bluuebunny/crossref_metadata_2025 huggingface dataset:
High and Variable Drag in a Sinuous Estuary With Intermittent Stratification
Authors: Bo Tong , Ralston David K. , Kranenburg Wouter M. , Geyer W. Rockwell , Traykovski Peter
Published: September 2021

In field observations from a sinuous estuary, the drag coefficient based on the momentum balance was in the range of , much greater than expected from bottom friction alone. also varied at tidal and seasonal timescales. was greater during flood tides than ebbs, most notably during spring tides. The ebb tide was negatively correlated with river discharge, while the flood tide showed no dependence on discharge. The large values of are explained by form drag from flow separation at sharp channel bends. Greater water depths during flood tides corresponded with increased values of , consistent with the expected depth dependence for flow separation, as flow separation becomes stronger in deeper water. Additionally, the strength of the adverse pressure gradient downstream of the bend apex, which is indicative of flow separation, correlated with during flood tides. While generally increased with water depth, decreased for the highest water levels that corresponded with overbank flow. The decrease in may be due to the inhibition of flow separation with flow over the vegetated marsh. The dependence of during ebbs on discharge corresponds with the inhibition of flow separation by a favoring baroclinic pressure gradient that is locally generated at the bend apex due to curvature‐induced secondary circulation. This effect increases with stratification, which increases with discharge. Additional factors may contribute to the high drag, including secondary circulation, multiple scales of bedforms, and shallow shoals, but the observations suggest that flow separation is the primary source.
Interannual Variability of the Latitude of Separation of the Brazil Current: Teleconnections and Oceanic Rossby Waves Propagation
Authors: Bodnariuk Nicolás , Simionato Claudia G. , Saraceno Martín , Osman Marisol , Diaz Leandro B.
Published: September 2021

The latitude of separation of the Brazil Current (LSBC) variability is analyzed with a view to unveiling the physical mechanisms that modulate the turning point of the Brazil Current at low frequencies. The global ocean reanalysis ORAP5.0 spanning the period 1979–2013 is employed for this purpose. Three characteristic periodicities of the LSBC variability are found on the basis of a Singular Spectrum Analysis: 2, 4 and 10 years. Lagged sea surface height (SSH) correlation maps relate these modulations to Rossby wave propagation. According to these maps, the biennial signal might be triggered by the Atlantic Niño and the Indian Ocean Dipole. In the last case, SSH anomalies propagate around the southern tip of Africa, connecting the Indian and Atlantic oceans. Correlation maps suggest that the 4‐year signal is triggered by both the Atlantic Niño and the ENSO in the equatorial Pacific Ocean. The ENSO‐related anomalies travel through the Indonesian Throughflow along the western Australian coast, where Rossby waves are excited. These anomalies propagate to the eastern coast of Madagascar and feed into the Agulhas Current, eventually leaking into the Atlantic basin. Finally, the decadal signal is associated to the leading mode of decadal variability of the South Pacific Ocean. SSH propagating patterns derived from ORAP5.0 data are also obtained with satellite altimetry during the overlapping period (1993–2013), which strengthens confidence in our results. The association of the LSCB modulations to characteristic climate variability modes suggests that the position of the LSCB could be predicted.
Retracted: True Gravity in Atmospheric Ekman Layer Dynamics
Authors: Chu Peter C.
Published: September 2021

True gravity is a three‐dimensional vector field, g(λ, φ, z) = igλ + jgφ + kgz, with (λ, φ, z) the (longitude, latitude, height) and (i, j, k) the corresponding unit vectors. The longitudinal‐latitudinal component of the true gravity, gh = igλ+jgφ, is neglected completely in meteorology through using the standard gravity (−g0k, g0 = 9.81 m/s2) or the effective gravity [−g(φ)K]. Here, k (or K) is normal to the Earth spherical (or ellipsoidal) surface. Such simplification of g(λ, φ, z) has never been challenged. This study uses the classical atmospheric Ekman layer dynamics as an example to illustrate the importance of gh. The standard gravity (−g0k) is replaced by the true gravity g in the classical atmospheric Ekman layer equation with a constant eddy viscosity (K) and a height‐dependent‐only density ρ(z) represented by an e‐folding stratification. New formulas for the Ekman spiral and Ekman pumping are obtained. The second derivative of the gravity disturbance (T), , causes the Ekman pumping in addition to the geostrophic vorticity (). With from the EIGEN‐6C4 static gravity model, and calculated from July sea level pressure (p) data from the Comprehensive Ocean‐Atmosphere Data Set, the global mean strength of the Ekman pumping over the world oceans is 3.69 cm s−1 due to gh, which is much larger than 0.33 cm s−1 due to the geostrophic vorticity. It implies the urgency to use the true gravity g(λ, φ, z) into atmospheric GCM and weather forecast although the results are obtained from specific density field and gravity model.
Divergent Responses of Dominant Forest Tree Species to Manipulated Canopy and Understory N Additions in Terms of Foliage Stoichiometric, Photosynthetic, and Hydraulic Traits
Authors: Zhang Zhenzhen , Zhao Ping , Ouyang Lei , Zhao Xiuhua , Zhu Liwei , Ni Guangyan
Published: September 2021

