bluuebunny/crossref_metadata_2025 huggingface dataset:
A new platform for ultra-high dose rate radiobiological research using the BELLA PW laser proton beamline
Authors: Bin Jianhui , Obst-Huebl Lieselotte , Mao Jian-Hua , Nakamura Kei , Geulig Laura D. , Chang Hang , Ji Qing , He Li , De Chant Jared , Kober Zachary , Gonsalves Anthony J. , Bulanov Stepan , Celniker Susan E. , Schroeder Carl B. , Geddes Cameron G. R. , Esarey Eric , Simmons Blake A. , Schenkel Thomas , Blakely Eleanor A. , Steinke Sven , Snijders Antoine M.
Published: January 2022

Radiotherapy is the current standard of care for more than 50% of all cancer patients. Improvements in radiotherapy (RT) technology have increased tumor targeting and normal tissue sparing. Radiations at ultra-high dose rates required for FLASH-RT effects have sparked interest in potentially providing additional differential therapeutic benefits. We present a new experimental platform that is the first one to deliver petawatt laser-driven proton pulses of 2 MeV energy at 0.2 Hz repetition rate by means of a compact, tunable active plasma lens beamline to biological samples. Cell monolayers grown over a 10 mm diameter field were exposed to clinically relevant proton doses ranging from 7 to 35 Gy at ultra-high instantaneous dose rates of 107 Gy/s. Dose-dependent cell survival measurements of human normal and tumor cells exposed to LD protons showed significantly higher cell survival of normal-cells compared to tumor-cells for total doses of 7 Gy and higher, which was not observed to the same extent for X-ray reference irradiations at clinical dose rates. These findings provide preliminary evidence that compact LD proton sources enable a new and promising platform for investigating the physical, chemical and biological mechanisms underlying the FLASH effect.
Effects of rTMS and tDCS on neuropathic pain after brachial plexus injury: a randomized placebo-controlled pilot study
Authors: Bonifácio de Assis Erickson Duarte , Martins Wanessa Kallyne Nascimento , de Carvalho Carolina Dias , Ferreira Clarice Martins , Gomes Ruth , de Almeida Rodrigues Evelyn Thais , Meira Ussânio Mororó , de Holanda Ledycnarf Januário , Lindquist Ana Raquel , Morya Edgard , Mendes Cristina Katya Torres Teixeira , de Assis Thaís Castro Gomes , de Oliveira Eliane Araújo , Andrade Suellen Marinho
Published: January 2022

Neuropathic pain after brachial plexus injury (NPBPI) is a highly disabling clinical condition and is increasingly prevalent due to increased motorcycle accidents. Currently, no randomized controlled trials have evaluated the effectiveness of non-invasive brain stimulation techniques such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct-current stimulation (tDCS) in patients suffering from NPBPI. In this study, we directly compare the efficacy of 10-Hz rTMS and anodal 2 mA tDCS techniques applied over the motor cortex (5 daily consecutive sessions) in 20 patients with NPBPI, allocated into 2 parallel groups (active or sham). The order of the sessions was randomised for each of these treatment groups according to a crossover design and separated by a 30-day interval. Scores for “continuous” and “paroxysmal” pain (primary outcome) were tabulated after the last stimulation day and 30 days after. Secondary outcomes included the improvement in multidimensional aspects of pain, anxiety state and quality of life from a qualitative and quantitative approach. Active rTMS and tDCS were both superior to sham in reducing continuous (p < 0.001) and paroxysmal (p = 0.002; p = 0.02) pain as well as in multidimensional aspects of pain (p = 0.001; p = 0.002) and anxiety state (p =  < 0.001; p = 0.005). Our results suggest rTMS and tDCS are able to treat NPBPI with little distinction in pain and anxiety state, which may promote the use of tDCS in brachial plexus injury pain management, as it constitutes an easier and more available technique.

Clinical Trial Registration: http://www.ensaiosclinicos.gov.br/, RBR-5xnjbc – Sep 3, 2018.
Assessment of 5-year outcomes of life satisfaction in survivors after rehabilitation programs: a multicenter clinical trial
Authors: Rahimi-Bashar Farshid , Salesi Mahmood , Gohari-Moghadam Keivan , Jouzdani Ali Fathi , Pourhoseingholi Mohamad Amin , Vahedian-Azimi Amir
Published: January 2022

Using a rehabilitation program for the survivors of acute respiratory distress syndrome (ARDS) could be one of the important and fundamental steps to improve the pulmonary function and health-related quality of life (HRQoL) of patients. This study was carried out to evaluate the effect of two rehabilitation techniques (Family-Based Empowerment Model (FECM)/Continuing Care Model (CCM), or both of them) on pulmonary function, and HRQoL in ARDS survivors. From December 2009 to June 2016, ARDS survivors from mixed medical-surgical ICUs at four academic teaching hospitals in Tehran, Iran, were randomly assigned to one of three intervention groups (A, B, or C) or a control group (D). Pre- and post-interventions, pulmonary functions and HRQoL status of patients in all groups were collected 48 times via clinical measurements and various questionnaires during 5 years of follow-up. Significantly improvement was seen in the intervention groups compared to the control group, and the greatest benefit was observed in patients who received mixed of FCEM and CCM rehabilitation techniques. Co-administration of FCEM and CCM can improve pulmonary function as well as the life satisfaction of ARDS survivors. As a result, the execution of the empowerment model by nurses is recommended for ARDS survivors and the participation of their families at the same time.

