bluuebunny/crossref_metadata_2025 huggingface dataset:
Positive feedback of SuFu negating protein 1 on Hedgehog signaling promotes colorectal tumor growth
Authors: Yan Zhengwei , Cheng Minzhang , Hu Guohui , Wang Yao , Zeng Shaopeng , Huang Aidi , Xu Linlin , Liu Yuan , Shi Chao , Deng Libin , Lu Quqin , Rao Hai , Lu Hua , Chen Ye-Guang , Luo Shiwen
Published: February 2021

Hedgehog (Hh) signaling plays a critical role in embryogenesis and tissue homeostasis, and its deregulation has been associated with tumor growth. The tumor suppressor SuFu inhibits Hh signaling by preventing the nuclear translocation of Gli and suppressing cell proliferation. Regulation of SuFu activity and stability is key to controlling Hh signaling. Here, we unveil SuFu Negating Protein 1 (SNEP1) as a novel Hh target, that enhances the ubiquitination and proteasomal degradation of SuFu and thus promotes Hh signaling. We further show that the E3 ubiquitin ligase LNX1 plays a critical role in the SNEP1-mediated degradation of SuFu. Accordingly, SNEP1 promotes colorectal cancer (CRC) cell proliferation and tumor growth. High levels of SNEP1 are detected in CRC tissues and are well correlated with poor prognosis in CRC patients. Moreover, SNEP1 overexpression reduces sensitivity to anti-Hh inhibitor in CRC cells. Altogether, our findings demonstrate that SNEP1 acts as a novel feedback regulator of Hh signaling by destabilizing SuFu and promoting tumor growth and anti-Hh resistance.
ERBB4 exonic deletions on chromosome 2q34 in patients with intellectual disability or epilepsy
Authors: Hyder Zerin , Van Paesschen Wim , Sabir Ataf , Sansbury Francis H. , Burke Katherine B. , Khan Naz , Chandler Kate E. , Cooper Nicola S. , Wright Ronnie , McHale Edward , Van Esch Hilde , Banka Siddharth
Published: February 2021

ERBB4 encodes the tyrosine kinase receptor HER4, a critical regulator of normal cell function and neurodevelopmental processes in the brain. One of the key ligands of HER4 is neureglin-1 (NRG1), and the HER4-NRG1 signalling pathway is essential in neural crest cell migration, and neuronal differentiation. Pharmacological inactivation of HER4 has been shown to hasten the progression of epileptogenesis in rodent models, and heterozygous ERBB4 null mice are shown to have cognitive deficits and delayed motor development. Thus far there is only a single case report in the literature of a heterozygous ERBB4 deletion in a patient with intellectual disability (ID). We identified nine subjects from five unrelated families with chromosome 2q34 deletions, resulting in heterozygous intragenic loss of multiple exons of ERBB4, associated with either non-syndromic ID or generalised epilepsy. In one family, the deletion segregated with ID in five affected relatives. Overall, this case series further supports that haploinsufficiency of ERBB4 leads to non-syndromic intellectual disability or epilepsy.
Evolutionary history and genetic connectivity across highly fragmented populations of an endangered daisy
Authors: Rodger Yael S. , Pavlova Alexandra , Sinclair Steve , Pickup Melinda , Sunnucks Paul
Published: February 2021

Conservation management can be aided by knowledge of genetic diversity and evolutionary history, so that ecological and evolutionary processes can be preserved. The Button Wrinklewort daisy (Rutidosis leptorrhynchoides) was a common component of grassy ecosystems in south-eastern Australia. It is now endangered due to extensive habitat loss and the impacts of livestock grazing, and is currently restricted to a few small populations in two regions >500 km apart, one in Victoria, the other in the Australian Capital Territory and nearby New South Wales (ACT/NSW). Using a genome-wide SNP dataset, we assessed patterns of genetic structure and genetic differentiation of 12 natural diploid populations. We estimated intrapopulation genetic diversity to scope sources for genetic management. Bayesian clustering and principal coordinate analyses showed strong population genetic differentiation between the two regions, and substantial substructure within ACT/NSW. A coalescent tree-building approach implemented in SNAPP indicated evolutionary divergence between the two distant regions. Among the populations screened, the last two known remaining Victorian populations had the highest genetic diversity, despite having among the lowest recent census sizes. A maximum likelihood population tree method implemented in TreeMix suggested little or no recent gene flow except potentially between very close neighbours. Populations that were more genetically distinctive had lower genetic diversity, suggesting that drift in isolation is likely driving population differentiation though loss of diversity, hence re-establishing gene flow among them is desirable. These results provide background knowledge for evidence-based conservation and support genetic rescue within and between regions to elevate genetic diversity and alleviate inbreeding.
Epigenetic responses of hare barley (Hordeum murinum subsp. leporinum) to climate change: an experimental, trait-based approach
Authors: Chano Víctor , Domínguez-Flores Tania , Hidalgo-Galvez Maria Dolores , Rodríguez-Calcerrada Jesús , Pérez-Ramos Ignacio Manuel
Published: February 2021

