bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gi/o protein-coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation
Authors: Dickerson Matthew T. , Dadi Prasanna K. , Zaborska Karolina E. , Nakhe Arya Y. , Schaub Charles M. , Dobson Jordyn R. , Wright Nicole M. , Lynch Joshua C. , Scott Claire F. , Robinson Logan D. , Jacobson David A. 
Published: October 2022

AbstractGi/o-coupled somatostatin or α2-adrenergic receptor activation stimulated β-cell NKA activity, resulting in islet Ca2+ fluctuations. Furthermore, intra-islet paracrine activation of β-cell Gi/o-GPCRs and NKAs by δ-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. β-cell membrane potential hyperpolarization resulting from Gi/o-GPCR activation was dependent on NKA phosphorylation by Src tyrosine kinases. Whereas, β-cell NKA function was inhibited by cAMP-dependent PKA activity. These data reveal that NKA-mediated β-cell membrane potential hyperpolarization is the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion.
CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma
Authors: Houles Thibault , Lavoie Geneviève , Nourreddine Sami , Cheung Winnie , Vaillancourt-Jean Éric , Guérin Célia M. , Bouttier Mathieu , Grondin Benoit , Lin Sichun , Saba-El-Leil Marc K. , Angers Stephane , Meloche Sylvain , Roux Philippe P. 
Published: October 2022

AbstractMelanoma is the deadliest form of skin cancer and considered intrinsically resistant to chemotherapy. Nearly all melanomas harbor mutations that activate the RAS/mitogen-activated protein kinase (MAPK) pathway, which contributes to drug resistance via poorly described mechanisms. Herein we show that the RAS/MAPK pathway regulates the activity of cyclin-dependent kinase 12 (CDK12), which is a transcriptional CDK required for genomic stability. We find that melanoma cells harbor constitutively high CDK12 activity, and that its inhibition decreases the expression of long genes containing multiple exons, including many genes involved in DNA repair. Conversely, our results show that CDK12 inhibition promotes the expression of short genes with few exons, including many growth-promoting genes regulated by the AP-1 and NF-κB transcription factors. Inhibition of these pathways strongly synergize with CDK12 inhibitors to suppress melanoma growth, suggesting promising drug combinations for more effective melanoma treatment.
Automated identification of sequence-tailored Cas9 proteins using massive metagenomic data
Authors: Ciciani Matteo , Demozzi Michele , Pedrazzoli Eleonora , Visentin Elisabetta , Pezzè Laura , Signorini Lorenzo Federico , Blanco-Miguez Aitor , Zolfo Moreno , Asnicar Francesco , Casini Antonio , Cereseto Anna , Segata Nicola 
Published: October 2022

AbstractThe identification of the protospacer adjacent motif (PAM) sequences of Cas9 nucleases is crucial for their exploitation in genome editing. Here we develop a computational pipeline that was used to interrogate a massively expanded dataset of metagenome and virome assemblies for accurate and comprehensive PAM predictions. This procedure allows the identification and isolation of sequence-tailored Cas9 nucleases by using the target sequence as bait. As proof of concept, starting from the disease-causing mutation P23H in the RHO gene, we find, isolate and experimentally validate a Cas9 which uses the mutated sequence as PAM. Our PAM prediction pipeline will be instrumental to generate a Cas9 nuclease repertoire responding to any PAM requirement.
Understanding radiation-thermal aging of polydimethylsiloxane rubber through molecular dynamics simulation
Authors: Lou Weitao , Xie Chaoyang , Guan Xuefei 
Published: October 2022

AbstractThe effect of radiation-thermal aging on the structure and properties of polydimethylsiloxane (PDMS) rubber at the micro-scale was investigated through molecular dynamics simulation. The aged PDMS models were constructed by incorporating the aging-induced chemical changes (hydroxyl groups, cross-linking, and scission of main chain). The simulation results show that the introduction of hydroxyl groups and cross-linking in molecular chains lower the chain mobility and the diffusion of the chains and oxygen molecules owing to the strong intermolecular interactions and long-chain structure, respectively. The introduction of short chains caused by the scission of main chains can enhance the mobility, diffusion, and flexibility of the chains and the diffusion range of oxygen molecules, resulting in the decrease in the free volume and Tg. In addition, the hardening effect of cross-linking and the softening effect of scission of main chain collectively contribute to the degradation of mechanical properties of the PDMS rubber.
Associations between urban birth or childhood trauma and first-episode schizophrenia mediated by low IQ
Authors: Xie Min , Zhao Zhengyang , Dai Minhan , Wu Yulu , Huang Yunqi , Liu Yunjia , Tang Yiguo , Xiao Liling , Wei Wei , Zhang Guangya , Du Xiangdong , Li Chuanwei , Guo Wanjun , Ma Xiaohong , Deng Wei , Wang Qiang , Li Tao 
Published: October 2022

