bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying regulators of parental imprinting by CRISPR/Cas9 screening in haploid human embryonic stem cells
Authors: Bar Shiran , Vershkov Dan , Keshet Gal , Lezmi Elyad , Meller Naama , Yilmaz Atilgan , Yanuka Ofra , Nissim-Rafinia Malka , Meshorer Eran , Eldar-Geva Talia , Benvenisty Nissim
Published: November 2021

In mammals, imprinted genes are regulated by differentially methylated regions (DMRs) that are inherited from germ cells, leading to monoallelic expression in accordance with parent-of-origin. Yet, it is largely unknown how imprinted DMRs are maintained in human embryos despite global DNA demethylation following fertilization. Here, we explored the mechanisms involved in imprinting regulation by employing human parthenogenetic embryonic stem cells (hpESCs), which lack paternal alleles. We show that although global loss of DNA methylation in hpESCs affects most imprinted DMRs, many paternally-expressed genes (PEGs) remain repressed. To search for factors regulating PEGs, we performed a genome-wide CRISPR/Cas9 screen in haploid hpESCs. This revealedATF7IPas an essential repressor of a set of PEGs, which we further show is also required for silencing sperm-specific genes. Our study reinforces an important role for histone modifications in regulating imprinted genes and suggests a link between parental imprinting and germ cell identity.
Enhanced gyrotropic birefringence and natural optical activity on electromagnon resonance in a helimagnet
Authors: Iguchi S. , Masuda R. , Seki S. , Tokura Y. , Takahashi Y.
Published: November 2021

Spontaneous symmetry breaking in crystalline solid often produces exotic nonreciprocal phenomena. As one such example, the unconventional optical rotation with nonreciprocity, which is termed gyrotropic birefringence, is expected to emerge from the magnetoelectric coupling. However, the fundamental nature of gyrotropic birefringence remains to be examined. Here w`e demonstrate the gyrotropic birefringence enhanced by the dynamical magnetoelectric coupling on the electrically active magnon resonance, i.e. electromagnon, in a multiferroic helimagnet. The helical spin order having both polarity and chirality is found to cause the giant gyrotropic birefringence in addition to the conventional gyrotropy, i.e. natural optical activity. It is demonstrated that the optical rotation of gyrotropic birefringence can be viewed as the nonreciprocal rotation of the optical principal axes, while the crystallographic and magnetic anisotropies are intact. The independent control of the nonreciprocal linear (gyrotropic birefringence) and circular (natural optical activity) birefringence/dichroism paves a way for the optically active devices.
A standardized gnotobiotic mouse model harboring a minimal 15-member mouse gut microbiota recapitulates SOPF/SPF phenotypes
Authors: Darnaud Marion , De Vadder Filipe , Bogeat Pascaline , Boucinha Lilia , Bulteau Anne-Laure , Bunescu Andrei , Couturier Céline , Delgado Ana , Dugua Hélène , Elie Céline , Mathieu Alban , Novotná Tereza , Ouattara Djomangan Adama , Planel Séverine , Saliou Adrien , Šrůtková Dagmar , Yansouni Jennifer , Stecher Bärbel , Schwarzer Martin , Leulier François , Tamellini Andrea
Published: November 2021

Mus musculusis the classic mammalian model for biomedical research. Despite global efforts to standardize breeding and experimental procedures, the undefined composition and interindividual diversity of the microbiota of laboratory mice remains a limitation. In an attempt to standardize the gut microbiome in preclinical mouse studies, here we report the development of a simplified mouse microbiota composed of 15 strains from 7 of the 20 most prevalent bacterial families representative of the fecal microbiota of C57BL/6J Specific (and Opportunistic) Pathogen-Free (SPF/SOPF) animals and the derivation of a standardized gnotobiotic mouse model called GM15. GM15 recapitulates extensively the functionalities found in the C57BL/6J SOPF microbiota metagenome, and GM15 animals are phenotypically similar to SOPF or SPF animals in two different facilities. They are also less sensitive to the deleterious effects of post-weaning malnutrition. In this work, we show that the GM15 model provides increased reproducibility and robustness of preclinical studies by limiting the confounding effect of fluctuation in microbiota composition, and offers opportunities for research focused on how the microbiota shapes host physiology in health and disease.
Hox genes regulate asexual reproductive behavior and tissue segmentation in adult animals
Authors: Arnold Christopher P. , Lozano Analí Migueles , Mann Frederick G. , Nowotarski Stephanie H. , Haug Julianna O. , Lange Jeffrey J. , Seidel Chris W. , Alvarado Alejandro Sánchez
Published: November 2021

Hox genes are highly conserved transcription factors renowned for their roles in the segmental patterning of the embryonic anterior-posterior (A/P) axis. We report functions for Hox genes in A/P tissue segmentation and transverse fission behavior underlying asexual reproduction in adult planarian flatworms,Schmidtea mediterranea. Silencing of each of theHoxfamily members identifies 5 Hox genes required for asexual reproduction. Among these, silencing ofhox3genes results in supernumerary fission segments, while silencing ofpost2beliminates segmentation altogether. The opposing roles ofhox3andpost2bin segmentation are paralleled in their respective regulation of fission behavior. Silencing ofhox3increases the frequency of fission behavior initiation while silencing ofpost2beliminates fission behavior entirely. Furthermore, we identify a network of downstream effector genes mediating Hox gene functions, providing insight into their respective mechanisms of action. In particular, we resolve roles forpost2band effector genes in the functions of the marginal adhesive organ in fission behavior regulation. Collectively, our study establishes adult stage roles for Hox genes in the regulation of tissue segmentation and behavior associated with asexual reproduction.
Increasing donor-acceptor spacing for reduced voltage loss in organic solar cells
Authors: Wang Jing , Jiang Xudong , Wu Hongbo , Feng Guitao , Wu Hanyu , Li Junyu , Yi Yuanping , Feng Xunda , Ma Zaifei , Li Weiwei , Vandewal Koen , Tang Zheng
Published: November 2021