Nitrogen (N) deposition effects on the stoichiometric balance and photosynthetic and hydraulic couplings in subtropical forests has drawn wide attentions. The previously adopted understory application of N fertilization is criticized because it might ignore foliar N retention for different species. This paper reports a fertilizing application from the canopy (CAN) and under the canopy (UAN) in a phosphorus (P) limited ecosystem. Foliage stoichiometric, photosynthetic, and hydraulic traits of six dominant species were measured and analyzed. Both treatments equally enhanced foliage N and N/P, but not foliage P, who was highly species‐specific depending on tree height, which implied enhanced P limitation. Decreased isotope abundance of 15N (δ15N) that approaching to the level in the urea fertilizer under CAN suggested the existence of canopy retention of N. Besides, N response sensitivity of N, P and δ15N that positively related to tree height (H) under CAN indicated different exposure to the added N, which promoted stoichiometric imbalance among species. The photosynthetic traits represented by net photosynthesis (An) increased under both treatments. A divergent foliar photosynthetic and hydraulic traits variation was identified by significant decreased stomatal conductance (gs) and An/gs for CAN treatments, which induced the elevated isotope abundance of 13C (δ13C). Correspondingly, foliage hydraulic traits that shifted to water use efficiency axis were identified only under CAN in principal component analysis. Overall, our results proved that the canopy absorption and species heterogeneity should be considered regarding foliar safety versus efficiency trade‐off in response to nitrogen additions in the future.
A human antibody against human endothelin receptor type A that exhibits antitumor potency
Authors: Ju Man-Seok , Ahn Hye-Mi , Han Seong-Gu , Ko Sanghwan , Na Jung-Hyun , Jo Migyeong , Lim Chung Su , Ko Byoung Joon , Yu Yeon Gyu , Lee Won-Kyu , Kim Youn-Jae , Jung Sang Taek
Published: September 2021

Endothelin receptor A (ETA), a class A G-protein-coupled receptor (GPCR), is involved in the progression and metastasis of colorectal, breast, lung, ovarian, and prostate cancer. We overexpressed and purified human endothelin receptor type A in Escherichia coli and reconstituted it with lipid and membrane scaffold proteins to prepare an ETA nanodisc as a functional antigen with a structure similar to that of native GPCR. By screening a human naive immune single-chain variable fragment phage library constructed in-house, we successfully isolated a human anti-ETA antibody (AG8) exhibiting high specificity for ETA in the β-arrestin Tango assay and effective inhibitory activity against the ET-1-induced signaling cascade via ETA using either a CHO-K1 cell line stably expressing human ETA or HT-29 colorectal cancer cells, in which AG8 exhibited IC50 values of 56 and 51 nM, respectively. In addition, AG8 treatment repressed the transcription of inhibin βA and reduced the ETA-induced phosphorylation of protein kinase B and extracellular regulated kinase. Furthermore, tumor growth was effectively inhibited by AG8 in a colorectal cancer mouse xenograft model. The human anti-ETA antibody isolated in this study could be used as a potential therapeutic for cancers, including colorectal cancer.
Unraveling the physiological roles of retinoic acid receptor-related orphan receptor α
Authors: Lee Ji Min , Kim Hyunkyung , Baek Sung Hee
Published: September 2021

Retinoic acid receptor-related orphan receptor-α (RORα) is a member of the orphan nuclear receptor family and functions as a transcriptional activator in response to circadian changes. Circadian rhythms are complex cellular mechanisms regulating diverse metabolic, inflammatory, and tumorigenic gene expression pathways that govern cyclic cellular physiology. Disruption of circadian regulators, including RORα, plays a critical role in tumorigenesis and facilitates the development of inflammatory hallmarks. Although RORα contributes to overall fitness among anticancer, anti-inflammatory, lipid homeostasis, and circadian clock mechanisms, the molecular mechanisms underlying the mode of transcriptional regulation by RORα remain unclear. Nonetheless, RORα has important implications for pharmacological prevention of cancer, inflammation, and metabolic diseases, and understanding context-dependent RORα regulation will provide an innovative approach for unraveling the functional link between cancer metabolism and rhythm changes.
Gut microbiota involved in leptospiral infections
Authors: Xie Xufeng , Liu Jiuxi , Chen Xi , Zhang Shilei , Tang Ruibo , Wu Xiaoyu , Zhang Wenlong , Cao Yongguo
Published: September 2021

Leptospirosis is a re-emerging zoonotic disease worldwide. Intestinal bleeding is a common but neglected symptom in severe leptospirosis. The regulatory mechanism of the gut microbiota on leptospirosis is still unclear. In this study, we found that Leptospira interrogans infection changed the composition of the gut microbiota in mice. Weight loss and an increased leptospiral load in organs were observed in the gut microbiota-depleted mice compared with those in the control mice. Moreover, fecal microbiota transplantation (FMT) to the microbiota-depleted mice reversed these effects. The phagocytosis response and inflammatory response in bone marrow-derived macrophages and thioglycolate-induced peritoneal macrophages were diminished in the microbiota-depleted mice after infection. However, the phagocytosis response and inflammatory response in resident peritoneal macrophage were not affected in the microbiota-depleted mice after infection. The diminished macrophage disappearance reaction (bacterial entry into the peritoneum acutely induced macrophage adherence to form local clots and out of the fluid phase) led to an increased leptospiral load in the peritoneal cavity in the microbiota-depleted mice. In addition, the impaired capacity of macrophages to clear leptospires increased leptospiral dissemination in Leptospira-infected microbiota-depleted mice. Our study identified the microbiota as an endogenous defense against L. interrogans infection. Modulating the structure and function of the gut microbiota may provide new individualized preventative strategies for the control of leptospirosis and related spirochetal infections.
CHD1L prevents lipopolysaccharide-induced hepatocellular carcinomar cell death by activating hnRNP A2/B1-nmMYLK axis
Authors: Wang Guangliang , Zhang Xiaofeng , Cheng Wei , Mo Yanxuan , Chen Juan , Cao Zhiming , Chen Xiaogang , Cui Huiqin , Liu Shanshan , Huang Li , Liu Ming , Ma Lei , Ma Ning-Fang
Published: September 2021

