bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial deletion of TBK1 contributes to BRB dysfunction via CXCR4 phosphorylation suppression
Authors: Zhao Bowen , Ni Yueqi , Zhang Hong , Zhao Yin , Li Lu
Published: October 2022

Blood-retinal barrier (BRB) dysfunction has been recognized as an early pathological feature in common eye diseases that cause blindness. The breakdown of endothelial cell-to-cell junctions is the main reason for BRB dysfunction, yet our understanding of junctional modulation remains limited. Here, we demonstrated that endothelial-specific deletion of TBK1 (Tbk1ΔEC) disrupted retinal vascular development, and induced vascular leakage. LC-MS/MS proteomic analysis was used to identify candidate substrates of TBK1. We found that TBK1 interacted with CXCR4, and the phosphorylation level of CXCR4-Serine 355 (Ser355) was decreased inTbk1ΔECretina samples. Furthermore, TBK1-mediated phosphorylation of CXCR4 at Ser355 played an indispensable role in maintaining endothelial junctions. Interestingly, we also detected an increased expression of TBK1 in diabetic retinopathy samples, which suggested an association between TBK1 and the disease. Taken together, these results provided insight into the mechanisms involved in the regulation of endothelial cell-to-cell junctions via TBK1-dependent CXCR4 phosphorylation.
Dearomatization of aromatic asmic isocyanides to complex cyclohexadienes
Authors: Altundas Bilal , Alwedi Embarek , Song Zhihui , Gogoi Achyut Ranjan , Dykstra Ryan , Gutierrez Osvaldo , Fleming Fraser F.
Published: October 2022

A dearomatization-dislocation-coupling cascade rapidly transforms aromatic isocyanides into highly functionalized cyclohexadienes. The facile cascade installs an exceptional degree of molecular complexity: three carbon-carbon bonds, two quaternary stereocenters, and three orthogonal functionalities, a cyclohexadiene, a nitrile, and an isocyanide. The tolerance of arylisocyanides makes the method among the mildest dearomatizations ever reported, typically occurring within minutes at −78 °C. Experimental and computational analyses implicate an electron transfer-initiated mechanism involving an unprecedented isocyanide rearrangement followed by radical-radical anion coupling. The dearomatization is fast, proceeds via a complex cascade mechanism supported by experimental and computational insight, and provides complex, synthetically valuable cyclohexadienes.
Improving public support for climate action through multilateralism
Authors: Bechtel Michael M. , Scheve Kenneth F. , van Lieshout Elisabeth
Published: October 2022

For decades, policymakers have been attempting to negotiate multilateral climate agreements. One of the motivations for securing cooperation among multiple states is the belief that the public will be more supportive of adopting costly climate policies if other countries do so, both because this makes it more likely that important sustainability goals will be reached and because those efforts resonate with widely held fairness norms. However, some recent research suggests that public approval of climate action is independent of the policy choices made by other countries. Here, we present two different experimental studies fielded in multiple countries showing that multilateralism significantly increases public approval of costly climate action. Multilateralism makes climate policy more appealing by improving effectiveness beliefs and the policy’s perceived fairness. Pursuing climate action within a multilateral setting does not only promise improved policy impacts, but may also generate higher levels of public support. Preregistration: This study has been pre-registered at AEA RCT Registry under #AEARCTR-0004090.
Nebulized fusion inhibitory peptide protects cynomolgus macaques from measles virus infection
Authors: Reynard Olivier , Gonzalez Claudia , Dumont Claire , Iampietro Mathieu , Ferren Marion , Le Guellec Sandrine , Laurie Lajoie , Mathieu Cyrille , Carpentier Gabrielle , Roseau Georges , Bovier Francesca T. , Zhu Yun , Le Pennec Deborah , Montharu Jérome , Addetia Amin , Greninger Alexander L. , Alabi Christopher A. , Brisebard Elise , Moscona Anne , Vecellio Laurent , Porotto Matteo , Horvat Branka
Published: October 2022

Measles is the most contagious airborne viral infection and the leading cause of child death among vaccine-preventable diseases. We show here that aerosolized lipopeptide fusion inhibitor, derived from heptad-repeat regions of the measles virus (MeV) fusion protein, blocks respiratory MeV infection in a non-human primate model, the cynomolgus macaque. We use a custom-designed mesh nebulizer to ensure efficient aerosol delivery of peptide to the respiratory tract and demonstrate the absence of adverse effects and lung pathology in macaques. The nebulized peptide efficiently prevents MeV infection, resulting in the complete absence of MeV RNA, MeV-infected cells, and MeV-specific humoral responses in treated animals. This strategy provides an additional means to fight against respiratory infection in non-vaccinated people, that can be readily translated to human trials. It presents a proof-of-concept for the aerosol delivery of fusion inhibitory peptides to protect against measles and other airborne viruses, including SARS-CoV-2, in case of high-risk exposure.
A doxycycline- and light-inducible Cre recombinase mouse model for optogenetic genome editing
Authors: Vizoso Miguel , E. J. Pritchard Colin , Bombardelli Lorenzo , van den Broek Bram , Krimpenfort Paul , Beijersbergen Roderick L. , Jalink Kees , van Rheenen Jacco
Published: October 2022