The high voltage losses ($${V}_{{loss}}$$

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o
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), originating from inevitable electron-phonon coupling in organic materials, limit the power conversion efficiency of organic solar cells to lower values than that of inorganic or perovskite solar cells. In this work, we demonstrate that this $${V}_{{loss}}$$

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can in fact be suppressed by controlling the spacing between the donor (D) and the acceptor (A) materials (DA spacing). We show that in typical organic solar cells, the DA spacing is generally too small, being the origin of the too-fast non-radiative decay of charge carriers ($${k}_{{nr}}$$

k

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), and it can be increased by engineering the non-conjugated groups, i.e., alkyl chain spacers in single component DA systems and side chains in high-efficiency bulk-heterojunction systems. Increasing DA spacing allows us to realize significantly reduced $${k}_{{nr}}$$

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and improved device voltage. This points out a new research direction for breaking the performance bottleneck of organic solar cells.
Twinning-assisted dynamic adjustment of grain boundary mobility
Authors: Huang Qishan , Zhu Qi , Chen Yingbin , Gong Mingyu , Li Jixue , Zhang Ze , Yang Wei , Wang Jian , Zhou Haofei , Wang Jiangwei
Published: November 2021

Grain boundary (GB) plasticity dominates the mechanical behaviours of nanocrystalline materials. Under mechanical loading, GB configuration and its local deformation geometry change dynamically with the deformation; the dynamic variation of GB deformability, however, remains largely elusive, especially regarding its relation with the frequently-observed GB-associated deformation twins in nanocrystalline materials. Attention here is focused on the GB dynamics in metallic nanocrystals, by means of well-designed in situ nanomechanical testing integrated with molecular dynamics simulations. GBs with low mobility are found to dynamically adjust their configurations and local deformation geometries via crystallographic twinning, which instantly changes the GB dynamics and enhances the GB mobility. This self-adjust twin-assisted GB dynamics is found common in a wide range of face-centred cubic nanocrystalline metals under different deformation conditions. These findings enrich our understanding of GB-mediated plasticity, especially the dynamic behaviour of GBs, and bear practical implication for developing high performance nanocrystalline materials through interface engineering.
Diversity, multifaceted evolution, and facultative saprotrophism in the European Batrachochytrium salamandrivorans epidemic
Authors: Kelly Moira , Pasmans Frank , Muñoz Jose F. , Shea Terrance P. , Carranza Salvador , Cuomo Christina A. , Martel An
Published: November 2021

While emerging fungi threaten global biodiversity, the paucity of fungal genome assemblies impedes thoroughly characterizing epidemics and developing effective mitigation strategies. Here, we generatede novogenomic assemblies for six outbreaks of the emerging pathogenBatrachochytrium salamandrivorans(Bsal). We reveal the European epidemic currently damaging amphibian populations to comprise multiple, highly divergent lineages demonstrating isolate-specific adaptations and metabolic capacities. In particular, we show extensive gene family expansions and acquisitions, through a variety of evolutionary mechanisms, and an isolate-specific saprotrophic lifecycle. This finding both explains the chytrid’s ability to divorce transmission from host density, producingBsal’s enigmatic host population declines, and is a key consideration in developing successful mitigation measures.
Observation of spin-space quantum transport induced by an atomic quantum point contact
Authors: Ono Koki , Higomoto Toshiya , Saito Yugo , Uchino Shun , Nishida Yusuke , Takahashi Yoshiro
Published: November 2021

Quantum transport is ubiquitous in physics. So far, quantum transport between terminals has been extensively studied in solid state systems from the fundamental point of views such as the quantized conductance to the applications to quantum devices. Recent works have demonstrated a cold-atom analog of a mesoscopic conductor by engineering a narrow conducting channel with optical potentials, which opens the door for a wealth of research of atomtronics emulating mesoscopic electronic devices and beyond. Here we realize an alternative scheme of the quantum transport experiment with ytterbium atoms in a two-orbital optical lattice system. Our system consists of a multi-component Fermi gas and a localized impurity, where the current can be created in the spin space by introducing the spin-dependent interaction with the impurity. We demonstrate a rich variety of localized-impurity-induced quantum transports, which paves the way for atomtronics exploiting spin degrees of freedom.
Complementary resource preferences spontaneously emerge in diauxic microbial communities
Authors: Wang Zihan , Goyal Akshit , Dubinkina Veronika , George Ashish B. , Wang Tong , Fridman Yulia , Maslov Sergei
Published: November 2021

