:

Physicians in integrated primary care settings often refer siblings to the same pediatric psychologist. The objective of this article is to assist psychologists in ethical decision making regarding such referrals, which, if accepted, mean entering multiple relationships.

Method:

Ethical issues related to sibling referrals, including risk for harm and ways to avoid it, as well as potential benefits, are discussed in the context of the APA’s Ethics Code and relevant literature.

Results:

An ethical decision-making framework for evaluating sibling referrals is applied to case examples.

Conclusions:

Pediatric psychologists must thoughtfully evaluate sibling referrals to identify when accepting sibling referrals is a reasonable risk. Use of a framework can facilitate decision making.

Implications for Impact Statement

When pediatric psychologists provide individual therapy to more than one child from the same family, there are ethical risks. However, having siblings receive services from the same psychologist is efficient and improves access to care. This article reviews ethical risks and benefits of providing individual therapy to siblings and proposes a decision-making framework to aid pediatric psychologists in deciding how to proceed given sibling referrals.
The chromatin remodeling protein BRG1 regulates HSC-myofibroblast differentiation and liver fibrosis
Authors: Zhu Yuwen , Kang Aoqi , Kuai Yameng , Guo Yan , Miao Xiulian , Zhu Li , Kong Ming , Li Nan
Published: December 2023

Excessive fibrogenic response in the liver disrupts normal hepatic anatomy and function heralding such end-stage liver diseases as hepatocellular carcinoma and cirrhosis. Myofibroblasts, derived primarily from hepatic stellate cells (HSCs), are the effector of liver fibrosis. In the present study we investigated the mechanism by which Brahma-related gene 1 (BRG1, encoded by Smarca4) regulates HSC-myofibroblast transition and the implication in intervention against liver fibrosis. We report that BRG1 expression was elevated during HSC maturation in cell culture, in animal models, and in human cirrhotic liver biopsy specimens. HSC-specific deletion of BRG1 attenuated liver fibrosis in several different animal models. In addition, BRG1 ablation in myofibroblasts ameliorated liver fibrosis. RNA-seq identified IGFBP5 as a novel target for BRG1. Over-expression of IGFBP5 partially rescued the deficiency in myofibroblast activation when BRG1 was depleted. On the contrary, IGFBP5 knockdown suppressed HSC-myofibroblast transition in vitro and mollified liver fibrosis in mice. Mechanistically, IGFBP5 interacted with Bat3 to stabilize the Bat3-TβR complex and sustain TGF-β signaling. In conclusion, our data provide compelling evidence that BRG1 is a pivotal regulator of liver fibrosis by programming HSC-myofibroblast transition.
Are disease-specific patient-reported outcomes measures (PROMs) used in cardiogenetics? A systematic review
Authors: van Pottelberghe Saar , Kupper Nina , Scheirlynck Esther , Amin Ahmad S. , Wilde Arthur A. M. , Hofman Nynke , Callus Edward , Biller Ruth , Nekkebroeck Julie , Van Dooren Sonia , Hes Frederik J. , van der Crabben Saskia N.
Published: December 2023

Patient-reported outcome measures (PROMs) are used to facilitate patient-centered care (PCC). While studies in patients with cardiac conditions have revealed poorer health-related quality of life (HRQoL) and elevated emotional stress, studies in inherited cardiac conditions (ICC) seem rare. A systematic review evaluated which (specific domains of) PROMs are used in patients with ICC. From three databases (PubMed, PsychINFO, and Web of Science) quantitative studies investigating PROMs in patients with ICC were included. A Cochrane-based assessment tool was used to evaluate quality and potential risk of bias per subdomain. Data from 17 eligible articles were extracted. Among the included studies, risk of bias was predominantly high (35%) or unclear (30%). Most (n = 14) studies used a generic health status measure (SF-36, SF-12); 3 studies used a disease-specific PROM (KCCQ- cardiomyopathy and MLFHQ-heart failure). In addition to HRQoL measures, several studies used affective psychological measures (i.e., HADS, CAQ-18, IES-R, and IPQ). The mental health component of the PROMs showed lower scores overall in patients with ICC compared to population norms. Nine studies using HADS and GAD-7/PHQ-9 showed a prevalence of clinically significant anxiety (17–47%) and depression levels (8.3–28%) that were higher than the population norm (8.3% and 6.3%, respectively). HRQoL in patients with ICC is primarily assessed with generic PROMs. Results further confirmed high psychological morbidity in this population. Generic PROMS measures evaluate overall health status, but lack sensitivity to ICC-specific factors like heredity-related concerns. We propose developing a PROM specific for ICC to optimize PCC.
CA3 hippocampal synaptic plasticity supports ripple physiology during memory consolidation
Authors: El Oussini Hajer , Zhang Chun-Lei , François Urielle , Castelli Cecilia , Lampin-Saint-Amaux Aurélie , Lepleux Marilyn , Molle Pablo , Velez Legeolas , Dejean Cyril , Lanore Frederic , Herry Cyril , Choquet Daniel , Humeau Yann
Published: December 2023