The impact of reduced rainfall and increased temperatures forecasted by climate change models on plant communities will depend on the capacity of plant species to acclimate and adapt to new environmental conditions. The acclimation process is mainly driven by epigenetic regulation, including structural and chemical modifications on the genome that do not affect the nucleotide sequence. In plants, one of the best-known epigenetic mechanisms is cytosine-methylation. We evaluated the impact of 30% reduced rainfall (hereafter “drought” treatment; D), 3 °C increased air temperature (“warming”; W), and the combination of D and W (WD) on the phenotypic and epigenetic variability ofHordeum murinumsubsp.leporinumL., a grass species of high relevance in Mediterranean agroforestry systems. A full factorial experiment was set up in a savannah-like ecosystem located in southwestern Spain.H. murinumexhibited a large phenotypic plasticity in response to climatic conditions. Plants subjected to warmer conditions (i.e., W and WD treatments) flowered earlier, and those subjected to combined stress (WD) showed a higher investment in leaf area per unit of leaf mass (i.e., higher SLA) and produced heavier seeds. Our results also indicated that both the level and patterns of methylation varied substantially with the climatic treatments, with the combination of D and W inducing a clearly different epigenetic response compared to that promoted by D and W separately. The main conclusion achieved in this work suggests a potential role of epigenetic regulation of gene expression for the maintenance of homoeostasis and functional stability under future climate change scenarios.
Erectile dysfunction in patients with anxiety disorders: a systematic review
Authors: Velurajah Rajalaxmi , Brunckhorst Oliver , Waqar Muhammad , McMullen Isabel , Ahmed Kamran
Published: February 2021

Men with anxiety disorders have been identified as high risk of developing erectile dysfunction (ED). The aim of this review is to define the prevalence and severity of ED in the male anxiety disorder population. A literature search of three electronic databases (PubMed, Embase and PsychINFO) and a grey literature registry was conducted. Inclusion criteria were studies that investigated adult males, documented diagnosis of anxiety disorders made by a qualified psychiatrist and use of a validated tool to diagnose ED such as International Index of Erectile Function or ICD-10/DSM-IV. The search yielded 1220 articles and 12 studies were selected. The anxiety disorders investigated were post-traumatic stress disorder, obsessive–compulsive disorder, social phobia/social anxiety disorder and panic disorder. We found that the median [IQR] prevalence of ED was 20.0 [5.1–41.2]% and the median [IQR] International Index of Erectile Function-5 scores were 17.62 [13.88–20.88], indicating a mild to moderate severity. Our review suggests a high prevalence of ED in the anxiety disorder population and ED may be more severe in this cohort, therefore advocating this is an important clinical topic. However, the evidence is limited due to the high heterogeneity between the studies and more research is required in this field.
Social networks predict the life and death of honey bees
Authors: Wild Benjamin , Dormagen David M. , Zachariae Adrian , Smith Michael L. , Traynor Kirsten S. , Brockmann Dirk , Couzin Iain D. , Landgraf Tim
Published: February 2021

In complex societies, individuals’ roles are reflected by interactions with other conspecifics. Honey bees (Apis mellifera) generally change tasks as they age, but developmental trajectories of individuals can vary drastically due to physiological and environmental factors. We introduce a succinct descriptor of an individual’s social network that can be obtained without interfering with the colony. This ‘network age’ accurately predicts task allocation, survival, activity patterns, and future behavior. We analyze developmental trajectories of multiple cohorts of individuals in a natural setting and identify distinct developmental pathways and critical life changes. Our findings suggest a high stability in task allocation on an individual level. We show that our method is versatile and can extract different properties from social networks, opening up a broad range of future studies. Our approach highlights the relationship of social interactions and individual traits, and provides a scalable technique for understanding how complex social systems function.
Dysregulated transcriptional responses to SARS-CoV-2 in the periphery
Authors: McClain Micah T. , Constantine Florica J. , Henao Ricardo , Liu Yiling , Tsalik Ephraim L. , Burke Thomas W. , Steinbrink Julie M. , Petzold Elizabeth , Nicholson Bradly P. , Rolfe Robert , Kraft Bryan D. , Kelly Matthew S. , Saban Daniel R. , Yu Chen , Shen Xiling , Ko Emily M. , Sempowski Gregory D. , Denny Thomas N. , Ginsburg Geoffrey S. , Woods Christopher W.
Published: February 2021

SARS-CoV-2 infection has been shown to trigger a wide spectrum of immune responses and clinical manifestations in human hosts. Here, we sought to elucidate novel aspects of the host response to SARS-CoV-2 infection through RNA sequencing of peripheral blood samples from 46 subjects with COVID-19 and directly comparing them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a powerful transcriptomic response in peripheral blood with conserved components that are heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, which persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95 [95% CI 0.92–0.98]). The transcriptome in peripheral blood reveals both diverse and conserved components of the immune response in COVID-19 and provides for potential biomarker-based approaches to diagnosis.
Ingredients for microbial life preserved in 3.5 billion-year-old fluid inclusions
Authors: Mißbach Helge , Duda Jan-Peter , van den Kerkhof Alfons M. , Lüders Volker , Pack Andreas , Reitner Joachim , Thiel Volker
Published: February 2021

