bluuebunny/crossref_metadata_2025 huggingface dataset:
Direct and maternal genetic parameters for growth traits in Jersey crossbred cattle
Authors: Vangchhia Nunhlupuii , Gayari Indrajit , Rahman Mokidur , Lalhmingmawii Sylvia , Bhakat Champak , Baneh Hasan , Mandal Ajoy
Published: May 2024

Growth data on Jersey crossbred calves, maintained at ICAR-National Dairy Research Institute, Eastern Regional Station, Kalyani, Nadia, West Bengal, India, were collected and analysed to assess the influence of maternal effects on growth traits of calves. Traits considered for this study were birth weight (BW) and weights at 3 months (W3M), 6 months (W6M), 9 months (W9M) and 12 months (W12M) of age. Least-squares analyses were employed to obtain the effects of non-genetic factors on the traits of interest. Determination of influence of maternal effects on growth traits was estimated by fitting three univariate animal models (including or excluding maternal effects) using Bayesian approach. The most appropriate model for each trait was selected based on Deviance Information Criterion. Direct heritability (h2) estimates for BW, W3M, W6M, W9M and W12M were 0.31 ± 0.08, 0.26 ± 0.10, 0.48 ± 0.10, 0.44 ± 0.11 and 0.39 ± 0.14, respectively, under the best model. Permanent environmental maternal effects (c2) varied from 0.04 to 0.12 for all traits. Existence of maternal effects for all ages reflects the importance of maternal components for these traits. Moderate to high heritability estimates for growth traits indicate the possibility of modest genetic progress for these traits through selection under prevalent management system.
Data on four species of Longidorus Micoletzky, 1922 (Nematoda: Longidoridae) from southern and southeastern Iran, including description of a new species
Authors: Monemi S. , Behdani M. , Mahdikhani-Moghadam E. , Amirzadi N. , Atighi M. R. , Ye W. , Jahanshahi Afshar F. , Pedram M.
Published: May 2024

Four species of the genus Longidorus were recovered from southern (Bushehr province) and southeastern (Southern Khorasan province) Iran. The first species, L. paratabrizicus n. sp. represents a new member to the genus and is characterised by 4.8–5.6 mm long females with anteriorly flattened lip region separated from the rest of the body by depression, amphidial fovea pocket-shaped without lobes, tail conical, dorsally convex, ventrally almost straight with bluntly rounded tip and males in population. By having similar lip region and tail shape, the new species most closely resembles five species viz. L. artemisiae, L. globulicauda, L. patuxentensis, L. sturhani, and L. tabrizicus. It represents the cryptic form of the last species. The second species belongs to L. mirus, recovered in both southern and southeastern Iran, representing the first record of the species after its original description. As an update to the characteristics of this species, it’s all juvenile developmental stages were recovered and described. The criteria to separate L. mirus from two closely related species, L. auratus and L. africanus, are discussed. The third species belongs to L. persicus, a new record in southern Iran. The fourth species, L. orientalis was recovered in high population density in association with date palm trees in Bushehr province. The phylogenetic relationships of the new species and recovered populations of L. mirus and L. persicus were reconstructed using two ribosomal markers and the resulted topologies were discussed.
A large cryptosporidiosis outbreak associated with an animal contact event in England: a retrospective cohort study, 2023
Authors: Peake Lewis , Bardsley Megan , Bartram Samantha , Bharuchi Shireen , Howkins Josh , Robinson Guy , Charlett André , Chalmers Rachel , Bird Sarah , Young Nick
Published: May 2024

Development of gastrointestinal illness after animal contact at petting farms is well described, as are factors such as handwashing and facility design that may modify transmission risk. However, further field evidence on other behaviours and interventions in the context of Cryptosporidium outbreaks linked to animal contact events is needed. Here, we describe a large outbreak of Cryptosporidium parvum (C. parvum) associated with a multi-day lamb petting event in the south-west of England in 2023 and present findings from a cohort study undertaken to investigate factors associated with illness. Detailed exposure questionnaires were distributed to email addresses of 647 single or multiple ticket bookings, and 157 complete responses were received. The outbreak investigation identified 23 laboratory-confirmed primary C. parvum cases. Separately, the cohort study identified 83 cases of cryptosporidiosis-like illness. Associations between illness and entering a lamb petting pen (compared to observing from outside the pen; odds ratio (OR) = 2.28, 95 per cent confidence interval (95% CI) 1.17 to 4.53) and self-reported awareness of diarrhoeal and vomiting disease transmission risk on farm sites at the time of visit (OR = 0.40, 95% CI 0.19 to 0.84) were observed. In a multivariable model adjusted for household clustering, awareness of disease transmission risk remained a significant protective factor (adjusted OR (aOR) = 0.07, 95% CI 0.01 to 0.78). The study demonstrates the likely under-ascertainment of cryptosporidiosis through laboratory surveillance and provides evidence of the impact that public health messaging could have.
Pathways to adolescent social anxiety: Testing interactions between neural social reward function and perceived social threat in daily life
Authors: Sequeira Stefanie L. , Silk Jennifer S. , Jones Neil P. , Forbes Erika E. , Hanson Jamie L. , Hallion Lauren S. , Ladouceur Cecile D.
Published: May 2024