The experimental need to engineer the genome both in time and space, has led to the development of several photoactivatable Cre recombinase systems. However, the combination of inefficient and non-intentional background recombination has prevented thus far the wide application of these systems in biological and biomedical research. Here, we engineer an optimized photoactivatable Cre recombinase system that we refer to as doxycycline- and light-inducible Cre recombinase (DiLiCre). Following extensive characterization in cancer cell and organoid systems, we generate a DiLiCre mouse line, and illustrated the biological applicability of DiLiCre for light-induced mutagenesis in vivo and positional cell-tracing by intravital microscopy. These experiments illustrate how newly formed HrasV12 mutant cells follow an unnatural movement towards the interfollicular dermis. Together, we develop an efficient photoactivatable Cre recombinase mouse model and illustrate how this model is a powerful genome-editing tool for biological and biomedical research.
Non-classical correlations over 1250 modes between telecom photons and 979-nm photons stored in 171Yb3+:Y2SiO5
Authors: Businger M. , Nicolas L. , Mejia T. Sanchez , Ferrier A. , Goldner P. , Afzelius Mikael
Published: October 2022

Quantum repeaters based on heralded entanglement require quantum nodes that are able to generate multimode quantum correlations between memories and telecommunication photons. The communication rate scales linearly with the number of modes, yet highly multimode quantum storage remains challenging. In this work, we demonstrate an atomic frequency comb quantum memory with a time-domain mode capacity of 1250 modes and a bandwidth of 100 MHz. The memory is based on a Y2SiO5 crystal doped with 171Yb3+ ions, with a memory wavelength of 979 nm. The memory is interfaced with a source of non-degenerate photon pairs at 979 and 1550 nm, bandwidth-matched to the quantum memory. We obtain strong non-classical second-order cross correlations over all modes, for storage times of up to 25 μs. The telecommunication photons propagated through 5 km of fiber before the release of the memory photons, a key capability for quantum repeaters based on heralded entanglement and feed-forward operations. Building on this experiment should allow distribution of entanglement between remote quantum nodes, with enhanced rates owing to the high multimode capacity.
A toxin-deformation dependent inhibition mechanism in the T7SS toxin-antitoxin system of Gram-positive bacteria
Authors: Wang Yongjin , Zhou Yang , Shi Chaowei , Liu Jiacong , Lv Guohua , Huang Huisi , Li Shengrong , Duan Liping , Zheng Xinyi , Liu Yue , Zhou Haibo , Wang Yonghua , Li Zhengqiu , Ding Ke , Sun Pinghua , Huang Yun , Lu Xiaoyun , Zhang Zhi-Min
Published: October 2022

Toxin EsaD secreted by some S. aureus strains through the type VII secretion system (T7SS) specifically kills those strains lacking the antitoxin EsaG. Here we report the structures of EsaG, the nuclease domain of EsaD and their complex, which together reveal an inhibition mechanism that relies on significant conformational change of the toxin. To inhibit EsaD, EsaG breaks the nuclease domain of EsaD protein into two independent fragments that, in turn, sandwich EsaG. The originally well-folded ββα-metal finger connecting the two fragments is stretched to become a disordered loop, leading to disruption of the catalytic site of EsaD and loss of nuclease activity. This mechanism is distinct from that of the other Type II toxin-antitoxin systems, which utilize an intrinsically disordered region on the antitoxins to cover the active site of the toxins. This study paves the way for developing therapeutic approaches targeting this antagonism.
The emergence and development of behavioral individuality in clonal fish
Authors: Laskowski Kate L. , Bierbach David , Jolles Jolle W. , Doran Carolina , Wolf Max
Published: October 2022

Behavioral individuality is a ubiquitous phenomenon in animal populations, yet the origins and developmental trajectories of individuality, especially very early in life, are still a black box. Using a high-resolution tracking system, we mapped the behavioral trajectories of genetically identical fish (Poecilia formosa), separated immediately after birth into identical environments, over the first 10 weeks of their life at 3 s resolution. We find that (i) strong behavioral individuality is present at the very first day after birth, (ii) behavioral differences at day 1 of life predict behavior up to at least 10 weeks later, and (iii) patterns of individuality strengthen gradually over developmental time. Our results establish a null model for how behavioral individuality can develop in the absence of genetic and environmental variation and provide experimental evidence that later-in-life individuality can be strongly shaped by factors pre-dating birth like maternal provisioning, epigenetics and pre-birth developmental stochasticity.
Structures of the CcmABCD heme release complex at multiple states
Authors: Li Jiao , Zheng Wan , Gu Ming , Han Long , Luo Yanmei , Yu Koukou , Sun Mengxin , Zong Yuliang , Ma Xiuxiu , Liu Bing , Lowder Ethan P. , Mendez Deanna L. , Kranz Robert G. , Zhang Kai , Zhu Jiapeng
Published: October 2022

Cytochromes c use heme as a cofactor to carry electrons in respiration and photosynthesis. The cytochrome c maturation system I, consisting of eight membrane proteins (CcmABCDEFGH), results in the attachment of heme to cysteine residues of cytochrome c proteins. Since all c-type cytochromes are periplasmic, heme is first transported to a periplasmic heme chaperone, CcmE. A large membrane complex, CcmABCD has been proposed to carry out this transport and linkage to CcmE, yet the structural basis and mechanisms underlying the process are unknown. We describe high resolution cryo-EM structures of CcmABCD in an unbound form, in complex with inhibitor AMP-PNP, and in complex with ATP and heme. We locate the ATP-binding site in CcmA and the heme-binding site in CcmC. Based on our structures combined with functional studies, we propose a hypothetic model of heme trafficking, heme transfer to CcmE, and ATP-dependent release of holoCcmE from CcmABCD. CcmABCD represents an ABC transporter complex using the energy of ATP hydrolysis for the transfer of heme from one binding partner (CcmC) to another (CcmE).
Natural variation of Dt2 determines branching in soybean
Authors: Liang Qianjin , Chen Liyu , Yang Xia , Yang Hui , Liu Shulin , Kou Kun , Fan Lei , Zhang Zhifang , Duan Zongbiao , Yuan Yaqin , Liang Shan , Liu Yucheng , Lu Xingtong , Zhou Guoan , Zhang Min , Kong Fanjiang , Tian Zhixi
Published: October 2022

