bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐term conservation efforts at flyway scale can halt the population decline in a globally endangered migratory raptor
Authors: Oppel S. , Dobrev V. , Arkumarev V. , Saravia‐Mullin V. , Bashmili K. , Bino T. , Bounas A. , Chardin A. , Dobrev D. , Duro K. , Kapsalis E. , Kret E. , Marchant M.‐P. , Nakev S. , Petrovski N. , Papaioannou H. , Popgeorgiev G. , Selgjekaj L. , Skartsi T. , Stamenov A. , Stoychev S. , Topi M. , Vavylis D. , Velevski M. , Vorpsi Z. , Weston J. , Xeka E. , Xherri X. , Yordanov E. , Nikolov S. C.
Published: November 2023

Many threatened species require ongoing management, which is often funded through short project cycles. Evaluating whether the management is effective in protecting a species is important to inform future management investments. For migratory species, management may affect only part of a species' annual cycle, and reversing a population decline is challenging to achieve and demonstrate. Here, we evaluate whether conservation management projects funded by the European LIFE programme to safeguard a migratory vulture population achieved their major objective of stabilizing the target breeding population. Between 2012 and 2022, an international alliance of conservation organizations implemented multiple actions to reduce poisoning, direct persecution, and electrocution and collision with power lines along the Eastern Mediterranean flyway. We monitored breeding territories of the Balkan population of the globally endangered Egyptian Vulture Neophron percnopterus between 2006 and 2022, and tracked 60 young birds with GPS transmitters since 2010. We used these data to examine whether population growth rate and survival probability had increased since project implementation. The mean annual survival probability of adult territorial birds increased by 1.9% since 2014 from 0.937 to 0.955, and the monthly survival probability of wild juvenile birds increased by 9.7% from 0.833 to 0.914 since 2018. The population growth rate across the Balkans increased by 6.9% from 0.939 before 2018 to 1.005 since 2018. This indicates that the Egyptian Vulture population has remained stable for the past 5 years (2018–2022), but at a population size that is only half (105 adult territorial birds in 2022) than at the beginning of the time series (204 in 2006). We caution that ongoing management along the flyway and reinforcement are required to ensure that the Egyptian Vulture population on the Balkans can recover, but we show that flyway‐scale collaboration of direct conservation actions can have lasting benefits for migratory species.
Letter: Tofacitinib, vedolizumab and ustekinumab in patients with ulcerative colitis
Authors: Chang Hui‐Chin , Gau Shuo‐Yan
Published: November 2023

LINKED CONTENT

This article is linked to Kochhar et al papers. To view these articles, visit https://doi.org/10.1111/apt.17570 and https://doi.org/10.1111/apt.17750
Editorial: On‐demand vonoprazan forNERD– when should it be ‘demanded’? Authors' reply
Authors: Fass Ronnie , Armstrong David
Published: November 2023

LINKED CONTENT

This article is linked to Fass et al papers. To view these articles, visithttps://doi.org/10.1111/apt.17728andhttps://doi.org/10.1111/apt.17737
Letter: Abdominal pain in patients with inflammatory bowel disease in remission ‐ A look beyond psychosocial factors. Authors' reply
Authors: Rezazadeh Ardabili Ashkan , Janssen Laura , Mujagic Zlatan
Published: November 2023

LINKED CONTENT

This article is linked to Janssen et al papers. To view these articles, visit https://doi.org/10.1111/apt.17718 and https://doi.org/10.1111/apt.17745
A phase 1 trial of AP30663, a KCa2 channel inhibitor in development for conversion of atrial fibrillation
Authors: Yfanti Christina , Vestbjerg Birgitte , van't Westende Juliette , Edvardsson Nils , Monfort Laia Meseguer , Olesen Morten Salling , Bentzen Bo Hjorth , Grunnet Morten , Eveleens Maarse Boukje C. , Diness Jonas Goldin , Kemme Michiel J. B. , Sørensen Ulrik , Moerland Matthijs , van Esdonk Michiel J. , Klaassen Erica S. , Gal Pim , Holst Anders G.
Published: November 2023

Aims

AP30663 is a novel compound under development for pharmacological conversion of atrial fibrillation by targeting the small conductance Ca2+ activated K+ (KCa2) channel. The aim of this extension phase 1 study was to test AP30663 at higher single doses compared to the first‐in‐human trial.

Methods

Sixteen healthy male volunteers were randomized into 2 cohorts: 6‐ and 8‐mg/kg intravenous single‐dose administration of AP30663 vs. placebo. Safety, pharmacokinetic and pharmacodynamic data were collected.

Results

AP30663 was associated with mild and transient infusion site reactions with no clustering of other adverse events but with an estimated maximum mean QTcF interval prolongation of 45.2 ms (95% confidence interval 31.5–58.9) in the 6 mg/kg dose level and 50.4 ms (95% confidence interval 36.7–64.0) with 8 mg/kg. Pharmacokinetics was dose proportional with terminal half‐life of around 3 h.