It is widely hypothesised that primeval life utilised small organic molecules as sources of carbon and energy. However, the presence of such primordial ingredients in early Earth habitats has not yet been demonstrated. Here we report the existence of indigenous organic molecules and gases in primary fluid inclusions in c. 3.5-billion-year-old barites (Dresser Formation, Pilbara Craton, Western Australia). The compounds identified (e.g., H2S, COS, CS2, CH4, acetic acid, organic (poly-)sulfanes, thiols) may have formed important substrates for purported ancestral sulfur and methanogenic metabolisms. They also include stable building blocks of methyl thioacetate (methanethiol, acetic acid) – a putative key agent in primordial energy metabolism and thus the emergence of life. Delivered by hydrothermal fluids, some of these compounds may have fuelled microbial communities associated with the barite deposits. Our findings demonstrate that early Archaean hydrothermal fluids contained essential primordial ingredients that provided fertile substrates for earliest life on our planet.
Single-cell transcriptional profiling of human thymic stroma uncovers novel cellular heterogeneity in the thymic medulla
Authors: Bautista Jhoanne L. , Cramer Nathan T. , Miller Corey N. , Chavez Jessica , Berrios David I. , Byrnes Lauren E. , Germino Joe , Ntranos Vasilis , Sneddon Julie B. , Burt Trevor D. , Gardner James M. , Ye Chun J. , Anderson Mark S. , Parent Audrey V.
Published: February 2021

The thymus’ key function in the immune system is to provide the necessary environment for the development of diverse and self-tolerant T lymphocytes. While recent evidence suggests that the thymic stroma is comprised of more functionally distinct subpopulations than previously appreciated, the extent of this cellular heterogeneity in the human thymus is not well understood. Here we use single-cell RNA sequencing to comprehensively profile the human thymic stroma across multiple stages of life. Mesenchyme, pericytes and endothelial cells are identified as potential key regulators of thymic epithelial cell differentiation and thymocyte migration. In-depth analyses of epithelial cells reveal the presence of ionocytes as a medullary population, while the expression of tissue-specific antigens is mapped to different subsets of epithelial cells. This work thus provides important insight on how the diversity of thymic cells is established, and how this heterogeneity contributes to the induction of immune tolerance in humans.
Notch2-mediated plasticity between marginal zone and follicular B cells
Authors: Lechner Markus , Engleitner Thomas , Babushku Tea , Schmidt-Supprian Marc , Rad Roland , Strobl Lothar J. , Zimber-Strobl Ursula
Published: February 2021

Follicular B (FoB) and marginal zone B (MZB) cells are functionally and spatially distinct mature B cell populations in the spleen, originating from a Notch2-dependent fate decision after splenic influx of immature transitional B cells. In the B cell follicle, a Notch2-signal is provided by DLL-1-expressing fibroblasts. However, it is unclear whether FoB cells, which are in close contact with these DLL-1 expressing fibroblasts, can also differentiate to MZB cells if they receive a Notch2-signal. Here, we show induced Notch2IC-expression in FoB cells re-programs mature FoB cells into bona fide MZB cells as is evident from the surface phenotype, localization, immunological function and transcriptome of these cells. Furthermore, the lineage conversion from FoB to MZB cells occurs in immunocompetent wildtype mice. These findings demonstrate plasticity between mature FoB and MZB cells that can be driven by a singular signaling event, the activation of Notch2.
Genome sequences reveal global dispersal routes and suggest convergent genetic adaptations in seahorse evolution
Authors: Li Chunyan , Olave Melisa , Hou Yali , Qin Geng , Schneider Ralf F. , Gao Zexia , Tu Xiaolong , Wang Xin , Qi Furong , Nater Alexander , Kautt Andreas F. , Wan Shiming , Zhang Yanhong , Liu Yali , Zhang Huixian , Zhang Bo , Zhang Hao , Qu Meng , Liu Shuaishuai , Chen Zeyu , Zhong Jia , Zhang He , Meng Lingfeng , Wang Kai , Yin Jianping , Huang Liangmin , Venkatesh Byrappa , Meyer Axel , Lu Xuemei , Lin Qiang
Published: February 2021

Seahorses have a circum-global distribution in tropical to temperate coastal waters. Yet, seahorses show many adaptations for a sedentary, cryptic lifestyle: they require specific habitats, such as seagrass, kelp or coral reefs, lack pelvic and caudal fins, and give birth to directly developed offspring without pronounced pelagic larval stage, rendering long-range dispersal by conventional means inefficient. Here we investigate seahorses’ worldwide dispersal and biogeographic patterns based on a de novo genome assembly ofHippocampus erectusas well as 358 re-sequenced genomes from 21 species. Seahorses evolved in the late Oligocene and subsequent circum-global colonization routes are identified and linked to changing dynamics in ocean currents and paleo-temporal seaway openings. Furthermore, the genetic basis of the recurring “bony spines” adaptive phenotype is linked to independent substitutions in a key developmental gene. Analyses thus suggest that rafting via ocean currents compensates for poor dispersal and rapid adaptation facilitates colonizing new habitats.
Aquila enables reference-assisted diploid personal genome assembly and comprehensive variant detection based on linked reads
Authors: Zhou Xin , Zhang Lu , Weng Ziming , Dill David L. , Sidow Arend
Published: February 2021