Shoot branching is fundamentally important in determining soybean yield. Here, through genome-wide association study, we identify one predominant association locus on chromosome 18 that confers soybean branch number in the natural population. Further analyses determine that Dt2 is the corresponding gene and the natural variations in Dt2 result in significant differential transcriptional levels between the two major haplotypes. Functional characterization reveals that Dt2 interacts with GmAgl22 and GmSoc1a to physically bind to the promoters of GmAp1a and GmAp1d and to activate their transcription. Population genetic investigation show that the genetic differentiation of Dt2 display significant geographic structure. Our study provides a predominant gene for soybean branch number and may facilitate the breeding of high-yield soybean varieties.
The gate injection-based field-effect synapse transistor with linear conductance update for online training
Authors: Seo Seokho , Kim Beomjin , Kim Donghoon , Park Seungwoo , Kim Tae Ryong , Park Junkyu , Jeong Hakcheon , Park See-On , Park Taehoon , Shin Hyeok , Kim Myung-Su , Choi Yang-Kyu , Choi Shinhyun
Published: October 2022

Neuromorphic computing, an alternative for von Neumann architecture, requires synapse devices where the data can be stored and computed in the same place. The three-terminal synapse device is attractive for neuromorphic computing due to its high stability and controllability. However, high nonlinearity on weight update, low dynamic range, and incompatibility with conventional CMOS systems have been reported as obstacles for large-scale crossbar arrays. Here, we propose the CMOS compatible gate injection-based field-effect transistor employing thermionic emission to enhance the linear conductance update. The dependence of the linearity on the conduction mechanism is examined by inserting an interfacial layer in the gate stack. To demonstrate the conduction mechanism, the gate current measurement is conducted under varying temperatures. The device based on thermionic emission achieves superior synaptic characteristics, leading to high performance on the artificial neural network simulation as 93.17% on the MNIST dataset.
Synthesis of N-acyl sulfenamides via copper catalysis and their use as S-sulfenylating reagents of thiols
Authors: Bai Ziqian , Zhu Shiyang , Hu Yiyao , Yang Peng , Chu Xin , He Gang , Wang Hao , Chen Gong
Published: October 2022

Sulfur–heteroatom bonds such as S–S and S–N are found in a variety of natural products and often play important roles in biological processes. Despite their widespread applications, the synthesis of sulfenamides, which feature S–N bonds that may be cleaved under mild conditions, remains underdeveloped. Here, we report a method for synthesis ofN-acyl sulfenamides via copper-catalyzed nitrene-mediatedS-amidation reaction of thiols with dioxazolones. This method is efficient, convenient, and broadly applicable. Moreover, the resultingN-acetyl sulfenamides are highly effectiveS-sulfenylation reagents for the synthesis of unsymmetrical disulfides under mild conditions. TheS-sulfenylation protocol enables facile access to sterically demanding disulfides that are difficult to synthesize by other means.
Dense dislocations enable high-performance PbSe thermoelectric at low-medium temperatures
Authors: Xu Liqing , Xiao Yu , Wang Sining , Cui Bo , Wu Di , Ding Xiangdong , Zhao Li-Dong
Published: October 2022

PbSe-based thermoelectric materials exhibit promising ZT values at medium temperature, but its near-room-temperature thermoelectric properties are overlooked, thus restricting its average ZT (ZTave) value at low-medium temperatures. Here, a high ZTave of 0.90 at low temperature (300–573 K) is reported in n-type PbSe-based thermoelectric material (Pb1.02Se0.72Te0.20S0.08−0.3%Cu), resulting in a large ZTave of 0.96 at low-medium temperatures (300–773 K). This high thermoelectric performance stems from its ultralow lattice thermal conductivity caused by dense dislocations through heavy Te/S alloying and Cu interstitial doping. The dislocation density evaluated by modified Williamson-Hall method reaches up to 5.4 × 1016 m−2 in Pb1.02Se0.72Te0.20S0.08−0.3%Cu. Moreover, the microstructure observation further uncloses two kinds of dislocations, namely screw and edge dislocations, with several to hundreds of nanometers scale in length. These dislocations in lattice can strongly intensify phonon scattering to minimize the lattice thermal conductivity and simultaneously maintain high carrier transport. As a result, with the reduced lattice thermal conductivity and optimized power factor in Pb1.02Se0.72Te0.20S0.08−0.3%Cu, its near-room-temperature thermoelectric performance is largely enhanced and exceeds previous PbSe-based thermoelectric materials.
The ex vivo human translaminar autonomous system to study spaceflight associated neuro-ocular syndrome pathogenesis
Authors: Peng Michael , Curry Stacy M. , Liu Yang , Lohawala Husain , Sharma Gaurav , Sharma Tasneem P.
Published: October 2022