Many microbes grow diauxically, utilizing the available resources one at a time rather than simultaneously. The properties of communities of microbes growing diauxically remain poorly understood, largely due to a lack of theory and models of such communities. Here, we develop and study a minimal model of diauxic microbial communities assembling in a serially diluted culture. We find that unlike co-utilizing communities, diauxic community assembly repeatably and spontaneously leads to communities with complementary resource preferences, namely communities where species prefer different resources as their top choice. Simulations and theory explain that the emergence of complementarity is driven by the disproportionate contribution of the top choice resource to the growth of a diauxic species. Additionally, we develop a geometric approach for analyzing serially diluted communities, with or without diauxie, which intuitively explains several additional emergent community properties, such as the apparent lack of species which grow fastest on a resource other than their most preferred resource. Overall, our work provides testable predictions for the assembly of natural as well as synthetic communities of diauxically shifting microbes.
G3BP1 inhibits Cul3SPOP to amplify AR signaling and promote prostate cancer
Authors: Mukhopadhyay Chandrani , Yang Chenyi , Xu Limei , Liu Deli , Wang Yu , Huang Dennis , Deonarine Lesa Dayal , Cyrta Joanna , Davicioni Elai , Sboner Andrea , Robinson Brian. D. , Chinnaiyan Arul M. , Rubin Mark A. , Barbieri Christopher E. , Zhou Pengbo
Published: November 2021

SPOP, an E3 ubiquitin ligase, acts as a prostate-specific tumor suppressor with several key substrates mediating oncogenic function. However, the mechanisms underlying SPOP regulation are largely unknown. Here, we have identified G3BP1 as an interactor of SPOP and functions as a competitive inhibitor of Cul3SPOP, suggesting a distinctive mode of Cul3SPOP inactivation in prostate cancer (PCa). Transcriptomic analysis and functional studies reveal a G3BP1-SPOP ubiquitin signaling axis that promotes PCa progression through activating AR signaling. Moreover, AR directly upregulates G3BP1 transcription to further amplify G3BP1-SPOP signaling in a feed-forward manner. Our study supports a fundamental role of G3BP1 in disabling the tumor suppressive Cul3SPOP, thus defining a PCa cohort independent of SPOP mutation. Therefore, there are significantly more PCa that are defective for SPOP ubiquitin ligase than previously appreciated, and these G3BP1high PCa are more susceptible to AR-targeted therapy.
Phosphorylation activates the yeast small heat shock protein Hsp26 by weakening domain contacts in the oligomer ensemble
Authors: Mühlhofer Moritz , Peters Carsten , Kriehuber Thomas , Kreuzeder Marina , Kazman Pamina , Rodina Natalia , Reif Bernd , Haslbeck Martin , Weinkauf Sevil , Buchner Johannes
Published: November 2021

Hsp26 is a small heat shock protein (sHsp) from S. cerevisiae. Its chaperone activity is activated by oligomer dissociation at heat shock temperatures. Hsp26 contains 9 phosphorylation sites in different structural elements. Our analysis of phospho-mimetic mutations shows that phosphorylation activates Hsp26 at permissive temperatures. The cryo-EM structure of the Hsp26 40mer revealed contacts between the conserved core domain of Hsp26 and the so-called thermosensor domain in the N-terminal part of the protein, which are targeted by phosphorylation. Furthermore, several phosphorylation sites in the C-terminal extension, which link subunits within the oligomer, are sensitive to the introduction of negative charges. In all cases, the intrinsic inhibition of chaperone activity is relieved and the N-terminal domain becomes accessible for substrate protein binding. The weakening of domain interactions within and between subunits by phosphorylation to activate the chaperone activity in response to proteotoxic stresses independent of heat stress could be a general regulation principle of sHsps.
Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation
Authors: Ryzhakov Grigory , Almuttaqi Hannah , Corbin Alastair L. , Berthold Dorothée L. , Khoyratty Tariq , Eames Hayley L. , Bullers Samuel , Pearson Claire , Ai Zhichao , Zec Kristina , Bonham Sarah , Fischer Roman , Jostins-Dean Luke , Travis Simon P. L. , Kessler Benedikt M. , Udalova Irina A.
Published: November 2021

Interferon regulating factor 5 (IRF5) is a multifunctional regulator of immune responses, and has a key pathogenic function in gut inflammation, but how IRF5 is modulated is still unclear. Having performed a kinase inhibitor library screening in macrophages, here we identify protein-tyrosine kinase 2-beta (PTK2B/PYK2) as a putative IRF5 kinase. PYK2-deficient macrophages display impaired endogenous IRF5 activation, leading to reduction of inflammatory gene expression. Meanwhile, a PYK2 inhibitor, defactinib, has a similar effect on IRF5 activation in vitro, and induces a transcriptomic signature in macrophages similar to that caused by IRF5 deficiency. Finally, defactinib reduces pro-inflammatory cytokines in human colon biopsies from patients with ulcerative colitis, as well as in a mouse colitis model. Our results thus implicate a function of PYK2 in regulating the inflammatory response in the gut via the IRF5 innate sensing pathway, thereby opening opportunities for related therapeutic interventions for inflammatory bowel diseases and other inflammatory conditions.
A somatic proteoglycan controls Notch-directed germ cell fate
Authors: Gopal Sandeep , Amran Aqilah , Elton Andre , Ng Leelee , Pocock Roger
Published: November 2021

