bluuebunny/crossref_metadata_2025 huggingface dataset:
The Formation of Coastal Turbidity Maximum by Tidal Pumping in Well‐Mixed Inner Shelves
Authors: Du Zhiyun , Yu Qian , Peng Yun , Wang Li , Lin Hangjie , Wang Yunwei , Gao Shu
Published: April 2022

Coastal turbidity maxima (CTMs) have been recognized on open coastal seas with elevated suspended sediment concentrations. Tidal pumping is often considered the major contributor to turbidity maxima in well‐mixed estuaries. However, its role in CTM formation on well‐mixed coasts remains unclear. Here, we propose a two‐dimensional depth‐averaged analytical model to explore residual sediment transport influenced by interactions between cross‐shore and along‐shore tidal currents. Observation data collected on the well‐mixed central Jiangsu coast (southern Yellow Sea), China, are analyzed by the model. The results display a persistent CTM close to the shore and show that the large along‐shore tidal velocity strongly influences the cross‐shore tidal pumping flux. The model calculation presents landward tidal pumping flux under horizontally homogeneous bed sediment distribution, illustrating the dominant role of tidal pumping in CTM formation within well‐mixed coastal water bodies. The model suggests that the significance of alongshore tidal current to cross‐shore sediment transport should be addressed in similar coastal environments.
The impact of educational attainment, intelligence and intellectual disability on schizophrenia: a Swedish population-based register and genetic study
Authors: Song Jie , Yao Shuyang , Kowalec Kaarina , Lu Yi , Sariaslan Amir , Szatkiewicz Jin P. , Larsson Henrik , Lichtenstein Paul , Hultman Christina M. , Sullivan Patrick F.
Published: April 2022

Schizophrenia (SCZ) is highly heterogenous and no subtypes characterizing treatment response or longitudinal course well. Cognitive impairment is a core clinical feature of SCZ and a determinant of poorer outcome. Genetic overlap between SCZ and cognitive traits is complex, with limited studies of comprehensive epidemiological and genomic evidence. To examine the relation between SCZ and three cognitive traits, educational attainment (EDU), premorbid cognitive ability, and intellectual disability (ID), we used two Swedish samples: a national cohort (14,230 SCZ cases and 3,816,264 controls) and a subsample with comprehensive genetic data (4992 cases and 6009 controls). Population-based analyses confirmed worse cognition as a risk factor for SCZ, and the pedigree and SNP-based genetic correlations were comparable. In the genotyped cases, those with high EDU and premorbid cognitive ability tended to have higher polygenetic risk scores (PRS) of EDU and intelligence and fewer rare exonic variants. Finally, by applying an empirical clustering method, we dissected SCZ cases into four replicable subgroups characterized by EDU and ID. In particular, the subgroup with higher EDU in the national cohort had fewer adverse outcomes including long hospitalization and death. In the genotyped subsample, this subgroup had higher PRS of EDU and no excess of rare genetic burdens than controls. In conclusion, we found extensive evidence of a robust relation between cognitive traits and SCZ, underscoring the importance of cognition in dissecting the heterogeneity of SCZ.
Effect of long-term paired associative stimulation on the modulation of cortical sensorimotor oscillations after spinal cord injury
Authors: Vanhanen Jukka , Parkkonen Lauri , Mäkelä Jyrki P. , Tolmacheva Alexandra , Shulga Anastasia , Rodionov Andrey , Kirveskari Erika
Published: April 2022

Study design

A prospective interventional case series.

Objectives

To explore changes in the modulation of cortical sensorimotor oscillations after long-term paired associative stimulation (PAS) in participants with spinal cord injury (SCI).

Setting

BioMag Laboratory, HUS Diagnostic Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Methods

Five patients with chronic incomplete SCI received unilateral spinal PAS to upper limb for 16–22 days. Changes in the modulation of sensorimotor oscillations in response to tactile stimulus and active and imaginary hand movements were assessed with magnetoencephalography recorded before and after the intervention.

Results

PAS restored the modulation of sensorimotor oscillations in response to active hand movement in four patients, whereas the modulation following tactile stimulation remained unaltered. The observed change was larger in the hemisphere that received PAS and preceded the clinical effect of the intervention.

Conclusions

Long-term spinal PAS treatment, which enhances the motor functions of SCI patients, also restores the modulation of cortical sensorimotor oscillations.
Improvement of episodic memory retention by a memory reactivation intervention across the lifespan: from younger adults to amnesic patients
Authors: Fernández Rodrigo S. , Picco Soledad , Beron Juan Cruz , Bavassi Luz , Campos Jorge , Allegri Ricardo F. , Pedreira María E.
Published: April 2022

Spontaneous reactivation of recently acquired memories is a fundamental mechanism of memory stabilization. Re-exposure to specific learned cues during sleep or awake states, namely targeted memory reactivation, has been shown to improve memory retention at long delays. Manipulation of memory reactivation could have potential clinical value in populations with memory deficits or cognitive decline. However, no previous study investigated a target memory reactivation approach on those populations. Here we tested the hypothesis that a reactivation-based intervention would improve episodic memory performance in healthy adults and amnestic patients. On Day 1, young adults, old adults and amnestic Mild Cognitive Impairment patients (n = 150) learned face-name pairs and 24 h later either received a reactivation intervention or a reactivation control (Day 2). On Day 3, associative and item memory were assessed. A robust Bayesian Generalized Mixed Model was implemented to estimate intervention effects on groups. Groups that underwent the reactivation-based intervention showed improved associative memory retention. Notably, amnestic patients benefited more from the intervention as they also had better item memory retention than controls. These findings support memory reactivation as stabilization and strengthening mechanism irrespectively of age and cognitive status, and provides proof-of-concept evidence that reactivation-based interventions could be implemented in the treatment and rehabilitation of populations with memory deficits.
Combining adoptive NK cell infusion with a dopamine-releasing peptide reduces senescent cells in aged mice
Authors: Bai Zongke , Yang Peiwei , Yu Fan , Li Zhong , Yao Zheng , Martinez Jean , Li Mengwei , Xu Hanmei
Published: April 2022