Recent theories suggest that for youth highly sensitive to incentives, perceiving more social threat may contribute to social anxiety (SA) symptoms. In 129 girls (ages 11–13) oversampled for shy/fearful temperament, we thus examined how interactions between neural responses to social reward (vs. neutral) cues (measured during anticipation of peer feedback) and perceived social threat in daily peer interactions (measured using ecological momentary assessment) predict SA symptoms two years later. No significant interactions emerged when neural reward function was modeled as a latent factor. Secondary analyses showed that higher perceived social threat was associated with more severe SA symptoms two years later only for girls with higher basolateral amygdala (BLA) activation to social reward cues at baseline. Interaction effects were specific to BLA activation to social reward (not threat) cues, though a main effect of BLA activation to social threat (vs. neutral) cues on SA emerged. Unexpectedly, interactions between social threat and BLA activation to social reward cues also predicted generalized anxiety and depression symptoms two years later, suggesting possible transdiagnostic risk pathways. Perceiving high social threat may be particularly detrimental for youth highly sensitive to reward incentives, potentially due to mediating reward learning processes, though this remains to be tested.
The use of artificially intelligent chatbots in English language learning: A systematic meta-synthesis study of articles published between 2010 and 2024
Authors: Koç Fatma Şeyma , Savaş Perihan
Published: May 2024

In this qualitative systematic meta-synthesis study, 57 studies from the international literature published between 2010 and 2024 on the use of voice-based artificially intelligent chatbots in English language learning were analyzed. The present study aimed to explore the most recent studies on this topic by investigating the theoretical frameworks, methodological and technological properties, user reports of chatbot usage experience, and pedagogical implementations. It sought to identify research and implementation trends for voice-based chatbots via qualitative data analysis methods. Based on the reviewed studies, this paper presents data-based pedagogical implications that align with the latest voice-based AI chatbot research trends.
Rapid Acceleration Bursts in the Van Allen Radiation Belt
Authors: Olifer L. , Morley S. K. , Ozeke L. G. , Mann I. R. , Kalliokoski M. M. H. , Henderson M. G. , Carver M. R. , Hoover A.
Published: May 2024

The fast Van Allen radiation belt electron dynamics during geomagnetic storms have not yet been fully explained, in part due to limitations of standard satellite missions in both orbit and the number of spacecraft. Here we overcome these limitations using measurements from the Global Positioning System (GPS) constellation during an acceleration event on 26 August 2018. We show that the acceleration of relativistic electrons occurs in two distinct bursts, each dominated by a different acceleration mechanism. The first burst enhances the radiation belt electrons by four orders of magnitude in 2 hr and is consistent with ULF‐wave radial diffusion. The second burst is likely caused by the local acceleration and delivers an order‐of‐magnitude increase in 20 min. This work demonstrates how distributed, operational measurements can be used to resolve phenomena not observable with previous capabilities, and that rapid energization of the radiation belt can occur much faster than previously reported.
A Taxonomy of Upper‐Mantle Stratification in the US
Authors: Carr Steve A. B. , Olugboji Tolulope
Published: May 2024

The investigation of upper mantle structure beneath the US has revealed a growing diversity of discontinuities within, across, and underneath the sub‐continental lithosphere. As the complexity and variability of these detected discontinuities increase—for example, velocity increase/decrease, number of layers and depth—it is hard to judge which constraints are robust and which explanatory models generalize to the largest set of constraints. Much work has been done to image discontinuities of interest using S‐waves that convert to P‐waves (or top‐side reflected SS waves). A higher resolution method using P‐to‐S scattered waves is preferred but often obscured by multiply reflected waves trapped in a shallower layer, limiting the visibility of deeper boundaries. Here, we address the interference problem and re‐evaluate upper mantle stratification using filtered P‐to‐S receiver functions (Ps‐RFs) interpreted using unsupervised machine‐learning. Robust insight into upper mantle layering is facilitated with CRISP‐RF: Clean Receiver‐Function Imaging using Sparse Radon Filters. Subsequent sequencing and clustering organizes the polarity‐filtered Ps‐RFs into distinct depth‐based clusters. We find three types of upper mantle stratification beneath the old and stable continental US: (a) intra‐lithosphere discontinuities (paired or single boundary), (b) transitional discontinuities (single boundary or with a top layer), and (c) sub‐lithosphere discontinuities. Our findings contribute a more nuanced understanding of mantle discontinuities, offering new perspectives on the nature of upper mantle layering beneath continents.
Disease-specific alterations in central fear network engagement during acquisition and extinction of conditioned interoceptive fear in inflammatory bowel disease
Authors: Lanters Laura R. , Öhlmann Hanna , Langhorst Jost , Theysohn Nina , Engler Harald , Icenhour Adriane , Elsenbruch Sigrid
Published: May 2024