Communication between the soma and germline optimizes germ cell fate programs. Notch receptors are key determinants of germ cell fate but how somatic signals direct Notch-dependent germ cell behavior is undefined. Here we demonstrate that SDN-1 (syndecan-1), a somatic transmembrane proteoglycan, controls expression of the GLP-1 (germline proliferation-1) Notch receptor in the Caenorhabditis elegans germline. We find that SDN-1 control of a somatic TRP calcium channel governs calcium-dependent binding of an AP-2 transcription factor (APTF-2) to the glp-1 promoter. Hence, SDN-1 signaling promotes GLP-1 expression and mitotic germ cell fate. Together, these data reveal SDN-1 as a putative communication nexus between the germline and its somatic environment to control germ cell fate decisions.
Magic in twisted transition metal dichalcogenide bilayers
Authors: Devakul Trithep , Crépel Valentin , Zhang Yang , Fu Liang
Published: November 2021

The long-wavelength moiré superlattices in twisted 2D structures have emerged as a highly tunable platform for strongly correlated electron physics. We study the moiré bands in twisted transition metal dichalcogenide homobilayers, focusing on WSe2, at small twist angles using a combination of first principles density functional theory, continuum modeling, and Hartree-Fock approximation. We reveal the rich physics at small twist angles θ < 4∘, and identify a particular magic angle at which the top valence moiré band achieves almost perfect flatness. In the vicinity of this magic angle, we predict the realization of a generalized Kane-Mele model with a topological flat band, interaction-driven Haldane insulator, and Mott insulators at the filling of one hole per moiré unit cell. The combination of flat dispersion and uniformity of Berry curvature near the magic angle holds promise for realizing fractional quantum anomalous Hall effect at fractional filling. We also identify twist angles favorable for quantum spin Hall insulators and interaction-induced quantum anomalous Hall insulators at other integer fillings.
HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications
Authors: Langelier Marie-France , Billur Ramya , Sverzhinsky Aleksandr , Black Ben E. , Pascal John M.
Published: November 2021

PARP1 and PARP2 produce poly(ADP-ribose) in response to DNA breaks. HPF1 regulates PARP1/2 catalytic output, most notably permitting serine modification with ADP-ribose. However, PARP1 is substantially more abundant in cells than HPF1, challenging whether HPF1 can pervasively modulate PARP1. Here, we show biochemically that HPF1 efficiently regulates PARP1/2 catalytic output at sub-stoichiometric ratios matching their relative cellular abundances. HPF1 rapidly associates/dissociates from multiple PARP1 molecules, initiating serine modification before modification initiates on glutamate/aspartate, and accelerating initiation to be more comparable to elongation reactions forming poly(ADP-ribose). This “hit and run” mechanism ensures HPF1 contributions to PARP1/2 during initiation do not persist and interfere with PAR chain elongation. We provide structural insights into HPF1/PARP1 assembled on a DNA break, and assess HPF1 impact on PARP1 retention on DNA. Our data support the prevalence of serine-ADP-ribose modification in cells and the efficiency of serine-ADP-ribose modification required for an acute DNA damage response.
Generation of a Gluconobacter oxydans knockout collection for improved extraction of rare earth elements
Authors: Schmitz Alexa M. , Pian Brooke , Medin Sean , Reid Matthew C. , Wu Mingming , Gazel Esteban , Barstow Buz
Published: November 2021

Bioleaching of rare earth elements (REEs), using microorganisms such as Gluconobacter oxydans, offers a sustainable alternative to environmentally harmful thermochemical extraction, but is currently not very efficient. Here, we generate a whole-genome knockout collection of single-gene transposon disruption mutants for G. oxydans B58, to identify genes affecting the efficacy of REE bioleaching. We find 304 genes whose disruption alters the production of acidic biolixiviant. Disruption of genes underlying synthesis of the cofactor pyrroloquinoline quinone (PQQ) and the PQQ-dependent membrane-bound glucose dehydrogenase nearly eliminates bioleaching. Disruption of phosphate-specific transport system genes enhances bioleaching by up to 18%. Our results provide a comprehensive roadmap for engineering the genome of G. oxydans to further increase its bioleaching efficiency.
Silicon: quantum dot photovoltage triodes
Authors: Zhou Wen , Zheng Li , Ning Zhijun , Cheng Xinhong , Wang Fang , Xu Kaimin , Xu Rui , Liu Zhongyu , Luo Man , Hu Weida , Guo Huijun , Zhou Wenjia , Yu Yuehui
Published: November 2021

Silicon is widespread in modern electronics, but its electronic bandgap prevents the detection of infrared radiation at wavelengths above 1,100 nanometers, which limits its applications in multiple fields such as night vision, health monitoring and space navigation systems. It is therefore of interest to integrate silicon with infrared-sensitive materials to broaden its detection wavelength. Here we demonstrate a photovoltage triode that can use silicon as the emitter but is also sensitive to infrared spectra owing to the heterointegrated quantum dot light absorber. The photovoltage generated at the quantum dot base region, attracting holes from silicon, leads to high responsivity (exceeding 410 A·W−1 with Vbias of −1.5 V), and a widely self-tunable spectral response. Our device has the maximal specific detectivity (4.73 × 1013 Jones with Vbias of −0.4 V) at 1,550 nm among the infrared sensitized silicon detectors, which opens a new path towards infrared and visible imaging in one chip with silicon technology compatibility.
Identifying an optimal dihydroartemisinin-piperaquine dosing regimen for malaria prevention in young Ugandan children
Authors: Wallender Erika , Ali Ali Mohamed , Hughes Emma , Kakuru Abel , Jagannathan Prasanna , Muhindo Mary Kakuru , Opira Bishop , Whalen Meghan , Huang Liusheng , Duvalsaint Marvin , Legac Jenny , Kamya Moses R. , Dorsey Grant , Aweeka Francesca , Rosenthal Philip J. , Savic Rada M.
Published: November 2021