Aging inducing the development of senescent cells (SNCs) in various tissues is considered as the main cause of the age-related diseases. Senotherapy has become a promising anti-aging therapy. However, the effectivity and side-effect of senolytic agents are still concern. Here, we observed the downregulation of senescence-related genes by adoptive infusion of natural killer (NK) cells in 26 cases in peripheral blood CD3+ T cells. NK cell treatment also significantly decreased levels of senescence markers and senescence-associated secretory phenotypes (SASPs) in three senescent adipose tissues when culturing them together. Interestingly, cytotoxic activity of mouse NK cells against SNCs was significantly enhanced by dopamine in vitro through D1-like receptors. Acein, dopamine-releasing peptide, promoted the adoptive infusion of NK cells in effectively eliminating SNCs in a variety of tissues and reduced local and systemic SASPs in aging mice but Acein alone did not have the senolytic effect. These data demonstrated that adoptive infusion of NK cells is an effective means in removing SNCs, and peptide Acein combined with NK cells further enhances this effect in aging mice.
IL-37 isoform D acts as an inhibitor of soluble ST2 to boost type 2 immune homeostasis in white adipose tissue
Authors: Li Chaoze , Zhao Mingsheng , Zhao Ming , Chen Nuo , Guo Yaxin , Du Yingxin , Zhang Yi , Cao Baihui , Zhan Bing , Guo Chun , Li Yuan , Li Yan , Shi Yongyu , Zhu Faliang , Zhang Lining , Wang Qun
Published: April 2022

White adipose tissue (WAT) homeostasis substantiated by type 2 immunity is indispensable to counteract obesity and metabolic disorders. IL-33/suppression of tumorigenicity (ST) 2 signaling promotes type 2 response in WAT, while potential regulators remain to be discovered. We identified human IL-37 isoform D (IL-37D) as an effective trigger for ST2-mediated type 2 immune homeostasis in WAT. IL-37D transgene amplified ST2+ immune cells, promoted M2 macrophage polarization and type 2 cytokine secretion in WAT that mediate beiging and inflammation resolution, thereby increasing energy expenditure, reducing obesity and insulin resistance in high-fat diet (HFD)-fed mice. Mechanistically, either endogenous or exogenous IL-37D inhibited soluble ST2 (sST2) production from WAT challenged with HFD or TNF-α. Recombinant sST2 impaired the beneficial effects of IL-37D transgene in HFD-fed mice, characterized by damaged weight loss, insulin action, and type 2 cytokine secretion from WAT. In adipose-derived stem cells, IL-37D inhibited TNF-α-stimulated sST2 expression through IL-1 receptor 8 (IL-1R8)-dependent NF-κB inactivation. Collectively, human IL-37D suppresses sST2 to boost type 2 immune homeostasis in WAT, which may be a promising therapy target for obesity and metabolic disorders.
JAC1 targets YY1 mediated JWA/p38 MAPK signaling to inhibit proliferation and induce apoptosis in TNBC
Authors: Zhai Zurong , Ren Yanlin , Shu Chuanjun , Chen Dongyin , Liu Xia , Liang Yan , Li Aiping , Zhou Jianwei
Published: April 2022

Triple negative breast cancer (TNBC) is a type of breast cancer with poor prognosis, and has no ideal therapeutic target and ideal medicine. Downregulation of JWA is closely related to the poor overall survival in many cancers including TNBC. In this study, we reported at the first time that JWA gene activating compound 1 (JAC1) inhibited the proliferation of TNBC in vitro and in vivo experimental models. JAC1 specifically bound to YY1 and eliminated its transcriptional inhibition of JWA gene. The rescued JWA induced G1 phase arrest and apoptosis in TNBC cells through the p38 MAPK signaling pathway. JAC1 also promoted ubiquitination and degradation of YY1. In addition, JAC1 disrupted the interaction between YY1 and HSF1, and suppressed the oncogenic role of HSF1 in TNBC through p-Akt signaling pathway. In conclusion, JAC1 suppressed the proliferation of TNBC through the JWA/P38 MAPK signaling and YY1/HSF1/p-Akt signaling. JAC1 maybe a potential therapeutic agent for TNBC.
Rapid screening of TCR-pMHC interactions by the YAMTAD system
Authors: Wang Lihui , Lan Xun
Published: April 2022

Personalized immunotherapy, such as cancer vaccine and TCR-T methods, demands rapid screening of TCR-pMHC interactions. While several screening approaches have been developed, their throughput is limited. Here, the Yeast Agglutination Mediated TCR antigen Discovery system (YAMTAD) was designed and demonstrated to allow fast and unbiased library-on-library screening of TCR-pMHC interactions. Our proof-of-principle study achieved high sensitivity and specificity in identifying antigens for a given TCR and identifying TCRs recognizing a given pMHC for modest library sizes. Finally, the enrichment of high-affinity TCR-pMHC interactions by YAMTAD in library-on-library screening was demonstrated. Given the high throughput (106–108 × 106–108 in theory) and simplicity (identifying TCR-pMHC interactions without purification of TCR and pMHC) of YAMTAD, this study provides a rapid but effective platform for TCR-pMHC interaction screening, with valuable applications in future personalized immunotherapy.
Progenitor species hold untapped diversity for potential climate-responsive traits for use in wheat breeding and crop improvement
Authors: Leigh Fiona J. , Wright Tally I. C. , Horsnell Richard A. , Dyer Sarah , Bentley Alison R.
Published: April 2022