The consolidation of recent memories depends on memory replays, also called ripples, generated within the hippocampus during slow-wave sleep, and whose inactivation leads to memory impairment. For now, the mobilisation, localisation and importance of synaptic plasticity events associated to ripples are largely unknown. To tackle this question, we used cell surface AMPAR immobilisation to block post-synaptic LTP within the hippocampal region of male mice during a spatial memory task, and show that: 1- hippocampal synaptic plasticity is engaged during consolidation, but is dispensable during encoding or retrieval. 2- Plasticity blockade during sleep results in apparent forgetting of the encoded rule. 3- In vivo ripple recordings show a strong effect of AMPAR immobilisation when a rule has been recently encoded. 4- In situ investigation suggests that plasticity at CA3-CA3 recurrent synapses supports ripple generation. We thus propose that post-synaptic AMPAR mobility at CA3 recurrent synapses is necessary for ripple-dependent rule consolidation.
Molecular sensitised probe for amino acid recognition within peptide sequences
Authors: Wu Xu , Borca Bogdana , Sen Suman , Koslowski Sebastian , Abb Sabine , Rosenblatt Daniel Pablo , Gallardo Aurelio , Mendieta-Moreno Jesús I. , Nachtigall Matyas , Jelinek Pavel , Rauschenbach Stephan , Kern Klaus , Schlickum Uta
Published: December 2023

The combination of low-temperature scanning tunnelling microscopy with a mass-selective electro-spray ion-beam deposition established the investigation of large biomolecules at nanometer and sub-nanometer scale. Due to complex architecture and conformational freedom, however, the chemical identification of building blocks of these biopolymers often relies on the presence of markers, extensive simulations, or is not possible at all. Here, we present a molecular probe-sensitisation approach addressing the identification of a specific amino acid within different peptides. A selective intermolecular interaction between the sensitiser attached at the tip-apex and the target amino acid on the surface induces an enhanced tunnelling conductance of one specific spectral feature, which can be mapped in spectroscopic imaging. Density functional theory calculations suggest a mechanism that relies on conformational changes of the sensitiser that are accompanied by local charge redistributions in the tunnelling junction, which, in turn, lower the tunnelling barrier at that specific part of the peptide.
Tracking exceptional points above the lasing threshold
Authors: Ji Kaiwen , Zhong Qi , Ge Li , Beaudoin Gregoire , Sagnes Isabelle , Raineri Fabrice , El-Ganainy Ramy , Yacomotti Alejandro M.
Published: December 2023

Recent studies on exceptional points (EPs) in non-Hermitian optical systems have revealed unique traits, including unidirectional invisibility, chiral mode switching and laser self-termination. In systems featuring gain/loss components, EPs are commonly accessed below the lasing threshold, i.e., in the linear regime. In this work, we experimentally demonstrate that EP singularities in coupled semiconductor nanolasers can be accessed above the lasing threshold, where they become branch points of a nonlinear dynamical system. Contrary to the common belief that unavoidable cavity detuning impedes the formation of EPs, here we demonstrate that such detuning is necessary for compensating the carrier-induced frequency shift, hence restoring the EP. Furthermore, we find that the pump imbalance at lasing EPs varies with the total pump power, enabling their continuous tracking. This work uncovers the unstable nature of EPs above laser threshold in coupled semiconductor lasers, offering promising opportunities for the realization of self-pulsing nanolaser devices and frequency combs.
On-chip phonon-magnon reservoir for neuromorphic computing
Authors: Yaremkevich Dmytro D. , Scherbakov Alexey V. , De Clerk Luke , Kukhtaruk Serhii M. , Nadzeyka Achim , Campion Richard , Rushforth Andrew W. , Savel’ev Sergey , Balanov Alexander G. , Bayer Manfred
Published: December 2023