Interoceptive fear, which is shaped by associative threat learning and memory processes, plays a central role in abnormal interoception and psychiatric comorbidity in conditions of the gut-brain axis. Although animal and human studies support that acute inflammation induces brain alterations in the central fear network, mechanistic knowledge in patients with chronic inflammatory conditions remains sparse. We implemented a translational fear conditioning paradigm to elucidate central fear network reactivity in patients with quiescent inflammatory bowel disease (IBD), compared to patients with irritable bowel syndrome (IBS) and healthy controls (HC). Using functional magnetic resonance imaging, conditioned differential neural responses within regions of the fear network were analyzed during acquisition and extinction learning. In contrast to HC and IBS, IBD patients demonstrated distinctly altered engagement of key regions of the central fear network, including amygdala and hippocampus, during differential interoceptive fear learning, with more pronounced responses to conditioned safety relative to pain-predictive cues. Aberrant hippocampal responses correlated with chronic stress exclusively in IBD. During extinction, differential engagement was observed in IBD compared to IBS patients within amygdala, ventral anterior insula, and thalamus. No group differences were found in changes of cue valence as a behavioral measure of fear acquisition and extinction. Together, the disease-specific alterations in neural responses during interoceptive fear conditioning in quiescent IBD suggest persisting effects of recurring intestinal inflammation on central fear network reactivity. Given the crucial role of interoceptive fear in abnormal interoception, these findings point towards inflammation-related brain alterations as one trajectory to bodily symptom chronicity and psychiatric comorbidity. Patients with inflammatory conditions of the gut-brain axis may benefit from tailored treatment approaches targeting maladaptive interoceptive fear.
The influence of acute lifestyle changes on NAFLD evolution in a multicentre cohort: a matter of body composition
Authors: Dallio Marcello , Sangineto Moris , Romeo Mario , Cipullo Marina , Coppola Annachiara , Mammone Simone , Di Gioia Giuseppe , Masarone Mario , Persico Marcello , Serviddio Gaetano , Federico Alessandro
Published: May 2024

Background

Unhealthy lifestyles represent a key element fueling Non-alcoholic fatty liver disease (NAFLD) onset and worsening. We aimed to evaluate the effects of forced acute lifestyle changes on NAFLD evolution.

Methods

187 NAFLD patients were followed two years pre- and two years during the lockdown social restrictions in three Italian medical centers. For each patient, biochemical, clinical, non-invasive liver fibrosis, nutritional, and body composition data were collected.

Results

An increase in fats and carbohydrate intake associated with impaired weekly physical activity during the lockdown was demonstrated as well as an increase in body mass index and waist-hip-ratio (p < 0.0001 for all). Total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, insulin, homeostatic model assessment for insulin resistance, and transaminases worsened during the lockdown (glucose: p = 0.0007; p < 0.0001 for the others). Moreover, NAFLD fibrosis score, liver stiffness, and controlled attenuation parameter were also impaired during the same period (p < 0.0001 for all). The bioelectrical impedance analysis (BIA) evidenced an increase of fat mass (FM), and a reduction of free fat mass (FFM) and body cell mass (BCM) (p < 0.0001 for all). The lockdown overall hepatocellular carcinoma (HCC) and Milan-out HCC occurrence revealed Hazard Ratio (HR): 2.398, 95% Confidence Interval (CI):1.16–5, p = 0.02, and HR:5.931, CI:2–17.6, p = 0.008 respectively. A liver disease stage and comorbidities independent association between both the assessed outcomes and body composition analysis in terms of mean values and variation (T1–T2 Δ) was demonstrated.

Conclusions

The acute lifestyle changes impacted NAFLD evolution via body composition modifications negatively influencing the HCC occurrence.
Notch signaling pathway in cancer: from mechanistic insights to targeted therapies
Authors: Shi Qingmiao , Xue Chen , Zeng Yifan , Yuan Xin , Chu Qingfei , Jiang Shuwen , Wang Jinzhi , Zhang Yaqi , Zhu Danhua , Li Lanjuan
Published: May 2024

Notch signaling, renowned for its role in regulating cell fate, organ development, and tissue homeostasis across metazoans, is highly conserved throughout evolution. The Notch receptor and its ligands are transmembrane proteins containing epidermal growth factor-like repeat sequences, typically necessitating receptor-ligand interaction to initiate classical Notch signaling transduction. Accumulating evidence indicates that the Notch signaling pathway serves as both an oncogenic factor and a tumor suppressor in various cancer types. Dysregulation of this pathway promotes epithelial-mesenchymal transition and angiogenesis in malignancies, closely linked to cancer proliferation, invasion, and metastasis. Furthermore, the Notch signaling pathway contributes to maintaining stem-like properties in cancer cells, thereby enhancing cancer invasiveness. The regulatory role of the Notch signaling pathway in cancer metabolic reprogramming and the tumor microenvironment suggests its pivotal involvement in balancing oncogenic and tumor suppressive effects. Moreover, the Notch signaling pathway is implicated in conferring chemoresistance to tumor cells. Therefore, a comprehensive understanding of these biological processes is crucial for developing innovative therapeutic strategies targeting Notch signaling. This review focuses on the research progress of the Notch signaling pathway in cancers, providing in-depth insights into the potential mechanisms of Notch signaling regulation in the occurrence and progression of cancer. Additionally, the review summarizes pharmaceutical clinical trials targeting Notch signaling for cancer therapy, aiming to offer new insights into therapeutic strategies for human malignancies.
Trends in cancer-related suicide in the United States: a population-based epidemiology study spanning 40 years of data
Authors: Liu Qiang , Qu Zheng , Dong Hao , Qi Yihang , Wu Juan , Zhang Wenxiang , Wang Xiangyu , Wang Zhongzhao , Fang Yi , Wang Jing
Published: May 2024