Climate change will have numerous impacts on crop production worldwide necessitating a broadening of the germplasm base required to source and incorporate novel traits. Major variation exists in crop progenitor species for seasonal adaptation, photosynthetic characteristics, and root system architecture. Wheat is crucial for securing future food and nutrition security and its evolutionary history and progenitor diversity offer opportunities to mine favourable functional variation in the primary gene pool. Here we provide a review of the status of characterisation of wheat progenitor variation and the potential to use this knowledge to inform the use of variation in other cereal crops. Although significant knowledge of progenitor variation has been generated, we make recommendations for further work required to systematically characterise underlying genetics and physiological mechanisms and propose steps for effective use in breeding. This will enable targeted exploitation of useful variation, supported by the growing portfolio of genomics and accelerated breeding approaches. The knowledge and approaches generated are also likely to be useful across wider crop improvement.
Male esthetic genital surgery: recommendations and gaps to be filled
Authors: Bettocchi Carlo , Checchia Andrea Alberto , Falagario Ugo Giovanni , Ricapito Anna , Busetto Gian Maria , Cormio Luigi , Carrieri Giuseppe
Published: April 2022

The reason behind the spread of penis enlargement practices over time is rooted in the virility that the appearance of the genitals can give a man, as well as an altered perception of his own body. The approach should be to modulate the interventions on the real needs of patients, carefully evaluating the history, the psychological picture, and possible surgical advantages. The aim of this study was to shed light on cosmetic surgery of male genitalia through minimally invasive and more radical techniques, with the purpose of laying the foundation for possible indications and recommendations for the future. A non-systematic literature review using the PubMed and Scopus databases was conducted to retrieve papers written in English on cosmetic surgery of the penis published over the past 15 years. Papers discussing cosmetic surgery in patients with concomitant pathologies associated with sexual dysfunction were excluded. The main outcomes recorded were change in penile dimensions in term of length and girth and surgical complications.
RNA aptamers specific for transmembrane p24 trafficking protein 6 and Clusterin for the targeted delivery of imaging reagents and RNA therapeutics to human β cells
Authors: Van Simaeys Dimitri , De La Fuente Adriana , Zilio Serena , Zoso Alessia , Kuznetsova Victoria , Alcazar Oscar , Buchwald Peter , Grilli Andrea , Caroli Jimmy , Bicciato Silvio , Serafini Paolo
Published: April 2022

The ability to detect and target β cells in vivo can substantially refine how diabetes is studied and treated. However, the lack of specific probes still hampers a precise characterization of human β cell mass and the delivery of therapeutics in clinical settings. Here, we report the identification of two RNA aptamers that specifically and selectively recognize mouse and human β cells. The putative targets of the two aptamers are transmembrane p24 trafficking protein 6 (TMED6) and clusterin (CLUS). When given systemically in immune deficient mice, these aptamers recognize the human islet graft producing a fluorescent signal proportional to the number of human islets transplanted. These aptamers cross-react with endogenous mouse β cells and allow monitoring the rejection of mouse islet allografts. Finally, once conjugated to saRNA specific for X-linked inhibitor of apoptosis (XIAP), they can efficiently transfect non-dissociated human islets, prevent early graft loss, and improve the efficacy of human islet transplantation in immunodeficient in mice.
Integrative analysis of non-small cell lung cancer patient-derived xenografts identifies distinct proteotypes associated with patient outcomes
Authors: Mirhadi Shideh , Tam Shirley , Li Quan , Moghal Nadeem , Pham Nhu-An , Tong Jiefei , Golbourn Brian J. , Krieger Jonathan R. , Taylor Paul , Li Ming , Weiss Jessica , Martins-Filho Sebastiao N. , Raghavan Vibha , Mamatjan Yasin , Khan Aafaque A. , Cabanero Michael , Sakashita Shingo , Huo Kugeng , Agnihotri Sameer , Ishizawa Kota , Waddell Thomas K. , Zadeh Gelareh , Yasufuku Kazuhiro , Liu Geoffrey , Shepherd Frances A. , Moran Michael F. , Tsao Ming-Sound
Published: April 2022

Non-small cell lung cancer (NSCLC) is the leading cause of cancer deaths worldwide. Only a fraction of NSCLC harbor actionable driver mutations and there is an urgent need for patient-derived model systems that will enable the development of new targeted therapies. NSCLC and other cancers display profound proteome remodeling compared to normal tissue that is not predicted by DNA or RNA analyses. Here, we generate 137 NSCLC patient-derived xenografts (PDXs) that recapitulate the histology and molecular features of primary NSCLC. Proteome analysis of the PDX models reveals 3 adenocarcinoma and 2 squamous cell carcinoma proteotypes that are associated with different patient outcomes, protein-phosphotyrosine profiles, signatures of activated pathways and candidate targets, and in adenocarcinoma, stromal immune features. These findings portend proteome-based NSCLC classification and treatment and support the PDX resource as a viable model for the development of new targeted therapies.
Integrated silicon carbide electro-optic modulator
Authors: Powell Keith , Li Liwei , Shams-Ansari Amirhassan , Wang Jianfu , Meng Debin , Sinclair Neil , Deng Jiangdong , Lončar Marko , Yi Xiaoke
Published: April 2022