Intermittent preventive treatment (IPT) with dihydroartemisinin-piperaquine (DP) is highly protective against malaria in children, but is not standard in malaria-endemic countries. Optimal DP dosing regimens will maximize efficacy and reduce toxicity and resistance selection. We analyze piperaquine (PPQ) concentrations (n = 4573), malaria incidence data (n = 326), and P. falciparum drug resistance markers from a trial of children randomized to IPT with DP every 12 weeks (n = 184) or every 4 weeks (n = 96) from 2 to 24 months of age (NCT02163447). We use nonlinear mixed effects modeling to establish malaria protective PPQ levels and risk factors for suboptimal protection. Compared to DP every 12 weeks, DP every 4 weeks is associated with 95% protective efficacy (95% CI: 84–99%). A PPQ level of 15.4 ng/mL reduces the malaria hazard by 95%. Malnutrition reduces PPQ exposure. In simulations, we show that DP every 4 weeks is optimal across a range of transmission intensities, and age-based dosing improves malaria protection in young or malnourished children.
GAPDH controls extracellular vesicle biogenesis and enhances the therapeutic potential of EV mediated siRNA delivery to the brain
Authors: Dar Ghulam Hassan , Mendes Cláudia C. , Kuan Wei-Li , Speciale Alfina A. , Conceição Mariana , Görgens André , Uliyakina Inna , Lobo Miguel J. , Lim Wooi F. , EL Andaloussi Samir , Mäger Imre , Roberts Thomas C. , Barker Roger A. , Goberdhan Deborah C. I. , Wilson Clive , Wood Matthew J. A.
Published: November 2021

Extracellular vesicles (EVs) are biological nanoparticles with important roles in intercellular communication, and potential as drug delivery vehicles. Here we demonstrate a role for the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in EV assembly and secretion. We observe high levels of GAPDH binding to the outer surface of EVs via a phosphatidylserine binding motif (G58), which promotes extensive EV clustering. Further studies in a Drosophila EV biogenesis model reveal that GAPDH is required for the normal generation of intraluminal vesicles in endosomal compartments, and promotes vesicle clustering. Fusion of the GAPDH-derived G58 peptide to dsRNA-binding motifs enables highly efficient loading of small interfering RNA (siRNA) onto the EV surface. Such vesicles efficiently deliver siRNA to multiple anatomical regions of the brain in a Huntington’s disease mouse model after systemic injection, resulting in silencing of the huntingtin gene in different regions of the brain.
HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway
Authors: Smith Alison E. , Ferraro Emanuela , Safonov Anton , Morales Cristina Bernado , Lahuerta Enrique J. Arenas , Li Qing , Kulick Amanda , Ross Dara , Solit David B. , de Stanchina Elisa , Reis-Filho Jorge , Rosen Neal , Arribas Joaquín , Razavi Pedram , Chandarlapaty Sarat
Published: November 2021

Inhibition of HER2 in HER2-amplified breast cancer has been remarkably successful clinically, as demonstrated by the efficacy of HER-kinase inhibitors and HER2-antibody treatments. Whilst resistance to HER2 inhibition is common in the metastatic setting, the specific programs downstream of HER2 driving resistance are not established. Through genomic profiling of 733 HER2-amplified breast cancers, we identify enrichment of somatic alterations that promote MEK/ERK signaling in metastatic tumors with shortened progression-free survival on anti-HER2 therapy. These mutations, including NF1 loss and ERBB2 activating mutations, are sufficient to mediate resistance to FDA-approved HER2 kinase inhibitors including tucatinib and neratinib. Moreover, resistant tumors lose AKT dependence while undergoing a dramatic sensitization to MEK/ERK inhibition. Mechanistically, this driver pathway switch is a result of MEK-dependent activation of CDK2 kinase. These results establish genetic activation of MAPK as a recurrent mechanism of anti-HER2 therapy resistance that may be effectively combated with MEK/ERK inhibitors.
Temporal variability in quantitative human gut microbiome profiles and implications for clinical research
Authors: Vandeputte Doris , De Commer Lindsey , Tito Raul Y. , Kathagen Gunter , Sabino João , Vermeire Séverine , Faust Karoline , Raes Jeroen
Published: November 2021