Conclusion

AP30663 in doses up to 8 mg/kg was associated with mild and transient infusion site reactions and an increase of the QTcF interval. Supporting Information support that the QTc effect may be explained by an off‐target inhibition of the IKr channel.
Exaggerating differences back and forth: Two levels of intergroup accentuation
Authors: Rothermund Patrick , Deutsch Roland
Published: November 2023

Social perceivers tend to exaggerate existing differences between groups, a phenomenon known as intergroup accentuation. In two preregistered experiments, we tested the hypothesis that accentuation originates in the initial learning of information about a novel group. In both experiments, perceivers exaggerated differences between two fictitious social groups that differed probabilistically in two dimensional traits. As hypothesized, accentuation was stronger for the group encountered second, confirming that accentuation originates partly in processes operating during the acquisition of group information. However, accentuation was also robust for the group encountered first, suggesting that it also occurs ‘backward’ even when group learning was unbiased. We discuss implications for stereotype formation generally and the perception of social minorities and out‐groups specifically. As these groups are often encountered second in social reality, stereotypes of them might be particularly polarized.
CATSHL syndrome, a new family and phenotypic expansion
Authors: Cannova Silvia , Meossi Camilla , Grilli Federico , Milani Donatella , Alberti Federica , Cesaretti Claudia , Marchisio Paola Giovanna , Crosti Francesca , Pezzani Lidia
Published: November 2023

We report the case of a 12‐year‐old girl and her father who both had marked postnatal tall stature, camptodactyly and clinodactyly, scoliosis and juvenile‐onset hearing loss. The CATSHL (CAmptodactyly – Tall stature – Scoliosis – Hearing Loss syndrome) syndrome was suspected, and molecular analysis revealed a hitherto unreported, monoallelic variant c.1861C>T (p.Arg621Cys) in FGFR3. This variant affects the same residue, but is different than, the variant p.Arg621His reported in the two families with dominant CATSHL described so far. Interestingly, peg‐shaped incisors were observed in the proband, a feature never reported in CATSHL but typical of another FGFR3‐related condition, LADD (Lacrimo – Auricolo – Dento – Digital) syndrome. The FGFR3 p.Arg621Cys variant seems to be a newly identified cause of CATSHL syndrome with some phenotypic overlap with the LADD syndrome.
Critical‐size defects reconstruction with four different bone grafts associated with e‐PTFE membrane: A histomorphometric experimental in vivo study
Authors: Fernandes Gustavo Vicentis Oliveira , Castro Filipe , Pereira Rafael Martins , Teixeira Wendel , Gehrke Sérgio , Joly Julio Cesar , Blanco Carrion Juan , Fernandes Juliana Campos Hasse
Published: November 2023

Objectives

The goal of this study was to assess the newly formed bone and the remnant biomaterial by comparing four different bone grafts used to treat critical‐size defects, associated or not with the non‐resorbable membrane.

Materials and Methods

Two calvaria critical‐size bone defects were created in 50 male Wistar rats. They were divided into blood (G1), autogenous (G2), bioglass (G3), hydroxyapatite (G4), and xenograft (G5) groups, associated or not with e‐PTFE. The experimental periods were 15 and 45 days. Sections were prepared for histomorphometric assessment. All data were analyzed by the mixed‐effects model with multiple comparisons (significance level, p < .05).

Results

A similar level of new bone was observed for all groups, associated with a high level of vascularization. G1 and G2 ensured sovereignty over the greater quantity of new bone. A non‐significant result was reported comparing groups with and without membranes. No significant result was found between the experimental synthetic biomaterials (G3 and G4). G5L achieved 22.0% of new bone after 45 days (p > .05). All groups had a stable volume of biomaterial kept in the short term (p > .05). G2 was the best material for new bone formation and final volume of biomaterial, followed by G4 < G5 < G3. Thus, it is possible that G4 had a better degradation profile among the experimental groups.

Conclusions

The best results were found in the autogenous group, with higher resorption and integration; non‐significative new bone was found among the experimental groups; and the regeneration of critical bone defects using an e‐PTFE barrier did not present significant results on new bone formation.
Probing Lexical Ambiguity in Chinese Characters via Their Word Formations: Convergence of Perceived and Computed Metrics
Authors: Wang Tianqi , Xu Xu , Xie Xurong , Ng Manwa Lawrence
Published: November 2023

Lexical ambiguity is pervasive in language, and the nature of the representations of an ambiguous word's multiple meanings is yet to be fully understood. With a special focus on Chinese characters, the present study first established that native speaker's perception about a character's number of meanings was heavily influenced by the availability of its distinct word formations, while whether these meanings would be perceived to be closely related was driven by further conceptual analysis. These notions were operationalized as two computed metrics, which assessed the degree of dispersion across individual word formations and the degree of propinquity across clusters of word formations, respectively, in a distributional semantic space. The observed correlations between the computed and the perceived metrics indicated that the utility of word formations to tap into meaning representations of Chinese characters was indeed cognitively plausible. The results have demonstrated the extent to which distributional semantics could inform about meaning representations of Chinese characters, which has theoretical implications for the representation of ambiguous words more generally.
Few‐shot learning for word‐level scene text script identification
Authors: Naosekpam Veronica , Sahu Nilkanta
Published: November 2023