AbstractExposure to urban birth, childhood trauma, and lower Intelligence Quotient (IQ) were the most well-established risk factors for schizophrenia in developed countries. In developing countries, whether urban birth is a risk factor for schizophrenia and how these factors are related to one another remain unclear. This study aimed to investigate whether IQ mediates the relationship between urban birth or childhood trauma and first-episode schizophrenia (FES) in China. Birthplace, childhood trauma questionnaire (CTQ), and IQ were collected from 144 patients with FES and 256 healthy controls (HCs). Hierarchical logistic regression analysis was conducted to investigate the associations between birthplace, childhood trauma, IQ, and FES. Furthermore, mediation analysis was used to explore the mediation of IQ in the relationship between birthplace or childhood trauma and FES. After adjusting for age, sex and educational attainment, the final model identified urban birth (odds ratio (OR) = 3.15, 95% CI = 1.54, 6.44) and childhood trauma (OR = 2.79, 95% CI = 1.92, 4.06) were associated an elevated risk for FES. The 52.94% total effect of birthplace on the risk of FES could be offset by IQ (indirect effect/direct effect). The association between childhood trauma and FES could be partly explained by IQ (22.5%). In total, the mediation model explained 70.5% of the total variance in FES. Our study provides evidence that urban birth and childhood trauma are associated with an increased risk of FES. Furthermore, IQ mediates the relationship between urban birth or childhood trauma and FES.
Prognostic associations of cortical gyrification in minimally medicated schizophrenia in an early intervention setting
Authors: Yunzhi Pan , Chen Xudong , Chen Eric , Lee Edwin , Zhening Liu , Ouyang Xuan , Palaniyappan Lena 
Published: October 2022

AbstractThe aberration in cortical gyrification seen in schizophrenia likely originates in the earliest phase of life, as gyrification begins in utero and reaches its peak in infancy. However, emerging observations have indicated a later reduction in gyrification, especially in early adulthood, may also occur in schizophrenia. At present, it is unclear whether the baseline and later gyrification reduction has any prognostic importance in schizophrenia. We address this question in a longitudinal design in patients minimally medicated at inception. About 108 minimally medicated (duration of medication = <14 days of antipsychotics) patients and 106 healthy controls underwent structural magnetic resonance imaging, with 34 patients being selectively re-scanned when clinically stable following antipsychotic treatment. The cortical surface from each structural image was reconstructed, and the local gyrification index and cortical thickness were computed for each vertex on the surface. We found minimally medicated schizophrenia patients during the first episode had a relatively higher gyrification in bilateral supramarginal, left superior temporal, and right posterior cingulate and paracentral regions. However, poor prognostic features were more likely in patients with lower baseline gyrification. Longitudinal reductions in left superior parietal and right precentral gyrification were associated with lower improvements in both positive and negative symptoms over time. The spatial pattern of longitudinal changes in gyrification was distinct from the changes in cortical thickness. These results indicated that schizophrenia is characterized by a relative hypergyrification in parieto-temporal and medial cortical areas at a group level at first presentation, but poor outcomes relate to lower-gyrification elsewhere both at the onset and during the early course. The early post-onset reduction of gyrification is rather limited in space and magnitude, but occurs unrelated to the progressive thinning, representing a distinct, prognostically important structural trajectory.
Impaired dynamic functional brain properties and their relationship to symptoms in never treated first-episode patients with schizophrenia
Authors: You Wanfang , Luo Lekai , Yao Li , Zhao Youjin , Li Qian , Wang Yuxia , Wang Yaxuan , Zhang Qian , Long Fenghua , Sweeney John A. , Gong Qiyong , Li Fei 
Published: October 2022