Chromodomain helicase/ATPase DNA-binding protein 1-like gene (CHD1L) has been characterized to be a driver gene in hepatocellular carcinoma (HCC). However, the intrinsic connections between CHD1L and intestinal dysbacteriosis-related inflammation reaction in HCC progression remain incompletely understood. In this study, a specific correlation between CHD1L and nonmuscle isoform of myosin light chain kinase (nmMLCK/nmMYLK), a newly identified molecule associated NF-κB signaling transduction, was disclosed in HCC. CHD1L promotes nmMYLK expression and prevents lipopolysaccharide (LPS) induced tumor cell death. In vitro experiment demonstrated that overexpressed nmMYLK is essential for CHD1L to maintain HCC cell alive, while knocking down nmMYLK significantly attenuate the oncogenic roles of CHD1L. Mechanism analysis revealed that nmMYLK can prevent Caspase-8 from combining with MyD88, an important linker of TLRs signaling pathway, while, knocking down nmMYLK facilitate the MyD88 combines with Caspase-8 and lead to the proteolytic cascade of Caspase as well as the consequent cell apoptosis. Mechanism analysis showed that CHD1L promotes the nmMYLK expression potentially through upregulating the heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1) expression, which can bind to myosin light chain kinase (MYLK) pre-mRNA and lead to the regnant translation of nmMYLK. In summary, this work characterizes a previously unknown role of CHD1L in preventing LPS-induced tumor cell death through activating hnRNP A2/B1-nmMYLK axis. Further inhibition of CHD1L and its downstream signaling could be a novel promising strategy in HCC treatment.
Circular RNA hsa_circ_0043280 inhibits cervical cancer tumor growth and metastasis via miR-203a-3p/PAQR3 axis
Authors: Zhang Chunyu , Liu Pan , Huang Jiaming , Liao Yuandong , Pan Chaoyun , Liu Junxiu , Du Qiqiao , Liu Tianyu , Shang Chunliang , Ooi Shiyin , Chen Run , Xia Meng , Jiang Hongye , Xu Manman , Zou Qiaojian , Zhou Yijia , Huang Hua , Pan Yuwen , Yuan Li , Wang Wei , Yao Shuzhong
Published: September 2021

Circular RNAs (circRNAs) are known to act as key regulators in a variety of malignancies. However, the role of circRNAs in cervical cancer (CCa) remains largely unknown. Herein, we demonstrated that a circRNA derived from the TADA2A gene (hsa_circ_0043280) was significantly downregulated in CCa and that this reduction in expression was correlated with a poor prognosis. Furthermore, our results demonstrated that hsa_circ_0043280 functions as a tumor suppressor to inhibit tumor growth and metastasis in CCa. Mechanistically, hsa_circ_0043280 competitively sponges miR-203a-3p and prevents miR-203a-3p from reducing the levels of PAQR3. Collectively, our results demonstrate that hsa_circ_0043280 plays a pivotal role in the development and metastasis of CCa, thus suggesting that hsa_circ_0043280 has significant potential as a prognostic biomarker and a therapeutic target for CCa.
Inhibition of DNMT-1 alleviates ferroptosis through NCOA4 mediated ferritinophagy during diabetes myocardial ischemia/reperfusion injury
Authors: Li Wenyuan , Li Wei , Wang Yao , Leng Yan , Xia Zhongyuan
Published: September 2021

The purpose of this study was to investigate whether inhibition of DNA (cytosine-5)-methyltransferase 1 (DNMT-1) alleviated ferroptosis through nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy during diabetes myocardial (DM) ischemia/reperfusion (I/R) injury (IRI). Rat DM + sham (DS), I/R, and DM + I/R (DIR), H9c2 cell high glucose (HG), hypoxia reoxygenation (H/R), and high-glucose hypoxia reoxygenation (HH/R) models were established. DNMT-1 inhibitor 5-Aza-2’-deoxycytidine (5-aza-CdR) was administered to rat and cell models. The protein level of DNMT-1, NCOA4, FTH, GPX4, Beclin-1, and P62 was detected by western blotting. Compared with normal sham (NS) group, myocardial tissue was injured in DS and I/R models. The level of DNMT-1, NCOA4, and ferroptosis was increased. Moreover, the cell injury was more serious in rat DIR or HH/R model. 5-Aza-CdR could reduce NCOA4-mediated ferritinophagy and myocardial injury in DIR and HH/R models. Moreover, the siRNA for NCOA4 could also reduce the level of ferritinophagy and cell injury in HH/R model. 5-Aza-CdR enhanced the protective effect for NCOA4-siRNA in the process of cell injury. Inhibition of DNMT-1 could reduce ferroptosis during DIR, which the NCOA4-mediated ferritinophagy might be regulated.
Social motility of biofilm-like microcolonies in a gliding bacterium
Authors: Li Chao , Hurley Amanda , Hu Wei , Warrick Jay W. , Lozano Gabriel L. , Ayuso Jose M. , Pan Wenxiao , Handelsman Jo , Beebe David J.
Published: September 2021