We introduce Aquila, a new approach to variant discovery in personal genomes, which is critical for uncovering the genetic contributions to health and disease. Aquila uses a reference sequence and linked-read data to generate a high quality diploid genome assembly, from which it then comprehensively detects and phases personal genetic variation. The contigs of the assemblies from our libraries cover >95% of the human reference genome, with over 98% of that in a diploid state. Thus, the assemblies support detection and accurate genotyping of the most prevalent types of human genetic variation, including single nucleotide polymorphisms (SNPs), small insertions and deletions (small indels), and structural variants (SVs), in all but the most difficult regions. All heterozygous variants are phased in blocks that can approach arm-level length. The final output of Aquila is a diploid and phased personal genome sequence, and a phased Variant Call Format (VCF) file that also contains homozygous and a few unphased heterozygous variants. Aquila represents a cost-effective approach that can be applied to cohorts for variation discovery or association studies, or to single individuals with rare phenotypes that could be caused by SVs or compound heterozygosity.
Crystal structure of a photosynthetic LH1-RC in complex with its electron donor HiPIP
Authors: Kawakami Tomoaki , Yu Long-Jiang , Liang Tai , Okazaki Koudai , Madigan Michael T. , Kimura Yukihiro , Wang-Otomo Zheng-Yu
Published: February 2021

Photosynthetic electron transfers occur through multiple components ranging from small soluble proteins to large integral membrane protein complexes. Co-crystallization of a bacterial photosynthetic electron transfer complex that employs weak hydrophobic interactions was achieved by using high-molar-ratio mixtures of a soluble donor protein (high-potential iron-sulfur protein, HiPIP) with a membrane-embedded acceptor protein (reaction center, RC) at acidic pH. The structure of the co-complex offers a snapshot of a transient bioenergetic event and revealed a molecular basis for thermodynamically unfavorable interprotein electron tunneling. HiPIP binds to the surface of the tetraheme cytochrome subunit in the light-harvesting (LH1) complex-associated RC in close proximity to the low-potential heme-1 group. The binding interface between the two proteins is primarily formed by uncharged residues and is characterized by hydrophobic features. This co-crystal structure provides a model for the detailed study of long-range trans-protein electron tunneling pathways in biological systems.
Innate cell profiles during the acute and convalescent phase of SARS-CoV-2 infection in children
Authors: Neeland Melanie R. , Bannister Samantha , Clifford Vanessa , Dohle Kate , Mulholland Kim , Sutton Philip , Curtis Nigel , Steer Andrew C. , Burgner David P. , Crawford Nigel W. , Tosif Shidan , Saffery Richard
Published: February 2021

Children have mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confirmed disease (COVID-19) compared to adults and the immunological mechanisms underlying this difference remain unclear. Here, we report acute and convalescent innate immune responses in 48 children and 70 adults infected with, or exposed to, SARS-CoV-2. We find clinically mild SARS-CoV-2 infection in children is characterised by reduced circulating subsets of monocytes (classical, intermediate, non-classical), dendritic cells and natural killer cells during the acute phase. In contrast, SARS-CoV-2-infected adults show reduced proportions of non-classical monocytes only. We also observe increased proportions of CD63+ activated neutrophils during the acute phase to SARS-CoV-2 in infected children. Children and adults exposed to SARS-CoV-2 but negative on PCR testing display increased proportions of low-density neutrophils that we observe up to 7 weeks post exposure. This study characterises the innate immune response during SARS-CoV-2 infection and household exposure in children.
Short-lived metal-centered excited state initiates iron-methionine photodissociation in ferrous cytochrome c
Authors: Reinhard Marco E. , Mara Michael W. , Kroll Thomas , Lim Hyeongtaek , Hadt Ryan G. , Alonso-Mori Roberto , Chollet Matthieu , Glownia James M. , Nelson Silke , Sokaras Dimosthenis , Kunnus Kristjan , Driel Tim Brandt van , Hartsock Robert W. , Kjaer Kasper S. , Weninger Clemens , Biasin Elisa , Gee Leland B. , Hodgson Keith O. , Hedman Britt , Bergmann Uwe , Solomon Edward I. , Gaffney Kelly J.
Published: February 2021

The dynamics of photodissociation and recombination in heme proteins represent an archetypical photochemical reaction widely used to understand the interplay between chemical dynamics and reaction environment. We report a study of the photodissociation mechanism for the Fe(II)-S bond between the heme iron and methionine sulfur of ferrous cytochrome c. This bond dissociation is an essential step in the conversion of cytochrome c from an electron transfer protein to a peroxidase enzyme. We use ultrafast X-ray solution scattering to follow the dynamics of Fe(II)-S bond dissociation and 1s3p (Kβ) X-ray emission spectroscopy to follow the dynamics of the iron charge and spin multiplicity during bond dissociation. From these measurements, we conclude that the formation of a triplet metal-centered excited state with anti-bonding Fe(II)-S interactions triggers the bond dissociation and precedes the formation of the metastable Fe high-spin quintet state.
High performance Wannier interpolation of Berry curvature and related quantities with WannierBerri code
Authors: Tsirkin Stepan S.
Published: February 2021

Wannier interpolation is a powerful tool for performing Brillouin zone integrals over dense grids of k points, which are essential to evaluate such quantities as the intrinsic anomalous Hall conductivity or Boltzmann transport coefficients. However, more complex physical problems and materials create harder numerical challenges, and computations with the existing codes become very expensive, which often prevents reaching the desired accuracy. In this article, I present a series of methods that boost the speed of Wannier interpolation by several orders of magnitude. They include a combination of fast and slow Fourier transforms, explicit use of symmetries, and recursive adaptive grid refinement among others. The proposed methodology has been implemented in the python code WannierBerri, which also aims to serve as a convenient platform for the future development of interpolation schemes for other phenomena.
Slow dynamics of disordered zigzag chain molecules in layered LiVS2 under electron irradiation
Authors: Katayama Naoyuki , Kojima Keita , Yamaguchi Tomoki , Hattori Sosuke , Tamura Shinya , Ohara Koji , Kobayashi Shintaro , Sugimoto Koudai , Ohta Yukinori , Saitoh Koh , Sawa Hiroshi
Published: February 2021