Spaceflight-Associated Neuro-ocular Syndrome (SANS) is a significant unexplained adverse reaction to long-duration spaceflight. We employ an ex vivo translaminar autonomous system (TAS) to recreate a human ocular ground-based spaceflight analogue model to study SANS pathogenesis. To recapitulate the human SANS conditions, human ocular posterior segments are cultured in the TAS model for 14 days. Translaminar pressure differentials are generated by simulating various flow rates within intracranial pressure (ICP) and intraocular (IOP) chambers to maintain hydrostatic pressures of ICP: IOP (12:16, 15:16, 12:21, 21:16 mmHg). In addition, optic nerves are mechanically kinked by 6- and 10-degree tilt inserts for the ICP: IOP;15:16 mmHg pressure paradigm. The TAS model successfully maintains various pressure differentials for all experimental groups over 14 days. Post culture, we determine inflammatory and extracellular component expression changes within posterior segments. To further characterize the SANS pathogenesis, axonal transport capacity, optic nerve degeneration and retinal functional are measured. Identifiable pathogenic alterations are observed in posterior segments by morphologic, apoptotic, and inflammatory changes including transport and functional deficits under various simulated SANS conditions. Here we report our TAS model provides a unique preclinical application system to mimic SANS pathology and a viable therapeutic testing device for countermeasures.
An integrated learning algorithm for early prediction of melon harvest
Authors: Qian Chunyang , Du Taihang , Sun Shuguang , Liu Wei , Zheng Haiguang , Wang Jianchun
Published: October 2022

Different modeling techniques must be applied to manage production and statistical estimation to predict the expected harvest. By calculating advanced production methods and the rational valuation of different factors, we can accurately capture the variety of growth characteristics and the expected yield. This paper obtained 32 feature variables related to melons, including phenological features, shape features, and color features. The Gradient Boosted Decision Tree (GBDT) network and the Grid Search (GS) hyperparameter seeking method was applied to calculate the degree of importance of all melon fruits' characteristics and construct prediction models for three expected harvest indexes of melon yield, sugar content, and endocarp hardness. To facilitate growers to carry out prediction and estimation in the field without destroying the melon fruits. The reduced feature variables were selected as inputs. The GBDT model was used to provide a significant advantage in prediction compared to both Random Forest (RF) and Support Vector Regression (SVR) methods. In addition, to verify the feasibility of using only reduced feature variables as input for the evaluation work, this study also compares the predictive effects of the model when all feature variables and only reduced feature variables are used. The GBDT prediction model proposed in this paper predicted melon yield, sugar content, and hardness using reduced features as input, and the model R2 could reach more than 90%. Therefore, this method can effectively help growers carry out early non-destructive inspection and growth prediction of melons in the field.
The impact of esophageal device insertion on cuff pressure of endotracheal tube: a literature review and meta-analysis
Authors: Hung Kuo-Chuan , Chang Ying-Jen , Chang Yang-Pei , Ho Chun-Ning , Lan Kuo-Mao , Chen Jen-Yin , Wang Li-Kai , Huang Ping-Wen , Sun Cheuk-Kwan
Published: October 2022

The impact of intraoperative esophageal device insertion (EDI) on endotracheal tube (ET) cuff inflation pressure remains unclear. Electronic databases including Medline, Embase, Google scholar, Web of Science™ and Cochrane Central Register of Controlled Trials were searched for studies involving EDI after placement of ETs from inception to July 7, 2022. The primary outcome was risk of high cuff pressure, while the secondary outcomes were increases in cuff pressure following EDI. Difference between adults and children was investigated with subgroup analysis. There were ten eligible studies (observation study, n = 9, randomized controlled study, n = 1) involving a total of 468 participants. EDI notably increased the risk of high cuff pressure (n = 7, risk ratio: 12.82, 95% confidence interval: 4.9 to 33.52, subgroup analysis:p = 0.008). There were significant elevations in cuff pressure in adults and children both during (13.42 and 7.88 cmH2O, respectively, subgroup analysis:p = 0.15) and after (10.09 and 3.99 cmH2O, respectively, subgroup analysis:p = 0.0003) EDI. Our results revealed an over 12-fold increase in the risk of high endotracheal tube cuff pressure in patients, especially adults, receiving EDI under endotracheal anesthesia. There were significant increases in both adults and children despite a higher increase in the former after device insertion.
High prevalence of chronic kidney disease and its related risk factors in rural areas of Northeast Thailand
Authors: Cha’on Ubon , Tippayawat Patcharaporn , Sae-ung Nattaya , Pinlaor Porntip , Sirithanaphol Wichien , Theeranut Ampornpan , Tungsanga Kriang , Chowchuen Prathana , Sharma Amod , Boonlakron Supakit , Anutrakulchai Sirirat
Published: October 2022