Owing to its attractive optical and electronic properties, silicon carbide is an emerging platform for integrated photonics. However an integral component of the platform is missing—an electro-optic modulator, a device which encodes electrical signals onto light. As a non-centrosymmetric crystal, silicon carbide exhibits the Pockels effect, yet a modulator has not been realized since the discovery of this effect more than three decades ago. Here we design, fabricate, and demonstrate a Pockels modulator in silicon carbide. Specifically, we realize a waveguide-integrated, small form-factor, gigahertz-bandwidth modulator that operates using complementary metal-oxide-semiconductor (CMOS)-level voltages on a thin film of silicon carbide on insulator. Our device is fabricated using a CMOS foundry compatible fabrication process and features no signal degradation, no presence of photorefractive effects, and stable operation at high optical intensities (913 kW/mm2), allowing for high optical signal-to-noise ratios for modern communications. Our work unites Pockels electro-optics with a CMOS foundry compatible platform in silicon carbide.
Mapping SP-C co-chaperone binding sites reveals molecular consequences of disease-causing mutations on protein maturation
Authors: Pobre-Piza Kristine F. R. , Mann Melissa J. , Flory Ashley R. , Hendershot Linda M.
Published: April 2022

BiP co-chaperones ERdj4, ERdj5, and GRP170 associate in cells with peptides predicted to be aggregation prone. Here, extending these findings to a full-length protein, we examine two Interstitial Lung Disease-associated mutants (ILD) of surfactant protein C (SP-C). The TANGO algorithm, which identifies sequences prone to formation of β strand aggregates, found three such regions in SP-C: the N-terminal transmembrane (TM) domain and two sites in the intermolecular chaperone BRICHOS domain. We show the ILD mutants disrupt di-sulfide bond formation in the BRICHOS domain and expose the aggregation-prone peptides leading to binding of ERdj4, ERdj5, and GRP170. The destabilized mutant BRICHOS domain fails to properly insert its TM region in the ER membrane, exposing part of the N-terminal TM domain site. Our studies with ILD-associated mutant proteins provide insights into the specificity of ERdj4, ERdj5, and GRP170, identify context-dependent differences in their binding, and reveal molecular consequences of disease-associated mutants on folding.
Porcine gut microbiota in mediating host metabolic adaptation to cold stress
Authors: Zhang Yu , Sun Lan , Zhu Run , Zhang Shiyu , Liu Shuo , Wang Yan , Wu Yinbao , Xing Sicheng , Liao Xindi , Mi Jiandui
Published: April 2022

The gut microbiota plays a key role in host metabolic ﻿thermogenesis by activating UCP1 and increasing the browning process of white adipose tissue (WAT), especially in cold environments. However, the crosstalk between the gut microbiota and the host, which lacks functional UCP1, making them susceptible to cold stress, has rarely been illustrated. We used male piglets as a model to evaluate the host response to cold stress via the gut microbiota (four groups: room temperature group, n = 5; cold stress group, n = 5; cold stress group with antibiotics, n = 5; room temperature group with antibiotics, n = 3). We found that host thermogenesis and insulin resistance increased the levels of serum metabolites such as glycocholic acid (GCA) and glycochenodeoxycholate acid (GCDCA) and altered the compositions and functions of the cecal microbiota under cold stress. The gut microbiota was characterized by increased levels of Ruminococcaceae, Prevotellaceae, and Muribaculaceae under cold stress. We found that piglets subjected to cold stress had increased expression of genes related to bile acid and short-chain fatty acid (SCFA) metabolism in their liver and fat lipolysis genes in their fat. In addition, the fat lipolysis genes CLPS, PNLIPRP1, CPT1B, and UCP3 were significantly increased in the fat of piglets under cold stress. However, the use of antibiotics showed a weakened or strengthened cold tolerance phenotype, indicating that the gut microbiota plays important role in host thermogenesis. Our results demonstrate that the gut microbiota-blood-liver and fat axis may regulate thermogenesis during cold acclimation in piglets.
The effects of microgravity on bone structure and function
Authors: Man Joey , Graham Taylor , Squires-Donelly Georgina , Laslett Andrew L.
Published: April 2022

Humans are spending an increasing amount of time in space, where exposure to conditions of microgravity causes 1–2% bone loss per month in astronauts. Through data collected from astronauts, as well as animal and cellular experiments conducted in space, it is evident that microgravity induces skeletal deconditioning in weight-bearing bones. This review identifies contentions in current literature describing the effect of microgravity on non-weight-bearing bones, different bone compartments, as well as the skeletal recovery process in human and animal spaceflight data. Experiments in space are not readily available, and experimental designs are often limited due to logistical and technical reasons. This review introduces a plethora of on-ground research that elucidate the intricate process of bone loss, utilising technology that simulates microgravity. Observations from these studies are largely congruent to data obtained from spaceflight experiments, while offering more insights behind the molecular mechanisms leading to microgravity-induced bone loss. These insights are discussed herein, as well as how that knowledge has contributed to studies of current therapeutic agents. This review also points out discrepancies in existing data, highlighting knowledge gaps in our current understanding. Further dissection of the exact mechanisms of microgravity-induced bone loss will enable the development of more effective preventative and therapeutic measures to protect against bone loss, both in space and possibly on ground.
Dopamine-induced changes to thalamic GABA concentration in impulsive Parkinson disease patients
Authors: Trujillo Paula , Song Alexander K. , Hay Kaitlyn R. , Aumann Megan , Yan Yan , Kang Hakmook , Donahue Manus J. , Claassen Daniel O.
Published: April 2022