Script identification of text in scene images has attracted massive attention recently. However, the existing techniques primarily emphasize on scripts where data are available abundantly, such as English, European, or East Asian. Although these methods are robust in dealing with high‐resource data, how these techniques will work on low‐resource scripts has yet to be discovered. For example, in India, there is a disparity among the text scripts across the country's demographic. To bridge the research gap for resource‐constraint script identification, we present a few‐shot learning network called the TextScriptFSLNet. This network does not require huge training data while achieving state‐of‐the‐art performance on benchmark datasets. Our proposed method acts in accordance with a ‐way ‐shot paradigm by splitting the train set as support and query set, respectively. The support set learns representative knowledge of each class and creates its prototypes. We use multi‐kernel spatial attention fused 2‐layer convolutional neural network and averaging technique to generate the prototype of each class. This spatial attention aids in grasping important information in an image and enriches the feature representation. To the best of our knowledge, the proposed work is the first of its kind in the scene text understanding domain. Additionally, we created a dataset called Indic‐FSL2023 comprising 10 of the 22 officially recognized Indian scripts. The proposed method achieves the highest accuracy among the tested methods on the newly created Indic‐FSL2023. Experiments are also conducted on MLe2e to demonstrate its versatility. Furthermore, we also showed how our proposed model performed concerning illumination changes and blur on scene text script images.
The development of tone discrimination in infancy: Evidence from a cross‐linguistic, multi‐lab report
Authors: Kalashnikova Marina , Singh Leher , Tsui Angeline , Altuntas Eylem , Burnham Denis , Cannistraci Ryan , Chin Ng Bee , Feng Ye , Fernández‐Merino Laura , Götz Antonia , Gustavsson Lisa , Hay Jessica , Höhle Barbara , Kager René , Lai Regine , Liu Liquan , Marklund Ellen , Nazzi Thierry , Oliveira Daniela Santos , Olstad Anne Marte Haug , Picaud Anthony , Schwarz Iris‐Corinna , Tsao Feng‐Ming , Wong Patrick C. M. , Woo Pei Jun
Published: November 2023

We report the findings of a multi‐language and multi‐lab investigation of young infants’ ability to discriminate lexical tones as a function of their native language, age and language experience, as well as of tone properties. Given the high prevalence of lexical tones across human languages, understanding lexical tone acquisition is fundamental for comprehensive theories of language learning. While there are some similarities between the developmental course of lexical tone perception and that of vowels and consonants, findings for lexical tones tend to vary greatly across different laboratories. To reconcile these differences and to assess the developmental trajectory of native and non‐native perception of tone contrasts, this study employed a single experimental paradigm with the same two pairs of Cantonese tone contrasts (perceptually similar vs. distinct) across 13 laboratories in Asia‐Pacific, Europe and North‐America testing 5‐, 10‐ and 17‐month‐old monolingual (tone, pitch‐accent, non‐tone) and bilingual (tone/non‐tone, non‐tone/non‐tone) infants. Across the age range and language backgrounds, infants who were not exposed to Cantonese showed robust discrimination of the two non‐native lexical tone contrasts. Contrary to this overall finding, the statistical model assessing native discrimination by Cantonese‐learning infants failed to yield significant effects. These findings indicate that lexical tone sensitivity is maintained from 5 to 17 months in infants acquiring tone and non‐tone languages, challenging the generalisability of the existing theoretical accounts of perceptual narrowing in the first months of life.

Research Highlights

This is a multi‐language and multi‐lab investigation of young infants’ ability to discriminate lexical tones.

This study included data from 13 laboratories testing 5‐, 10‐, and 17‐month‐old monolingual (tone, pitch‐accent, non‐tone) and bilingual (tone/non‐tone, non‐tone/non‐tone) infants.

Overall, infants discriminated a perceptually similar and a distinct non‐native tone contrast, although there was no evidence of a native tone‐language advantage in discrimination.

These results demonstrate maintenance of tone discrimination throughout development.
Modeling familial and sporadic Parkinson's disease in small fishes
Authors: Yamanaka Tomoyuki , Matsui Hideaki
Published: November 2023

The establishment of animal models for Parkinson's disease (PD) has been challenging. Nevertheless, once established, they will serve as valuable tools for elucidating the causes and pathogenesis of PD, as well as for developing new strategies for its treatment. Following the recent discovery of a series of PD causative genes in familial cases, teleost fishes, including zebrafish and medaka, have often been used to establish genetic PD models because of their ease of breeding and gene manipulation, as well as the high conservation of gene orthologs. Some of the fish lines can recapitulate PD phenotypes, which are often more pronounced than those in rodent genetic models. In addition, a new experimental teleost fish, turquoise killifish, can be used as a sporadic PD model, because it spontaneously manifests age‐dependent PD phenotypes. Several PD fish models have already made significant contributions to the discovery of novel PD pathological features, such as cytosolic leakage of mitochondrial DNA and pathogenic phosphorylation in α‐synuclein. Therefore, utilizing various PD fish models with distinct degenerative phenotypes will be an effective strategy for identifying emerging facets of PD pathogenesis and therapeutic modalities.
Computer‐aided design and computer‐aided manufacturing poly (methyl methacrylate) interim veneers for immediate esthetic restoration of autotransplanted teeth
Authors: Sans Francesc Abella , Vidal‐Ponsoda Carla , Caponi Lucas Queiroz , Cayón Miguel Roig , Nagendrababu Venkateshbabu
Published: November 2023