In Thailand, chronic kidney disease (CKD) screening was reported in 2009 with an overall prevalence of 17.5% and the highest at 22.2% in the northeastern region. This study aimed to find out CKD prevalence of the Kidney Disease Improving Global Outcomes criteria and their related risk factors in the rural community. A population-based study was conducted in the rural sub-districts of northeastern Thailand. Data of socio-demographic status, lifestyle, underlying diseases, blood pressure, and body mass index were recorded. Blood and urine analysis was conducted along with ultrasonography of kidneys. Specimen collection and analyses were repeated after 3 months, and the factors associated with CKD were studied by logistic regression analysis. A total of 2205 participants with a mean age of 57.8 ± 11.7 years and female predominance (66.7%) completed the study. The prevalence of CKD was 26.8%, i.e., stages 1 (7.3%); stage 2 (9.0%); stage 3a (6.0%); stage 3b (2.8%); stage 4 (1.4%); and stage 5 (0.3%). Hypertension, diabetes mellitus, and renal stones were the major underlying diseases. Only 3.5% of the participants were aware of having CKD. An increase in age, male, unemployment, current smoking, diabetes, hypertension, underweight, anemia, hyperuricemia, and leukocytosis were significantly associated factors with the disease. The study revealed that CKD has developed as a significant public health problem in rural northeastern Thailand and one out of every four people has CKD. Therefore, early interventions are essential for the proper management and prevention of CKD.
Polygenic Health Index, General Health, and Pleiotropy: Sibling Analysis and Disease Risk Reduction
Authors: Widen Erik , Lello Louis , Raben Timothy G. , Tellier Laurent C. A. M. , Hsu Stephen D. H.
Published: October 2022

We construct a polygenic health index as a weighted sum of polygenic risk scores for 20 major disease conditions, including, e.g., coronary artery disease, type 1 and 2 diabetes, schizophrenia, etc. Individual weights are determined by population-level estimates of impact on life expectancy. We validate this index in odds ratios and selection experiments using unrelated individuals and siblings (pairs and trios) from the UK Biobank. Individuals with higher index scores have decreased disease risk across almost all 20 diseases (no significant risk increases), and longer calculated life expectancy. When estimated Disability Adjusted Life Years (DALYs) are used as the performance metric, the gain from selection among ten individuals (highest index score vs average) is found to be roughly 4 DALYs. We find no statistical evidence for antagonistic trade-offs in risk reduction across these diseases. Correlations between genetic disease risks are found to be mostly positive and generally mild. These results have important implications for public health and also for fundamental issues such as pleiotropy and genetic architecture of human disease conditions.
A systematic study of pulse and pulse reverse plating on acid copper bath for decorative and functional applications
Authors: Mariani Elena , Giurlani Walter , Bonechi Marco , Dell’Aquila Vincenzo , Innocenti Massimo
Published: October 2022

Today industrial electroplating is mainly carried out using direct current even if the use of modulated currents could offer greats opportunities. Adjusting the amplitude and length of the current’s pulses it is possible to control grain size, porosity and homogeneity of the deposits; the use of modulated currents could also decrease the environmental impact of deposition processes as they require a much lower percentage of organic additives. The aim of this work is to assess, through both theoretical and experimental investigation, how the deposition parameters affect the various characteristics of the deposit. We used a commercial acid copper bath for the depositions performing both pulse and reverse pulse sequences. The coatings have been characterised by estimating the deposition yield, homogeneity, hardness and reflectivity. Using pulsed currents, we obtained shinier and brighter films respect to those produced with stationary currents; the deposition efficiency was also improved. Bipolar currents, on the other hand, favour more homogeneous deposits over the entire deposition area, and are less affected by the edge effect.
TNF overexpression and dexamethasone treatment impair chondrogenesis and bone growth in an additive manner
Authors: Zhao Yunhan , Celvin Bettina , Denis Maria C. , Karagianni Niki , Aulin Cecilia , Zaman Farasat , Sävendahl Lars
Published: October 2022

Children with chronic inflammation are often treated with glucocorticoids (GCs) and many of them experience growth retardation. It is poorly understood how GCs interact with inflammatory cytokines causing growth failure as earlier experimental studies have been performed in healthy animals. To address this gap of knowledge, we used a transgenic mouse model where human TNF is overexpressed (huTNFTg) leading to chronic polyarthritis starting from the first week of age. Our results showed that femur bone length and growth plate height were significantly decreased in huTNFTg mice compared to wild type animals. In the growth plates of huTNFTg mice, increased apoptosis, suppressed Indian hedgehog, decreased hypertrophy, and disorganized chondrocyte columns were observed. Interestingly, the GC dexamethasone further impaired bone growth, accelerated chondrocyte apoptosis and reduced the number of chondrocyte columns in huTNFTg mice. We conclude that TNF and dexamethasone separately suppress chondrogenesis and bone growth when studied in an animal model of chronic inflammation. Our data give a possible mechanistic explanation to the commonly observed growth retardation in children with chronic inflammatory diseases treated with GCs.
Heterogeneity of treatment effect of interferon-β1b and lopinavir–ritonavir in patients with Middle East respiratory syndrome by cytokine levels
Authors: Arabi Yaseen M. , Asiri Ayed Y. , Assiri Abdullah M. , Abdullah Mashan L. , Aljami Haya A. , Balkhy Hanan H. , Al Jeraisy Majed , Mandourah Yasser , AlJohani Sameera , Al Harbi Shmeylan , Jokhdar Hani A. Aziz , Deeb Ahmad M. , Memish Ziad A. , Jose Jesna , Ghazal Sameeh , Al Faraj Sarah , Al Mekhlafi Ghaleb A. , Sherbeeni Nisreen Murad , Elzein Fatehi Elnour , Hayden Frederick G. , Fowler Robert A. , AlMutairi Badriah M. , Al-Dawood Abdulaziz , Alharbi Naif Khalaf
Published: October 2022