Electronic instabilities in transition metal compounds often spontaneously form orbital molecules, which consist of orbital-coupled metal ions at low temperature. Recent local structural studies utilizing the pair distribution function revealed that preformed orbital molecules appear disordered even in the high-temperature paramagnetic phase. However, it is unclear whether preformed orbital molecules are dynamic or static. Here, we provide clear experimental evidence of the slow dynamics of disordered orbital molecules realized in the high-temperature paramagnetic phase of LiVS2, which exhibits vanadium trimerization upon cooling below 314 K. Unexpectedly, the preformed orbital molecules appear as a disordered zigzag chain that fluctuate in both time and space under electron irradiation. Our findings should advance studies on soft matter physics realized in an inorganic material due to disordered orbital molecules.
A database of high-density surface electromyogram signals comprising 65 isometric hand gestures
Authors: Malešević Nebojša , Olsson Alexander , Sager Paulina , Andersson Elin , Cipriani Christian , Controzzi Marco , Björkman Anders , Antfolk Christian
Published: February 2021

Control of contemporary, multi-joint prosthetic hands is commonly realized by using electromyographic signals from the muscles remaining after amputation at the forearm level. Although this principle is trying to imitate the natural control structure where muscles control the joints of the hand, in practice, myoelectric control provides only basic hand functions to an amputee using a dexterous prosthesis. This study aims to provide an annotated database of high-density surface electromyographic signals to aid the efforts of designing robust and versatile electromyographic control interfaces for prosthetic hands. The electromyographic signals were recorded using 128 channels within two electrode grids positioned on the forearms of 20 able-bodied volunteers. The participants performed 65 different hand gestures in an isometric manner. The hand movements were strictly timed using an automated recording protocol which also synchronously recorded the electromyographic signals and hand joint forces. To assess the quality of the recorded signals several quantitative assessments were performed, such as frequency content analysis, channel crosstalk, and the detection of poor skin-electrode contacts.
Author Correction: Conventional analysis methods underestimate the plant-available pools of calcium, magnesium and potassium in forest soils
Authors: Bel Jérémie , Legout Arnaud , Saint-André Laurent , Hall Steven J. , Löfgren Stefan , Laclau Jean-Paul , van der Heijden Gregory
Published: February 2021

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Age-dependence of electromagnetic power and heat deposition in near-surface tissues in emerging 5G bands
Authors: Sacco Giulia , Pisa Stefano , Zhadobov Maxim
Published: February 2021

With the development of 5th generation (5G) mobile networks people of different ages will be exposed in the upper part of the microwave spectrum. From the perspective of non-ionizing radiation dosimetry, an accurate analysis of age-dependent electromagnetic power deposition and resulting heating is required. In this study, we evaluate the effect of age on exposure at 26 GHz and 60 GHz. A near-surface tissue model illuminated by a plane wave is used to asses the exposure considering both frequency-independent and frequency-dependent limits. The age-related variation of the skin thickness and tissue electromagnetic properties has been considered. Moreover, the blood flow decrease rate has been taken into account to assess the age-dependent heating. Our results demonstrate that the overall variations of the power density, specific absorption rate (SAR) and heating in the near-surface tissues are limited to about 10–15%. These variations are mainly due to the tissue permittivity and blood flow change with age. In contrast to the transmitted power density that increases with age, the peak SAR decreases at both frequencies. The peak steady-state heating increases from 5 to 70 years old by roughly 11% at 26 GHz and 13% at 60 GHz.
Machine learning classifies predictive kinematic features in a mouse model of neurodegeneration
Authors: Huang Ruyi , Nikooyan Ali A. , Xu Bo , Joseph M. Selvan , Damavandi Hamidreza Ghasemi , von Trotha Nathan , Li Lilian , Bhattarai Ashok , Zadeh Deeba , Seo Yeji , Liu Xingquan , Truong Patrick A. , Koo Edward H. , Leiter J. C. , Lu Daniel C.
Published: February 2021