Bacterial biofilms are aggregates of surface-associated cells embedded in an extracellular polysaccharide (EPS) matrix, and are typically stationary. Studies of bacterial collective movement have largely focused on swarming motility mediated by flagella or pili, in the absence of a biofilm. Here, we describe a unique mode of collective movement by a self-propelled, surface-associated biofilm-like multicellular structure. Flavobacterium johnsoniae cells, which move by gliding motility, self-assemble into spherical microcolonies with EPS cores when observed by an under-oil open microfluidic system. Small microcolonies merge, creating larger ones. Microscopic analysis and computer simulation indicate that microcolonies move by cells at the base of the structure, attached to the surface by one pole of the cell. Biochemical and mutant analyses show that an active process drives microcolony self-assembly and motility, which depend on the bacterial gliding apparatus. We hypothesize that this mode of collective bacterial movement on solid surfaces may play potential roles in biofilm dynamics, bacterial cargo transport, or microbial adaptation. However, whether this collective motility occurs on plant roots or soil particles, the native environment for F. johnsoniae, is unknown.
Brief segments of neurophysiological activity enable individual differentiation
Authors: da Silva Castanheira Jason , Orozco Perez Hector Domingo , Misic Bratislav , Baillet Sylvain
Published: September 2021

Large, openly available datasets and current analytic tools promise the emergence of population neuroscience. The considerable diversity in personality traits and behaviour between individuals is reflected in the statistical variability of neural data collected in such repositories. Recent studies with functional magnetic resonance imaging (fMRI) have concluded that patterns of resting-state functional connectivity can both successfully distinguish individual participants within a cohort and predict some individual traits, yielding the notion of an individual’s neural fingerprint. Here, we aim to clarify the neurophysiological foundations of individual differentiation from features of the rich and complex dynamics of resting-state brain activity using magnetoencephalography (MEG) in 158 participants. We show that akin to fMRI approaches, neurophysiological functional connectomes enable the differentiation of individuals, with rates similar to those seen with fMRI. We also show that individual differentiation is equally successful from simpler measures of the spatial distribution of neurophysiological spectral signal power. Our data further indicate that differentiation can be achieved from brain recordings as short as 30 seconds, and that it is robust over time: the neural fingerprint is present in recordings performed weeks after their baseline reference data was collected. This work, thus, extends the notion of a neural or brain fingerprint to fast and large-scale resting-state electrophysiological dynamics.
Conserved ancestral tropical niche but different continental histories explain the latitudinal diversity gradient in brush-footed butterflies
Authors: Chazot Nicolas , Condamine Fabien L. , Dudas Gytis , Peña Carlos , Kodandaramaiah Ullasa , Matos-Maraví Pável , Aduse-Poku Kwaku , Elias Marianne , Warren Andrew D. , Lohman David J. , Penz Carla M. , DeVries Phil , Fric Zdenek F. , Nylin Soren , Müller Chris , Kawahara Akito Y. , Silva-Brandão Karina L. , Lamas Gerardo , Kleckova Irena , Zubek Anna , Ortiz-Acevedo Elena , Vila Roger , Vane-Wright Richard I. , Mullen Sean P. , Jiggins Chris D. , Wheat Christopher W. , Freitas Andre V. L. , Wahlberg Niklas
Published: September 2021

The global increase in species richness toward the tropics across continents and taxonomic groups, referred to as the latitudinal diversity gradient, stimulated the formulation of many hypotheses to explain the underlying mechanisms of this pattern. We evaluate several of these hypotheses to explain spatial diversity patterns in a butterfly family, the Nymphalidae, by assessing the contributions of speciation, extinction, and dispersal, and also the extent to which these processes differ among regions at the same latitude. We generate a time-calibrated phylogeny containing 2,866 nymphalid species (~45% of extant diversity). Neither speciation nor extinction rate variations consistently explain the latitudinal diversity gradient among regions because temporal diversification dynamics differ greatly across longitude. The Neotropical diversity results from low extinction rates, not high speciation rates, and biotic interchanges with other regions are rare. Southeast Asia is also characterized by a low speciation rate but, unlike the Neotropics, is the main source of dispersal events through time. Our results suggest that global climate change throughout the Cenozoic, combined with tropical niche conservatism, played a major role in generating the modern latitudinal diversity gradient of nymphalid butterflies.
SPOP mutation induces DNA methylation via stabilizing GLP/G9a
Authors: Zhang Jianong , Gao Kun , Xie Hongyan , Wang Dejie , Zhang Pingzhao , Wei Ting , Yan Yuqian , Pan Yunqian , Ye Wenbin , Chen Huifen , Shi Qing , Li Yao , Zhao Shi-min , Hou Xiaonan , Weroha Saravut J. , Wang Yuzhuo , Zhang Jun , Karnes R. Jeffrey , He Housheng Hansen , Wang Liguo , Wang Chenji , Huang Haojie
Published: September 2021

Mutations in SPOP E3 ligase gene are reportedly associated with genome-wide DNA hypermethylation in prostate cancer (PCa) although the underlying mechanisms remain elusive. Here, we demonstrate that SPOP binds and promotes polyubiquitination and degradation of histone methyltransferase and DNMT interactor GLP. SPOP mutation induces stabilization of GLP and its partner protein G9a and aberrant upregulation of global DNA hypermethylation in cultured PCa cells and primary PCa specimens. Genome-wide DNA methylome analysis shows that a subset of tumor suppressor genes (TSGs) including FOXO3, GATA5, and NDRG1, are hypermethylated and downregulated in SPOP-mutated PCa cells. DNA methylation inhibitor 5-azacytidine effectively reverses expression of the TSGs examined, inhibits SPOP-mutated PCa cell growth in vitro and in mice, and enhances docetaxel anti-cancer efficacy. Our findings reveal the GLP/G9a-DNMT module as a mediator of DNA hypermethylation in SPOP-mutated PCa. They suggest that SPOP mutation could be a biomarker for effective treatment of PCa with DNA methylation inhibitor alone or in combination with taxane chemotherapeutics.
Unraveling the functional role of DNA demethylation at specific promoters by targeted steric blockage of DNA methyltransferase with CRISPR/dCas9
Authors: Sapozhnikov Daniel M. , Szyf Moshe
Published: September 2021