AbstractStudies of dynamic functional connectivity (dFC) and topology can provide novel insights into the neurophysiology of brain dysfunction in schizophrenia and its relation to core symptoms of psychosis. Limited investigations of these disturbances have been conducted with never-treated first-episode patients to avoid the confounds of treatment or chronic illness. Therefore, we recruited 95 acutely ill, first-episode, never-treated patients with schizophrenia and examined brain dFC patterns relative to healthy controls using resting-state functional magnetic resonance imaging and a sliding-window approach. We compared the dynamic attributes at the group level and found patients spent more time in a hypoconnected state and correspondingly less time in a hyperconnected state. Patients demonstrated decreased dynamics of nodal efficiency and eigenvector centrality (EC) in the right medial prefrontal cortex, which was associated with psychosis severity reflected in Positive and Negative Syndrome Scale ratings. We also observed increased dynamics of EC in temporal and sensorimotor regions. These findings were supported by validation analysis. To supplement the group comparison analyses, a support vector classifier was used to identify the dynamic attributes that best distinguished patients from controls at the individual level. Selected features for case-control classification were highly coincident with the properties having significant between-group differences. Our findings provide novel neuroimaging evidence about dynamic characteristics of brain physiology in acute schizophrenia. The clinically relevant atypical pattern of dynamic shifting between brain states in schizophrenia may represent a critical aspect of illness pathophysiology underpinning its defining cognitive, behavioral, and affective features.
The trophic niche of subterranean populations of Speleomantes italicus
Authors: Lunghi Enrico , Cianferoni Fabio , Corti Claudia , Zhao Yahui , Manenti Raoul , Ficetola Gentile Francesco , Mancinelli Giorgio 
Published: October 2022

AbstractThe determination of a species trophic niche can clarify its functional role within a food web and how prey resources are used in relation with the spatial and temporal variability of environmental conditions. This information may result particularly useful for the implementation of conservation plans of endangered species having a cryptic behaviour or living in places difficult to be surveyed. Here we present the first long-term study on the trophic niche of the Italian cave salamanderSpeleomantes italicus, a strictly protected facultative cave species that seasonally exploits surface environments (e.g., forested areas) as well as both natural and artificial subterranean environments. We analysed the diet variation of six populations ofS. italicusinhabiting natural caves, surveyed 24 times in a full year. During the surveys, all sampled individuals were subjected to stomach flushing and the ingested prey were identified and enumerated; furthermore, salamanders’ body condition was also evaluated. The results of the analyses provided the first comprehensive, year-round assessment of the diet for aSpeleomantesspecies. Remarkable divergences in terms of trophic niche and body condition were observed between the studied populations. We found a discrepancy in the foraging activity of the populations located in different areas; specifically, the individuals that experienced sub-optimal microclimatic conditions poorly performed in foraging. Furthermore, we found temporal and spatial variability in the body condition of individuals. Our study highlighted a remarkably high spatial and temporal divergence in the trophic habits of conspecific populations, a feature that may represent one of the major factors promoting the variability of multiple population traits.
Prognostic significance of systemic inflammatory response markers in patients with superficial esophageal squamous cell carcinomas
Authors: Chen Chi-Jen , Lee Ching-Tai , Tsai Ying-Nan , Tseng Chao-Ming , Chen Tzu-Haw , Hsu Ming-Hung , Wang Chih-Chun , Wang Wen-Lun 
Published: October 2022

AbstractEndoscopic resection or esophagectomy has becoming the standard treatment for superficial esophageal squamous cell carcinomas (SESCC), but some patients may develop disease progression or second primary cancers after the therapies. Neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) reflect the balance between pro-cancer inflammatory and anti-cancer immune responses, however their roles in SESCC are still unknown. We consecutively enrolled patients with newly diagnosed SESCC (clinical stage Tis or T1N0M0) who were treated at our institute. Pre-treatment NLR, LMR and PLR were assessed and then correlated with clinical factors and long-term survival. A total of 156 patients were enrolled (152 males, 4 females; median age: 52.2 years), of whom 104 received endoscopic resection and 52 were treated with esophagectomy or chemoradiation.. During a mean follow-up period of 60.1 months, seventeen patients died of ESCCs, and 45 died of second primary cancers. The 5-year ESCC-specific survival and 5-year overall survival rate were 86% and 57%, respectively. LMR (P < 0.05) and NLR (P < 0.05), but not PLR were significantly correlated with overall survival. Receiver operating characteristic curve analysis showed optimal LMR and NLR cut-off values of 4 and 2.5, respectively, to predict a poor prognosis. Patients with a high NLR or low LMR tended to have longer tumor length, larger circumferential extension, and presence of second primary cancers. Multivariate Cox regression analysis showed that presence of second primary cancers (HR: 5.05, 95%CI: 2.75–9.28), low LMR (HR: 2.56, 95%CI: 1.09–6.03) were independent risk factors for poor survival. A low pre-treatment LMR may be a non-invasive pretreatment predictor of poor prognosis to guide the surveillance program, suggesting that anti-cancer immunity may play a role in the early events of esophageal squamous cancer.
Photocatalytic aerobic oxidative functionalization (PAOF) reaction of benzyl alcohols by GO-MIL-100(Fe) composite in glycerol/K2CO3 deep eutectic solvent
Authors: Abbasi Sepideh , Naimi-Jamal Mohammad Reza , Javanshir Shahrzad , Heydari Akbar 
Published: October 2022