Animal and human data indicate variable effects of interferons in treating coronavirus infections according to inflammatory status and timing of therapy. In this sub-study of the MIRACLE trial (MERS-CoV Infection Treated with a Combination of Lopinavir–Ritonavir and Interferon β-1b), we evaluated the heterogeneity of treatment effect of interferon-β1b and lopinavir–ritonavir versus placebo among hospitalized patients with MERS on 90-day mortality, according to cytokine levels and timing of therapy. We measured plasma levels of 17 cytokines at enrollment and tested the treatment effect on 90-day mortality according to cytokine levels (higher versus lower levels using the upper tertile (67%) as a cutoff point) and time to treatment (≤ 7 days versus > 7 days of symptom onset) using interaction tests. Among 70 included patients, 32 received interferon-β1b and lopinavir–ritonavir and 38 received placebo. Interferon-β1b and lopinavir–ritonavir reduced mortality in patients with lower IL-2, IL-8 and IL-13 plasma concentrations but not in patients with higher levels (p-value for interaction = 0.09, 0.07, and 0.05, respectively) and with early but not late therapy (p = 0.002). There was no statistically significant heterogeneity of treatment effect according to other cytokine levels. Further work is needed to evaluate whether the assessment of inflammatory status can help in identifying patients with MERS who may benefit from interferon-β1b and lopinavir–ritonavir.

Trial registration: This is a sub-study of the MIRACLE trial (ClinicalTrials.gov number, NCT02845843).
Maternal pre-pregnancy obesity and offspring hyperactivity-inattention symptoms at 5 years in preterm and term children: a multi-cohort analysis
Authors: Dow Courtney , Lorthe Elsa , Marchand-Martin Laetitia , Galera Cédric , Tafflet Muriel , Ancel Pierre-Yves , Charles Marie-Aline , Heude Barbara
Published: October 2022

The objective of this study was to determine the relationship between maternal pre-pregnancy body mass index (BMI) and child hyperactivity-inattention symptoms (HIS) at 5 years, including preterm and term-born children, and to determine whether this association varied with gestational age. Maternal pre-pregnancy BMI and offspring HIS were assessed in 10,898 participants born ≥ 33 weeks of gestation from the ELFE cohort and 2646 children born between 23 and 34 weeks from the EPIPAGE 2 cohort. Reported pre-pregnancy weight (kg) and measured height (m) were collected from mothers at inclusion and used to classify BMI (kg/m2). Child HIS were evaluated using the Strengths and Difficulties Questionnaire around 5 years of age. Logistic regression estimated odds ratios (OR) of a high HIS score (≥ 90th percentile) in the ELFE cohort and generalized estimated equations were used in EPIPAGE 2 to account for non-independence of multiple births. As a negative control, paternal BMI was also considered as an exposure of interest in sensitivity analyses. Maternal pre-pregnancy obesity and overweight were associated with child HIS at 5 years in ELFE (adjusted OR [aOR] for obesity 1.27 [1.06, 1.53]; overweight aOR 1.16 [1.00, 1.36]) and pre-pregnancy obesity was associated with high HIS scores in preterm infants of EPIPAGE 2 (aOR 1.48 [1.06, 2.08]). In ELFE, the magnitude of the association increased with decreasing gestational age (interaction p = 0.02). High maternal pre-pregnancy BMI is associated with greater likelihood of high HIS scores in both at-term and preterm children at 5 years of age.
The Fitness-Corrected Block Model, or how to create maximum-entropy data-driven spatial social networks
Authors: Bernaschi Massimo , Celestini Alessandro , Guarino Stefano , Mastrostefano Enrico , Saracco Fabio
Published: October 2022

Models of networks play a major role in explaining and reproducing empirically observed patterns. Suitable models can be used to randomize an observed network while preserving some of its features, or to generate synthetic graphs whose properties may be tuned upon the characteristics of a given population. In the present paper, we introduce the Fitness-Corrected Block Model, an adjustable-density variation of the well-known Degree-Corrected Block Model, and we show that the proposed construction yields a maximum entropy model. When the network is sparse, we derive an analytical expression for the degree distribution of the model that depends on just the constraints and the chosen fitness-distribution. Our model is perfectly suited to define maximum-entropy data-driven spatial social networks, where each block identifies vertices having similar position (e.g., residence) and age, and where the expected block-to-block adjacency matrix can be inferred from the available data. In this case, the sparse-regime approximation coincides with a phenomenological model where the probability of a link binding two individuals is directly proportional to their sociability and to the typical cohesion of their age-groups, whereas it decays as an inverse-power of their geographic distance. We support our analytical findings through simulations of a stylized urban area.
The influence of riparian woody vegetation on bankfull alluvial river morphodynamics
Authors: Török Gergely T. , Parker Gary
Published: October 2022

Exploring the effects of bank vegetation on fluvial morphodynamics has long been an essential part of fluvial morphodynamic-related research. In a practical sense, a central question is: does increased vegetation density increase or decrease the channel width? Several aspects concerning the role of vegetation may result in examples of both width decrease and increase. In this study, we examined more than 170 alluvial river sections. Our goal was to detect the phenomena that ultimately determine riparian woody vegetation-induced width variation. We found that bed material is a governing factor. In the case of fine-grained material, i.e. median size D50 < 2 mm, increasingly densely forested riparian vegetation reduces the bankfull Shields number, and destabilizes the banks toward a wider bankfull channel. In the case of coarse-grained material (i.e. median size D50 ≥ 16 mm), the effect is the opposite; increased density is correlated with a higher bankfull Shields number and a narrower bankfull channel. The extent of the role of vegetation varies depending on the ratio of characteristic root zone depth to channel depth and channel width. We present an improved estimator for bankfull Shields number, which considers riparian vegetation density. The bankfull Shields number can be estimated up to 19% more accurately with our corrected estimator.
Wildtype heterogeneity contributes to clonal variability in genome edited cells
Authors: Westermann Lukas , Li Yong , Göcmen Burulca , Niedermoser Matthias , Rhein Kilian , Jahn Johannes , Cascante Isabel , Schöler Felix , Moser Niklas , Neubauer Björn , Hofherr Alexis , Behrens Yvonne Lisa , Göhring Gudrun , Köttgen Anna , Köttgen Michael , Busch Tilman
Published: October 2022