Impulsivity is inherent to behavioral disorders such as substance abuse and binge eating. While the role of dopamine in impulse behavior is well established, γ-aminobutyric acid (GABA) therapies have promise for the treatment of maladaptive behaviors. In Parkinson disease (PD), dopaminergic therapies can result in the development of impulsive and compulsive behaviors, and this clinical syndrome shares similar pathophysiology to that seen in addiction, substance abuse, and binge-eating disorders. We hypothesized that impulsive PD patients have a reduced thalamic GABAergic response to dopamine therapy. To test this hypothesis, we employed GABA magnetic resonance spectroscopy, D2-like receptor PET imaging, and clinical and quantitative measures of impulsivity in PD patients (n = 33), before and after dopamine agonist administration. We find a blunted thalamic GABA response to dopamine agonists in patients with elevated impulsivity (p = 0.027). These results emphasize how dopamine treatment differentially augments thalamic GABA concentrations, which may modify behavioral impulsivity.
Evolution patterns of probable REM sleep behavior disorder predicts Parkinson’s disease progression
Authors: Ye Guanyu , Xu Xiaomeng , Zhou Liche , Zhao Aonan , Zhu Lin , Liu Jun
Published: April 2022

The course of REM sleep behavior disorder (RBD) variates in the early stage of Parkinson’s disease. We aimed to delineate the association between the evolution pattern of probable RBD (pRBD) and the progression of Parkinson’s disease (PD). 281 de novo PD patients from the Parkinson’s Progression Markers Initiative database were included. Patients were followed up for a mean of 6.8 years and were classified into different groups according to the evolution patterns of pRBD. Disease progression was compared among groups using survival analysis, where the endpoint was defined as progression to Hoehn-Yahr stage 3 or higher for motor progression and progression to mild cognitive impairment for cognitive decline. At the 4th year of follow-up, four types of pRBD evolution patterns were identified: (1) non-RBD-stable (55.5%): patients persistently free of pRBD; (2) late-RBD (12.1%): patients developed pRBD during follow-up; (3) RBD-stable (24.9%): patients showed persistent pRBD, and (4) RBD-reversion (7.5%): patients showed pRBD at baseline which disappeared during follow-up. The RBD-reversion type showed the fastest motor progression while the RBD-stable type showed the fastest cognitive decline. At baseline, the RBD-reversion type showed the most severe gray matter atrophy in the middle frontal gyrus, while the RBD-stable type showed gray matter atrophy mainly in the para-hippocampal gyrus. Four types of early pRBD evolution patterns featured different brain lesions and predicted different courses of motor and cognitive decline in PD.
Intravitreal antisense oligonucleotide sepofarsen in Leber congenital amaurosis type 10: a phase 1b/2 trial
Authors: Russell Stephen R. , Drack Arlene V. , Cideciyan Artur V. , Jacobson Samuel G. , Leroy Bart P. , Van Cauwenbergh Caroline , Ho Allen C. , Dumitrescu Alina V. , Han Ian C. , Martin Mitchell , Pfeifer Wanda L. , Sohn Elliott H. , Walshire Jean , Garafalo Alexandra V. , Krishnan Arun K. , Powers Christian A. , Sumaroka Alexander , Roman Alejandro J. , Vanhonsebrouck Eva , Jones Eltanara , Nerinckx Fanny , De Zaeytijd Julie , Collin Rob W. J. , Hoyng Carel , Adamson Peter , Cheetham Michael E. , Schwartz Michael R. , den Hollander Wilhelmina , Asmus Friedrich , Platenburg Gerard , Rodman David , Girach Aniz
Published: April 2022

CEP290-associated Leber congenital amaurosis type 10 (LCA10) is a retinal disease resulting in childhood blindness. Sepofarsen is an RNA antisense oligonucleotide targeting the c.2991+1655A>G variant in the CEP290 gene to treat LCA10. In this open-label, phase 1b/2 (NCT03140969), 12-month, multicenter, multiple-dose, dose-escalation trial, six adult patients and five pediatric patients received ≤4 doses of intravitreal sepofarsen into the worse-seeing eye. The primary objective was to evaluate sepofarsen safety and tolerability via the frequency and severity of ocular adverse events (AEs); secondary objectives were to evaluate pharmacokinetics and efficacy via changes in functional outcomes. Six patients received sepofarsen 160 µg/80 µg, and five patients received sepofarsen 320 µg/160 µg. Ten of 11 (90.9%) patients developed ocular AEs in the treated eye (5/6 with 160 µg/80 µg; 5/5 with 320 µg/160 µg) versus one of 11 (9.1%) in the untreated eye; most were mild in severity and dose dependent. Eight patients developed cataracts, of which six (75.0%) were categorized as serious (2/3 with 160 µg/80 µg; 4/5 with 320 µg/160 µg), as lens replacement was required. As the 160-µg/80-µg group showed a better benefit–risk profile, higher doses were discontinued or not initiated. Statistically significant improvements in visual acuity and retinal sensitivity were reported (post hoc analysis). The manageable safety profile and improvements reported in this trial support the continuation of sepofarsen development.
SLEAP: A deep learning system for multi-animal pose tracking
Authors: Pereira Talmo D. , Tabris Nathaniel , Matsliah Arie , Turner David M. , Li Junyu , Ravindranath Shruthi , Papadoyannis Eleni S. , Normand Edna , Deutsch David S. , Wang Z. Yan , McKenzie-Smith Grace C. , Mitelut Catalin C. , Castro Marielisa Diez , D’Uva John , Kislin Mikhail , Sanes Dan H. , Kocher Sarah D. , Wang Samuel S.-H. , Falkner Annegret L. , Shaevitz Joshua W. , Murthy Mala
Published: April 2022