Trial registration: NCT02787720 (ClinicalTrial.gov, 24/05/2016).
Multi-hazard spatial modeling via ensembles of machine learning and meta-heuristic techniques
Authors: Bordbar Mojgan , Aghamohammadi Hossein , Pourghasemi Hamid Reza , Azizi Zahra
Published: January 2022

Considering the large number of natural disasters on the planet, many areas in the world are at risk of these hazards; therefore, providing an integrated map as a guide map for multiple natural hazards can be applied to save human lives and reduce financial losses. This study designed a multi-hazard map for three important hazards (earthquakes, floods, and landslides) to identify endangered areas in Kermanshah province located in western Iran using ensemble SWARA-ANFIS-PSO and SWARA-ANFIS-GWO models. In the first step, flood and landslide inventory maps were generated to identify at-risk areas. Then, the occurrence places for each hazard were divided into two groups for training susceptibility models (70%) and testing the models applied (30%). Factors affecting these hazards, including altitude, slope aspect, slope degree, plan curvature, distance to rivers, distance to roads, distance to the faults, rainfall, lithology, and land use, were used to generate susceptibility maps. The SWARA method was used to weigh the subclasses of the influencing factors in floods and landslides. In addition, a peak ground acceleration (PGA) map was generated to investigate earthquakes in the study area. In the next step, the ANFIS machine learning algorithm was used in combination with PSO and GWO meta-heuristic algorithms to train the data, and SWARA-ANFIS-PSO and SWARA-ANFIS-GWO susceptibility maps were separately generated for flood and landslide hazards. The predictive ability of the implemented models was validated using the receiver operating characteristics (ROC), root mean square error (RMSE), and mean square error (MSE) methods. The results showed that the SWARA-ANFIS-PSO ensemble model had the best performance in generating flood susceptibility maps with ROC = 0.936, RMS = 0.346, and MSE = 0.120. Furthermore, this model showed excellent results (ROC = 0.894, RMS = 0.410, and MSE = 0.168) for generating a landslide map. Finally, the best maps and PGA map were combined, and a multi-hazard map (MHM) was obtained for Kermanshah Province. This map can be used by managers and planners as a practical guide for sustainable development.
Pulmonary nodules detection based on multi-scale attention networks
Authors: Zhang Hui , Peng Yanjun , Guo Yanfei
Published: January 2022

Pulmonary nodules are the main manifestation of early lung cancer. Therefore, accurate detection of nodules in CT images is vital for lung cancer diagnosis. A 3D automatic detection system of pulmonary nodules based on multi-scale attention networks is proposed in this paper to use multi-scale features of nodules and avoid network over-fitting problems. The system consists of two parts, nodule candidate detection (determining the locations of candidate nodules), false positive reduction (minimizing the number of false positive nodules). Specifically, with Res2Net structure, using pre-activation operation and convolutional quadruplet attention module, the 3D multi-scale attention block is designed. It makes full use of multi-scale information of pulmonary nodules by extracting multi-scale features at a granular level and alleviates over-fitting by pre-activation. The U-Net-like encoder-decoder structure is combined with multi-scale attention blocks as the backbone network of Faster R-CNN for detection of candidate nodules. Then a 3D deep convolutional neural network based on multi-scale attention blocks is designed for false positive reduction. The extensive experiments on LUNA16 and TianChi competition datasets demonstrate that the proposed approach can effectively improve the detection sensitivity and control the number of false positive nodules, which has clinical application value.
Orthogonal proteomics methods to unravel the HOTAIR interactome
Authors: Delhaye Louis , De Bruycker Edith , Volders Pieter-Jan , Fijalkowska Daria , De Sutter Delphine , Degroeve Sven , Martens Lennart , Mestdagh Pieter , Eyckerman Sven
Published: January 2022

Accumulating evidence highlights the role of long non-coding RNAs (lncRNAs) in cellular homeostasis, and their dysregulation in disease settings. Most lncRNAs function by interacting with proteins or protein complexes. While several orthogonal methods have been developed to identify these proteins, each method has its inherent strengths and limitations. Here, we combine two RNA-centric methods ChIRP-MS and RNA-BioID to obtain a comprehensive list of proteins that interact with the well-known lncRNA HOTAIR. Overexpression of HOTAIR has been associated with a metastasis-promoting phenotype in various cancers. Although HOTAIR is known to bind with PRC2 and LSD1 protein complexes, only very limited unbiased comprehensive approaches to map its interactome have been performed. Both ChIRP-MS and RNA-BioID data sets show an association of HOTAIR with mitoribosomes, suggesting that HOTAIR has functions independent of its (post-)transcriptional mode-of-action.
Upregulated heme biosynthesis increases obstructive sleep apnea severity: a pathway-based Mendelian randomization study
Authors: Wang Heming , Kurniansyah Nuzulul , Cade Brian E. , Goodman Matthew O. , Chen Han , Gottlieb Daniel J. , Gharib Sina A. , Purcell Shaun M. , Lin Xihong , Saxena Richa , Zhu Xiaofeng , Durda Peter , Tracy Russel , Liu Yongmei , Taylor Kent D. , Johnson W. Craig , Gabriel Stacey , Smith Joshua D. , Aguet François , Ardlie Kirstin , Blackwell Tom , Reiner Alexander P. , Rotter Jerome I. , Rich Stephen S. ,   TOPMed Sleep Traits Working Group, Ayas Najib , Burkardt Deepika , Cade Brian , Chen Han , Clarkson-Townsend Danielle , Dutta Joyita , Ekunwe Lynette , Floyd Caitlin , Gharib Sina , Goodman Matthew , Gottlieb Daniel , Granot-Hershkovitz Einat , Hale Lauren , Hanly Patrick , Heemann Scott , Hsiung Chao , Huang Tianyi , Justice Anne , Keenan Brendan , Lane Jacqueline , Liang Jingjing , Lin Xihong , Liu Jiayan , Lorincz-Comi Noah , Magalang Ulysses , Mazzotti Diego R. , Mei Hao , Mikulla Julie , Miller Amy , Moafi-Madani Miremad , Ngo Debby , O’Connell Jeff , Ochs-Balcom Heather , Pack Allan , Patel Sanjay , Purcell Shaun , Redline Susan , Saxena Richa , Soemedi Rachel , Sofer Tamar , Sul Jae Hoon , Sunyaev Shamil , Tchio Cynthia , Wang Heming , Wilson Ava , Xia Lluvia , Zhang Man , Zhou Hufeng , Zhu Xiaofeng , Redline Susan , Sofer Tamar
Published: January 2022