AbstractAn MIL-100 (Fe)/graphene oxide (GO) hybrid, a fairly-known composite, was made through a simple one-step procedure and played a highlighted role in the photo-induced oxidative functionalization of the benzylic C–H bond. To identify the given binary composite, various techniques were applied: FT-IR, P-XRD, SEM, nitrogen absorption–desorption analysis, TGA, TEM, and UV–Visible DRS spectra. Proportions of GO used within the structure of the prepared composite differently ranged from low to high amount, and the most optimized ratio met at 38.5% of GO as the most efficient catalyst. Additionally, the reaction ran in Glycerol/K2CO3 (2:1) as the optimal solvent. The elemental roles of O2·− and OH− were supposed to be the major ones for running a tandem oxidation-Knoevenagel reaction. The heterogeneity and reusability of the catalyst were also examined and confirmed after five successive runs.
Analog and RF performance optimization for gate all around tunnel FET using broken-gap material
Authors: Kumar Pankaj , Koley Kalyan , Mech Bhubon C. , Maurya Ashish , Kumar Subindu 
Published: October 2022

AbstractMany times, the fabricated cylindrical gate-all-around tunnel FET (GAA TFET) has an uneven radius due to several etching and deposition processes involved while fabricating the device, which show notable variations in the performance of the device. In this report, III–V uneven GAA TFET is studied by considering the uneven radius as elliptical in shape for all possible variations, which shows a significant impact on analog and RF figure of merits (FOMs). The performance of the optimized devices is compared with their circular structure and with their maximum deviation in elliptical geometry for all possible variations in device channel and gate oxide. The variations in its device channel and gate oxide have shown a significant impact on the performance of the device. The analog and RF FOMs are studied, including the transconductance generation factor (gm/IDS), intrinsic gain (gmRO), capacitances (CGS, CGD), cut-off frequency (fT), and gate delay (τm).
Coupling phenotypic changes to extinction and survival in an endemic prey community threatened by an invasive snake
Authors: Piquet Julien C. , Maestresalas Borja , López-Darias Marta 
Published: October 2022

AbstractWhen facing novel invasive predators, native prey can either go extinct or survive through exaptation or phenotypic shifts (either plastic or adaptive). Native prey can also reflect stress-mediated responses against invasive predators, affecting their body condition. Although multiple native prey are likely to present both types of responses against a single invader, community-level studies are infrequent. The invasive California kingsnake (Lampropeltis californiae) a good example to explore invasive predators’ effects on morphology and body condition at a community level, as this invader is known to locally extinct the Gran Canaria giant lizard (Gallotia stehlini) and to notably reduce the numbers of the Gran Canaria skink (Chalcides sexlineatus) and the Boettger’s gecko (Tarentola boettgeri). By comparing a set of morphological traits and body condition (i.e. body index and ectoparasite load) between invaded and uninvaded areas for the three squamates, we found clear evidence of a link between a lack of phenotypic change and extinction, asG. stehliniwas the single native prey that did not show morphological shifts. On the other side, survivingC. sexlineatusandT. boettgeriexhibited phenotypic differences in several morphological traits that could reflect plastic responses that contribute to their capacity to cope with the snake. Body condition responses varied among species, indicating the potential existence of simultaneous consumptive and non-consumptive effects at a community level. Our study further highlights the importance addressing the impact of invasive predators from a community perspective in order to gain a deeper understanding of their effect in native ecosystems.
Quasi-experimental analysis of new mining developments as a driver of deforestation in Zambia
Authors: Morley Jonathan , Buchanan Graeme , Mitchard Edward T. A. , Keane Aidan 
Published: October 2022