The desire to understand how the brain generates and patterns behavior has driven rapid methodological innovation in tools to quantify natural animal behavior. While advances in deep learning and computer vision have enabled markerless pose estimation in individual animals, extending these to multiple animals presents unique challenges for studies of social behaviors or animals in their natural environments. Here we present Social LEAP Estimates Animal Poses (SLEAP), a machine learning system for multi-animal pose tracking. This system enables versatile workflows for data labeling, model training and inference on previously unseen data. SLEAP features an accessible graphical user interface, a standardized data model, a reproducible configuration system, over 30 model architectures, two approaches to part grouping and two approaches to identity tracking. We applied SLEAP to seven datasets across flies, bees, mice and gerbils to systematically evaluate each approach and architecture, and we compare it with other existing approaches. SLEAP achieves greater accuracy and speeds of more than 800 frames per second, with latencies of less than 3.5 ms at full 1,024 × 1,024 image resolution. This makes SLEAP usable for real-time applications, which we demonstrate by controlling the behavior of one animal on the basis of the tracking and detection of social interactions with another animal.
Exome sequencing of individuals with Huntington’s disease implicates FAN1 nuclease activity in slowing CAG expansion and disease onset
Authors: McAllister Branduff , Donaldson Jasmine , Binda Caroline S. , Powell Sophie , Chughtai Uroosa , Edwards Gareth , Stone Joseph , Lobanov Sergey , Elliston Linda , Schuhmacher Laura-Nadine , Rees Elliott , Menzies Georgina , Ciosi Marc , Maxwell Alastair , Chao Michael J. , Hong Eun Pyo , Lucente Diane , Wheeler Vanessa , Lee Jong-Min , MacDonald Marcy E. , Long Jeffrey D. , Aylward Elizabeth H. , Landwehrmeyer G. Bernhard , Rosser Anne E. ,   REGISTRY Investigators of the European Huntington’s disease network, Paulsen Jane S. ,   PREDICT-HD Investigators of the Huntington Study Group, Williams Nigel M. , Gusella James F. , Monckton Darren G. , Allen Nicholas D. , Holmans Peter , Jones Lesley , Massey Thomas H.
Published: April 2022

The age at onset of motor symptoms in Huntington’s disease (HD) is driven byHTTCAG repeat length but modified by other genes. In this study, we used exome sequencing of 683 patients with HD with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We discovered damaging coding variants in candidate modifier genes identified in previous genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier-onset HD. Nuclease activities of purified variants in vitro correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion similar to those observed with completeFAN1knockout. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.
Datasets for characterizing extreme events relevant to hydrologic design over the conterminous United States
Authors: Sun Ning , Yan Hongxiang , Wigmosta Mark S. , Coleman Andre M. , Leung L. Ruby , Hou Zhangshuan
Published: April 2022

Despite the close linkage between extreme floods and snowmelt, particularly through rain-on-snow (ROS), hydrologic infrastructure is mostly designed based on standard precipitation Intensity-Duration-Frequency curves (PREC-IDF) that neglect snow processes in runoff generation. For snow-dominated regions, such simplification could result in substantial errors in estimating extreme events and infrastructure design risk. To address this long-standing problem, we applied the Next Generation IDF (NG-IDF) technique to estimate design basis extreme events for different durations and return periods in the conterminous United States (CONUS) to distinctly represent the contribution of rain, snowmelt, and ROS events to the amount of water reaching the land surface. A suite of datasets were developed to characterize the magnitude, trend, seasonality, and dominant mechanism of extreme events for over 200,000 locations. Infrastructure design risk associated with the use of PREC-IDF was estimated. Accuracy of the model simulations used in the analyses was confirmed by long-term snow data at over 200 Snowpack Telemetry stations. The presented spatially continuous datasets are readily usable and instrumental for supporting site-specific infrastructure design.
DarkCideS 1.0, a global database for bats in karsts and caves
Authors: Tanalgo Krizler C. , Tabora John Aries G. , de Oliveira Hernani Fernandes Magalhães , Haelewaters Danny , Beranek Chad T. , Otálora-Ardila Aída , Bernard Enrico , Gonçalves Fernando , Eriksson Alan , Donnelly Melissa , González Joel Monzón , Ramos Humberto Fernández , Rivas Alberto Clark , Webala Paul W. , Deleva Stanimira , Dalhoumi Ridha , Maula Jaycelle , Lizarro Dennis , Aguirre Luis F. , Bouillard Nils , Quibod Ma. Niña Regina M. , Barros Jennifer , Turcios-Casco Manfredo Alejandro , Martínez Marcio , Ordoñez-Mazier Diego Iván , Orellana José Alejandro Soler , Ordoñez-Trejo Eduardo J. , Ordoñez Danny , Chornelia Ada , Lu Jian Mei , Xing Chen , Baniya Sanjeev , Muylaert Renata L. , Dias-Silva Leonardo Henrique , Ruadreo Nittaya , Hughes Alice Catherine
Published: April 2022