Autotransplanted teeth in the maxillary anterior region should be restored or reshaped as soon as possible for functional and esthetic reasons as well as the well‐being of the patient. However, such tooth restorations are frequently not carried out immediately after tooth transplantation because the process could have a negative impact on the healing process. The development of a simple, immediate, and atraumatic esthetic interim restoration would be of great benefit to both the clinician and patient and address all the concerns caused by immediately preparing the tooth postoperatively and cementing a permanent restoration. This report describes the use of CAD‐CAM technology to create poly (methyl methacrylate) veneers preoperatively that can be cemented extraorally on the extracted donor tooth for the immediate and interim recontouring of autotransplanted anterior teeth.
Too big not to fail: emerging evidence for size‐induced senescence
Authors: Manohar Sandhya , Neurohr Gabriel E.
Published: November 2023

Cellular senescence refers to a permanent and stable state of cell cycle exit. This process plays an important role in many cellular functions, including tumor suppression. It was first noted that senescence is associated with increased cell size in the early 1960s; however, how this contributes to permanent cell cycle exit was poorly understood until recently. In this review, we discuss new findings that identify increased cell size as not only a consequence but also a cause of permanent cell cycle exit. We highlight recent insights into how increased cell size alters normal cellular physiology and creates homeostatic imbalances that contribute to senescence induction. Finally, we focus on the potential clinical implications of these findings in the context of cell cycle arrest‐causing cancer therapeutics and speculate on how tumor cell size changes may impact outcomes in patients treated with these drugs.
RETRACTED: Effects of intramedullary nailing and internal fixation plates on postoperative wound infection and pain in patients with distal tibia fractures: A meta‐analysis
Authors: Kou Fei , Li Teng
Published: November 2023

A meta‐analysis was performed to assess the effects of intramedullary nailing (IMN) and internal fixation plates (IFP) on postoperative wound infection and pain in patients with distal tibia fractures, to provide evidence for the selection of surgical options for this group of patients. Computerised searches were performed on PubMed, Cochrane Library, EMBASE, MEDLINE, CNKI and Wanfang databases from the inception of each library to August 2023. All published randomised controlled trials (RCTs) comparing IMN with IFP for the treatment of patients with distal tibial fractures were selected. Literature screening, data extraction and literature evaluation were independently completed by two researchers. Data analysis was performed using the Review Manager 5.4 software. Overall, 25 RCTs with a total of 2011 patients were finally included, comprised by 1009 patients in the IMN group and 1002 patients in the IFP group. The rate of wound infection was significantly lower in the IMN group than that in the IFP group (5.05% vs. 9.58%, odds ratio [OR]: 0.52, 95% confidence intervals [CIs]: 0.37–0.73, p < 0.001). Meanwhile, the IMN group had a significantly higher rate of joint pain than that of the IFP group (14.57% vs. 2.90%, OR: 4.93, 95% CIs: 3.02–8.03, p < 0.00001), whereas the difference between the two surgical procedures in terms of operative time was not statistically significant (standardised mean differences: 0.08 95% CIs: −0.58–0.74, p = 0.82). Current clinical evidence suggests that both IMN and IFP are excellent treatments for distal tibial fractures. Although IMN is better in reducing postoperative wound infection, the risk of postoperative pain is higher. Thus, an appropriate surgical procedure should be selected in clinical practice in accordance with the actual situation of the patient, and IFP is used to reduce the incidence of postoperative joint pain when the anterior tibial soft tissue of the distal tibial fracture is in good condition, and vice versa. IMN is used to reduce the risk of infection.
The Impact of Sovereign Wealth Funds on Corporate Value and Performance
Authors: Fernandes Nuno
Published: November 2023

The last few years have seen a remarkable increase in the participation of sovereign wealth funds (SWFs) in global capital markets. In this article, the author draws on a unique dataset of SWF international holdings—one that dates back to the year 2002 and includes individual SWF holdings in more than 8,000 companies in 58 countries—to provide evidence of the impact of SWFs on corporate values and operating performance.

Contrary to claims that SWFs expropriate minority investors and pursue political agendas, the main finding of the author's study is that SWF ownership is associated with positive changes in both corporate market values and operating returns. In support of these findings, the author also identifies three important ways that SWFs work to increase the performance and value of the companies they invest in: (1) as long‐term holders that provide a stable source of financing; (2) as representatives of deep pools of international capital in search of global diversification opportunities that are likely to provide companies with a lower‐cost (as well as more “patient”) source of equity capital; and (3) as politically well‐connected strategic investors that enable their companies to leverage important connections when accessing new product markets.
Why do nurses miss nursing care? A qualitative meta‐synthesis
Authors: Peng Mengyun , Saito Shinya , Mo Wenping , Guan Hong
Published: November 2023

Aim

The aim of this qualitative meta‐synthesis was to discover the factors impacting on missed nursing care of nurses through systematic thinking.

Background

Although nurses are responsible for high‐quality care, missed nursing care is common, endangering patient safety. Understanding of the causes related to missed nursing care could help nursing managers improve the quality of nursing care.

Design

A qualitative meta‐synthesis guided by the Preferred Reporting Items for Systematic Reviews and Meta‐analyses (PRISMA).

Methods

As a method designed to contribute to knowledge development, meta‐synthesis allows for integration of qualitative study findings using thematic synthesis. Six databases were searched up to October 2021; nine studies met the inclusion and quality assessment criteria and meta‐synthesis were conducted.