Obstructive sleep apnea (OSA) is a common disorder associated with increased risk of cardiovascular disease and mortality. Iron and heme metabolism, implicated in ventilatory control and OSA comorbidities, was associated with OSA phenotypes in recent admixture mapping and gene enrichment analyses. However, its causal contribution was unclear. In this study, we performed pathway-level transcriptional Mendelian randomization (MR) analysis to investigate the causal relationships between iron and heme related pathways and OSA. In primary analysis, we examined the expression level of four iron/heme Reactome pathways as exposures and four OSA traits as outcomes using cross-tissue cis-eQTLs from the Genotype-Tissue Expression portal and published genome-wide summary statistics of OSA. We identify a significant putative causal association between up-regulated heme biosynthesis pathway with higher sleep time percentage of hypoxemia (p = 6.14 × 10–3). This association is supported by consistency of point estimates in one-sample MR in the Multi-Ethnic Study of Atherosclerosis using high coverage DNA and RNA sequencing data generated by the Trans-Omics for Precision Medicine project. Secondary analysis for 37 additional iron/heme Gene Ontology pathways did not reveal any significant causal associations. This study suggests a causal association between increased heme biosynthesis and OSA severity.
Identification of type of threading dislocation causing reverse leakage in GaN p–n junctions after continuous forward current stress
Authors: Narita Tetsuo , Kanechika Masakazu , Kojima Jun , Watanabe Hiroki , Kondo Takeshi , Uesugi Tsutomu , Yamaguchi Satoshi , Kimoto Yasuji , Tomita Kazuyoshi , Nagasato Yoshitaka , Ikeda Satoshi , Kosaki Masayoshi , Oka Tohru , Suda Jun
Published: January 2022

Power devices are operated under harsh conditions, such as high currents and voltages, and so degradation of these devices is an important issue. Our group previously found significant increases in reverse leakage current after applying continuous forward current stress to GaN p–n junctions. In the present study, we identified the type of threading dislocations that provide pathways for this reverse leakage current. GaN p–n diodes were grown by metalorganic vapor phase epitaxy on freestanding GaN(0001) substrates with threading dislocation densities of approximately 3 × 105 cm−2. These diodes exhibited a breakdown voltage on the order of 200 V and avalanche capability. The leakage current in some diodes in response to a reverse bias was found to rapidly increase with continuous forward current injection, and leakage sites were identified by optical emission microscopy. Closed-core threading screw dislocations (TSDs) were found at five emission spots based on cross-sectional transmission electron microscopy analyses using two-beam diffraction conditions. The Burgers vectors of these dislocations were identified as [0001] using large-angle convergent-beam electron diffraction. Thus, TSDs for which b = 1c are believed to provide current leakage paths in response to forward current stress.
Gastric cancer cell death analyzed by live cell imaging of spheroids
Authors: Alzeeb George , Arzur Danielle , Trichet Valérie , Talagas Matthieu , Corcos Laurent , Le Jossic-Corcos Catherine
Published: January 2022

Gastric cancer (GC) is the third cause of cancer-related mortality worldwide and is often diagnosed at advanced stages of the disease. This makes the development of more comprehensive models and efficient treatments crucial. One option is based on repurposing already marketed drugs as adjuvants to chemotherapy. Accordingly, we have previously developed the combination of docetaxel and the cholesterol-lowering drug, lovastatin, as a powerful trigger of HGT-1 human GC cells’ apoptosis using 2D cultures. Because 3D models, known as spheroids, are getting recognized as possibly better suited than 2Ds in toxicological research, we aimed to investigate the efficacy of this drug combination with such a model. We established monocellular spheroids from two human (GC) cell lines, HGT-1 and AGS, and bicellular spheroids from these cells mixed with cancer-associated fibroblasts. With these, we surveyed drug-induced cytotoxicity with MTT assays. In addition, we used the Incucyte live imaging and analysis system to follow spheroid growth and apoptosis. Taken together, our results showed that the lovastatin + docetaxel combination was an efficient strategy to eliminate GC cells grown in 2D or 3D cultures, lending further support in favor of repurposing lovastatin as an adjuvant to taxane-based anticancer treatment.
Reference intervals for coagulation parameters in non-pregnant and pregnant women
Authors: Fu Mengyu , Liu Junjie , Xing Jinfang , Dai Yanpeng , Ding Yanzi , Dong Kainan , Zhang Xuewei , Yuan Enwu
Published: January 2022