Reservoir computing is a concept involving mapping signals onto a high-dimensional phase space of a dynamical system called “reservoir” for subsequent recognition by an artificial neural network. We implement this concept in a nanodevice consisting of a sandwich of a semiconductor phonon waveguide and a patterned ferromagnetic layer. A pulsed write-laser encodes input signals into propagating phonon wavepackets, interacting with ferromagnetic magnons. The second laser reads the output signal reflecting a phase-sensitive mix of phonon and magnon modes, whose content is highly sensitive to the write- and read-laser positions. The reservoir efficiently separates the visual shapes drawn by the write-laser beam on the nanodevice surface in an area with a size comparable to a single pixel of a modern digital camera. Our finding suggests the phonon-magnon interaction as a promising hardware basis for realizing on-chip reservoir computing in future neuromorphic architectures.
Maternal antibiotic exposure enhances ILC2 activation in neonates via downregulation of IFN1 signaling
Authors: Xu Haixu , Yi Xianfu , Cui Zhaohai , Li Hui , Zhu Lin , Zhang Lijuan , Chen JiaLe , Fan Xutong , Zhou Pan , Li Mulin Jun , Yu Ying , Liu Qiang , Huang Dandan , Yao Zhi , Zhou Jie
Published: December 2023

Microbiota have an important function in shaping and priming neonatal immunity, although the cellular and molecular mechanisms underlying these effects remain obscure. Here we report that prenatal antibiotic exposure causes significant elevation of group 2 innate lymphoid cells (ILC2s) in neonatal lungs, in both cell numbers and functionality. Downregulation of type 1 interferon signaling in ILC2s due to diminished production of microbiota-derived butyrate represents the underlying mechanism. Mice lacking butyrate receptor GPR41 (Gpr41-/-) or type 1 interferon receptor IFNAR1 (Ifnar1-/-) recapitulate the phenotype of neonatal ILC2s upon maternal antibiotic exposure. Furthermore, prenatal antibiotic exposure induces epigenetic changes in ILC2s and has a long-lasting deteriorative effect on allergic airway inflammation in adult offspring. Prenatal supplementation of butyrate ameliorates airway inflammation in adult mice born to antibiotic-exposed dams. These observations demonstrate an essential role for the microbiota in the control of type 2 innate immunity at the neonatal stage, which suggests a therapeutic window for treating asthma in early life.
C5 methylation confers accessibility, stability and selectivity to picrotoxinin
Authors: Tong Guanghu , Griffin Samantha , Sader Avery , Crowell Anna B. , Beavers Ken , Watson Jerry , Buchan Zachary , Chen Shuming , Shenvi Ryan A.
Published: December 2023

Minor changes to complex structures can exert major influences on synthesis strategy and functional properties. Here we explore two parallel series of picrotoxinin (PXN, 1) analogs and identify leads with selectivity between mammalian and insect ion channels. These are the first SAR studies of PXN despite its >100-year history and are made possible by advances in total synthesis. We observe a remarkable stabilizing effect of a C5 methyl, which completely blocks C15 alcoholysis via destabilization of an intermediate twist-boat conformer; suppression of this secondary hydrolysis pathway increases half-life in plasma. C5 methylation also decreases potency against vertebrate ion channels (γ-Aminobutyric acid type A (GABAA) receptors) but maintains or increases antagonism of homologous invertebrate GABA-gated chloride channels (resistance to dieldrin (RDL) receptors). Optimal 5MePXN analogs appear to change the PXN binding pose within GABAARs by disruption of a hydrogen bond network. These discoveries were made possible by the lower synthetic burden of 5MePXN (2) and were illuminated by the parallel analog series, which allowed characterization of the role of the synthetically simplifying C5 methyl in channel selectivity. These are the first SAR studies to identify changes to PXN that increase the GABAA-RDL selectivity index.
Revealing the room temperature superplasticity in bulk recrystallized molybdenum
Authors: Chen Wenshuai , Li Xiyao , Jin Shenbao , Yang Lunwei , Li Yan , He Xueliang , Zhang Wanting , Wu Yinxing , Hui Zhilin , Yang Zhimin , Yang Jian , Xiao Wei , Sha Gang , Wang Jiangwei , Zhou Zenglin
Published: December 2023