Results

Three themes related to the causes why nurses missed nursing care were found. The themes included intrinsic resources (professional and ethical values, ambiguous nurse role, prioritization, education system, and knowledge), system structure (staff and resources shortage, heavy workload but limited time, and organizational management failure), and social environment (communication, working relationship and skill mix, and inappropriate ward layout).

Conclusion

The phenomenon of missed nursing care is a global tissue, with variations in its elements but also notable similarities. Meta‐synthesis provides evidence of intrinsic and extrinsic factors that contribute to missed nursing care.

Relevance to Clinical Practice

Recognizing and understanding the causes of missed nursing care is essential for nursing managers to ensure patient safety and the provision of high‐quality care.
Transvenous permanent pacemaker implantation after debranching thoracic endovascular aortic repair; A case series
Authors: Kashiwagi Manabu , Kuroi Akio , Higashimoto Natsuki , Katayama Yosuke , Terada Kosei , Honda Kentaro , Tanaka Atsushi
Published: November 2023

Debranching thoracic endovascular aortic repair may disturb the implantation of a cardiac implantable electronic device in the anterior thoracic region. In case 1, the bypass graft between the right axillary artery, left axillary artery, and left common carotid artery disturbed pacemaker implantation from the left anterior thoracic region. Therefore, right‐sided implantation was selected. By contrast, in case 2, the bypass graft between axillary arteries in the anterior thoracic region was visible on fluoroscopy, and we performed conventional left‐sided pacemaker implantation with extra‐thoracic puncture. The pacemaker implantations were successful in both cases. The implantation strategies were affected by the number of debranched arteries and visibility of the bypass graft.
Editing the 19 kDa alpha‐zein gene family generates non‐opaque2‐based quality protein maize
Authors: Hurst J. Preston , Sato Shirley , Ferris Tyler , Yobi Abou , Zhou You , Angelovici Ruthie , Clemente Tom E. , Holding David R.
Published: November 2023

Maize grain is deficient in lysine. While the opaque2 mutation increases grain lysine, o2 is a transcription factor that regulates a wide network of genes beyond zeins, which leads to pleiotropic and often negative effects. Additionally, the drastic reduction in 19 kDa and 22 kDa alpha‐zeins causes a floury kernel, unsuitable for agricultural use. Quality protein maize (QPM) overcame the undesirable kernel texture through the introgression of modifying alleles. However, QPM still lacks a functional o2 transcription factor, which has a penalty on non‐lysine amino acids due to the o2 mutation. CRISPR/cas9 gives researchers the ability to directly target genes of interest. In this paper, gene editing was used to specifically target the 19 kDa alpha zein gene family. This allows for proteome rebalancing to occur without an o2 mutation and without a total alpha‐zein knockout. The results showed that editing some, but not all, of the 19 kDa zeins resulted in up to 30% more lysine. An edited line displayed an increase of 30% over the wild type. While not quite the 55% lysine increase displayed by QPM, the line had little collateral impact on other amino acid levels compared to QPM. Additionally, the edited line containing a partially reduced 19 kDa showed an advantage in kernel texture that had a complete 19 kDa knockout. These results serve as proof of concept that editing the 19 kDa alpha‐zein family alone can enhance lysine while retaining vitreous endosperm and a functional O2 transcription factor.
Sedimentary record of bottom currents and internal tides in a modern highstand submarine canyon head
Authors: Normandeau Alexandre , Dafoe Lynn T. , Li Michael Z. , Campbell D. Calvin , Jenner Kimberley A.
Published: November 2023

The evolution of submarine canyons is primarily controlled by turbidity currents, which erode and fill them over time; however, many other hydrodynamic currents operate within canyons. Bottom currents from these other hydrodynamic processes, including internal tides, can be dominant processes, but their deposits are seldom recognized in sediment cores or the rock record. This study combines autonomous underwater vehicle swath bathymetry imagery and sub‐bottom profiles, high‐resolution sediment core analyses (X‐ray imagery and thin sections), and previously collected seabed video and flow measurements within Logan Canyon head (eastern Canada) to provide a detailed, modern record of facies associated with hydrodynamic processes in a canyon head. These results suggest that bottom currents are responsible for maintaining gullies on canyon sidewalls and an axial channel on the canyon floor. Thin sections of sediment cores reveal that muddy sand in the canyon head consists of mud aggregates and silt and fine‐grained sand, both behaving similarly in terms of flow dynamics. Three facies are present at macro‐scale and micro‐scale: laminated, partially laminated and bioturbated sandy mud. Sedimentary structures include rhythmic sand and mud aggregate couplets, planar to wavy laminations, current ripple cross‐laminations and fining‐upward successions, which are attributed to bottom currents induced by internal tides. Bioturbated facies, characterized by discrete biogenic structures and cross‐cutting relationships, predominate and overprint a mottled background. A mottled bioturbation fabric also alternates with or locally disrupts layering within the partially laminated facies. Internal tide currents, capable of bedload transport and forming ripples, were measured during a monitoring period in the canyon head, followed by rapid re‐establishment of benthos and associated biogenic structures, supporting the core interpretations. Preservation of sedimentary facies associated with these internal tides occurs when the sedimentation rate outpaces the rate of bioturbation, likely during stormier conditions on the shelf. These results represent observations of sedimentary facies associated with modern bottom currents and internal tides, and can be used to interpret similar occurrences within the rock record.
Detection of the novel HLA‐A*29:183 allele in a Russian individual
Authors: Ananeva Anastasiia , Kadirov Azat , Andryushkina Anna V. , Shagimardanova Elena I.
Published: November 2023