While clinical gut microbiota research is ever-expanding, extending reference knowledge of healthy between- and within-subject gut microbiota variation and its drivers remains essential; in particular, temporal variability is under-explored, and a comparison with cross-sectional variation is missing. Here, we perform daily quantitative microbiome profiling on 713 fecal samples from 20 Belgian women over six weeks, combined with extensive anthropometric measurements, blood panels, dietary data, and stool characteristics. We show substantial temporal variation for most major gut genera; we find that for 78% of microbial genera, day-to-day absolute abundance variation is substantially larger within than between individuals, with up to 100-fold shifts over the study period. Diversity, and especially evenness indicators also fluctuate substantially. Relative abundance profiles show similar but less pronounced temporal variation. Stool moisture, and to a lesser extent diet, are the only significant host covariates of temporal microbiota variation, while menstrual cycle parameters did not show significant effects. We find that the dysbiotic Bact2 enterotype shows increased between- and within-subject compositional variability. Our results suggest that to increase diagnostic as well as target discovery power, studies could adopt a repeated measurement design and/or focus analysis on community-wide microbiome descriptors and indices.
Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage
Authors: Carotenuto Pietro , Amato Francesco , Lampis Andrea , Rae Colin , Hedayat Somaieh , Previdi Maria C. , Zito Domenico , Raj Maya , Guzzardo Vincenza , Sclafani Francesco , Lanese Andrea , Parisi Claudia , Vicentini Caterina , Said-Huntingford Ian , Hahne Jens C. , Hallsworth Albert , Kirkin Vladimir , Young Kate , Begum Ruwaida , Wotherspoon Andrew , Kouvelakis Kyriakos , Azevedo Sergio Xavier , Michalarea Vasiliki , Upstill-Goddard Rosie , Rao Sheela , Watkins David , Starling Naureen , Sadanandam Anguraj , Chang David K. , Biankin Andrew V. , Jamieson Nigel B. , Scarpa Aldo , Cunningham David , Chau Ian , Workman Paul , Fassan Matteo , Valeri Nicola , Braconi Chiara
Published: November 2021

FOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome.
Temperature effects on carbon storage are controlled by soil stabilisation capacities
Authors: Hartley Iain P. , Hill Tim C. , Chadburn Sarah E. , Hugelius Gustaf
Published: November 2021

Physical and chemical stabilisation mechanisms are now known to play a critical role in controlling carbon (C) storage in mineral soils, leading to suggestions that climate warming-induced C losses may be lower than previously predicted. By analysing > 9,000 soil profiles, here we show that, overall, C storage declines strongly with mean annual temperature. However, the reduction in C storage with temperature was more than three times greater in coarse-textured soils, with limited capacities for stabilising organic matter, than in fine-textured soils with greater stabilisation capacities. This pattern was observed independently in cool and warm regions, and after accounting for potentially confounding factors (plant productivity, precipitation, aridity, cation exchange capacity, and pH). The results could not, however, be represented by an established Earth system model (ESM). We conclude that warming will promote substantial soil C losses, but ESMs may not be predicting these losses accurately or which stocks are most vulnerable.
Quantum mechanical rotation of a photon polarization by Earth’s gravitational field
Authors: Noh Hansol , Alsing Paul M. , Ahn Doyeol , Miller Warner A. , Park Namkyoo
Published: November 2021

We describe the quantum mechanical rotation of a photon state, the Wigner rotation—a quantum effect that couples a transformation of a reference frame to a particle’s spin, to investigate geometric phases induced by Earth’s gravitational field for observers in various orbits. We find a potentially measurable quantum phase of the Wigner rotation angle in addition to the rotation of standard fame, the latter of which is computed and agrees well with the geodetic rotation. When an observer is in either a circular or a spiraling orbit containing non-zero angular momentum, the additional quantum phase contributes 10−6 degree to 10−4 degree respectively, depending on the altitude of the Earth orbit. In the former case, the additional quantum phase is dominant over the near-zero classical geodetic rotation. Our results show that the Wigner rotation represents a non-trivial semi-classical effect of quantum field theory on a background classical gravitational field.
Sauropodomorph evolution across the Triassic–Jurassic boundary: body size, locomotion, and their influence on morphological disparity
Authors: Apaldetti Cecilia , Pol Diego , Ezcurra Martín D. , Martínez Ricardo N.
Published: November 2021

Sauropodomorph dinosaurs were the dominant medium to large-sized herbivores of most Mesozoic continental ecosystems, being characterized by their long necks and reaching a size unparalleled by other terrestrial animals (> 60 tonnes). Our study of morphological disparity across the entire skeleton shows that during the Late Triassic the oldest known sauropodomorphs occupied a small region of morphospace, subsequently diversifying both taxonomically and ecologically, and shifting to a different and broader region of the morphospace. After the Triassic–Jurassic boundary event, there are no substancial changes in sauropodomorph morphospace occupation. Almost all Jurassic sauropodomorph clades stem from ghost lineages that cross the Triassic–Jurassic boundary, indicating that variations after the extinction were more related to changes of pre-existing lineages (massospondylids, non-gravisaurian sauropodiforms) rather than the emergence of distinct clades or body plans. Modifications in the locomotion (bipedal to quadrupedal) and the successive increase in body mass seem to be the main attributes driving sauropodomorph morphospace distribution during the Late Triassic and earliest Jurassic. The extinction of all non-sauropod sauropodomorphs by the Toarcian and the subsequent diversification of gravisaurian sauropods represent a second expansion of the sauropodomorph morphospace, representing the onset of the flourishing of these megaherbivores that subsequently dominated in Middle and Late Jurassic terrestrial assemblages.
Effects of size and position of an unconnected aluminum electrode on bipolar anodization in an AC electric field
Authors: Takeuchi Ryo , Asoh Hidetaka
Published: November 2021