Body-centered cubic refractory metallic materials exhibit excellent high-temperature strength, but often suffer from brittle intergranular fracture due to the recrystallization-induced enrichment of trace elements at grain boundaries (GBs). Here, we report a fully-recrystallized pure molybdenum (Mo) material with room temperature (RT) superplasticity, fabricated by a facile method of powder metallurgy, Y-type hot rolling and annealing. By engineering the ultralow concentration of O at GBs, the inherent GB brittleness of Mo can be largely eliminated, which, in conjunction with high fractions of soft texture and low angle GBs, enables a significant development of ordered dislocation networks and the effective dislocation transmission across low angle GBs. Synergy of these factors greatly suppress the brittle intergranular fracture of Mo, contributing to an enhanced deformability of 108.7% at RT. These findings should have general implication for fabricating a broad class of refractory metals and alloys toward harsh applications.
A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity
Authors: Ji Linong , Jiang Hongwei , Cheng Zhifeng , Qiu Wei , Liao Lin , Zhang Yawei , Li Xiaoli , Pang Shuguang , Zhang Lihui , Chen Liming , Yang Tao , Li Yan , Qu Shen , Wen Jie , Gu Jieyu , Deng Huan , Wang Yanqi , Li Li , Han-Zhang Han , Ma Qingyang , Qian Lei
Published: December 2023

Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. We evaluated the efficacy and safety of 24-week treatment of mazdutide up to 6 mg in Chinese overweight adults or adults with obesity, as an interim analysis of a randomised, two-part (low doses up to 6 mg and high dose of 9 mg), double-blind, placebo-controlled phase 2 trial (ClinicalTrials.gov, NCT04904913). Overweight adults (body-mass index [BMI] ≥24 kg/m2) accompanied by hyperphagia and/or at least one obesity-related comorbidity or adults with obesity (BMI ≥ 28 kg/m2) were randomly assigned (3:1:3:1:3:1) to once-weekly mazdutide 3 mg, 4.5 mg, 6 mg or matching placebo at 20 hospitals in China. The primary endpoint was the percentage change from baseline to week 24 in body weight. A total of 248 participants were randomised to mazdutide 3 mg (n = 62), 4.5 mg (n = 63), 6 mg (n = 61) or placebo (n = 62). The mean percentage changes from baseline to week 24 in body weight were −6.7% (SE 0.7) with mazdutide 3 mg, −10.4% (0.7) with 4.5 mg, −11.3% (0.7) with 6 mg and 1.0% (0.7) with placebo, with treatment difference versus placebo ranging from −7.7% to −12.3% (all p < 0.0001). All mazdutide doses were well tolerated and the most common adverse events included diarrhoea, nausea and upper respiratory tract infection. In summary, in Chinese overweight adults or adults with obesity, 24-week treatment with mazdutide up to 6 mg was safe and led to robust and clinically meaningful body weight reduction.
Molecular basis for proofreading by the unique exonuclease domain of Family-D DNA polymerases
Authors: Betancurt-Anzola Leonardo , Martínez-Carranza Markel , Delarue Marc , Zatopek Kelly M. , Gardner Andrew F. , Sauguet Ludovic
Published: December 2023

Replicative DNA polymerases duplicate entire genomes at high fidelity. This feature is shared among the three domains of life and is facilitated by their dual polymerase and exonuclease activities. Family D replicative DNA polymerases (PolD), found exclusively in Archaea, contain an unusual RNA polymerase-like catalytic core, and a unique Mre11-like proofreading active site. Here, we present cryo-EM structures of PolD trapped in a proofreading mode, revealing an unanticipated correction mechanism that extends the repertoire of protein domains known to be involved in DNA proofreading. Based on our experimental structures, mutants of PolD were designed and their contribution to mismatch bypass and exonuclease kinetics was determined. This study sheds light on the convergent evolution of structurally distinct families of DNA polymerases, and the domain acquisition and exchange mechanism that occurred during the evolution of the replisome in the three domains of life.
Automating General Movements Assessment with quantitative deep learning to facilitate early screening of cerebral palsy
Authors: Gao Qiang , Yao Siqiong , Tian Yuan , Zhang Chuncao , Zhao Tingting , Wu Dan , Yu Guangjun , Lu Hui
Published: December 2023

The Prechtl General Movements Assessment (GMA) is increasingly recognized for its role in evaluating the integrity of the developing nervous system and predicting motor dysfunctions, particularly in conditions such as cerebral palsy (CP). However, the necessity for highly trained professionals has hindered the adoption of GMA as an early screening tool in some countries. In this study, we propose a deep learning-based motor assessment model (MAM) that combines infant videos and basic characteristics, with the aim of automating GMA at the fidgety movements (FMs) stage. MAM demonstrates strong performance, achieving an Area Under the Curve (AUC) of 0.967 during external validation. Importantly, it adheres closely to the principles of GMA and exhibits robust interpretability, as it can accurately identify FMs within videos, showing substantial agreement with expert assessments. Leveraging the predicted FMs frequency, a quantitative GMA method is introduced, which achieves an AUC of 0.956 and enhances the diagnostic accuracy of GMA beginners by 11.0%. The development of MAM holds the potential to significantly streamline early CP screening and revolutionize the field of video-based quantitative medical diagnostics.
Csu pili dependent biofilm formation and virulence of Acinetobacter baumannii
Authors: Ahmad Irfan , Nadeem Aftab , Mushtaq Fizza , Zlatkov Nikola , Shahzad Muhammad , Zavialov Anton V. , Wai Sun Nyunt , Uhlin Bernt Eric
Published: December 2023