One nucleotide substitution in codon 211 of HLA‐A*29:01:01:01 results in the novel HLA‐A*29:183 allele.
M‐type potassium currents differentially affect activation of motoneuron subtypes and tune recruitment gain
Authors: Sharples Simon A. , Broadhead Matthew J. , Gray James A. , Miles Gareth B.
Published: November 2023

The size principle is a key mechanism governing the orderly recruitment of motor units and is believed to be dependent on passive properties of the constituent motoneurons. However, motoneurons are endowed with voltage‐sensitive ion channels that create non‐linearities in their input–output functions. Here we describe a role for the M‐type potassium current, conducted by KCNQ channels, in the control of motoneuron recruitment in mice. Motoneurons were studied with whole‐cell patch clamp electrophysiology in transverse spinal slices and identified based on delayed (fast) and immediate (slow) onsets of repetitive firing. M‐currents were larger in delayed compared to immediate firing motoneurons, which was not reflected by variations in the presence of Kv7.2 or Kv7.3 subunits. Instead, a more depolarized spike threshold in delayed‐firing motoneurons afforded a greater proportion of the total M‐current to become activated within the subthreshold voltage range, which translated to a greater influence on their recruitment with little influence on their firing rates. Pharmacological activation of M‐currents also influenced motoneuron recruitment at the population level, producing a rightward shift in the recruitment curve of monosynaptic reflexes within isolated mouse spinal cords. These results demonstrate a prominent role for M‐type potassium currents in regulating the function of motor units, which occurs primarily through the differential control of motoneuron subtype recruitment. More generally, these findings highlight the importance of active properties mediated by voltage‐sensitive ion channels in the differential control of motoneuron recruitment, which is a key mechanism for the gradation of muscle force.

image

Key points

M‐currents exert an inhibitory influence on spinal motor output.

This inhibitory influence is exerted by controlling the recruitment, but not the firing rate, of high‐threshold fast‐like motoneurons, with limited influence on low‐threshold slow‐like motoneurons.

Preferential control of fast motoneurons may be linked to a larger M‐current that is activated within the subthreshold voltage range compared to slow motoneurons.

Larger M‐currents in fast compared to slow motoneurons are not accounted for by differences in Kv7.2 or Kv7.3 channel composition.

The orderly recruitment of motoneuron subtypes is shaped by differences in the contribution of voltage‐gated ion channels, including KCNQ channels.

KCNQ channels may provide a target to dynamically modulate the recruitment gain across the motor pool and readily adjust movement vigour.
RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS
Authors: Shimizu Mikito , Shiraishi Naoyuki , Tada Satoru , Sasaki Tsutomu , Beck Goichi , Nagano Seiichi , Kinoshita Makoto , Sumi Hisae , Sugimoto Tomoyuki , Ishida Yoko , Koda Toru , Ishikura Teruyuki , Sugiyama Yasuko , Kihara Keigo , Kanakura Minami , Nakajima Tsuneo , Takeda Shuko , Takahashi Masanori P. , Yamashita Toshihide , Okuno Tatsusada , Mochizuki Hideki
Published: November 2023

Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone–collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.
Rapidly determining the 3D structure of proteins by surface-enhanced Raman spectroscopy
Authors: Ma Hao , Yan Sen , Lu Xinyu , Bao Yi-Fan , Liu Jia , Liao Langxing , Dai Kun , Cao Maofeng , Zhao Xiaojiao , Yan Hao , Wang Hai-Long , Peng Xiaohui , Chen Ningyu , Feng Huishu , Zhu Lilin , Yao Guangbao , Fan Chunhai , Wu De-Yin , Wang Binju , Wang Xiang , Ren Bin
Published: November 2023

Despite great advances in protein structure analysis, label-free and ultrasensitive methods to obtain the natural and dynamic three-dimensional (3D) structures are still urgently needed. Surface-enhanced Raman spectroscopy (SERS) can be a good candidate, whereas the complexity originated from the interactions between the protein and the gradient surface electric field makes it extremely challenging to determine the protein structure. Here, we propose a deciphering strategy for accurate determination of 3D protein structure from experimental SERS spectra in seconds by simply summing SERS spectra of isolated amino acids in electric fields of different strength with their orientations in protein. The 3D protein structure can be reconstructed by comparing the experimental spectra obtained in a well-defined gap-mode SERS configuration with the simulated spectra. The gradient electric field endows SERS with a unique advantage to section biomolecules with atomic precision, which makes SERS a competent tool for monitoring biomolecular events under physiological conditions.
Disruption of the autism gene and chromatin regulator KDM5A alters hippocampal cell identity
Authors: El Hayek Lauretta , DeVries Darlene , Gogate Ashlesha , Aiken Ariel , Kaur Kiran , Chahrour Maria H.
Published: November 2023