Motor deficits are observed in Alzheimer’s disease (AD) prior to the appearance of cognitive symptoms. To investigate the role of amyloid proteins in gait disturbances, we characterized locomotion in APP-overexpressing transgenic J20 mice. We used three-dimensional motion capture to characterize quadrupedal locomotion on a treadmill in J20 and wild-type mice. Sixteen J20 mice and fifteen wild-type mice were studied at two ages (4- and 13-month). A random forest (RF) classification algorithm discriminated between the genotypes within each age group using a leave-one-out cross-validation. The balanced accuracy of the RF classification was 92.3 ± 5.2% and 93.3 ± 4.5% as well as False Negative Rate (FNR) of 0.0 ± 0.0% and 0.0 ± 0.0% for the 4-month and 13-month groups, respectively. Feature ranking algorithms identified kinematic features that when considered simultaneously, achieved high genotype classification accuracy. The identified features demonstrated an age-specific kinematic profile of the impact of APP-overexpression. Trunk tilt and unstable hip movement patterns were important in classifying the 4-month J20 mice, whereas patterns of shoulder and iliac crest movement were critical for classifying 13-month J20 mice. Examining multiple kinematic features of gait simultaneously could also be developed to classify motor disorders in humans.
A geo-chemo-mechanical study of a highly polluted marine system (Taranto, Italy) for the enhancement of the conceptual site model
Authors: Cotecchia F. , Vitone C. , Sollecito F. , Mali M. , Miccoli D. , Petti R. , Milella D. , Ruggieri G. , Bottiglieri O. , Santaloia F. , De Bellis P. , Cafaro F. , Notarnicola M. , Todaro F. , Adamo F. , Di Nisio A. , Lanzolla A. M. L. , Spadavecchia M. , Moretti M. , Agrosì G. , De Giosa F. , Fago P. , Lacalamita M. , Lisco S. , Manzari P. , Mesto E. , Romano G. , Scardino G. , Schingaro E. , Siniscalchi A. , Tempesta G. , Valenzano E. , Mastronuzzi G. , Cardellicchio N. , Di Leo A. , Spada L. , Giandomenico S. , Calò M. , Uricchio V. F. , Mascolo G. , Bagnuolo G. , Ciannarella R. , Tursi A. , Cipriano G. , Cotugno P. , Sion L. , Carlucci R. , Capasso G. , De Chiara G. , Pisciotta G. , Velardo R. , Corbelli V.
Published: February 2021

The paper presents the results of the analysis of the geo-chemo-mechanical data gathered through an innovative multidisciplinary investigation campaign in the Mar Piccolo basin, a heavily polluted marine bay aside the town of Taranto (Southern Italy). The basin is part of an area declared at high environmental risk by the Italian government. The cutting-edge approach to the environmental characterization of the site was promoted by the Special Commissioner for urgent measures of reclamation, environmental improvements and redevelopment of Taranto and involved experts from several research fields, who cooperated to gather a new insight into the origin, distribution, mobility and fate of the contaminants within the basin. The investigation campaign was designed to implement advanced research methodologies and testing strategies. Differently from traditional investigation campaigns, aimed solely at the assessment of the contamination state within sediments lying in the top layers, the new campaign provided an interpretation of the geo-chemo-mechanical properties and state of the sediments forming the deposit at the seafloor. The integrated, multidisciplinary and holistic approach, that considered geotechnical engineering, electrical and electronical engineering, geological, sedimentological, mineralogical, hydraulic engineering, hydrological, chemical, geochemical, biological fields, supported a comprehensive understanding of the influence of the contamination on the hydro-mechanical properties of the sediments, which need to be accounted for in the selection and design of the risk mitigation measures. The findings of the research represent the input ingredients of the conceptual model of the site, premise to model the evolutionary contamination scenarios within the basin, of guidance for the environmental risk management. The study testifies the importance of the cooperative approach among researchers of different fields to fulfil the interpretation of complex polluted eco-systems.
The role of long intergenic non-coding RNA for kinase activation (LINK-A) as an oncogene in non-small cell lung carcinoma
Authors: Maleki Parichehr , Mowla Seyed Javad , Taheri Mohammad , Ghafouri-Fard Soudeh , Raheb Jamshid
Published: February 2021

The oncogenic role of long intergenic non-coding RNA for kinase activation (LINK-A) has been appraised in triple-negative breast cancer. However, the molecular function of LINK-A is still unclear in most cancers including lung cancer. The present study aimed to evaluate the impact of down-regulation of LINK-A in A549 and Calu-3 cell lines as cellular models of non-small cell lung carcinoma (NSCLC). We used the RNA interference system to knock down LINK-A. LINK-A expression was significantly reduced by siRNA transfection in A549 and Calu-3 cell lines. LINK-A down-regulation significantly reduced cell viability, colony-forming ability and cell migration, as measured by MTT, colony formation and invasion assays. Finally, cell cycle analysis and Annexin-V/7AAD staining indicated that apoptosis was influenced by LINK-A silencing. Taken together, LINK-A can be proposed as an oncogene in NSCLC.
Deep learning identifies morphological features in breast cancer predictive of cancer ERBB2 status and trastuzumab treatment efficacy
Authors: Bychkov Dmitrii , Linder Nina , Tiulpin Aleksei , Kücükel Hakan , Lundin Mikael , Nordling Stig , Sihto Harri , Isola Jorma , Lehtimäki Tiina , Kellokumpu-Lehtinen Pirkko-Liisa , von Smitten Karl , Joensuu Heikki , Lundin Johan
Published: February 2021