Understanding biodiversity patterns as well as drivers of population declines, and range losses provides crucial baselines for monitoring and conservation. However, the information needed to evaluate such trends remains unstandardised and sparsely available for many taxonomic groups and habitats, including the cave-dwelling bats and cave ecosystems. We developed the DarkCideS 1.0 (https://darkcides.org/), a global database of bat caves and species synthesised from publicly available information and datasets. The DarkCideS 1.0 is by far the largest database for cave-dwelling bats, which contains information for geographical location, ecological status, species traits, and parasites and hyperparasites for 679 bat species are known to occur in caves or use caves in part of their life histories. The database currently contains 6746 georeferenced occurrences for 402 cave-dwelling bat species from 2002 cave sites in 46 countries and 12 terrestrial biomes. The database has been developed to be collaborative and open-access, allowing continuous data-sharing among the community of bat researchers and conservation biologists to advance bat research and comparative monitoring and prioritisation for conservation.
Lipid phosphate phosphatase 3 in smooth muscle cells regulates angiotensin II-induced abdominal aortic aneurysm formation
Authors: Van Hoose Patrick M. , Yang Liping , Kraemer Maria , Ubele Margo , Morris Andrew J. , Smyth Susan S.
Published: April 2022

Genetic variants that regulate lipid phosphate phosphatase 3 (LPP3) expression are risk factors for the development of atherosclerotic cardiovascular disease. LPP3 is dynamically upregulated in the context of vascular inflammation with particularly heightened expression in smooth muscle cells (SMC), however, the impact of LPP3 on vascular pathology is not fully understood. We investigated the role of LPP3 and lysophospholipid signaling in a well-defined model of pathologic aortic injury and observed Angiotensin II (Ang II) increases expression of PLPP3 in SMCs through nuclear factor kappa B (NF-κB) signaling Plpp3 global reduction (Plpp3+/−) or SMC-specific deletion (SM22-Δ) protects hyperlipidemic mice from AngII-mediated aneurysm formation. LPP3 expression regulates SMC differentiation state and lowering LPP3 levels promotes a fibroblast-like phenotype. Decreased inactivation of bioactive lysophosphatidic acid (LPA) in settings of LPP3 deficiency may underlie these phenotypes because deletion of LPA receptor 4 in mice promotes early aortic dilation and rupture in response to AngII. LPP3 expression and LPA signaling influence SMC and vessel wall responses that are important for aortic dissection and aneurysm formation. These findings could have important implications for therapeutics targeting LPA metabolism and signaling in ongoing clinical trials.
Metabotropic glutamate receptor 5 knockout rescues obesity phenotype in a mouse model of Huntington’s disease
Authors: Santos Rebeca P. M. , Ribeiro Roberta , Ferreira-Vieira Talita H. , Aires Rosaria D. , de Souza Jessica M. , Oliveira Bruna S. , Lima Anna Luiza D. , de Oliveira Antônio Carlos P. , Reis Helton J. , de Miranda Aline S. , Vieira Erica M. L. , Ribeiro Fabiola M. , Vieira Luciene B.
Published: April 2022

Obesity represents a global health problem and is characterized by metabolic dysfunctions and a low-grade chronic inflammatory state, which can increase the risk of comorbidities, such as atherosclerosis, diabetes and insulin resistance. Here we tested the hypothesis that the genetic deletion of metabotropic glutamate receptor 5 (mGluR5) may rescue metabolic and inflammatory features present in BACHD mice, a mouse model of Huntington’s disease (HD) with an obese phenotype. For that, we crossed BACHD and mGluR5 knockout mice (mGluR5−/−) in order to obtain the following groups: Wild type (WT), mGluR5−/−, BACHD and BACHD/mGluR5−/− (double mutant mice). Our results showed that the double mutant mice present decreased body weight as compared to BACHD mice in all tested ages and reduced visceral adiposity as compared to BACHD at 6 months of age. Additionally, 12-month-old double mutant mice present increased adipose tissue levels of adiponectin, decreased leptin levels, and increased IL-10/TNF ratio as compared to BACHD mice. Taken together, our preliminary data propose that the absence of mGluR5 reduce weight gain and visceral adiposity in BACHD mice, along with a decrease in the inflammatory state in the visceral adipose tissue (VAT), which may indicate that mGluR5 may play a role in adiposity modulation.
Plasma proteomics reveals crosstalk between lipid metabolism and immunity in dairy cows receiving essential fatty acids and conjugated linoleic acid
Authors: Veshkini Arash , Hammon Harald M. , Vogel Laura , Viala Didier , Delosière Mylène , Tröscher Arnulf , Déjean Sébastien , Ceciliani Fabrizio , Sauerwein Helga , Bonnet Muriel
Published: April 2022

Essential fatty acids (EFA) and conjugated linoleic acids (CLA) are unsaturated fatty acids with immune-modulatory effects, yet their synergistic effect is poorly understood in dairy cows. This study aimed at identifying differentially abundant proteins (DAP) and their associated pathways in dairy cows supplied with a combination of EFA and CLA during the transition from antepartum (AP) to early postpartum (PP). Sixteen Holstein cows were abomasally infused with coconut oil as a control (CTRL) or a mixture of EFA (linseed + safflower oil) and CLA (Lutalin, BASF) (EFA + CLA) from − 63 to + 63 days relative to parturition. Label-free quantitative proteomics was performed on plasma samples collected at days − 21, + 1, + 28, and + 63. During the transition time, DAP, consisting of a cluster of apolipoproteins (APO), including APOE, APOH, and APOB, along with a cluster of immune-related proteins, were related to complement and coagulation cascades, inflammatory response, and cholesterol metabolism. In response to EFA + CLA, specific APO comprising APOC3, APOA1, APOA4, and APOC4 were increased in a time-dependent manner; they were linked to triglyceride-enriched lipoprotein metabolisms and immune function. Altogether, these results provide new insights into metabolic and immune adaptation and crosstalk between them in transition dairy cows divergent in EFA + CLA status.
Effects of combined abiotic stresses on nutrient content of European wheat and implications for nutritional security under climate change
Authors: Galani Yamdeu Joseph Hubert , Hansen Emilie Marie Øst , Droutsas Ioannis , Holmes Melvin , Challinor Andrew Juan , Mikkelsen Teis Nørgaard , Orfila Caroline
Published: April 2022