Chromatin regulation plays a pivotal role in establishing and maintaining cellular identity and is one of the top pathways disrupted in autism spectrum disorder (ASD). The hippocampus, composed of distinct cell types, is often affected in patients with ASD. However, the specific hippocampal cell types and their transcriptional programs that are dysregulated in ASD are unknown. Using single-nucleus RNA sequencing, we show that the ASD gene, lysine demethylase 5A (
KDM5A
), regulates the development of specific subtypes of excitatory and inhibitory neurons. We found that KDM5A is essential for establishing hippocampal cell identity by controlling a differentiation switch early in development. Our findings define a role for the chromatin regulator KDM5A in establishing hippocampal cell identity and contribute to the emerging convergent mechanisms across ASD.
Bright and sensitive red voltage indicators for imaging action potentials in brain slices and pancreatic islets
Authors: Han Yi , Yang Junqi , Li Yuan , Chen Yu , Ren Huixia , Ding Ran , Qian Weiran , Ren Keyuan , Xie Beichen , Deng Mengying , Xiao Yinghan , Chu Jun , Zou Peng
Published: November 2023

Genetically encoded voltage indicators (GEVIs) allow the direct visualization of cellular membrane potential at the millisecond time scale. Among these, red-emitting GEVIs have been reported to support multichannel recordings and manipulation of cellular activities with reduced autofluorescence background. However, the limited sensitivity and dimness of existing red GEVIs have restricted their applications in neuroscience. Here, we report a pair of red-shifted opsin-based GEVIs, Cepheid1b and Cepheid1s, with improved dynamic range, brightness, and photostability. The improved dynamic range is achieved by a rational design to raise the electrochromic Förster resonance energy transfer efficiency, and the higher brightness and photostability are approached with separately engineered red fluorescent proteins. With Cepheid1 indicators, we recorded complex firings and subthreshold activities of neurons on acute brain slices and observed heterogeneity in the voltage‑calcium coupling on pancreatic islets. Overall, Cepheid1 indicators provide a strong tool to investigate excitable cells in various sophisticated biological systems.
Charge-clustering induced fast ion conduction in 2LiX-GaF
3
: A strategy for electrolyte design
Authors: Patel Sawankumar V. , Lacivita Valentina , Liu Haoyu , Truong Erica , Jin Yongkang , Wang Eric , Miara Lincoln , Kim Ryounghee , Gwon Hyeokjo , Zhang Rongfu , Hung Ivan , Gan Zhehong , Jung Sung-Kyun , Hu Yan-Yan
Published: November 2023

2LiX-GaF
3
(X = Cl, Br, I) electrolytes offer favorable features for solid-state batteries: mechanical pliability and high conductivities. However, understanding the origin of fast ion transport in 2LiX-GaF
3
has been challenging. The ionic conductivity order of 2LiCl-GaF
3
(3.20 mS/cm) > 2LiBr-GaF
3
(0.84 mS/cm) > 2LiI-GaF
3
(0.03 mS/cm) contradicts binary LiCl (10
−12
S/cm) < LiBr (10
−10
S/cm) < LiI (10
−7
S/cm). Using multinuclear
7
Li,
71
Ga,
19
F solid-state nuclear magnetic resonance and density functional theory simulations, we found that Ga(F,X)

n

polyanions boost Li
+
-ion transport by weakening Li
+
-X
−
interactions via charge clustering. In 2LiBr-GaF
3
and 2LiI-GaF
3
, Ga-X coordination is reduced with decreased F participation, compared to 2LiCl-GaF
3
. These insights will inform electrolyte design based on charge clustering, applicable to various ion conductors. This strategy could prove effective for producing highly conductive multivalent cation conductors such as Ca
2+
and Mg
2+
, as charge clustering of carboxylates in proteins is found to decrease their binding to Ca
2+
and Mg
2+
.
Time-resolving state-specific molecular dissociation with XUV broadband absorption spectroscopy
Authors: Magunia Alexander , Rebholz Marc , Appi Elisa , Papadopoulou Christina C. , Lindenblatt Hannes , Trost Florian , Meister Severin , Ding Thomas , Straub Michael , Borisova Gergana D. , Lee Junhee , Jin Rui , von der Dellen Alexander , Kaiser Christian , Braune Markus , Düsterer Stefan , Ališauskas Skirmantas , Lang Tino , Heyl Christoph , Manschwetus Bastian , Grunewald Sören , Frühling Ulrike , Tajalli Ayhan , Wahid Ammar Bin , Silletti Laura , Calegari Francesca , Mosel Philip , Morgner Uwe , Kovacev Milutin , Thumm Uwe , Hartl Ingmar , Treusch Rolf , Moshammer Robert , Ott Christian , Pfeifer Thomas
Published: November 2023