Established reference intervals (RIs) of coagulation parameters generally based on the general population are not applicable to specific women. In order to accurately evaluate the coagulation status of non-pregnant women and pregnant women, specific RIs should be established. Our study recruited 465 non-pregnant women and 1972 pregnant women aged 20–45 years. Eight tests including antithrombin (AT), protein C (PC), free protein S (fPS), lupus anticoagulant (LA), D-dimer, fibrin/fibrinogen degradation products (FDP), coagulation factor VII (FVII), and factor VIII (FVIII) were performed on ACL TOP automated coagulation instrument. The RIs for these tests were established in non-pregnant and pregnant women at different gestational weeks. Compared to the non-pregnant group, the medians of AT and fPS were lower, while the medians of PC, LA normalized ratio, D-dimer, FDP, FVII, and FVIII were higher. During pregnancy, AT and fPS activity showed a decreasing trend, with the increase of gestational age. PC activity, LA normalized ratio, D-dimer concentrations, FDP concentrations, FVII, and FVIII activity presented an increasing trend, with the increase of gestational age. The non-pregnant women-specific RIs and the gestational age-specific RIs of AT, PC, fPS, LA normalized ratio, D-dimer, FDP, FVII, and FVIII needed to be established for accurate clinical diagnoses.
Effects of working memory load on frontal connectivity in children with autism spectrum disorder: a fNIRS study
Authors: Han Yvonne M. Y. , Chan Ming-Chung , Chan Melody M. Y. , Yeung Michael K. , Chan Agnes S.
Published: January 2022

Individuals with autism spectrum disorder (ASD) perform poorly in working memory (WM) tasks, with some literature suggesting that their impaired performance is modulated by WM load. While some neuroimaging and neurophysiological studies have reported altered functional connectivity during WM processing in individuals with autism, it remains largely unclear whether such alterations are moderated by WM load. The present study aimed to examine the effect of WM load on functional connectivity within the prefrontal cortex (PFC) in ASD using functional near-infrared spectroscopy (fNIRS). Twenty-two children with high-functioning ASD aged 8–12 years and 24 age-, intelligent quotient (IQ)-, sex- and handedness-matched typically developing (TD) children performed a number n-back task with three WM loads (0-back, 1-back, and 2-back). Hemodynamic changes in the bilateral lateral and medial PFC during task performance were monitored using a multichannel NIRS device. Children with ASD demonstrated slower reaction times, specifically during the “low load” condition, than TD children. In addition, the ASD and TD groups exhibited differential load-dependent functional connectivity changes in the lateral and medial PFC of the right but not the left hemisphere. These findings indicate that WM impairment in high-functioning ASD is paralleled by load-dependent alterations in right, but not left, intrahemispheric connectivity during WM processing in children with ASD. A disruption of functional neural connections that support different cognitive processes may underlie poor performance in WM tasks in ASD.
The dynamic gut microbiota of zoophilic members of the Anopheles gambiae complex (Diptera: Culicidae)
Authors: Singh Ashmika , Allam Mushal , Kwenda Stanford , Khumalo Zamantungwa T. H. , Ismail Arshad , Oliver Shüné V.
Published: January 2022

The gut microbiota of mosquitoes plays a critical role in the life history of the animal. There is a growing body of research characterising the gut microbiota of a range of mosquito species, but there is still a paucity of information on some members of the Anopheles gambiae complex. In this study, the gut microbiota of four laboratory strains were characterised. SENN (Anopheles arabiensis—insecticide susceptible major vector), SENN DDT (Anopheles arabiensis—insecticide resistant major vector), MAFUS (Anopheles merus—minor vector) and SANGWE (Anopheles quadriannulatus—non-vector) were used in this study. The microbiota of fourth instar larvae, 3-day old, 15-day old non-blood fed and 15-day old blood fed females were characterised by MALDI-TOF mass spectroscopy and 16 s rRNA gene sequencing by next generation sequencing. The four strains differed in species richness but not diversity. The major vectors differ in β-diversity from that of the minor and non-vectors. There was no difference in α- or β-diversity in 15 non-blood fed females and 15-day old females that had 3 blood meals before day 15. These differences may be related to a mixture of the effect of insecticide resistance phenotype as well as a potential relationship to vector competence to a limited extent. Bacterial diversity is affected by species and age. There is also a potential relationship between the differences in gut microbiota and capacity to transmit parasites. This genetic background of the mosquitoes, however, play a major role, and must be considered in this relationship.
Microstructure of unsaturated loess and its influence on strength characteristics
Authors: Wei Ya-zhi , Yao Zhi-hua , Chong Xiao-lei , Zhang Jian-hua , Zhang Jun
Published: January 2022

Previous studies have shown that structure has a significant influence on the mechanical deformation of unsaturated loess, but there is little published information focused on the influence mechanism of microstructure and mesostructure on the mechanical properties of loess. In this paper, the unsaturated undisturbed loess and its remolded loess under the same physical condition were taken as the research objects. The unsaturated triaxial shear tests with constant suction and net confining pressure were carried out, and the microstructure differences between the two are compared by using SEM and CT scanning to reveal the influence of structure on strength characteristics. The test results show that the cohesion and internal friction angle of undisturbed loess are greater than those of remolded loess. The angle of undisturbed soil particles is obvious, and the particles are bracket contact with good cementation. The remolded loess particles are close to round shape, and the particles are inlaid contact with destroyed cementation. The average radius of undisturbed soil is higher than that of remolded soil, indicating that there are bracket pores in undisturbed soil, but the bracket structure and macropores are deformed during shear deformation, and good structural and cementation ensure the strength of loess specimens.
Characterization of a novel non-steroidal glucocorticoid receptor agonist optimized for topical treatment
Authors: Eirefelt Stefan , Stahlhut Martin , Svitacheva Naila , Carnerup Martin A. , Da Rosa Joel Mauricio Correa , Ewald David Adrian , Marstrand Troels T. , Krogh-Madsen Mikkel , Dünstl Georg , Dack Kevin Neil , Ollerstam Anna , Norsgaard Hanne
Published: January 2022