Climate change is causing problems for agriculture, but the effect of combined abiotic stresses on crop nutritional quality is not clear. Here we studied the effect of 10 combinations of climatic conditions (temperature, CO2, O3 and drought) under controlled growth chamber conditions on the grain yield, protein, and mineral content of 3 wheat varieties. Results show that wheat plants under O3 exposure alone concentrated + 15 to + 31% more grain N, Fe, Mg, Mn P and Zn, reduced K by − 5%, and C did not change. Ozone in the presence of elevated CO2 and higher temperature enhanced the content of Fe, Mn, P and Zn by 2–18%. Water-limited chronic O3 exposure resulted in + 9 to + 46% higher concentrations of all the minerals, except K. The effect of climate abiotic factors could increase the ability of wheat to meet adult daily dietary requirements by + 6% to + 12% for protein, Zn and Fe, but decrease those of Mg, Mn and P by − 3% to − 6%, and K by − 62%. The role of wheat in future nutrition security is discussed.
Stem cell transplant for mantle cell lymphoma in Taiwan
Authors: Wang Yu-Hung , Hsieh Ching-Yun , Hsiao Liang-Tsai , Lin Tung-Liang , Liu Yi-Chang , Yao Ming , Tan Tran-Der , Ko Bor-Sheng
Published: April 2022

Mantle cell lymphoma (MCL) is a B-cell lymphoma featuring an aggressive course and a progressive relapsing pattern. International guidelines recommend early consolidative autologous stem cell transplant (auto-SCT) for eligible patients while reserving allogeneic SCT (allo-SCT) as therapy for refractory cases. Since data describing the implementation of transplants in the Asian population with MCL are limited, we aimed to analyze post-SCT outcomes of 99 MCL patients from the Taiwan Bone Marrow Transplant Registry database. The median age was 56 years, and 11% of the patients had blastoid variant MCL. Ninety-four patients received auto-SCT, while 13 patients received allo-SCT, eight of which received allo-SCT after failing auto-SCT. Before auto-SCT, 52% of the patients were in their first complete remission (CR1). Overall, 37 patients (39%) relapsed after auto-SCT. The median post-auto-SCT progression-free survival and overall survival (OS) were 43.6 months and not reached, respectively. Blastoid variant MCL, transplant not received in CR1, and disease progression within 12 months post-auto-SCT independently predicted inferior OS in multivariable analysis. The median post-allo-SCT OS was 74 months. Two patients (15%) died of MCL recurrence post-allo-SCT. Three patients with refractory diseases were salvaged with ibrutinib or venetoclax to allo-SCT. Treatment strategies incorporating novel agents warrant further optimization.
Age-related enhancement in visuomotor learning by a dual-task
Authors: Wang Tony S. L. , Martinez Miles , Festa Elena K. , Heindel William C. , Song Joo-Hyun
Published: April 2022

Many daily activities require performance of multiple tasks integrating cognitive and motor processes. While the fact that both processes go through deterioration and changes with aging has been generally accepted, not much is known about how aging interacts with stages of motor skill acquisition under a cognitively demanding situation. To address this question, we combined a visuomotor adaptation task with a secondary cognitive task. We made two primary findings beyond the expected age-related performance deterioration. First, while young adults showed classical dual-task cost in the early motor learning phase dominated by explicit processes, older adults instead strikingly displayed enhanced performance in the later stage, dominated by implicit processes. For older adults, the secondary task may have facilitated a shift to their relatively intact implicit learning processes that reduced reliance on their already-deficient explicit processes during visuomotor adaptation. Second, we demonstrated that consistently performing the secondary task in learning and re-learning phases can operate as an internal task-context and facilitate visuomotor memory retrieval later regardless of age groups. Therefore, our study demonstrated age-related similarities and differences in integrating concurrent cognitive load with motor skill acquisition which, may in turn, contributes to the understanding of a shift in balance across multiple systems.
The ischemic time window of ectopic endometrial tissue crucially determines its ability to develop into endometriotic lesions
Authors: Rudzitis-Auth Jeannette , Huwer Sarah I. , Scheuer Claudia , Menger Michael D. , Laschke Matthias W.
Published: April 2022

Endometriosis develop from shed endometrial fragments via retrograde menstruation. This affects the survival, proliferation and vascularization of the tissue and its final ability to form endometriotic lesions. Within this study, uterine tissue samples from donor mice were precultivated for 24 h or 72 h to simulate avascular periods. Their morphology, microvessel density, apoptotic activity and expression of angiogenesis-related proteins were analyzed in vitro. The formation of endometriotic lesions in vivo was assessed after transplantation of precultivated uterine tissue samples to the abdominal wall and dorsal skinfold chambers by means of high-resolution ultrasound, intravital fluorescence microscopy, histology and immunohistochemistry. In vitro, 72-h-precultivated uterine tissue samples exhibit extensive areas of tissue necrosis and high numbers of apoptotic cells as well as a significantly reduced cell and microvessel density. These samples failed to develop into endometriotic lesions. In contrast, the 24-h-precultivated samples showed, that their early vascularization and growth in vivo was improved when compared to controls. This indicates that avascular periods have a strong impact on the survival of ectopic endometrial tissue and the chance for the development of endometriosis.