Genome editing tools such as CRISPR/Cas9 enable the rapid and precise manipulation of genomes. CRISPR-based genome editing has greatly simplified the study of gene function in cell lines, but its widespread use has also highlighted challenges of reproducibility. Phenotypic variability among different knockout clones of the same gene is a common problem confounding the establishment of robust genotype–phenotype correlations. Optimized genome editing protocols to enhance reproducibility include measures to reduce off-target effects. However, even if current state-of-the-art protocols are applied phenotypic variability is frequently observed. Here we identify heterogeneity of wild-type cells as an important and often neglected confounding factor in genome-editing experiments. We demonstrate that isolation of individual wild-type clones from an apparently homogenous stable cell line uncovers significant phenotypic differences between clones. Strikingly, we observe hundreds of differentially regulated transcripts (477 up- and 306 downregulated) when comparing two populations of wild-type cells. Furthermore, we show a variety of cellular and biochemical alterations in different wild-type clones in a range that is commonly interpreted as biologically relevant in genome-edited cells. Heterogeneity of wild-type cells thus contributes to variability in genome-edited cells when these are generated through isolation of clones. We show that the generation of monoclonal isogenic wild-type cells prior to genomic manipulation reduces phenotypic variability. We therefore propose to generate matched isogenic control cells prior to genome editing to increase reproducibility.
CRISPR-Cas9 Arabidopsis mutants of genes for ARPC1 and ARPC3 subunits of ARP2/3 complex reveal differential roles of complex subunits
Authors: Bellinvia Erica , García-González Judith , Cifrová Petra , Martinek Jan , Sikorová Lenka , Havelková Lenka , Schwarzerová Kateřina
Published: October 2022

Protein complex Arp2/3 has a conserved role in the nucleation of branched actin filaments. It is constituted of seven subunits, including actin-like subunits ARP2 and ARP3 plus five other subunits called Arp2/3 Complex Component 1 to 5, which are not related to actin. Knock-out plant mutants lacking individual plant ARP2/3 subunits have a typical phenotype of distorted trichomes, altered pavement cells shape and defects in cell adhesion. While knock-out mutant Arabidopsis plants for most ARP2/3 subunits have been characterized before, Arabidopsis plant mutants missing ARPC1 and ARPC3 subunits have not yet been described. Using CRISPR/Cas9, we generated knock-out mutants lacking ARPC1 and ARPC3 subunits. We confirmed that the loss of ARPC1 subunits results in the typical ARP2/3 mutant phenotype. However, the mutants lacking ARPC3 subunits resulted in plants with surprisingly different phenotypes. Our results suggest that plant ARP2/3 complex function in trichome shaping does not require ARPC3 subunit, while the fully assembled complex is necessary for the establishment of correct cell adhesion in the epidermis.
Identifying the impact of rainfall variability on conflicts at the monthly level
Authors: Coulibaly Thierry Yerema , Managi Shunsuke
Published: October 2022

Research on the relationship between rainfall variability and conflicts has yielded contradictory results. This study is the first to show that the significance of the impact of rainfall variability on conflicts depends on the temporal unit of analysis. We prove this point by comparing the statistical significance of the linkages between georeferenced conflicts and rainfall variabilities at the monthly and annual levels with panel data analyses from 1989 to 2020. We find that a 10 percent increase in monthly rainfall decreases the risk of conflict incidence by 0.0298 percent, but annual rainfall variability is not statistically linked to conflict outbreaks. These statistically significant disparities result from the aggregation of data dispersion and the disregard for the timing of the impact of rainfall on conflicts. These findings highlight the importance of information on monthly rainfall variation when estimating the impact of rainfall on conflicts.
Comparisons of quantitative approaches for assessing microglial morphology reveal inconsistencies, ecological fallacy, and a need for standardization
Authors: Green Tabitha R. F. , Murphy Sean M. , Rowe Rachel K.
Published: October 2022

Microglial morphology is used to measure neuroinflammation and pathology. For reliable inference, it is critical that microglial morphology is accurately quantified and that results can be easily interpreted and compared across studies and laboratories. The process through which microglial morphology is quantified is a key methodological choice and little is known about how this choice may bias conclusions. We applied five of the most commonly used ImageJ-based methods for quantifying the microglial morphological response to a stimulus to identical photomicrographs and individual microglial cells isolated from these photomicrographs, which allowed for direct comparisons of results generated using these approaches. We found a lack of comparability across methods that analyzed full photomicrographs, with significant discrepancies in results among the five methods. Quantitative methods to analyze microglial morphology should be selected based on several criteria, and combinations of these methods may give the most biologically accurate representation of microglial morphology.
On the morphology of electrostatic solitary waves in the Earth’s aurora
Authors: Varghese Steffy Sara , Singh Kuldeep , Kourakis Ioannis
Published: October 2022