Despite four decades of research to support the association between DNA methylation and gene expression, the causality of this relationship remains unresolved. Here, we reaffirm that experimental confounds preclude resolution of this question with existing strategies, including recently developed CRISPR/dCas9 and TET-based epigenetic editors. Instead, we demonstrate a highly effective method using only nuclease-dead Cas9 and guide RNA to physically block DNA methylation at specific targets in the absence of a confounding flexibly-tethered enzyme, thereby enabling the examination of the role of DNA demethylation per se in living cells, with no evidence of off-target activity. Using this method, we probe a small number of inducible promoters and find the effect of DNA demethylation to be small, while demethylation of CpG-rich FMR1 produces larger changes in gene expression. This method could be used to reveal the extent and nature of the contribution of DNA methylation to gene regulation.
A general approach to protein folding using thermostable exoshells
Authors: Sadeghi Samira , Deshpande Siddharth , Vallerinteavide Mavelli Girish , Aksoyoglu Alphan , Bafna Jayesh , Winterhalter Mathias , Kini R. Manjunatha , Lane David P. , Drum Chester L.
Published: September 2021

In vitro protein folding is a complex process which often results in protein aggregation, low yields and low specific activity. Here we report the use of nanoscale exoshells (tES) to provide complementary nanoenvironments for the folding and release of 12 highly diverse protein substrates ranging from small protein toxins to human albumin, a dimeric protein (alkaline phosphatase), a trimeric ion channel (Omp2a) and the tetrameric tumor suppressor, p53. These proteins represent a unique diversity in size, volume, disulfide linkages, isoelectric point and multi versus monomeric nature of their functional units. Protein encapsulation within tES increased crude soluble yield (3-fold to >100-fold), functional yield (2-fold to >100-fold) and specific activity (3-fold to >100-fold) for all the proteins tested. The average soluble yield was 6.5 mg/100 mg of tES with charge complementation between the tES internal cavity and the protein substrate being the primary determinant of functional folding. Our results confirm the importance of nanoscale electrostatic effects and provide a solution for folding proteins in vitro.
Zebrafish capable of generating future state prediction error show improved active avoidance behavior in virtual reality
Authors: Torigoe Makio , Islam Tanvir , Kakinuma Hisaya , Fung Chi Chung Alan , Isomura Takuya , Shimazaki Hideaki , Aoki Tazu , Fukai Tomoki , Okamoto Hitoshi
Published: September 2021

Animals make decisions under the principle of reward value maximization and surprise minimization. It is still unclear how these principles are represented in the brain and are reflected in behavior. We addressed this question using a closed-loop virtual reality system to train adult zebrafish for active avoidance. Analysis of the neural activity of the dorsal pallium during training revealed neural ensembles assigning rules to the colors of the surrounding walls. Additionally, one third of fish generated another ensemble that becomes activated only when the real perceived scenery shows discrepancy from the predicted favorable scenery. The fish with the latter ensemble escape more efficiently than the fish with the former ensembles alone, even though both fish have successfully learned to escape, consistent with the hypothesis that the latter ensemble guides zebrafish to take action to minimize this prediction error. Our results suggest that zebrafish can use both principles of goal-directed behavior, but with different behavioral consequences depending on the repertoire of the adopted principles.
Reconfigurable Stochastic neurons based on tin oxide/MoS2 hetero-memristors for simulated annealing and the Boltzmann machine
Authors: Yan Xiaodong , Ma Jiahui , Wu Tong , Zhang Aoyang , Wu Jiangbin , Chin Matthew , Zhang Zhihan , Dubey Madan , Wu Wei , Chen Mike Shuo-Wei , Guo Jing , Wang Han
Published: September 2021

Neuromorphic hardware implementation of Boltzmann Machine using a network of stochastic neurons can allow non-deterministic polynomial-time (NP) hard combinatorial optimization problems to be efficiently solved. Efficient implementation of such Boltzmann Machine with simulated annealing desires the statistical parameters of the stochastic neurons to be dynamically tunable, however, there has been limited research on stochastic semiconductor devices with controllable statistical distributions. Here, we demonstrate a reconfigurable tin oxide (SnOx)/molybdenum disulfide (MoS2) heterogeneous memristive device that can realize tunable stochastic dynamics in its output sampling characteristics. The device can sample exponential-class sigmoidal distributions analogous to the Fermi-Dirac distribution of physical systems with quantitatively defined tunable “temperature” effect. A BM composed of these tunable stochastic neuron devices, which can enable simulated annealing with designed “cooling” strategies, is conducted to solve the MAX-SAT, a representative in NP-hard combinatorial optimization problems. Quantitative insights into the effect of different “cooling” strategies on improving the BM optimization process efficiency are also provided.
Mapping protein interactions in the active TOM-TIM23 supercomplex
Authors: Gomkale Ridhima , Linden Andreas , Neumann Piotr , Schendzielorz Alexander Benjamin , Stoldt Stefan , Dybkov Olexandr , Kilisch Markus , Schulz Christian , Cruz-Zaragoza Luis Daniel , Schwappach Blanche , Ficner Ralf , Jakobs Stefan , Urlaub Henning , Rehling Peter
Published: September 2021