Glucocorticoids (GCs) are commonly used topical treatments for skin diseases but are associated with both local and systemic side effects. In this study, we describe a selective non-steroidal glucocorticoid receptor (GR) agonist for topical use, LEO 134310, which is rapidly deactivated in the blood resulting in low systemic exposure and a higher therapeutic index in the TPA-induced skin inflammation mouse model compared with betamethasone valerate (BMV) and clobetasol propionate (CP). Selectivity of LEO 134310 for GR was confirmed within a panel of nuclear receptors, including the mineralocorticoid receptor (MR), which has been associated with induction of skin atrophy. Topical treatment with LEO 134310 in minipigs did not result in any significant reduction in epidermal thickness in contrast to significant epidermal thinning induced by treatment with BMV and CP. Thus, the profile of LEO 134310 may potentially provide an effective and safer treatment option for skin diseases compared with currently used glucocorticoids.
Intranasal calcitonin gene-related peptide administration impairs fear memory retention in mice through the PKD/p-HDAC5/Npas4 pathway
Authors: Hashikawa-Hobara Narumi , Yoneyama Yoshikazu , Fujiwara Kyoushiro , Hashikawa Naoya
Published: January 2022

The calcitonin gene-related peptide (CGRP) suppresses fear memory retention in mice. Although intracerebroventricular administration of CGRP alters the fear memory processes, making it a promising therapeutic strategy for post-traumatic stress disorder (PTSD), direct brain injection into patients is not practical. Therefore, we propose that intranasal application may be an effective way to deliver CGRP to the brain. This study tested whether CGRP nasal administration exerts the same effect as intracerebroventricular administration using C57BL6J mice. The amount of CGRP in the cerebrospinal fluid and hippocampus 30 min after nasal administration of CGRP was significantly higher when compared with saline. Intranasal CGRP also elicited photophobic behaviors similar to intracerebroventricular injection. Moreover, intranasal CGRP decreased fear memory retention but did not affect reactivation and extinction of fear memory. We found intranasal CGRP significantly increased the expression of protein kinase D (PKD), phosphorylated histone deacetylase 5 (p-HDAC5) and neuronal PAS domain protein 4 (Npas4) in the hippocampus. CGRP-mediated impairment of fear memory and Npas4 expression increases were attenuated significantly by the CGRP receptor antagonist BIBN4096. Together, our data demonstrate that intranasal CGRP delivery activates the PKD/p-HDAC5/Npas4 pathway, decreases fear memory retention.
Ependymoma associated protein Zfta is expressed in immature ependymal cells but is not essential for ependymal development in mice
Authors: Herranz-Pérez Vicente , Nakatani Jin , Ishii Masaki , Katada Toshiaki , García-Verdugo Jose Manuel , Ohata Shinya
Published: January 2022

The fusion protein of uncharacterised zinc finger translocation associated (ZFTA) and effector transcription factor of tumorigenic NF-κB signalling, RELA (ZFTA-RELA), is expressed in more than two-thirds of supratentorial ependymoma (ST-EPN-RELA), but ZFTA’s expression profile and functional analysis in multiciliated ependymal (E1) cells have not been examined. Here, we showed the mRNA expression of mouse Zfta peaks on embryonic day (E) 17.5 in the wholemount of the lateral walls of the lateral ventricle. Zfta was expressed in the nuclei of FoxJ1-positive immature E1 (pre-E1) cells in E18.5 mouse embryonic brain. Interestingly, the transcription factors promoting ciliogenesis (ciliary TFs) (e.g., multicilin) and ZFTA-RELA upregulated luciferase activity using a 5′ upstream sequence of ZFTA in cultured cells. Zftatm1/tm1 knock-in mice did not show developmental defects or abnormal fertility. In the Zftatm1/tm1 E1 cells, morphology, gene expression, ciliary beating frequency and ependymal flow were unaffected. These results suggest that Zfta is expressed in pre-E1 cells, possibly under the control of ciliary TFs, but is not essential for ependymal development or flow. This study sheds light on the mechanism of the ZFTA-RELA expression in the pathogenesis of ST-EPN-RELA: Ciliary TFs initiate ZFTA-RELA expression in pre-E1 cells, and ZFTA-RELA enhances its own expression using positive feedback.
Innovative composite tool use by Goffin’s cockatoos (Cacatua goffiniana)
Authors: Osuna-Mascaró Antonio J. , Mundry Roger , Tebbich Sabine , Beck Sarah R. , Auersperg Alice M. I.
Published: January 2022

Composite tool use (using more than one tool simultaneously to achieve an end) has played a significant role in the development of human technology. Typically, it depends on a number of specific and often complex spatial relations and there are thus very few reported cases in non-human animals (e.g., specific nut-cracking techniques in chimpanzees and capuchin monkeys). The innovative strategies underlying the innovation and spread of tool manufacture and associative tool use (using > 1 tools) across tool using animals is an important milestone towards a better understanding of the evolution of human technology. We tested Goffin’s cockatoos on a composite tool problem, the ‘Golf Club Task’, that requires the use of two objects in combination (one used to control the free movement of a second) to get a reward. We demonstrate that these parrots can innovate composite tool use by actively controlling the position of the end effector and movement of both objects involved in a goal directed manner. The consistent use of different techniques by different subjects highlights the innovative nature of the individual solutions. To test whether the solution could be socially transmitted, we conducted a second study, which provided only tentative evidence for emulative learning. To our knowledge, this indicates that the cognitive preconditions for composite tool use have also evolved outside the primate lineage.
Planar ultrasonic transducer based on a metasurface piezoelectric ring array for subwavelength acoustic focusing in water
Authors: Hur Shin , Choi Hyunggyu , Yoon Gil Ho , Kim Nam Woon , Lee Duck-Gyu , Kim Yong Tae
Published: January 2022