The treatment of patients with ERBB2 (HER2)-positive breast cancer with anti-ERBB2 therapy is based on the detection of ERBB2 gene amplification or protein overexpression. Machine learning (ML) algorithms can predict the amplification of ERBB2 based on tumor morphological features, but it is not known whether ML-derived features can predict survival and efficacy of anti-ERBB2 treatment. In this study, we trained a deep learning model with digital images of hematoxylin–eosin (H&E)-stained formalin-fixed primary breast tumor tissue sections, weakly supervised by ERBB2 gene amplification status. The gene amplification was determined by chromogenic in situ hybridization (CISH). The training data comprised digitized tissue microarray (TMA) samples from 1,047 patients. The correlation between the deep learning–predicted ERBB2 status, which we call H&E-ERBB2 score, and distant disease-free survival (DDFS) was investigated on a fully independent test set, which included whole-slide tumor images from 712 patients with trastuzumab treatment status available. The area under the receiver operating characteristic curve (AUC) in predicting gene amplification in the test sets was 0.70 (95% CI, 0.63–0.77) on 354 TMA samples and 0.67 (95% CI, 0.62–0.71) on 712 whole-slide images. Among patients with ERBB2-positive cancer treated with trastuzumab, those with a higher than the median morphology–based H&E-ERBB2 score derived from machine learning had more favorable DDFS than those with a lower score (hazard ratio [HR] 0.37; 95% CI, 0.15–0.93; P = 0.034). A high H&E-ERBB2 score was associated with unfavorable survival in patients with ERBB2-negative cancer as determined by CISH. ERBB2-associated morphology correlated with the efficacy of adjuvant anti-ERBB2 treatment and can contribute to treatment-predictive information in breast cancer.
Conductive hearing loss during development does not appreciably alter the sharpness of cochlear tuning
Authors: Ye Yi , Ihlefeld Antje , Rosen Merri J.
Published: February 2021

An increasing number of studies show that listeners often have difficulty hearing in situations with background noise, despite normal tuning curves in quiet. One potential source of this difficulty could be sensorineural changes in the auditory periphery (the ear). Signal in noise detection deficits also arise in animals raised with developmental conductive hearing loss (CHL), a manipulation that induces acoustic attenuation to model how sound deprivation changes the central auditory system. This model attributes perceptual deficits to central changes by assuming that CHL does not affect sensorineural elements in the periphery that could raise masked thresholds. However, because of efferent feedback, altering the auditory system could affect cochlear elements. Indeed, recent studies show that adult-onset CHL can cause cochlear synapse loss, potentially calling into question the assumption of an intact periphery in early-onset CHL. To resolve this issue, we tested the long-term peripheral effects of CHL via developmental bilateral malleus displacement. Using forward masking tuning curves, we compared peripheral tuning in animals raised with CHL vs age-matched controls. Using compound action potential measurements from the round window, we assessed inner hair cell synapse integrity. Results indicate that developmental CHL can cause minor synaptopathy. However, developmental CHL does not appreciably alter peripheral frequency tuning.
Bone loss markers in the earliest Pacific Islanders
Authors: Miszkiewicz Justyna J. , Valentin Frédérique , Vrahnas Christina , Sims Natalie A. , Vongsvivut Jitraporn , Tobin Mark J. , Clark Geoffrey
Published: February 2021

Kingdom of Tonga in Polynesia is one of the most obese nations where metabolic conditions, sedentary lifestyles, and poor quality diet are widespread. These factors can lead to poor musculoskeletal health. However, whether metabolic abnormalities such as osteoporosis occurred in archaeological populations of Tonga is unknown. We employed a microscopic investigation of femur samples to establish whether bone loss afflicted humans in this Pacific region approximately 3000 years ago. Histology, laser confocal microscopy, and synchrotron Fourier-transform infrared microspectroscopy were used to measure bone vascular canal densities, bone porosity, and carbonate and phosphate content of bone composition in eight samples extracted from adult Talasiu males and females dated to 2650 BP. Compared to males, samples from females had fewer vascular canals, lower carbonate and phosphate content, and higher bone porosity. Although both sexes showed evidence of trabecularised cortical bone, it was more widespread in females (35.5%) than males (15.8%). Our data suggest experiences of advanced bone resorption, possibly as a result of osteoporosis. This provides first evidence for microscopic bone loss in a sample of archaeological humans from a Pacific population widely afflicted by metabolic conditions today.
Incidence and remission of aeroallergen sensitization in adults in Northern Finland: 15 years longitudinal study
Authors: Haarala Anna Karoliina , Sinikumpu Suvi-Päivikki , Vaaramo Eeva , Jokelainen Jari , Timonen Markku , Auvinen Juha , Pekkanen Juha , Lampi Jussi , Huilaja Laura
Published: February 2021

Studies on the longitudinal changes in sensitization to aeroallergens in adult populations are sparse. The aim was to evaluate changes in sensitization to aeroallergens [birch, timothy, cat and house dust mite (HDM)] in an unselected adult population aged from 31 to 46 years. Data were gathered from a cohort of adults (Northern Finland Birth Cohort 1966) who had been skin prick tested (SPT) with birch, timothy, cat and HDM allergens at the age of 31 years and at age 46 (n = 5484 and 5373 respectively). Data from both time points were available for 3409 participants, who made up the cohort of the longitudinal study. The overall prevalence of sensitization to any of the selected allergens was 30.3% (n = 1661) in 31-year-olds and 30.7% (n = 1649) in 46-year-olds. In general, men were more sensitized (P < 0.001) and also had more polysensitization (P < 0.001) compared to women. In longitudinal sub-population incidence of sensitization was 7.1%. Birch was the most prevalent new sensitizer, however, the difference was not statistically significant when compared to cat. We conclude that new sensitization, demonstrated by positive findings in SPT, can still occur in middle age and this should be taken into account when managing allergic manifestations in adults as sensitization can be considered the first step in developing clinical allergy.
Molecular diagnosis of non-syndromic hearing loss patients using a stepwise approach
Authors: Wang Jing , Xiang Jiale , Chen Lisha , Luo Hongyu , Xu Xiuhua , Li Nan , Cui Chunming , Xu Jingjing , Song Nana , Peng Jiguang , Peng Zhiyu
Published: February 2021