Large cohort studies examining trends in cancer-related suicide are lacking. We analyzed data from the Surveillance, Epidemiology, and End Results (SEER) database, encompassing a total of 4,870,410 patients diagnosed with cancer from 1975 to 2017 in the United States. Joinpoint regression was used to estimate the annual percent change (APC) and average annual percentage change (AAPC) of age-adjusted rates of suicide. In the past 40 years, we revealed a gradual increase in cancer-related suicide rates from 1975 to 1989, followed by a gradual decrease from 1989 to 2013, and a marked decrease from 2013 to 2017. These trends suggested the potential impact of advancements in psychosocial care for patients with cancer in contributing to the observed decrease in suicide rates.
A novel mutation of DNA2 regulates neuronal cell membrane potential and epileptogenesis
Authors: Liu Yuting , Yang Haiyan , Gan Siyi , He Lu , Zeng Rongrong , Xiao Ting , Wu Liwen
Published: May 2024

Mesial temporal lobe epilepsy (MTLE) is one of the most intractable epilepsies. Previously, we reported that mitochondrial DNA deletions were associated with epileptogenesis. While the underlying mechanism of mitochondrial DNA deletions during epileptogenesis remain unknown. In this study, a novel somatic mutation of DNA2 gene was identified in the hippocampal tissue of two MTLE patients carrying mitochondrial DNA deletions, and this mutation decreased the full-length expression of DNA2 protein significantly, aborting its normal functions. Then, we knocked down the DNA2 protein in zebrafish, and we demonstrated that zebrafish with DNA2 deficiency showed decreased expression of mitochondrial complex II–IV, and exhibited hallmarks of epileptic seizures, including abnormal development of the zebrafish and epileptiform discharge signals in brain, compared to the Cas9-control group. Moreover, our cell-based assays showed that DNA2 deletion resulted in accumulated mitochondrial DNA damage, abnormal oxidative phosphorylation and decreased ATP production in cells. Inadequate ATP generation in cells lead to declined Na+, K+-ATPase activity and change of cell membrane potential. Together, these disorders caused by DNA2 depletion increased cell apoptosis and inhibited the differentiation of SH-SY5Y into branched neuronal phenotype. In conclusion, DNA2 deficiency regulated the cell membrane potential via affecting ATP production by mitochondria and Na+, K+-ATPase activity, and also affected neuronal cell growth and differentiation. These disorders caused by DNA2 dysfunction are important causes of epilepsy. In summary, we are the first to report the pathogenic somatic mutation of DNA2 gene in the patients with MTLE disease, and we uncovered the mechanism of DNA2 regulating the epilepsy. This study provides new insight into the pathogenesis of epilepsy and underscore the value of DNA2 in epilepsy.
Expectations, needs and mid-term outcomes in people accessing to secondary findings from ES: 1st French mixed study (FIND Study)
Authors: Viora-Dupont Eléonore , Robert Françoise , Chassagne Aline , Pélissier Aurore , Staraci Stéphanie , Sanlaville Damien , Edery Patrick , Lesca Gaetan , Putoux Audrey , Pons Linda , Cadenes Amandine , Baurand Amandine , Sawka Caroline , Bertolone Geoffrey , Spetchian Myrtille , Yousfi Meriem , Salvi Dominique , Gautier Elodie , Vitobello Antonio , Denommé-Pichon Anne-Sophie , Bruel Ange-Line , Tran Mau-Them Frédéric , Faudet Anne , Keren Boris , Labalme Audrey , Chatron Nicolas , Abel Carine , Dupuis-Girod Sophie , Poisson Alice , Buratti Julien , Mignot Cyril , Afenjar Alexandra , Whalen Sandra , Charles Perrine , Heide Solveig , Mouthon Linda , Moutton Sébastien , Sorlin Arthur , Nambot Sophie , Briffaut Anne-Sophie , Asensio Marie-Laure , Philippe Christophe , Thauvin-Robinet Christel , Héron Delphine , Rossi Massimiliano , Meunier-Bellard Nicolas , Gargiulo Marcela , Peyron Christine , Binquet Christine , Faivre Laurence
Published: May 2024

Generation and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N = 340; qualitative N = 26). Three groups of actionable SF were rendered: predisposition to late-onset actionable diseases; genetic counseling; pharmacogenomics. Participants expressed strong interest in obtaining SF and a high satisfaction level when a SF is reported. The medical actionability of the SF reinforced parents’ sense of taking action for their child and was seen as an opportunity. While we observed no serious psychological concerns, we showed that these results could have psychological consequences, in particular for late-onset actionable diseases SF, within families already dealing with rare diseases. This study shows that participants remain in favor of accessing SF despite the potential psychological, care, and lifestyle impacts, which are difficult to anticipate. The establishment of a management protocol, including the support of a multidisciplinary team, would be necessary if national policy allows the reporting of these data.
Intermittency in the not-so-smooth elastic turbulence
Authors: Singh Rahul K. , Perlekar Prasad , Mitra Dhrubaditya , Rosti Marco E.
Published: May 2024