The effects of the size and position of an aluminum bipolar electrode (BPE) on the uniformity of formation of anodic porous alumina in an alternating current electric field were investigated. Anodized specimens were dyed, and the resistance was measured after the specimens were anodized again. Phenomena observed during film formation indicated that the BPEs had unique potential distributions that strongly depended on their length and width. The color variations and electrical resistance of the BPEs were symmetrical and varied from the centers of the BPEs to their ends. When multiple BPEs were processed at the same time, their position in the non-uniform electric field was demonstrated to be an important factor for controlling the uniformity of film formation. The best results were obtained when the BPE was placed at the center of the defined space.
Behavioural effects of task-relevant neuromodulation by rTMS on giving-up
Authors: Miyauchi Eri , Kawasaki Masahiro
Published: November 2021

Recent studies suggest that online repetitive transcranial magnetic stimulation (rTMS) can induce local entrainment of ongoing endogenous oscillatory activity during a task. This effect may impact cognitive performance, depending on the function of the oscillation. In this study, we aimed to investigate the effects of stimulation frequency and target location that are relevant to the cognitive processes of giving-up. We first investigated the correlations between the EEG oscillations and cognitive giving-up processes during problem-solving tasks (Experiment 1). We then conducted online rTMS to examine the frequency-dependent stimulation effects of rTMS on the performance of problem-solving tasks and ongoing oscillations (Experiment 2). The results of Experiment 1 suggested that the frontal theta rhythm is associated with the giving-up processes and that the frontal alpha rhythm is associated with problem-solving behaviour. Accordingly, we hypothesised that rTMS at the theta frequency would induce ongoing theta activity and accelerate the giving-up behaviour, while rTMS at the alpha frequency would induce ongoing alpha activity and slow down the giving-up behaviour in Experiment 2. The results showed that theta-frequency rTMS application induced an increase in theta amplitudes and shortened the giving-up response. Alpha-frequency rTMS application induced an increase in alpha amplitudes, but did not change giving-up responses. Considering the close resemblance between giving-up behaviour and rumination in depression, neuromodulation of cognitive giving-up processes may lead to a new intervention to treat depression by rTMS. Furthermore, this study strengthens the hypothesis that modulating task-relevant oscillations by rTMS could induce behavioural changes related to cognitive performance.
The mechanisms and mechanical energy of human gait initiation from the lower-limb joint level perspective
Authors: Zhao Guoping , Grimmer Martin , Seyfarth Andre
Published: November 2021

This study aims to improve our understanding of gait initiation mechanisms and the lower-limb joint mechanical energy contributions. Healthy subjects were instructed to initiate gait on an instrumented track to reach three self-selected target velocities: slow, normal and fast. Lower-limb joint kinematics and kinetics of the first five strides were analyzed. The results show that the initial lateral weight shift is achieved by hip abduction torque on the lifting leg (leading limb). Before the take-off of the leading limb, the forward body movement is initiated by decreasing ankle plantarflexion torque, which results in an inverted pendulum-like passive forward fall. The hip flexion/extension joint has the greatest positive mechanical energy output in the first stride of the leading limb, while the ankle joint contributes the most positive mechanical energy in the first stride of the trailing limb (stance leg). Our results indicate a strong correlation between control of the frontal plane and the sagittal plane joints during gait initiation. The identified mechanisms and the related data can be used as a guideline for improving gait initiation with wearable robots such as exoskeletons and prostheses.
Urinary concentrations of neonicotinoid insecticides were related to renal tubular dysfunction and neuropsychological complaints in Dry-zone of Sri Lanka
Authors: Taira Kumiko , Kawakami Tomonori , Weragoda Sujithra Kaushaliya , Herath H. M. Ayala S. , Ikenaka Yoshinori , Fujioka Kazutoshi , Hemachandra Madhubhani , Pallewatta Nirmalie , Aoyama Yoshiko , Ishizuka Mayumi , Bonmatin Jean-Marc , Komori Makiko
Published: November 2021

Neonicotinoids are systemic insecticides used since the 1990’s , that possess renal tubular toxicity. We conducted a field-based descriptive study in the North Central Dry-zone of Sri Lanka, where chronic kidney disease (CKD) of unknown etiology has been increasing since the 1990’s. To elucidate the relationship between renal tubular dysfunctions and urinary neonicotinoids concentrations, we collected spot urine samples from15 CKD patients, 15 family members, and 62 neighbors in 2015, analyzed two renal tubular biomarkers, Cystatin-C and L-FABP, quantified seven neonicotinoids and a metabolite N-desmethyl-acetamiprid by LC–MS/MS; and we investigated their symptoms using a questionnaire. Cystatin-C and L-FABP had a positive correlation (p < 0.001). N-Desmethyl-acetamiprid was detected in 92.4% of the urine samples, followed by dinotefuran (17.4%), thiamethoxam (17.4%), clothianidin (9.8%), thiacloprid and imidacloprid. Dinotefuran and thiacloprid have never been registered in Sri Lanka. In High Cystatin-C group (> 70 μg/gCre, n = 7), higher urinary concentration of dinotefuran (p = 0.009), and in Zero Cystatin-C group (< LOQ, n = 7), higher N-desmethyl-acetamiprid (p = 0.013), dinotefuran (p = 0.049), and thiacloprid (p = 0.035), and more complaints of chest pains, stomachache, skin eruption and diarrhea (p < 0.05) were found than in Normal Cystatin-C group (n = 78). Urinary neonicotinoids may be one of the potential risk factors for renal tubular dysfunction in this area.
Facial threat affects trust more strongly than facial attractiveness in women than it does in men
Authors: Brustkern Johanna , Heinrichs Markus , Walker Mirella , Schiller Bastian
Published: November 2021