Acinetobacter baumannii has emerged as one of the most common extensive drug-resistant nosocomial bacterial pathogens. Not only can the bacteria survive in hospital settings for long periods, but they are also able to resist adverse conditions. However, underlying regulatory mechanisms that allow A. baumannii to cope with these conditions and mediate its virulence are poorly understood. Here, we show that bi-stable expression of the Csu pili, along with the production of poly-N-acetyl glucosamine, regulates the formation of Mountain-like biofilm-patches on glass surfaces to protect bacteria from the bactericidal effect of colistin. Csu pilus assembly is found to be an essential component of mature biofilms formed on glass surfaces and of pellicles. By using several microscopic techniques, we show that clinical isolates of A. baumannii carrying abundant Csu pili mediate adherence to epithelial cells. In addition, Csu pili suppressed surface-associated motility but enhanced colonization of bacteria into the lungs, spleen, and liver in a mouse model of systemic infection. The screening of c-di-GMP metabolizing protein mutants of A. baumannii 17978 for the capability to adhere to epithelial cells led us to identify GGDEF/EAL protein AIS_2337, here denoted PdeB, as a major regulator of Csu pili-mediated virulence and biofilm formation. Moreover, PdeB was found to be involved in the type IV pili-regulated robustness of surface-associated motility. Our findings suggest that the Csu pilus is not only a functional component of mature A. baumannii biofilms but also a major virulence factor promoting the initiation of disease progression by mediating bacterial adherence to epithelial cells.
Optimal adjuvant therapy in older (≥70 years of age) women with low-risk early-stage breast cancer
Authors: Chadha M. , White J. , Swain S. M. , Rakovitch E. , Jagsi R. , Whelan T. , Sparano J. A.
Published: December 2023

Older women are under-represented in breast cancer (BC) clinical trials, and treatment guidelines are primarily based on BC studies in younger women. Studies uniformly report an increased incidence of local relapse with omission of breast radiation therapy. Review of the available literature suggests very low rates of distant relapse in women ≥70 years of age. The incremental benefit of endocrine therapy in decreasing rate of distant relapse and improving disease-free survival in older patients with low-risk BC remains unclear. Integration of molecular genomic assays in diagnosis and treatment of estrogen receptor positive BC presents an opportunity for optimizing risk-tailored adjuvant therapies in ways that may permit treatment de-escalation among older women with early-stage BC. The prevailing knowledge gap and lack of risk-specific adjuvant therapy guidelines suggests a compelling need for prospective trials to inform selection of optimal adjuvant therapy, including omission of adjuvant endocrine therapy in older women with low risk BC.
Plasma metabolites of aromatic amino acids associate with clinical severity and gut microbiota of Parkinson’s disease
Authors: Chen Szu-Ju , Wu Yu-Jun , Chen Chieh-Chang , Wu Yu-Wei , Liou Jyh-Ming , Wu Ming-Shiang , Kuo Ching-Hua , Lin Chin-Hsien
Published: December 2023