Elastic turbulence is the chaotic fluid motion resulting from elastic instabilities due to the addition of polymers in small concentrations at very small Reynolds ($${{{{{{{\rm{Re}}}}}}}}$$
Re
) numbers. Our direct numerical simulations show that elastic turbulence, though a low $${{{{{{{\rm{Re}}}}}}}}$$
Re
phenomenon, has more in common with classical, Newtonian turbulence than previously thought. In particular, we find power-law spectra for kinetic energy E(k) ~ k−4 and polymeric energy Ep(k) ~ k−3/2, independent of the Deborah (De) number. This is further supported by calculation of scale-by-scale energy budget which shows a balance between the viscous term and the polymeric term in the momentum equation. In real space, as expected, the velocity field is smooth, i.e., the velocity difference across a length scale r, δu ~ r but, crucially, with a non-trivial sub-leading contribution r3/2 which we extract by using the second difference of velocity. The structure functions of second difference of velocity up to order 6 show clear evidence of intermittency/multifractality. We provide additional evidence in support of this intermittent nature by calculating moments of rate of dissipation of kinetic energy averaged over a ball of radius r, εr, from which we compute the multifractal spectrum.
C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer
Authors: Li Xi , Poire Alfonso , Jeong Kang Jin , Zhang Dong , Ozmen Tugba Yildiran , Chen Gang , Sun Chaoyang , Mills Gordon B.
Published: May 2024

Although Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have been approved in multiple diseases, including BRCA1/2 mutant breast cancer, responses are usually transient requiring the deployment of combination therapies for optimal efficacy. Here we thus explore mechanisms underlying sensitivity and resistance to PARPi using two intrinsically PARPi sensitive (T22) and resistant (T127) syngeneic murine breast cancer models in female mice. We demonstrate that tumor associated macrophages (TAM) potentially contribute to the differential sensitivity to PARPi. By single-cell RNA-sequencing, we identify a TAM_C3 cluster, expressing genes implicated in anti-inflammatory activity, that is enriched in PARPi resistant T127 tumors and markedly decreased by PARPi in T22 tumors. Rps19/C5aR1 signaling is selectively elevated in TAM_C3. C5aR1 inhibition or transferring C5aR1hicells increases and decreases PARPi sensitivity, respectively. High C5aR1 levels in human breast cancers are associated with poor responses to immune checkpoint blockade. Thus, targeting C5aR1 may selectively deplete pro-tumoral macrophages and engender sensitivity to PARPi and potentially other therapies.
Programmable quantum emitter formation in silicon
Authors: Jhuria K. , Ivanov V. , Polley D. , Zhiyenbayev Y. , Liu W. , Persaud A. , Redjem W. , Qarony W. , Parajuli P. , Ji Q. , Gonsalves A. J. , Bokor J. , Tan L. Z. , Kanté B. , Schenkel T.
Published: May 2024

Silicon-based quantum emitters are candidates for large-scale qubit integration due to their single-photon emission properties and potential for spin-photon interfaces with long spin coherence times. Here, we demonstrate local writing and erasing of selected light-emitting defects using femtosecond laser pulses in combination with hydrogen-based defect activation and passivation at a single center level. By choosing forming gas (N2/H2) during thermal annealing of carbon-implanted silicon, we can select the formation of a series of hydrogen and carbon-related quantum emitters, including T and Ci centers while passivating the more common G-centers. The Ci center is a telecom S-band emitter with promising optical and spin properties that consists of a single interstitial carbon atom in the silicon lattice. Density functional theory calculations show that the Ci center brightness is enhanced by several orders of magnitude in the presence of hydrogen. Fs-laser pulses locally affect the passivation or activation of quantum emitters with hydrogen for programmable formation of selected quantum emitters.
Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales
Authors: Meyer Jochen , Yu Kwanha , Luna-Figueroa Estefania , Deneen Benjamin , Noebels Jeffrey
Published: May 2024

The emergence of glioblastoma in cortical tissue initiates early and persistent neural hyperexcitability with signs ranging from mild cognitive impairment to convulsive seizures. The influence of peritumoral synaptic density, expansion dynamics, and spatial contours of excess glutamate upon higher order neuronal network modularity is unknown. We combined cellular and widefield imaging of calcium and glutamate fluorescent reporters in two glioblastoma mouse models with distinct synaptic microenvironments and infiltration profiles. Functional metrics of neural ensembles are dysregulated during tumor invasion depending on the stage of malignant progression and tumor cell proximity. Neural activity is differentially modulated during periods of accelerated and inhibited tumor expansion. Abnormal glutamate accumulation precedes and outpaces the spatial extent of baseline neuronal calcium signaling, indicating these processes are uncoupled in tumor cortex. Distinctive excitability homeostasis patterns and functional connectivity of local and remote neuronal populations support the promise of precision genetic diagnosis and management of this devastating brain disease.
Human neutralizing antibodies target a conserved lateral patch on H7N9 hemagglutinin head
Authors: Jia Manxue , Zhao Hanjun , Morano Nicholas C. , Lu Hong , Lui Yin-Ming , Du Haijuan , Becker Jordan E. , Yuen Kwok-Yung , Ho David D. , Kwong Peter D. , Shapiro Lawrence , To Kelvin Kai-Wang , Wu Xueling
Published: May 2024