Nuclear-encoded mitochondrial proteins destined for the matrix have to be transported across two membranes. The TOM and TIM23 complexes facilitate the transport of precursor proteins with N-terminal targeting signals into the matrix. During transport, precursors are recognized by the TIM23 complex in the inner membrane for handover from the TOM complex. However, we have little knowledge on the organization of the TOM-TIM23 transition zone and on how precursor transfer between the translocases occurs. Here, we have designed a precursor protein that is stalled during matrix transport in a TOM-TIM23-spanning manner and enables purification of the translocation intermediate. Combining chemical cross-linking with mass spectrometric analyses and structural modeling allows us to map the molecular environment of the intermembrane space interface of TOM and TIM23 as well as the import motor interactions with amino acid resolution. Our analyses provide a framework for understanding presequence handover and translocation during matrix protein transport.
Approaching disorder-tolerant semiconducting polymers
Authors: Yan Xinwen , Xiong Miao , Deng Xin-Yu , Liu Kai-Kai , Li Jia-Tong , Wang Xue-Qing , Zhang Song , Prine Nathaniel , Zhang Zhuoqiong , Huang Wanying , Wang Yishan , Wang Jie-Yu , Gu Xiaodan , So Shu Kong , Zhu Jia , Lei Ting
Published: September 2021

Doping has been widely used to control the charge carrier concentration in organic semiconductors. However, in conjugated polymers, n-doping is often limited by the tradeoff between doping efficiency and charge carrier mobilities, since dopants often randomly distribute within polymers, leading to significant structural and energetic disorder. Here, we screen a large number of polymer building block combinations and explore the possibility of designing n-type conjugated polymers with good tolerance to dopant-induced disorder. We show that a carefully designed conjugated polymer with a single dominant planar backbone conformation, high torsional barrier at each dihedral angle, and zigzag backbone curvature is highly dopable and can tolerate dopant-induced disorder. With these features, the designed diketopyrrolopyrrole (DPP)-based polymer can be efficiently n-doped and exhibit high n-type electrical conductivities over 120 S cm−1, much higher than the reference polymers with similar chemical structures. This work provides a polymer design concept for highly dopable and highly conductive polymeric semiconductors.
Dataset for predicting single-spot proton ranges in proton therapy of prostate cancer
Authors: Freitas Hugo , Magalhaes Martins Paulo , Tessonnier Thomas , Ackermann Benjamin , Brons Stephan , Seco Joao
Published: September 2021

The number of radiotherapy patients treated with protons has increased from less than 60,000 in 2007 to more than 220,000 in 2019. However, the considerable uncertainty in the positioning of the Bragg peak deeper in the patient raised new challenges in the proton therapy of prostate cancer (PCPT). Here, we describe and share a dataset where 43 single-spot anterior beams with defined proton energies were delivered to a prostate phantom with an inserted endorectal balloon (ERB) filled either with water only or with a silicon-water mixture. The nuclear reactions between the protons and the silicon yield a distinct prompt gamma energy line of 1.78 MeV. Such energy peak could be identified by means of prompt gamma spectroscopy (PGS) for the protons hitting the ERB with a three-sigma threshold. The application of a background-suppression technique showed an increased rejection capability for protons hitting the prostate and the ERB with water only. We describe each dataset, document the full processing chain, and provide the scripts for the statistical analysis.
Dihydroergotamine and triptan use to treat migraine during pregnancy and the risk of adverse pregnancy outcomes
Authors: Bérard Anick , Strom Shannon , Zhao Jin-Ping , Kori Shashi , Albrecht Detlef
Published: September 2021

Migraine is prevalent during pregnancy. Antimigraine medications such as dihydroergotamine (DHE) and triptans have been associated with adverse pregnancy outcomes in individual studies but lack of consensus remains. We compared the risk of prematurity, low birth weight (LBW), major congenital malformations (MCM), and spontaneous abortions (SA) associated with gestational use of DHE or triptans. Three cohort and one nested-case–control analyses were conducted within the Quebec Pregnancy Cohort to assess the risk of prematurity, LBW, MCM, and SA. Exposure was defined dichotomously as use of DHE or triptan during pregnancy. Generalized estimation equations were built to quantify the associations, adjusting for potential confounders. 233,900 eligible pregnancies were included in the analyses on prematurity, LBW, and MCM; 29,104 cases of SA were identified. Seventy-eight subjects (0.03%) were exposed to DHE and 526 (0.22%) to triptans. Adjusting for potential confounders, DHE and triptans were associated with increased risks of prematurity, LBW, MCM, and SA but not all estimates were statistically significant. DHE was associated with the risk of prematurity (aRR: 4.12, 95% CI 1.21–13.99); triptans were associated with the risk of SA (aOR: 1.63, 95% CI 1.34–1.98). After considering maternal migraine, all antimigraine specific medications increased the risk of some adverse pregnancy outcomes, but estimates were unstable.
Intravenous injection of cyclophilin A realizes the transient and reversible opening of barrier of neural vasculature through basigin in endothelial cells
Authors: Nakada-Honda Narumi , Cui Dan , Matsuda Satoshi , Ikeda Eiji
Published: September 2021