Gut microbial proteolytic metabolism has been reportedly altered in Parkinson’s disease (PD). However, the circulating aromatic amino acids (AAA) described in PD are inconsistent. Here we aimed to investigate plasma AAA profiles in a large cohort of PD patients, and examine their correlations with clinical severity and gut microbiota changes. We enrolled 500 participants including 250 PD patients and 250 neurologically normal controls. Plasma metabolites were measured using liquid chromatography mass spectrometry. Faecal samples were newly collected from 154 PD patients for microbiota shotgun metagenomic sequencing combined with data derived from 96 PD patients reported before. Data were collected regarding diet, medications, and motor and non-motor symptoms of PD. Compared to controls, PD patients had higher plasma AAA levels, including phenylacetylglutamine (PAGln), p-cresol sulfate (Pcs), p-cresol glucuronide (Pcg), and indoxyl sulfate (IS). Multivariable linear regression analyses, with adjustment for age, sex, and medications, revealed that the plasma levels of PAGln (coefficient 4.49, 95% CI 0.40–8.58, P = 0.032) and Pcg (coefficient 1.79, 95% CI 0.07–3.52, P = 0.042) positively correlated with motor symptom severity but not cognitive function. After correcting for abovementioned potential confounders, these AAA metabolites were also associated with the occurrence of constipation in PD patients (all P < 0.05). Furthermore, plasma levels of AAA metabolites were correlated with the abundance of specific gut microbiota species, including Bacteroides sp. CF01-10NS, Bacteroides vulgatus, and Clostridium sp. AF50-3. In conclusion, elevated plasma AAA metabolite levels correlated with disease characteristics in PD, suggesting that upregulated proteolytic metabolism may contribute to the pathophysiology of PD.
A Pvs25 mRNA vaccine induces complete and durable transmission-blocking immunity to Plasmodium vivax
Authors: Kunkeaw Nawapol , Nguitragool Wang , Takashima Eizo , Kangwanrangsan Niwat , Muramatsu Hiromi , Tachibana Mayumi , Ishino Tomoko , Lin Paulo J. C. , Tam Ying K. , Pichyangkul Sathit , Tsuboi Takafumi , Pardi Norbert , Sattabongkot Jetsumon
Published: December 2023

Plasmodium vivax (P. vivax) is the major malaria parasite outside of Africa and no vaccine is available against it. A vaccine that interrupts parasite transmission (transmission-blocking vaccine, TBV) is considered highly desirable to reduce the spread of P. vivax and to accelerate its elimination. However, the development of a TBV against this pathogen has been hampered by the inability to culture the parasite as well as the low immunogenicity of the vaccines developed to date. Pvs25 is the most advanced TBV antigen candidate for P. vivax. However, in previous phase I clinical trials, TBV vaccines based on Pvs25 yielded low antibody responses or had unacceptable safety profiles. As the nucleoside-modified mRNA–lipid nanoparticle (mRNA–LNP) vaccine platform proved to be safe and effective in humans, we generated and tested mRNA–LNP vaccines encoding several versions of Pvs25 in mice. We found that in a prime-boost vaccination schedule, all Pvs25 mRNA–LNP vaccines elicited robust antigen-specific antibody responses. Furthermore, when compared with a Pvs25 recombinant protein vaccine formulated with Montanide ISA-51 adjuvant, the full-length Pvs25 mRNA–LNP vaccine induced a stronger and longer-lasting functional immunity. Seven months after the second vaccination, vaccine-induced antibodies retained the ability to fully block P. vivax transmission in direct membrane feeding assays, whereas the blocking activity induced by the protein/ISA-51 vaccine dropped significantly. Taken together, we report on mRNA vaccines targeting P. vivax and demonstrate that Pvs25 mRNA–LNP outperformed an adjuvanted Pvs25 protein vaccine suggesting that it is a promising candidate for further testing in non-human primates.
Hong Kong Corpus of Chinese Sentence and Passage Reading
Authors: Wu Yushu , Kit Chunyu
Published: December 2023

Recent years have witnessed a mushrooming of reading corpora that have been built by means of eye tracking. This article showcases theHong Kong Corpus of Chinese Sentence and Passage Reading(HKC for brevity), featured by a natural reading of logographic scripts and unspaced words. It releases 28 eye-movement measures of 98 native speakers reading simplified Chinese in two scenarios: 300 one-line single sentences and 7 multiline passages of 5,250 and 4,967 word tokens, respectively. To verify its validity and reusability, we carried out (generalised) linear mixed-effects modelling on the capacity of visual complexity, word frequency, and reading scenario to predict eye-movement measures. The outcomes manifest significant impacts of these typical (sub)lexical factors on eye movements, replicating previous findings and giving novel ones. The HKC provides a valuable resource for exploring eye movement control; the study contrasts the different scenarios of single-sentence and passage reading in hopes of shedding new light on both the universal nature of reading and the unique characteristics of Chinese reading.
Feasibility study on cardiac resynchronization in the treatment of heart failure by single left bundle branch pacing
Authors: Du Yadong , Pu Lijin , Hua Baotong , Lu Yanzhou , Wang Xiuli , Zhao Ling
Published: December 2023