Avian influenza A virus H7N9 causes severe human infections with >30% fatality. Currently, there is no H7N9-specific prevention or treatment for humans. Here, from a 2013 H7N9 convalescent case in Hong Kong, we isolate four hemagglutinin (HA)-reactive monoclonal antibodies (mAbs), with three directed to the globular head domain (HA1) and one to the stalk domain (HA2). Two clonally related HA1-directed mAbs, H7.HK1 and H7.HK2, potently neutralize H7N9 and protect female mice from lethal H7N9/AH1 challenge. Cryo-EM structures reveal that H7.HK1 and H7.HK2 bind to a β14-centered surface and disrupt the 220-loop that makes hydrophobic contacts with sialic acid on an adjacent protomer, thereby blocking viral entry. Sequence analysis indicates the lateral patch targeted by H7.HK1 and H7.HK2 to be conserved among influenza subtypes. Both H7.HK1 and H7.HK2 retain HA1 binding and neutralization capacity to later H7N9 isolates from 2016–2017, consistent with structural data showing that the antigenic mutations during this timeframe occur at their epitope peripheries. The HA2-directed mAb H7.HK4 lacks neutralizing activity but when used in combination with H7.HK2 moderately augments female mouse protection. Overall, our data reveal antibodies to a conserved lateral HA1 supersite that confer neutralization, and when combined with a HA2-directed non-neutralizing mAb, augment protection.
Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform
Authors: Odorčić Ivica , Hamed Mohamed Belal , Lismont Sam , Chávez-Gutiérrez Lucía , Efremov Rouslan G.
Published: May 2024

Deposition of amyloid-β (Aβ) peptides in the brain is a hallmark of Alzheimer’s disease. Aβs are generated through sequential proteolysis of the amyloid precursor protein by the γ-secretase complexes (GSECs). Aβ peptide length, modulated by the Presenilin (PSEN) and APH-1 subunits of GSEC, is critical for Alzheimer’s pathogenesis. Despite high relevance, mechanistic understanding of the proteolysis of Aβ, and its modulation by APH-1, remain incomplete. Here, we report cryo-EM structures of human GSEC (PSEN1/APH-1B) reconstituted into lipid nanodiscs in apo form and in complex with the intermediate Aβ46 substrate without cross-linking. We find that three non-conserved and structurally divergent APH-1 regions establish contacts with PSEN1, and that substrate-binding induces concerted rearrangements in one of the identified PSEN1/APH-1 interfaces, providing structural basis for APH-1 allosteric-like effects. In addition, the GSEC-Aβ46 structure reveals an interaction between Aβ46 and loop 1PSEN1, and identifies three other H-bonding interactions that, according to functional validation, are required for substrate recognition and efficient sequential catalysis.
OsSRF8 interacts with OsINP1 and OsDAF1 to regulate pollen aperture formation in rice
Authors: Chen Keyi , Wang Qiming , Yu Xiaowen , Wang Chaolong , Gao Junwen , Zhang Shihao , Cheng Siqi , You Shimin , Zheng Hai , Lu Jiayu , Zhu Xufei , Lei Dekun , Jian Anqi , He Xiaodong , Yu Hao , Chen Yun , Zhou Mingli , Li Kai , He Ling , Tian Yunlu , Liu Xi , Liu Shijia , Jiang Ling , Bao Yiqun , Wang Haiyang , Zhao Zhigang , Wan Jianmin
Published: May 2024

In higher plants, mature male gametophytes have distinct apertures. After pollination, pollen grains germinate, and a pollen tube grows from the aperture to deliver sperm cells to the embryo sac, completing fertilization. In rice, the pollen aperture has a single-pore structure with a collar-like annulus and a plug-like operculum. A crucial step in aperture development is the formation of aperture plasma membrane protrusion (APMP) at the distal polar region of the microspore during the late tetrad stage. Previous studies identified OsINP1 and OsDAF1 as essential regulators of APMP and pollen aperture formation in rice, but their precise molecular mechanisms remain unclear. We demonstrate that the Poaceae-specific OsSRF8 gene, encoding a STRUBBELIG-receptor family 8 protein, is essential for pollen aperture formation in Oryza sativa. Mutants lacking functional OsSRF8 exhibit defects in APMP and pollen aperture formation, like loss-of-function OsINP1 mutants. OsSRF8 is specifically expressed during early anther development and initially diffusely distributed in the microsporocytes. At the tetrad stage, OsSRF8 is recruited by OsINP1 to the pre-aperture region through direct protein-protein interaction, promoting APMP formation. The OsSRF8-OsINP1 complex then recruits OsDAF1 to the APMP site to co-regulate annulus formation. Our findings provide insights into the mechanisms controlling pollen aperture formation in cereal species.
Structural domain in the Titin N2B-us region binds to FHL2 in a force-activation dependent manner
Authors: Sun Yuze , Liu Xuyao , Huang Wenmao , Le Shimin , Yan Jie
Published: May 2024

Titin N2B unique sequence (N2B-us) is a 572 amino acid sequence that acts as an elastic spring to regulate muscle passive elasticity. It is thought to lack stable tertiary structures and is a force-bearing region that is regulated by mechanical stretching. In this study, the conformation of N2B-us and its interaction with four-and-a-half LIM domain protein 2 (FHL2) are investigated using AlphaFold2 predictions and single-molecule experimental validation. Surprisingly, a stable alpha/beta structural domain is predicted and confirmed in N2B-us that can be mechanically unfolded at forces of a few piconewtons. Additionally, more than twenty FHL2 LIM domain binding sites are predicted to spread throughout N2B-us. Single-molecule manipulation experiments reveals the force-dependent binding of FHL2 to the N2B-us structural domain. These findings provide insights into the mechano-sensing functions of N2B-us and its interactions with FHL2.
Hairpin protein partitioning from the ER to lipid droplets involves major structural rearrangements
Authors: Dhiman Ravi , Perera Rehani S. , Poojari Chetan S. , Wiedemann Haakon T. A. , Kappl Reinhard , Kay Christopher W. M. , Hub Jochen S. , Schrul Bianca
Published: May 2024