The development of a new ultrasonic transducer capable of improved focusing performance has become a necessity to overcome the limitations of conventional ultrasonic transducer technology. In this study, we designed and optimized a metasurface piezoelectric ring device, and using multiphysics finite element analysis, we examined the performance of a planar ultrasonic transducer consisting of this device, a matching layer, a backing layer, and housing in producing a needle-like subwavelength focusing beam in water. For practical experiments, a metasurface piezoelectric ring device was fabricated using a laser ablation process. Subsequently, using a pulse-echo test, we found that the − 6 dB bandwidth of a planar ultrasonic transducer with a center frequency of 1.0 MHz was 37.5%. In addition, the results of an ultrasonic-focusing performance test showed that the full width at half-maximum of the axial subwavelength focusing beam was 0.78λ, and the full lateral width at half-maximum of the subwavelength lateral focusing beam was 7.03λ at a distance of 10.89λ. The needle-like focused ultrasonic beam technology implemented with a piezoelectric ring array based new planar ultrasound transducer is expected to be used in high-resolution imaging devices or medical ultrasound focusing devices in the future.
Sodium–calcium exchanger isoform-3 targeted Withania somnifera (L.) Dunal therapeutic intervention ameliorates cognition in the 5xFAD mouse model of Alzheimer’s disease
Authors: Afewerky Henok Kessete , Li Hao , Zhang Tongmei , Li Xinyan , Mahaman Yacoubou Abdoul Razak , Duan Limin , Qin Pengwei , Zheng Jiequn , Pei Lei , Lu Youming
Published: January 2022

The third isoform of the Na+–Ca2+ exchanger (NCX3) is crucial for a physiological fine-tuning of the Ca2+ fluxes in excitable tissues. In this view, the NCX3 accounts for the aberrant Ca2+ influx seen during neuronal excitotoxicity, such as in Alzheimer’s disease (AD). However, little is known about NCX3 regulation and functional properties. Withania somnifera (L.) Dunal (W. somnifera), a traditional indigenous plant widely recognized for having numerous medicinal values, was undertaken to determine its potential therapeutic benefit against aggregated Aβ1–42-induced NCX3 dysregulation and the thereof cognition impairment in 5xFAD mice. The undertaken sourced dried roots of authenticated W. somnifera physicochemical compositional tests satisfied standards of pharmacognostic quality, and further phytochemical analysis of the roots methanol extract revealed the roots constitute several antioxidants. Following an intra-gastric gavage administration of synthesized W. somnifera roots methanolic extract from postnatal day 30 (P30) to P75, in vivo cognitional studies and then neurochemical examinations of the NCX3 expression level, Aβ plaque deposition, and antioxidant activities in the AD-associated brain regions of 4-month-old 5xFAD mice suggests that the oxidative stress normalizing effects of W. somnifera constituents, operating on the NCX3, may have a therapeutic role in the improvement of cognition in AD.
Classification of brain tumours in MR images using deep spatiospatial models
Authors: Chatterjee Soumick , Nizamani Faraz Ahmed , Nürnberger Andreas , Speck Oliver
Published: January 2022

A brain tumour is a mass or cluster of abnormal cells in the brain, which has the possibility of becoming life-threatening because of its ability to invade neighbouring tissues and also form metastases. An accurate diagnosis is essential for successful treatment planning, and magnetic resonance imaging is the principal imaging modality for diagnosing brain tumours and their extent. Deep Learning methods in computer vision applications have shown significant improvement in recent years, most of which can be credited to the fact that a sizeable amount of data is available to train models, and the improvements in the model architectures yield better approximations in a supervised setting. Classifying tumours using such deep learning methods has made significant progress with the availability of open datasets with reliable annotations. Typically those methods are either 3D models, which use 3D volumetric MRIs or even 2D models considering each slice separately. However, by treating one spatial dimension separately or by considering the slices as a sequence of images over time, spatiotemporal models can be employed as “spatiospatial” models for this task. These models have the capabilities of learning specific spatial and temporal relationships while reducing computational costs. This paper uses two spatiotemporal models, ResNet (2+1)D and ResNet Mixed Convolution, to classify different types of brain tumours. It was observed that both these models performed superior to the pure 3D convolutional model, ResNet18. Furthermore, it was also observed that pre-training the models on a different, even unrelated dataset before training them for the task of tumour classification improves the performance. Finally, Pre-trained ResNet Mixed Convolution was observed to be the best model in these experiments, achieving a macro F1-score of 0.9345 and a test accuracy of 96.98%, while at the same time being the model with the least computational cost.
Reliability and validity of ultrasound to measure of muscle mass following allogeneic hematopoietic stem cell transplantation
Authors: Hashida Nao , Tada Yuma , Suzuki Masayuki , Ito Kumiko , Kato Yuji , Tamiya Hironari , Ishikawa Jun
Published: January 2022