Electrostatic solitary waves (ESWs) have been detected in abundance in Space plasma observations, both by satellites in near-Earth plasma environments as well as by planetary missions, e.g. Cassini in Saturn or MAVEN in Mars. In their usual form, these are manifested as a bipolar electric field corresponding to a bell-shaped pulse in the electrostatic potential. Recent studies have suggested the existence of alternative forms of ESWs, including flat-top solitary waves (FTSWs) and supersolitary waves (SSWs), both of which are often encountered in Space observations such as in polar cap boundary layer, the auroral acceleration region and elsewhere. This article focuses on the existence and characterization of different types of electrostatic solitary waves in multicomponent Space plasmas. Relying on a multi-fluid plasma model, comprising two types of ions and two different electron populations, we have identified the conditions for existence of flat-top solitary waves and supersolitons, in contrast to “standard" solitary waves. Both ion species are models as cold fluids, for simplicity. Our analysis reveals that the coexistence of the two electron populations is pivotal for the formation of such non-standard electrostatic structures, and that their characteristic parameters (temperature, density ratio) plays a decisive role in their generation and structural characteristics. Nonetheless, while supersolitary waves may exist in a wide range of parameter values (as confirmed by earlier theoretical studies), it appears that flat-top solitary waves will occur in a narrow window in the parameter region, which may explain their scarce (but non-negligible) frequency of observation. Our theoretical findings confirm and validate the existence of alternative (non-conventional) ESW waveforms in auroral plasma (in addition to the ubiquitous bipolar electric field form), where such an electron coexistence is typically observed.
Combinatorial gene targeting in primary human hematopoietic stem and progenitor cells
Authors: Bäckström Alexandra , Yudovich David , Žemaitis Kristijonas , Nilsén Falck Ludvig , Subramaniam Agatheeswaran , Larsson Jonas
Published: October 2022

The CRISPR/Cas9 system offers enormous versatility for functional genomics but many applications have proven to be challenging in primary human cells compared to cell lines or mouse cells. Here, to establish a paradigm for multiplexed gene editing in primary human cord blood-derived hematopoietic stem and progenitor cells (HSPCs), we used co-delivery of lentiviral sgRNA vectors expressing either Enhanced Green Fluorescent Protein (EGFP) or Kusabira Orange (KuO), together with Cas9 mRNA, to simultaneously edit two genetic loci. The fluorescent markers allow for tracking of either single- or double-edited cells, and we could achieve robust double knockout of the cell surface molecules CD45 and CD44 with an efficiency of ~ 70%. As a functional proof of concept, we demonstrate that this system can be used to model gene dependencies for cell survival, by simultaneously targeting the cohesin genes STAG1 and STAG2. Moreover, we show combinatorial effects with potential synergy for HSPC expansion by targeting the Aryl Hydrocarbon Receptor (AHR) in conjunction with members of the CoREST complex. Taken together, our traceable multiplexed CRISPR/Cas9 system enables studies of genetic dependencies and cooperation in primary HSPCs, and has important implications for modelling polygenic diseases, as well as investigation of the underlying mechanisms of gene interactions.
Live slow-frozen human tumor tissues viable for 2D, 3D, ex vivo cultures and single-cell RNAseq
Authors: Restivo Gaetana , Tastanova Aizhan , Balázs Zsolt , Panebianco Federica , Diepenbruck Maren , Ercan Caner , Preca Bodgan-T. , Hafner Jürg , Weber Walter P. , Kurzeder Christian , Vetter Marcus , Soysal Simone Münst , Beisel Christian , Bentires-Alj Mohamed , Piscuoglio Salvatore , Krauthammer Michael , Levesque Mitchell P.
Published: October 2022

Biobanking of surplus human healthy and disease-derived tissues is essential for diagnostics and translational research. An enormous amount of formalin-fixed and paraffin-embedded (FFPE), Tissue-Tek OCT embedded or snap-frozen tissues are preserved in many biobanks worldwide and have been the basis of translational studies. However, their usage is limited to assays that do not require viable cells. The access to intact and viable human material is a prerequisite for translational validation of basic research, for novel therapeutic target discovery, and functional testing. Here we show that surplus tissues from multiple solid human cancers directly slow-frozen after resection can subsequently be used for different types of methods including the establishment of 2D, 3D, and ex vivo cultures as well as single-cell RNA sequencing with similar results when compared to freshly analyzed material.
Affinity microfluidics enables high-throughput protein degradation analysis in cell-free extracts
Authors: Brio Lev , Wasserman Danit , Michaely-Barbiro Efrat , Barazany-Gal Gal , Gerber Doron , Tzur Amit
Published: October 2022

Protein degradation mediated by the ubiquitin-proteasome pathway regulates signaling events in many physiological and pathological conditions. In vitro degradation assays have been instrumental in the understanding of how cell proliferation and other fundamental cellular processes are regulated. These assays are direct, time-specific and highly informative but also laborious, typically relying on low-throughput polyacrylamide gel-electrophoresis followed by autoradiography or immunoblotting. We present protein degradation on chip (pDOC), a MITOMI-based integrated microfluidic technology for discovery and analysis of proteins degradation in cell-free extracts. The platform accommodates hundreds of microchambers on which protein degradation is assayed quickly, simultaneously and using minute amounts of reagents in one or many physiochemical environments. Essentially, pDOC provides a sensitive multiplex alternative to the conventional degradation assay, with relevance to biomedical and translational research associated with regulated proteolysis.