Lipid droplet (LD) function relies on proteins partitioning between the endoplasmic reticulum (ER) phospholipid bilayer and the LD monolayer membrane to control cellular adaptation to metabolic changes. It has been proposed that these hairpin proteins integrate into both membranes in a similar monotopic topology, enabling their passive lateral diffusion during LD emergence at the ER. Here, we combine biochemical solvent-accessibility assays, electron paramagnetic resonance spectroscopy and intra-molecular crosslinking experiments with molecular dynamics simulations, and determine distinct intramembrane positionings of the ER/LD protein UBXD8 in ER bilayer and LD monolayer membranes. UBXD8 is deeply inserted into the ER bilayer with a V-shaped topology and adopts an open-shallow conformation in the LD monolayer. Major structural rearrangements are required to enable ER-to-LD partitioning. Free energy calculations suggest that such structural transition is unlikely spontaneous, indicating that ER-to-LD protein partitioning relies on more complex mechanisms than anticipated and providing regulatory means for this trans-organelle protein trafficking.
Adopting yield-improving practices to meet maize demand in Sub-Saharan Africa without cropland expansion
Authors: Aramburu-Merlos Fernando , Tenorio Fatima A. M. , Mashingaidze Nester , Sananka Alex , Aston Stephen , Ojeda Jonathan J. , Grassini Patricio
Published: May 2024

Maize demand in Sub-Saharan Africa is expected to increase 2.3 times during the next 30 years driven by demographic and dietary changes. Over the past two decades, the area cropped with maize has expanded by 17 million hectares in the region, with limited yield increase. Following this trend could potentially result in further maize cropland expansion and the need for imports to satisfy domestic demand. Here, we use data collected from 14,773 smallholder fields in the region to identify agronomic practices that can improve farm yield gains. We find that agronomic practices related to cultivar selection, and nutrient, pest, and crop management can double on-farm yields and provide an additional 82 million tons of maize within current cropped area. Research and development investments should be oriented towards agricultural practices with proven capacity to raise maize yields in the region.
Break down the decentralization-security-privacy trilemma in management of distributed energy systems
Authors: Sun Qinghan , Ma Huan , Zhao Tian , Xin Yonglin , Chen Qun
Published: May 2024

Distributed energy systems encompass a diverse range of generation and storage solutions on the user side, where decentralized management schemes to maximize the overall social welfare are preferred considering their dispersed ownership. However, either security or privacy problems occur in recently proposed schemes. Here we report a decentralized framework leveraging the strengths of blockchain and parallelizable mathematical algorithms to overcome these potential drawbacks. The system owners bid cost functions and operating constraints through masked but coupled management subproblems, which are redistributed by the blockchain to be verifiably solved by competent peers. Such processes are iteratively executed as decisions and shadow prices are exchanged among participants, until an equilibrium is reached. The interactive framework ensures decentralized, privacy-preserving, and secure management of multiple energy sources, and reduces the total cost by 3.0 ~ 7.5% in the test system. Our results benefit the energy prosumers and promote a more active and competitive power grid.
Spa2 remodels ADP-actin via molecular condensation under glucose starvation
Authors: Ma Qianqian , Surya Wahyu , He Danxia , Yang Hanmeng , Han Xiao , Nai Mui Hoon , Lim Chwee Teck , Torres Jaume , Miao Yansong
Published: May 2024

Actin nucleotide-dependent actin remodeling is essential to orchestrate signal transduction and cell adaptation. Rapid energy starvation requires accurate and timely reorganization of the actin network. Despite distinct treadmilling mechanisms of ADP- and ATP-actin filaments, their filament structures are nearly identical. How other actin-binding proteins regulate ADP-actin filament assembly is unclear. Here, we show that Spa2 which is the polarisome scaffold protein specifically remodels ADP-actin upon energy starvation in budding yeast. Spa2 triggers ADP-actin monomer nucleation rapidly through a dimeric core of Spa2 (aa 281-535). Concurrently, the intrinsically disordered region (IDR, aa 1-281) guides Spa2 undergoing phase separation and wetting on the surface of ADP-G-actin-derived F-actin and bundles the filaments. Both ADP-actin-specific nucleation and bundling activities of Spa2 are actin D-loop dependent. The IDR and nucleation core of Spa2 are evolutionarily conserved by coexistence in the fungus kingdom, suggesting a universal adaptation mechanism in the fungal kingdom in response to glucose starvation, regulating ADP-G-actin and ADP-F-actin with high nucleotide homogeneity.
Organization of corticocortical and thalamocortical top-down inputs in the primary visual cortex
Authors: Liu Yanmei , Zhang Jiahe , Jiang Zhishan , Qin Meiling , Xu Min , Zhang Siyu , Ma Guofen
Published: May 2024