The electronic and nuclear dynamics inside molecules are essential for chemical reactions, where different pathways typically unfold on ultrafast timescales. Extreme ultraviolet (XUV) light pulses generated by free-electron lasers (FELs) allow atomic-site and electronic-state selectivity, triggering specific molecular dynamics while providing femtosecond resolution. Yet, time-resolved experiments are either blind to neutral fragments or limited by the spectral bandwidth of FEL pulses. Here, we combine a broadband XUV probe pulse from high-order harmonic generation with an FEL pump pulse to observe dissociation pathways leading to fragments in different quantum states. We temporally resolve the dissociation of a specific O
2
+
state into two competing channels by measuring the resonances of ionic and neutral fragments. This scheme can be applied to investigate convoluted dynamics in larger molecules relevant to diverse science fields.
Preclinical, randomized phase 1, and compassionate use evaluation of REGN4461, a leptin receptor agonist antibody for leptin deficiency
Authors: Altarejos Judith Y. , Pangilinan Jeffrey , Podgrabinska Simona , Akinci Baris , Foss-Freitas Maria , Neidert Adam H. , Ray Yonaton , Zheng Wenjun , Kim Steven , Kamat Vishal , Huang Meilin , Min Soo , Mastaitis Jason , Dominguez-Gutierrez Giselle , Kim Jee-Hae , Stevis Panayiotis , Huang Tammy , Zambrowicz Brian , Olson William C. , Godin Stephen , Bradley Elizabeth , Gewitz Andrew D. , Baker Mark , Hench Rita , Davenport Matthew S. , Chenevert Thomas L. , DiPaola Frank , Yancopoulos George D. , Murphy Andrew J. , Herman Gary A. , Musser Bret J. , Dansky Hayes , Harp Joyce , Gromada Jesper , Sleeman Mark W. , Oral Elif A. , Olenchock Benjamin A.
Published: November 2023

Deficiency in the adipose-derived hormone leptin or leptin receptor signaling causes class 3 obesity in individuals with genetic loss-of-function mutations in leptin or its receptor LEPR and metabolic and liver disease in individuals with hypoleptinemia secondary to lipoatrophy such as in individuals with generalized lipodystrophy. Therapies that restore leptin-LEPR signaling may resolve these metabolic sequelae. We developed a fully human monoclonal antibody (mAb), REGN4461 (mibavademab), that activates the human LEPR in the absence or presence of leptin. In obese leptin knockout mice, REGN4461 normalized body weight, food intake, blood glucose, and insulin sensitivity. In a mouse model of generalized lipodystrophy, REGN4461 alleviated hyperphagia, hyperglycemia, insulin resistance, dyslipidemia, and hepatic steatosis. In a phase 1, randomized, double-blind, placebo-controlled two-part study, REGN4461 was well tolerated with an acceptable safety profile. Treatment of individuals with overweight or obesity with REGN4461 decreased body weight over 12 weeks in those with low circulating leptin concentrations (<8 ng/ml) but had no effect on body weight in individuals with higher baseline leptin. Furthermore, compassionate-use treatment of a single patient with atypical partial lipodystrophy and a history of undetectable leptin concentrations associated with neutralizing antibodies to metreleptin was associated with noteable improvements in circulating triglycerides and hepatic steatosis. Collectively, these translational data unveil an agonist LEPR mAb that may provide clinical benefit in disorders associated with relatively low leptin concentrations.
Evidence for the contribution of the gut microbiome to obesity and its reversal
Authors: de Wit Douwe F. , Hanssen Nordin M. J. , Wortelboer Koen , Herrema Hilde , Rampanelli Elena , Nieuwdorp Max
Published: November 2023

Obesity has become a worldwide pandemic affecting more than 650 million people and is associated with a high burden of morbidity. Alongside traditional risk factors for obesity, the gut microbiome has been identified as a potential factor in weight regulation. Although rodent studies suggest a link between the gut microbiome and body weight, human evidence for causality remains scarce. In this Review, we postulate that existing evidence remains to establish a contribution of the gut microbiome to the development of obesity in humans but that modified probiotic strains and supraphysiological dosages of microbial metabolites may be beneficial in combatting obesity.
Evaluating vaccine-elicited antibody activities against
Neisseria gonorrhoeae
: cross-protective responses elicited by the 4CMenB meningococcal vaccine
Authors: Gray Mary C. , Thomas Keena S. , Lamb Evan R. , Werner Lacie M. , Connolly Kristie L. , Jerse Ann E. , Criss Alison K.
Published: November 2023

The bacterial pathogen
Neisseria gonorrhoeae
is an urgent global health problem due to increasing numbers of infections, coupled with rampant antibiotic resistance. Vaccines against gonorrhea are being prioritized to combat drug-resistant
N. gonorrhoeae
. Meningococcal serogroup B vaccines such as four-component meningococcal B vaccine (4CMenB) are predicted by epidemiology studies to cross-protect individuals from natural infection with
N. gonorrhoeae
and elicit antibodies that cross-react with
N. gonorrhoeae
. Evaluation of vaccine candidates for gonorrhea requires a suite of assays for predicting efficacy
in vitro
and in animal models of infection, including the role of antibodies elicited by immunization. Here, we present the development and optimization of assays to evaluate antibody functionality after immunization of mice: antibody binding to intact
N. gonorrhoeae
, serum bactericidal activity, and opsonophagocytic killing activity using primary human neutrophils [polymorphonuclear leukocytes (PMNs)]. These assays were developed with purified antibodies against
N. gonorrhoeae
and used to evaluate serum from mice that were vaccinated with 4CMenB or given alum as a negative control. Results from these assays will help prioritize gonorrhea vaccine candidates for advanced preclinical to early clinical studies and will contribute to identifying correlates and mechanisms of immune protection against
N. gonorrhoeae
.