Trust is essential in initiating social relationships. Due to the differential evolution of sex hormones as well as the fitness burdens of producing offspring, evaluations of a potential mating partner’s trustworthiness likely differ across sexes. Here, we explore unknown sex-specific effects of facial attractiveness and threat on trusting other-sex individuals. Ninety-three participants (singles; 46 women) attracted by the other sex performed an incentivized trust game. They had to decide whether to trust individuals of the other sex represented by a priori-created face stimuli gradually varying in the intensities of both attractiveness and threat. Male and female participants trusted attractive and unthreatening-looking individuals more often. However, whereas male participants’ trust behavior was affected equally by attractiveness and threat, female participants’ trust behavior was more strongly affected by threat than by attractiveness. This indicates that a partner’s high facial attractiveness might compensate for high facial threat in male but not female participants. Our findings suggest that men and women prioritize attractiveness and threat differentially, with women paying relatively more attention to threat cues inversely signaling parental investment than to attractiveness cues signaling reproductive fitness. This difference might be attributable to an evolutionary, biologically sex-specific decision regarding parental investment and reproduction behavior.
Transpiration rates of red maple (Acer rubrum L.) differ between management contexts in urban forests of Maryland, USA
Authors: Ponte Sarah , Sonti Nancy F. , Phillips Tuana H. , Pavao-Zuckerman Mitchell A.
Published: November 2021

The hydrological functioning of urban trees can reduce stormwater runoff, mitigate the risk of flood, and improve water quality in developed areas. Tree canopies intercept rainfall and return water to the atmosphere through transpiration, while roots increase infiltration and storage in the soil. Despite this, the amount of stormwater that trees remove through these functions in urban settings is not well characterized, limiting the use of urban forests as practical stormwater management strategies. To address this gap, we use ecohydrological approaches to assess the transpiration rates of urban trees in different management settings. Our research questions are: Do transpiration rates of trees of the same species vary among different management contexts? Do relationships between environmental drivers and transpiration change among management contexts? These management settings included single trees over turfgrass and a cluster of trees over turfgrass in Montgomery County, MD, and closed canopy forest with a leaf litter layer in Baltimore, MD. We used sap flux sensors installed in 18 mature red maple (Acer rubrum L.) trees to characterize transpiration rates during the growing season. We also measured soil volumetric water content, air temperature, relative humidity, and precipitation at each site. In agreement with our initial hypothesis, we found that single trees had nearly three times the daily sum of sap flux density (JS) of closed canopy trees. When averaged over the entire measurement period, JS was approximately 260, 195, and 91 g H2O cm−2 day−1 for single trees, cluster trees and closed canopy trees, respectively. Additionally, single trees were more responsive to VPD than closed canopy and cluster trees. These results provide a better understanding of the influence of management context on urban tree transpiration and can help to identify targets to better manage urban forest settings to reduce urban stormwater runoff.
An exceptional G(2) extension of the Standard Model from the correspondence with Cayley–Dickson algebras automorphism groups
Authors: Masi Nicolò
Published: November 2021

In this article I propose a new criterion to extend the Standard Model of particle physics from a straightforward algebraic conjecture: the symmetries of physical microscopic forces originate from the automorphism groups of main Cayley–Dickson algebras, from complex numbers to octonions and sedenions. This correspondence leads to a natural enlargement of the Standard Model color sector, from aSU(3) gauge group to an exceptional Higgs-brokenG(2) group, following the octonionic automorphism relation guideline. In this picture, an additional ensemble of massiveG(2)-gluons emerges, which is separated from the particle dynamics of the Standard Model.
Comprehensive molecular-genetic analysis of mid-frequency sensorineural hearing loss
Authors: Pavlenkova Zuzana , Varga Lukas , Borecka Silvia , Karhanek Miloslav , Huckova Miloslava , Skopkova Martina , Profant Milan , Gasperikova Daniela
Published: November 2021

The genetic heterogeneity of sensorineural hearing loss (SNHL) is a major hurdle to the detection of disease-causing variants. We aimed to identify underlying causal genes associated with mid-frequency hearing loss (HL), which contributes to less than about 1% of SNHL cases, by whole exome sequencing (WES). Thirty families segregating mid-frequency SNHL, in whom biallelic GJB2 mutations had been previously excluded, were selected from among 851 families in our DNA repository of SNHL. DNA samples from the probands were subjected to WES analysis and searched for candidate variants associated with SNHL. We were able to identify the genetic aetiology in six probands (20%). In total, we found three pathogenic and three likely pathogenic variants in four genes (COL4A5, OTOGL, TECTA, TMPRSS3). One more proband was a compound heterozygote for a pathogenic variant and a variant of uncertain significance (VUS) in MYO15A gene. To date, MYO15A and TMPRSS3 have not yet been described in association with mid-frequency SNHL. In eight additional probands, eight candidate VUS variants were detected in five genes (DIAPH1, MYO7A, TECTA, TMC1, TSPEAR). Seven of these 16 variants have not yet been published or mentioned in the available databases. The most prevalent gene was TECTA, identified in 23% of all tested families. Furthermore, we confirmed the hypothesis that a substantive portion of cases with this conspicuous audiogram shape is a consequence of a genetic disorder.