Unified visual perception requires integration of bottom-up and top-down inputs in the primary visual cortex (V1), yet the organization of top-down inputs in V1 remains unclear. Here, we used optogenetics-assisted circuit mapping to identify how multiple top-down inputs from higher-order cortical and thalamic areas engage V1 excitatory and inhibitory neurons. Top-down inputs overlap in superficial layers yet segregate in deep layers. Inputs from the medial secondary visual cortex (V2M) and anterior cingulate cortex (ACA) converge on L6 Pyrs, whereas ventrolateral orbitofrontal cortex (ORBvl) and lateral posterior thalamic nucleus (LP) inputs are processed in parallel in Pyr-type-specific subnetworks (Pyr←ORBvl and Pyr←LP) and drive mutual inhibition between them via local interneurons. Our study deepens understanding of the top-down modulation mechanisms of visual processing and establishes that V2M and ACA inputs in L6 employ integrated processing distinct from the parallel processing of LP and ORBvl inputs in L5.
Structure-based network analysis predicts pathogenic variants in human proteins associated with inherited retinal disease
Authors: Hauser Blake M. , Luo Yuyang , Nathan Anusha , Al-Moujahed Ahmad , Vavvas Demetrios G. , Comander Jason , Pierce Eric A. , Place Emily M. , Bujakowska Kinga M. , Gaiha Gaurav D. , Rossin Elizabeth J.
Published: May 2024

Advances in gene sequencing technologies have accelerated the identification of genetic variants, but better tools are needed to understand which are causal of disease. This would be particularly useful in fields where gene therapy is a potential therapeutic modality for a disease-causing variant such as inherited retinal disease (IRD). Here, we apply structure-based network analysis (SBNA), which has been successfully utilized to identify variant-constrained amino acid residues in viral proteins, to identify residues that may cause IRD if subject to missense mutation. SBNA is based entirely on structural first principles and is not fit to specific outcome data, which makes it distinct from other contemporary missense prediction tools. In 4 well-studied human disease-associated proteins (BRCA1, HRAS, PTEN, and ERK2) with high-quality structural data, we find that SBNA scores correlate strongly with deep mutagenesis data. When applied to 47 IRD genes with available high-quality crystal structure data, SBNA scores reliably identified disease-causing variants according to phenotype definitions from the ClinVar database. Finally, we applied this approach to 63 patients at Massachusetts Eye and Ear (MEE) with IRD but for whom no genetic cause had been identified. Untrained models built using SBNA scores and BLOSUM62 scores for IRD-associated genes successfully predicted the pathogenicity of novel variants (AUC = 0.851), allowing us to identify likely causative disease variants in 40 IRD patients. Model performance was further augmented by incorporating orthogonal data from EVE scores (AUC = 0.927), which are based on evolutionary multiple sequence alignments. In conclusion, SBNA can used to successfully identify variants as causal of disease in human proteins and may help predict variants causative of IRD in an unbiased fashion.
Extending PROXIMAL to predict degradation pathways of phenolic compounds in the human gut microbiota
Authors: Balzerani Francesco , Blasco Telmo , Pérez-Burillo Sergio , Valcarcel Luis V. , Hassoun Soha , Planes Francisco J.
Published: May 2024

Despite significant advances in reconstructing genome-scale metabolic networks, the understanding of cellular metabolism remains incomplete for many organisms. A promising approach for elucidating cellular metabolism is analysing the full scope of enzyme promiscuity, which exploits the capacity of enzymes to bind to non-annotated substrates and generate novel reactions. To guide time-consuming costly experimentation, different computational methods have been proposed for exploring enzyme promiscuity. One relevant algorithm is PROXIMAL, which strongly relies on KEGG to define generic reaction rules and link specific molecular substructures with associated chemical transformations. Here, we present a completely new pipeline, PROXIMAL2, which overcomes the dependency on KEGG data. In addition, PROXIMAL2 introduces two relevant improvements with respect to the former version: i) correct treatment of multi-step reactions and ii) tracking of electric charges in the transformations. We compare PROXIMAL and PROXIMAL2 in recovering annotated products from substrates in KEGG reactions, finding a highly significant improvement in the level of accuracy. We then applied PROXIMAL2 to predict degradation reactions of phenolic compounds in the human gut microbiota. The results were compared to RetroPath RL, a different and relevant enzyme promiscuity method. We found a significant overlap between these two methods but also complementary results, which open new research directions into this relevant question in nutrition.
Long-term intravital subcellular imaging with confocal scanning light-field microscopy
Authors: Lu Zhi , Zuo Siqing , Shi Minghui , Fan Jiaqi , Xie Jingyu , Xiao Guihua , Yu Li , Wu Jiamin , Dai Qionghai
Published: May 2024

Long-term observation of subcellular dynamics in living organisms is limited by background fluorescence originating from tissue scattering or dense labeling. Existing confocal approaches face an inevitable tradeoff among parallelization, resolution and phototoxicity. Here we present confocal scanning light-field microscopy (csLFM), which integrates axially elongated line-confocal illumination with the rolling shutter in scanning light-field microscopy (sLFM). csLFM enables high-fidelity, high-speed, three-dimensional (3D) imaging at near-diffraction-limit resolution with both optical sectioning and low phototoxicity. By simultaneous 3D excitation and detection, the excitation intensity can be reduced below 1 mW mm−2, with 15-fold higher signal-to-background ratio over sLFM. We imaged subcellular dynamics over 25,000 timeframes in optically challenging environments in different species, such as migrasome delivery in mouse spleen, retractosome generation in mouse liver and 3D voltage imaging in Drosophila. Moreover, csLFM facilitates high-fidelity, large-scale neural recording with reduced crosstalk, leading to high orientation selectivity to visual stimuli, similar to two-photon microscopy, which aids understanding of neural coding mechanisms.