To examine the feasibility of single left bundle branch pacing for cardiac resynchronization therapy (CRT) by carrying out a frequency adaptive atrioventricular delay (RAAVD) algorithm and automatic optimization of the single left bundle branch pacing atrioventricular interval (AVI) based on the right atrioventricular interval (RAS–RVS). Thirty-six patients with CRT class Ia indications according to the European Society of Cardiology 2016 guidelines and implanted with RAAVD functional three-chamber pacemakers were prospectively enrolled in this study. Patients were divided into a single left bundle branch pacing group (n = 21) and a standard biventricular pacing group (n = 15). The optimization of the two groups was performed under standard cardiac colour Doppler ultrasound, followed by the comparison of the QRS width, cardiac function improvement, and echocardiography indicators. The ratio of AVI to the right atrial-right ventricular interval (RAS–RVS) after single LV pacing optimization was defined as the single left bundle branch pacing coefficient (LUBBPε). In comparison to the BVP, the QRS was significantly narrowed (P = 0.017), accompanied by a significantly increased proportion of patients with NYHA class I and II, as well as the 6MWT. Compared with standard biventricular pacing, LVEDD was significantly shortened (P = 0.045), accompanied by significantly improved LAD, AVVTI, EA distance/RR, IVMD, and TS-SD after the operation. RAS–RVS was 156 ± 33 ms, the optimized AVI was 102 ± 10 ms, and LUBBPε was calculated to be 0.66 ± 0.06. Depending on the LUBBPε, a three-chamber pacemaker with a single left bundle branch pacing system was developed based on RAS–RVS-optimized AVI automatically. A three-chamber pacemaker with single left bundle branch pacing can achieve CRT based on RAS–RVS, reaching the optimal AVI of 66% of RAS–RVS.
The bactericidal and antibiofilm effects of a lysine-substituted hybrid peptide, CM-10K14K, on biofilm-forming Staphylococcus epidermidis
Authors: Klubthawee Natthaporn , Wongchai Mathira , Aunpad Ratchaneewan
Published: December 2023

Staphylococci, notably biofilm-forming Staphylococcus epidermidis, have been recognized as global nosocomial pathogens in medical device-related infections. Their potential to attach to and form biofilm on indwelling catheters are significant factors impeding conventional treatment. Due to their extensive antimicrobial and antibiofilm actions, antimicrobial peptides (AMPs) have attracted interest as promising alternative compounds for curing difficult-to-treat, biofilm-forming bacterial infections. Cecropin A-melittin or CM, a well-known hybrid peptide, exhibits broad-spectrum antimicrobial activity, however it also possesses high toxicity. In the current study, a series of hybrid CM derivatives was designed using an amino acid substitution strategy to explore potential antibacterial and antibiofilm peptides with low toxicity. Among the derivatives, CM-10K14K showed the least hemolysis along with potent antibacterial activity against biofilm-forming S. epidermidis (MICs = 3.91 μg/mL) and rapid killing after 15 min exposure (MBCs = 7.81 μg/mL). It can prevent the formation of S. epidermidis biofilm and also exhibited a dose-dependent eradication activity on mature or established S. epidermidis biofilm. In addition, it decreased the development of biofilm by surviving bacteria, and formation of biofilm on the surface of CM-10K14K-impregnated catheters. Released CM-10K14K decreased planktonic bacterial growth and inhibited biofilm formation by S. epidermidis in a dose-dependent manner for 6 and 24 h post-exposure. Impregnation of CM-10K14K prevented bacterial attachment on catheters and thus decreased formation of extensive biofilms. SEM images supported the antibiofilm activity of CM-10K14K. Flow cytometry analysis and TEM images demonstrated a membrane-active mechanism of CM-10K14K, inducing depolarization and permeabilization, and subsequent membrane rupture leading to cell death. The presence of an interaction with bacterial DNA was verified by gel retardation assay. These antibacterial and antibiofilm activities of CM-10K14K suggest its potential application to urinary catheters for prevention of biofilm-forming colonization or for treatment of medical devices infected with S. epidermidis.
UAV path planning based on third-party risk modeling
Authors: Tang Haoyang , Zhu Qiang , Qin Bo , Song Ruoyang , Li Zhe
Published: December 2023

Drones play an important role in modern cities, they bring convenience but also bring corresponding risks. Falling drones can cause casualties or damage to urban facilities and serious property damage, which increases the third-party risk problem. An effective way to reduce these third-party risks is to avoid high-risk areas in path planning, but most current path planning methods are optimized to minimize flight distance, and third-party risk costs are rarely considered. In this paper, a comprehensive risk-cost UAV path planning method is proposed, which evaluates urban risk by establishing a third-party risk model that incorporates obstacle risk, death risk, and property loss risk. This paper proposes a Min-cost A* algorithm based on city risk assessment, and smooths the generated low-risk path through the improved Floyd algorithm. The results show that the path planning method can effectively reduce the risk in the flight path, improve the reliability of the UAV flight path in the urban environment, and solve the problem of planning the third-party risk path of the UAV.
Soil microbial improvement using enriched vinasse as a new abundant waste
Authors: Kariminia Tahereh , Rowshanzamir Mohammad A. , Abtahi S. Mahdi , Soleimanian-Zad Sabihe , Bak Hamid Mortazavi , Baghbanan Alireza
Published: December 2023