Neural vasculature forms the blood–brain barrier against the delivery of systemically administered therapeutic drugs into parenchyma of neural tissues. Therefore, procedures to open the blood–brain barrier with minimal damage to tissues would lead to the great progress in therapeutic strategy for intractable neural diseases. In this study, through analyses with mouse in vitro brain microvascular endothelial cells and in vivo neural vasculature, we demonstrate that the administration of cyclophilin A (CypA), a ligand of basigin which is expressed in barrier-forming endothelial cells, realizes the artificial opening of blood–brain barrier. Monolayers of endothelial cells lost their barrier properties through the disappearance of claudin-5, an integral tight junction molecule, from cell membranes in a transient and reversible manner. Furthermore, the intravenous injection of a single dose of CypA into mice resulted in the opening of blood–brain barrier for a certain period which enabled the enhanced delivery of systemically administered doxorubicin into the parenchyma of neural tissues. These findings that the pre-injection of a single dose of CypA realizes an artificial, transient as well as reversible opening of blood–brain barrier are considered to be a great step toward the establishment of therapeutic protocols to overcome the intractability of neural diseases.
Proteomic and molecular dynamic investigations of PTM-induced structural fluctuations in breast and ovarian cancer
Authors: Tikhonov Dmitry , Kulikova Liudmila , Kopylov Arthur T. , Rudnev Vladimir , Stepanov Alexander , Malsagova Kristina , Izotov Alexander , Kulikov Dmitry , Zulkarnaev Alexey , Enikeev Dmitry , Potoldykova Natalia , Kaysheva Anna L.
Published: September 2021

Post-translational processing leads to conformational changes in protein structure that modulate molecular functions and change the signature of metabolic transformations and immune responses. Some post-translational modifications (PTMs), such as phosphorylation and acetylation, are strongly related to oncogenic processes and malignancy. This study investigated a PTM pattern in patients with gender-specific ovarian or breast cancer. Proteomic profiling and analysis of cancer-specific PTM patterns were performed using high-resolution UPLC-MS/MS. Structural analysis, topology, and stability of PTMs associated with sex-specific cancers were analyzed using molecular dynamics modeling. We identified highly specific PTMs, of which 12 modified peptides from eight distinct proteins derived from patients with ovarian cancer and 6 peptides of three proteins favored patients from the group with breast cancer. We found that all defined PTMs were localized in the compact and stable structural motifs exposed outside the solvent environment. PTMs increase the solvent-accessible surface area of the modified moiety and its active environment. The observed conformational fluctuations are still inadequate to activate the structural degradation and enhance protein elimination/clearance; however, it is sufficient for the significant modulation of protein activity.
Profiles of microRNA in aqueous humor of normal tension glaucoma patients using RNA sequencing
Authors: Seong Hyemin , Cho Hyun-kyung , Kee Changwon , Song Dae Hyun , Cho Min-Chul , Kang Sang Soo
Published: September 2021

We aimed to identify and compare microRNAs (miRNAs) from individual aqueous humor samples between normal-tension glaucoma (NTG) patients and normal controls. Aqueous humor (80 to 120 µl) was collected before cataract surgery. Six stable NTG patients and seven age-matched controls were included in the final analysis. RNA sequencing was conducted for RNA samples extracted from the 13 aqueous humor samples, and bioinformatics analysis was employed for the miRNA targets and related pathways. Two hundred and twenty-eight discrete miRNAs were detected in the aqueous humor and consistently expressed in all samples. Eight significantly upregulated miRNAs were found in the NTG patients compared to the controls (fold-change > 2, p < 0.05). They were hsa-let-7a-5p, hsa-let-7c-5p, hsa-let-7f-5p, hsa-miR-192-5p, hsa-miR-10a-5p, hsa-miR-10b-5p, hsa-miR-375, and hsa-miR-143-3p. These miRNAs were predicted to be associated with the biological processes of apoptosis, autophagy, neurogenesis, and aging in the gene ontology categories. The related Kyoto encyclopedia of genes and genomes pathways were extracellular matrix-receptor interaction, mucin-type O-glycan biosynthesis, biotin metabolism, and signaling pathways regulating the pluripotency of stem cells. The differentially expressed miRNA in the NTG samples compared to the controls suggest the possible roles of miRNA in the pathogenesis of NTG. The underlying miRNA-associated pathways further imply novel targets for the pathogenesis of NTG.
Artificial intelligence-based detection of epimacular membrane from color fundus photographs
Authors: Shao Enhua , Liu Congxin , Wang Lei , Song Dan , Guo Libin , Yao Xuan , Xiong Jianhao , Wang Bin , Hu Yuntao
Published: September 2021

Epiretinal membrane (ERM) is a common ophthalmological disorder of high prevalence. Its symptoms include metamorphopsia, blurred vision, and decreased visual acuity. Early diagnosis and timely treatment of ERM is crucial to preventing vision loss. Although optical coherence tomography (OCT) is regarded as a de facto standard for ERM diagnosis due to its intuitiveness and high sensitivity, ophthalmoscopic examination or fundus photographs still have the advantages of price and accessibility. Artificial intelligence (AI) has been widely applied in the health care industry for its robust and significant performance in detecting various diseases. In this study, we validated the use of a previously trained deep neural network based-AI model in ERM detection based on color fundus photographs. An independent test set of fundus photographs was labeled by a group of ophthalmologists according to their corresponding OCT images as the gold standard. Then the test set was interpreted by other ophthalmologists and AI model without knowing their OCT results. Compared with manual diagnosis based on fundus photographs alone, the AI model had comparable accuracy (AI model 77.08% vs. integrated manual diagnosis 75.69%, χ2 = 0.038, P = 0.845, McNemar’s test), higher sensitivity (75.90% vs. 63.86%, χ2 = 4.500, P = 0.034, McNemar’s test), under the cost of lower but reasonable specificity (78.69% vs. 91.80%, χ2 = 6.125, P = 0.013, McNemar’s test). Thus our AI model can serve as a possible alternative for manual diagnosis in ERM screening.
Capturing spike train temporal pattern with wavelet average coefficient for brain machine interface
Authors: Wen Shixian , Yin Allen , Tseng Po-He , Itti Laurent , Lebedev Mikhail A. , Nicolelis Miguel
Published: September 2021