Hearing loss is one of the most common birth disorders in humans, with an estimated prevalence of 1–3 in every 1000 newborns. This study investigates the molecular etiology of a hearing loss cohort using a stepwise strategy to effectively diagnose patients and address the challenges posed by the genetic heterogeneity and variable mutation spectrum of hearing loss. In order to target known pathogenic variants, multiplex PCR plus next-generation sequencing was applied in the first step; patients which did not receive a diagnosis from this were further referred for exome sequencing. A total of 92 unrelated patients with nonsyndromic hearing loss were enrolled in the study. In total, 64% (59/92) of the patients were molecularly diagnosed, 44 of them in the first step by multiplex PCR plus sequencing. Exome sequencing resulted in eleven diagnoses (23%, 11/48) and four probable diagnoses (8%, 4/48) among the 48 patients who were not diagnosed in the first step. The rate of secondary findings from exome sequencing in our cohort was 3% (2/58). This research presents a molecular diagnosis spectrum of 92 non-syndromic hearing loss patients and demonstrates the benefits of using a stepwise diagnostic approach in the genetic testing of nonsyndromic hearing loss.
Endoscopic management versus radical nephroureterectomy for localized upper tract urothelial carcinoma in a high endemic region
Authors: Chen Yung-Tai , Yu Chih-Chin , Yeh Hsin-Chih , Lee Hsiang-Ying , Jiang Yuan-Hong , Lee Yu-Khun , Kuei Chia-Hao , Wu Chia-Chang , Huang Chao-Yuan , Lin Wei-Yu , Yang Cheng Kuang , Tsai Yao Chou
Published: February 2021

Our aim was to analyze the clinical and survival differences among patients who underwent the two main treatment modalities, endoscopic ablation and radical nephroureterectomy. This study examined all patients who had undergone endoscopic management and RNU between Jul. 1988 and Mar. 2019 from the Taiwan UTUC registry. The inclusion criteria were low stage UTUC in RNU and all cases in endoscopic managed UTUC with a curative intent. The demographic and clinical characteristics were included for analysis. In total, 84 cases in the endoscopic group and 272 cases in the RNU group were enrolled for final analysis. The median follow-up period were 33.5 and 42.0 months in endoscopic and RNU group, respectively (p = 0.082). Comparison of Kaplan–Meier estimated survival curves between groups, the endoscopic group was associated with similar overall survival (OS), cancer specific survival (CSS), and intravesical recurrence free survival (IVRS) but demonstrated inferior disease free survival (DFS) (p = 0.188 for OS, p = 0.493 for CSS and p < 0.001 for DFS). Endoscopic management of UTUC was as safe as RNU in UTUC endemic region.
Caffeine may disrupt the impact of real-time drowsiness on cognitive performance: a double-blind, placebo-controlled small-sample study
Authors: Aidman E. , Balin M. , Johnson K. , Jackson S. , Paech G. M. , Pajcin M. , Yates C. , Mitchelson E. , Kamimori G. H. , Fidock J. , Vedova C. Della , Banks S.
Published: February 2021

Caffeine is widely used to promote alertness and cognitive performance under challenging conditions, such as sleep loss. Non-digestive modes of delivery typically reduce variability of its effect. In a placebo-controlled, 50-h total sleep deprivation (TSD) protocol we administered four 200 mg doses of caffeine-infused chewing-gum during night-time circadian trough and monitored participants' drowsiness during task performance with infra-red oculography. In addition to the expected reduction of sleepiness, caffeine was found to disrupt its degrading impact on performance errors in tasks ranging from standard cognitive tests to simulated driving. Real-time drowsiness data showed that caffeine produced only a modest reduction in sleepiness (compared to our placebo group) but substantial performance gains in vigilance and procedural decisions, that were largely independent of the actual alertness dynamics achieved. The magnitude of this disrupting effect was greater for more complex cognitive tasks.
Shear stress affects the architecture and cohesion of Chlorella vulgaris biofilms
Authors: Fanesi A. , Lavayssière M. , Breton C. , Bernard O. , Briandet R. , Lopes F.
Published: February 2021

The architecture of microalgae biofilms has been poorly investigated, in particular with respect to shear stress, which is a crucial factor in biofilm-based reactor design and operation. To investigate how microalgae biofilms respond to different hydrodynamic regimes, the architecture and cohesion of Chlorella vulgaris biofilms were studied in flow-cells at three shear stress: 1.0, 6.5 and 11.0 mPa. Biofilm physical properties and architecture dynamics were monitored using a set of microscopic techniques such as, fluorescence recovery after photobleaching (FRAP) and particle tracking. At low shear, biofilms cohesion was heterogeneous resulting in a strong basal (close to the substrate) layer and in more loose superficial ones. Higher shear (11.0 mPa) significantly increased the cohesion of the biofilms allowing them to grow thicker and to produce more biomass, likely due to a biological response to resist the shear stress. Interestingly, an acclimation strategy seemed also to occur which allowed the biofilms to preserve their growth rate at the different hydrodynamic regimes. Our results are in accordance with those previously reported for bacteria biofilms, revealing some general physical/mechanical rules that govern microalgae life on substrates. These results may bring new insights about how to improve productivity and stability of microalgae biofilm-based systems.