This study proposes the use of vinasse, an inexpensive and readily available waste biopolymer, as a fundamental component of a waste culture medium that can enhance the effectiveness and cost-efficiency of the microbial-induced calcite precipitation (MICP) method for sustainable soil improvement. Vinasse enriched with urea, sodium caseinate, or whey protein concentrate is employed to optimize bacterial growth and urease activity of Sporosarcina pasteurii (S. pasteurii) bacterium. The best culture medium is analyzed using Taguchi design of experiments (TDOE) and statistical analysis, considering the concentration of vinasse and urea as effective parameters during growth time. To test the best culture medium for bio-treated soil, direct shear tests were performed on loose and bio-treated sand. The results demonstrate a substantial cost reduction from $0.455 to $0.005 per liter when using the new culture medium (vinasse and urea) compared to the conventional Nutrient Broth (NB) culture medium. Additionally, the new medium enhances soil shear strength, increasing the friction angle by 2.5 degrees and cohesion to 20.7 kPa compared to the conventional medium. Furthermore, the recycling of vinasse as a waste product can promote the progress of a circular economy and reduce environmental pollution. As ground improvement is essential for many construction projects, especially those that require high shear strength or are built on loose soil, this study provides a promising approach to achieving cost-effective and sustainable soil microbial improvement using enriched vinasse.
Hybrid global search with enhanced INC MPPT under partial shading condition
Authors: Zaki Mohamed , Shahin Ahmed , Eskender Saad , Elsayes Mohamed A.
Published: December 2023

The photovoltaic system is quickly emerging as a highly favored option among renewable energy sources. However, it faces several significant challenges, including variable solar irradiance, temperature, and partial shading. Unfortunately, conventional Maximum Power Point Trackers (MPPTs) cannot accurately track partial shading. Artificial intelligence and optimization techniques have been proposed as alternatives, but they require extensive training and can take a long time to achieve maximum power point (MPP) under partial shading circumstances. In this paper, a dynamic and fast-moving method of MPP tracking is proposed for use under both uniform solar irradiance and partial shade. This method combines an enhanced incremental conductance (INC) algorithm with a global search algorithm that looks at how well solar cells work when partly shaded. Simulation investigations are performed to validate the method's applicability and ensure that it reaches the most accurate value of MPP with a short-tracking time of less than 0.2 s and a steady-state error of less than 0.3% of the PV power. The results confirm the efficacy of the suggested tracking method under uniform solar irradiance and partial shade.
APOBEC-1 deletion enhances cisplatin-induced acute kidney injury
Authors: Guo Xiaojia , Blanc Valerie , Davidson Nicholas O. , Velazquez Heino , Chen Tian-min , Moledina Dennis G. , Moeckel Gilbert W. , Safirstein Robert L. , Desir Gary V.
Published: December 2023

Cisplatin (CP) induces acute kidney injury (AKI) whereby proximal tubules undergo regulated necrosis. Repair is almost complete after a single dose. We now demonstrate a role for Apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec-1) that is prominently expressed at the interface between acute and chronic kidney injury (CKD), in the recovery from AKI. Apobec-1 knockout (KO) mice exhibited greater mortality than in wild type (WT) and more severe AKI in both CP- and unilateral ischemia reperfusion (IR) with nephrectomy. Specifically, plasma creatinine (pCr) 2.6 ± 0.70 mg/dL for KO, n = 10 and 0.16 ± 0.02 for WT, n = 6, p < 0.0001 in CP model and 1.34 ± 0.22 mg/dL vs 0.75 ± 0.06, n = 5, p < 0.05 in IR model. The kidneys of Apobec-1 KO mice showed increased necrosis, increased expression of KIM-1, NGAL, RIPK1, ASCL4 and increased lipid accumulation compared to WT kidneys (p < 0.01). Neutrophils and activated T cells were both increased, while macrophages were reduced in kidneys of Apobec-1 KO animals. Overexpression of Apobec-1 in mouse proximal tubule cells protected against CP-induced cytotoxicity. These findings suggest that Apobec-1 mediates critical pro-survival responses to renal injury and increasing Apobec-1 expression could be an effective strategy to mitigate AKI.