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients frequently show physical dysfunction due to loss of muscle mass. This study aimed to clarify the reliability and validity of ultrasound in evaluating muscle mass and to analyze the patterns of change in muscle mass before and after allo-HSCT. We conducted a prospective observational study using data from 68 patients who had undergone their first allo-HSCT. We evaluated the thickness of the quadriceps, biceps, and suprahyoid muscle. Three individual evaluators underwent this examination for each muscle before transplantation and on days 30, 90, and 180 after allo-HSCT. Inter-rater reliability was calculated using the interclass correlation (ICC), and the level of correlation between muscle mass measured by ultrasound and psoas muscle mass assessed using computed tomography (CT) was assessed using Pearson correlation. ICC values ranged from 0.897 to 0.977 in the measurement. The correlation scores were 0.730, 0.546 and 0.579 between psoas muscle and the biceps, quadriceps, and suprahyoid muscle. The thickness of the biceps and quadriceps muscle were both significantly decreased after allo-HSCT from baseline. These results showed that the ultrasound technique was a reliable tool for evaluating muscle mass and detecting changes in muscle mass following allo-HSCT.
Effect of subjective vertical perception on lateral flexion posture of patients with Parkinson’s disease
Authors: Mikami Kyohei , Shiraishi Makoto , Kamo Tsutomu
Published: January 2022

In a retrospective study we tested our hypothesis that the subjective postural vertical ratio (SPV ratio), i.e., the subjective postural vertical measured in relation to the lateral flexion axis, is predictive of lateral trunk flexion in patients with Parkinson's disease (PD). Twenty-five patients were included. The SPV angle, i.e., the subjective perception of a vertical position with reference to the vertical axis, and the SPV ratio, i.e., the SPV angle with reference to the axis of lateral flexion, were calculated. The SPV ratio (r = 0.698, P = 0.001) and LTF angle (r =  − 0.601, P = 0.001) correlated with change in the LTF angle at 1 year. The SPV ratio was significantly smaller in patients for whom lateral trunk flexion improved (n = 12) than in those for whom it did not improve (n = 13) (0.99 ± 0.78 vs 1.66 ± 0.71, P = 0.011). The AUC under the ROC curve of the SPV ratio for discrimination of improvement was 0.795 (95% confidence interval: 0.61–0.98). We found that the SPV ratio is associated with change in the LTF and that it can conceivably be used to predict the likelihood of improvement in PD-associated lateral trunk flexion.
Precision cancer genome testing needs proficiency testing involving all stakeholders
Authors: Maekawa Masato , Taniguchi Terumi , Nishio Kazuto , Sakai Kazuko , Matsushita Kazuyuki , Nakatani Kaname , Ishige Takayuki , Ikejiri Makoto , Nishihara Hiroshi , Sunami Kuniko , Yatabe Yasushi , Hatanaka Kanako C. , Hatanaka Yutaka , Yamamoto Yoshihiro , Fukuyama Keita , Oda Shinya , Saito Kayoko , Yokomura Mamoru , Kubo Yuji , Sato Hiroko , Tanaka Yoshinori , Fuchioka Misa , Yamasaki Tadashi , Matsuda Koichiro , Kurachi Kiyotaka , Funai Kazuhiro , Baba Satoshi , Iwaizumi Moriya
Published: January 2022

To implement precision oncology, analytical validity as well as clinical validity and utility are important. However, proficiency testing (PT) to assess validity has not yet been systematically performed in Japan. To investigate the quality of next-generation sequencing (NGS) platforms and cancer genome testing prevalent in laboratories, we performed pilot PT using patient samples. We prepared genomic DNA from the cancer tissue and peripheral blood of 5 cancer patients and distributed these to 15 laboratories. Most participating laboratories successfully identified the pathogenic variants, except for two closely located KRAS variants and 25 bp delins in EGFR. Conversely, the EGFR L858R variant was successfully identified, and the allele frequency was similar for all the laboratories. A high DNA integrity number led to excellent depth and reliable NGS results. By conducting this pilot study using patient samples, we were able to obtain a glimpse of the current status of cancer genome testing at participating laboratories. To enhance domestic cancer genome testing, it is important to conduct local PT and to involve the parties concerned as organizers and participants.
Barrier removal and dynamics of intermittent stream habitat regulate persistence and structure of fish community
Authors: Kukuła Krzysztof , Bylak Aneta
Published: January 2022

Barrier effects observed in the presence of weirs are exacerbated by low water levels. We conducted a 10-year study to assess the ecological effects of stream restoration while analysing the possibility of a seasonal lack of hydrological continuity, with multiple measurements before and after restoring stream structural continuity. The research hypothesis assumes that in intermittent streams, there would be little or no change in the fish community downstream the barrier before vs. after barrier removal, and a significant change upstream the barrier before vs. after. Our results indicate, that by removing small barriers, their detrimental effects on the longitudinal passage of riverine fishes and fish assemblages can be rehabilitated. In the wet season, fish migrants from the mainstem river appeared in the downstream section of the stream. Stream intermittency, however, placed a habitat filter over the assemblage. Thus, after barrier removal, only two small-bodied fish species that tolerate periodic oxygen deficiencies and rising water temperatures gradually shifted upstream and formed stable populations. We emphasize, that we should not refrain from restoring the longitudinal continuity of intermittent streams, because they periodically provide fish valuable refugia and can also be a source of new generations and strengthen fish populations in mainstem river.
Genomic landscape and immune-related gene expression profiling of epithelial ovarian cancer after neoadjuvant chemotherapy
Authors: Lodewijk I. , Bernardini A. , Suárez-Cabrera C. , Bernal E. , Sánchez R. , Garcia J. L. , Rojas K. , Morales L. , Wang S. , Han X. , Dueñas M. , Paramio J. M. , Manso L.
Published: January 2022