AbstractMining is a vital part of the global, and many national, economies. Mining also has the potential to drive extensive land cover change, including deforestation, with impacts reaching far from the mine itself. Understanding the amount of deforestation associated with mining is important for conservationists, governments, mining companies, and consumers, yet accurate quantification is rare. We applied statistical matching, a quasi-experimental methodology, along with Bayesian hierarchical generalized linear models to assess the impact on deforestation of new mining developments in Zambia from 2000 to present. Zambia is a globally significant producer of minerals and mining contributes ~ 10% of its gross domestic product and ~ 77% of its exports. Despite extensive deforestation in mining impacted land, we found no evidence that any of the 22 mines we analysed increased deforestation compared with matched control sites. The extent forest lost was therefore no different than would likely have happened without the mines being present due to other drivers of deforestation in Zambia. This suggests previous assessments based on correlative methodologies may overestimate the deforestation impact of mining. However, mining can have a range of impacts on society, biodiversity, and the local environment that are not captured by our analysis.
Two-year outcomes of the APOLLON observational study of intravitreal aflibercept monotherapy in France in patients with diabetic macular edema
Authors: Korobelnik Jean-François , Daien Vincent , Faure Céline , Tadayoni Ramin , Giocanti-Aurégan Audrey , Dot Corinne , Kodjikian Laurent , Massin Pascale ,   the APOLLON study investigators, Faure Céline , Tadayoni Ramin , Giocanti-Aurégan Audrey , Dot Corinne , Kodjikian Laurent , Massin Pascale , Abada Samir , Akesbi Jad , Akninb Isabelle , Alfonsi Nicolas , Allieu Sandrine , Arndt Carl , Atmani Karim , Baillif Stephanie , Benouaich Xavier , Benzerroug Mounir , Béral Laurence , Bodaghi Barham , Bonicel Pierre , Bourhis Alexandre , Cartry Guilhem , Chiambaretta Frédéric , Chiquet Christophe , Creuzot-Garcher Catherine , Darugar Adil , De Bats Flore , Delyfer Marie-Noelle , Di Nolfo Michel , Dominguez Marcel , Dugas Brice , Genevois Olivier , Guyomarch Jérôme , Halfon Jérémie , Hera Ruxandra , Jankowski Olivier , Klinger Valérie , Koch Edouard , Laib Soumia , Le Lez Marie-Laure , Lebreton Olivier , Lecleire-Collet Amélie , Marc Caroline , Margescu Victor , Mauget-Faÿsse Martine , Milazzo Solange , Montcriol Anne-Lise , Nefzaoui Chaker , Oubraham Hassiba , Plavosin Paul , Rebollo Olivier , Ribstein Gilles , Righini Maud , Rothschild Pierre-Raphaël , Rumen Franck , Rysanek Boris , Saleh Maher , Sampo Magali , Schauer Philippe , Scheer Sarah , Theron Jean-Philippe , Zerbib Jennyfer 
Published: October 2022

AbstractAPOLLON (NCT02924311) was a prospective observational study to evaluate the effectiveness of intravitreal aflibercept (IVT-AFL) treatment of diabetic macular edema (DME) over 24 months in routine clinical practice in France. The primary endpoint was mean change from baseline in best-corrected visual acuity (BCVA; Early Treatment Diabetic Retinopathy Study letters) by 12 months, and safety was monitored throughout the study. Of 402 patients enrolled across 61 participating clinics and hospitals in France, 168 patients were followed for at least 24 months and included in the effectiveness analyses (79 treatment-naïve and 89 previously treated). After 24 months of IVT-AFL treatment, the mean (± standard deviation [SD]) change in BCVA from baseline was + 6.5 (± 10.7) letters in treatment-naïve patients (p < 0.001) and + 1.6 (± 17.0) letters in previously treated patients (p = 0.415) from a baseline of 63.8 (± 13.6) and 60.5 (± 16.5) letters. The mean number of IVT-AFL treatments over 24 months was 11.3 (± 4.9) and 11.9 (± 4.7) for treatment-naïve and previously treated patients. This final analysis of the APOLLON study indicated that following 24 months of IVT-AFL treatment in routine clinical practice in France, treatment-naïve patients with DME achieved significant gains in visual acuity and previously treated patients maintained prior visual acuity gains.Trial registration number: NCT02924311.