Motor brain machine interfaces (BMIs) directly link the brain to artificial actuators and have the potential to mitigate severe body paralysis caused by neurological injury or disease. Most BMI systems involve a decoder that analyzes neural spike counts to infer movement intent. However, many classical BMI decoders (1) fail to take advantage of temporal patterns of spike trains, possibly over long time horizons; (2) are insufficient to achieve good BMI performance at high temporal resolution, as the underlying Gaussian assumption of decoders based on spike counts is violated. Here, we propose a new statistical feature that represents temporal patterns or temporal codes of spike events with richer description—wavelet average coefficients (WAC)—to be used as decoder input instead of spike counts. We constructed a wavelet decoder framework by using WAC features with a sliding-window approach, and compared the resulting decoder against classical decoders (Wiener and Kalman family) and new deep learning based decoders ( Long Short-Term Memory) using spike count features. We found that the sliding-window approach boosts decoding temporal resolution, and using WAC features significantly improves decoding performance over using spike count features.
Cross-cultural validation of the stroke riskometer using generalizability theory
Authors: Medvedev Oleg , Truong Quoc Cuong , Merkin Alexander , Borotkanics Robert , Krishnamurthi Rita , Feigin Valery
Published: September 2021

The Stroke Riskometer mobile application is a novel, validated way to provide personalized stroke risk assessment for individuals and motivate them to reduce their risks. Although this app is being used worldwide, its reliability across different countries has not yet been rigorously investigated using appropriate methodology. The Generalizability Theory (G-Theory) is an advanced statistical method suitable for examining reliability and generalizability of assessment scores across different samples, cultural and other contexts and for evaluating sources of measurement errors. G-Theory was applied to the Stroke Riskometer data sampled from 1300 participants in 13 countries using two-facet nested observational design (person by item nested in the country). The Stroke Riskometer demonstrated strong reliability in measuring stroke risks across the countries with coefficients G relative and absolute of 0.84, 95%CI [0.79; 0.89] and 0.82, 95%CI [0.76; 0.88] respectively. D-study analyses revealed that the Stroke Riskometer has optimal reliability in its current form in measuring stroke risk for each country and no modifications are required. These results suggest that the Stroke Riskometer’s scores are generalizable across sample population and countries permitting cross-cultural comparisons. Further studies investigating reliability of the Stroke Riskometer over time in longitudinal study design are warranted.
New early phenotypic markers for cucumber green mottle mosaic virus disease in cucumbers exposed to fluctuating extreme temperatures
Authors: Molad Ori , Smith Elisheva , Luria Neta , Sela Noa , Lachman Oded , Bakelman Elena , Leibman Diana , Dombrovsky Aviv
Published: September 2021

Studies of early stages of cucumber green mottle mosaic virus (CGMMV) disease have been recently focused on plant molecular responses. However, extreme diurnal environmental temperatures, characteristic of global climate changes, could affect plant susceptibility and disease phenotype progression. Our studies of CGMMV disease progression, under simulated extreme temperature waves, have revealed two new disease initiation phenotypes that developed gradually, preceding severe symptom manifestations of post-recovery CGMMV systemic infections. 'Early post-recovery stage' bright yellow islands (BYIs) with defined boundaries amid asymptomatic leaf blades were first emerging followed by 'late post-recovery stage' BYIs with diffused boundaries. A deduced CGMMV disease progression scheme, postulating BYI symptom occurrence time-windows, revealed BYIs in field grown cucumber plants exposed to extreme diurnal temperatures. Profiling ontology of cucumber differentially expressed genes in BYIs vs the associated dark-green surrounding tissues disclosed activation of jasmonic acid (JA) pathway in 'early post-recovery stage' BYIs. JA signaling was inactivated in 'late post-recovery stage' BYIs concomitant with increasing expressions of JA signaling inhibitors and downregulation of JA responsive phenylpropanoid pathway. Our results disclosed a new phenotypic description of CGMMV disease initiation, characteristic of cucumbers grown under extreme environmental temperature fluctuations. The BYI phenotypes could define a time-window for CGMMV disease management applications.
Usefulness of computed tomography-measured psoas muscle thickness per height for predicting mortality in patients undergoing hemodialysis
Authors: Yajima Takahiro , Arao Maiko , Yajima Kumiko , Takahashi Hiroshi
Published: September 2021

Computed tomography (CT)-measured psoas muscle thickness standardized for height (PMTH) has emerged as a promising predictor of mortality. The study aimed to investigate whether PMTH could accurately predict mortality in patients undergoing hemodialysis. We examined 207 patients (mean age: 63.1 years; men: 66.2%) undergoing hemodialysis for more than 6 months in hospital affiliated clinic. PMTH was calculated at the L3 vertebra level using CT. Patients were divided according to the PMTH cut-off points: 8.44 mm/m in women and 8.85 mm/m in men; thereafter, they were combined into low and high PMTH groups. PMTH was independently correlated with the simplified creatinine index (β = 0.213, P = 0.021) and geriatric nutritional risk index (β = 0.295, P < 0.0001) in multivariate regression analysis. During a median follow-up of 3.7 (1.8–6.4) years, 76 patients died, including 41 from cardiovascular causes. In the multivariate Cox regression analysis, low PMTH (adjusted hazard ratio, 2.48; 95% confidence interval, 1.36–4.70) was independently associated with an increased risk of all-cause mortality. The addition of binary PMTH groups to the baseline risk model tended to improve net reclassification improvement (0.460, p = 0.060). In conclusion, PMTH may be an indicator of protein energy wasting and a useful tool for predicting mortality in patients undergoing hemodialysis.