Platinum-based neoadjuvant chemotherapy followed by interval debulking surgery is an accepted treatment for patients with stage III or IV epithelial ovarian cancer who are not suitable for primary debulking surgery. The identification of suitable adjuvant treatments in these patients is an unmet need. Here, we explore potential genomic characteristics (mutational and immune-associated expression profiles) in a series of patients undergoing neoadjuvant chemotherapy. Tumor samples from biopsy and interval debulking surgery were analyzed for mutational landscape and immune profiling, together with detailed immunohistochemistry using different immune cell markers, and correlated with clinicopathological characteristics and potential response to neoadjuvant chemotherapy. No major differences in the mutational landscape were observed in paired biopsy and surgery samples. Genomic loss of heterozygosity was found to be higher in patients with total/near-total tumor response. The immune gene expression profile after neoadjuvant chemotherapy revealed activation of several immune regulation-related pathways in patients with no/minimal or partial response. In parallel, neoadjuvant therapy caused a significant increase of tumor-infiltrating lymphocyte population abundance, primarily due to an augmentation of the CD8+ T cell population. Remarkably, these changes occurred irrespective of potential homologous recombination defects, such as those associated with BRCA1/2 mutations. Our study strengthens the use of loss of heterozygosity as a biomarker of homologous repair deficiency. The changes of immune states during neoadjuvant chemotherapy reveal the dynamic nature of tumor-host immune interactions and suggest the potential use of immune checkpoint inhibitors or their combination with poly-ADP polymerase inhibitors in high stage and grade epithelial ovarian cancer patients undergoing neoadjuvant therapy.
PhenoPad: Building AI enabled note-taking interfaces for patient encounters
Authors: Wang Jixuan , Yang Jingbo , Zhang Haochi , Lu Helen , Skreta Marta , Husić Mia , Arbabi Aryan , Sultanum Nicole , Brudno Michael
Published: January 2022

Current clinical note-taking approaches cannot capture the entirety of information available from patient encounters and detract from patient-clinician interactions. By surveying healthcare providers’ current note-taking practices and attitudes toward new clinical technologies, we developed a patient-centered paradigm for clinical note-taking that makes use of hybrid tablet/keyboard devices and artificial intelligence (AI) technologies. PhenoPad is an intelligent clinical note-taking interface that captures free-form notes and standard phenotypic information via a variety of modalities, including speech and natural language processing techniques, handwriting recognition, and more. The output is unobtrusively presented on mobile devices to clinicians for real-time validation and can be automatically transformed into digital formats that would be compatible with integration into electronic health record systems. Semi-structured interviews and trials in clinical settings rendered positive feedback from both clinicians and patients, demonstrating that AI-enabled clinical note-taking under our design improves ease and breadth of information captured during clinical visits without compromising patient-clinician interactions. We open source a proof-of-concept implementation that can lay the foundation for broader clinical use cases.
Importance of CSF-based Aβ clearance with age in humans increases with declining efficacy of blood-brain barrier/proteolytic pathways
Authors: Elbert Donald L. , Patterson Bruce W. , Lucey Brendan P. , Benzinger Tammie L. S. , Bateman Randall J.
Published: January 2022

The kinetics of amyloid beta turnover within human brain is still poorly understood. We previously found a dramatic decline in the turnover of Aβ peptides in normal aging. It was not known if brain interstitial fluid/cerebrospinal fluid (ISF/CSF) fluid exchange, CSF turnover, blood-brain barrier function or proteolysis were affected by aging or the presence of β amyloid plaques. Here, we describe a non-steady state physiological model developed to decouple CSF fluid transport from other processes. Kinetic parameters were estimated using: (1) MRI-derived brain volumes, (2) stable isotope labeling kinetics (SILK) of amyloid-β peptide (Aβ), and (3) lumbar CSF Aβ concentration during SILK. Here we show that changes in blood-brain barrier transport and/or proteolysis were largely responsible for the age-related decline in Aβ turnover rates. CSF-based clearance declined modestly in normal aging but became increasingly important due to the slowing of other processes. The magnitude of CSF-based clearance was also lower than that due to blood-brain barrier function plus proteolysis. These results suggest important roles for blood-brain barrier transport and proteolytic degradation of Aβ in the development Alzheimer’s Disease in humans.
Strain and pseudo-magnetic fields in optical lattices from density-assisted tunneling
Authors: Jamotte Maxime , Goldman Nathan , Di Liberto Marco
Published: January 2022

Applying time-periodic modulations is routinely used to control and design synthetic matter in quantum-engineered settings. In lattice systems, this approach is explored to engineer band structures with non-trivial topological properties, but also to generate exotic interaction processes. A prime example is density-assisted tunneling, by which the hopping amplitude of a particle between neighboring sites explicitly depends on their respective occupations. Here, we show how density-assisted tunneling can be tailored in view of simulating the effects of strain in synthetic graphene-type systems. Specifically, we consider a mixture of two atomic species on a honeycomb optical lattice: one species forms a Bose-Einstein condensate in an anisotropic harmonic trap, whose inhomogeneous density profile induces an effective uniaxial strain for the second species through density-assisted tunneling processes. In direct analogy with strained graphene, the second species experiences a pseudo-magnetic field, hence exhibiting relativistic Landau levels and the valley Hall effect. Our proposed scheme introduces a unique platform for the investigation of strain-induced gauge fields, opening the door to future studies of their possible interplay with quantum fluctuations and collective excitations.