bluuebunny/crossref_metadata_2025 huggingface dataset:
Local and substrate-specific S-palmitoylation determines subcellular localization of Gαo
Authors: Solis Gonzalo P. , Kazemzadeh Arghavan , Abrami Laurence , Valnohova Jana , Alvarez Cecilia , van der Goot F. Gisou , Katanaev Vladimir L.
Published: April 2022

Peripheral membrane proteins (PMPs) associate with cellular membranes through post-translational modifications like S-palmitoylation. The Golgi apparatus is generally viewed as the transitory station where palmitoyl acyltransferases (PATs) modify PMPs, which are then transported to their ultimate destinations such as the plasma membrane (PM). However, little substrate specificity among the many PATs has been determined. Here we describe the inherent partitioning of Gαo – α-subunit of heterotrimeric Go proteins – to PM and Golgi, independent from Golgi-to-PM transport. A minimal code within Gαo N-terminus governs its compartmentalization and re-coding produces G protein versions with shifted localization. We establish the S-palmitoylation at the outer nuclear membrane assay (“SwissKASH”) to probe substrate specificity of PATs in intact cells. With this assay, we show that PATs localizing to different membrane compartments display remarkable substrate selectivity, which is the basis for PMP compartmentalization. Our findings uncover a mechanism governing protein localization and establish the basis for innovative drug discovery.
Loss of vascular endothelial notch signaling promotes spontaneous formation of tertiary lymphoid structures
Authors: Fleig Susanne , Kapanadze Tamar , Bernier-Latmani Jeremiah , Lill Julia K. , Wyss Tania , Gamrekelashvili Jaba , Kijas Dustin , Liu Bin , Hüsing Anne M. , Bovay Esther , Jirmo Adan Chari , Halle Stephan , Ricke-Hoch Melanie , Adams Ralf H. , Engel Daniel R. , von Vietinghoff Sibylle , Förster Reinhold , Hilfiker-Kleiner Denise , Haller Hermann , Petrova Tatiana V. , Limbourg Florian P.
Published: April 2022

Tertiary lymphoid structures (TLS) are lymph node-like immune cell clusters that emerge during chronic inflammation in non-lymphoid organs like the kidney, but their origin remains not well understood. Here we show, using conditional deletion strategies of the canonical Notch signaling mediatorRbpj, that loss of endothelial Notch signaling in adult mice induces the spontaneous formation of bona fide TLS in the kidney, liver and lung, based on molecular, cellular and structural criteria. These TLS form in a stereotypical manner around parenchymal arteries, while secondary lymphoid structures remained largely unchanged. This effect is mediated by endothelium of blood vessels, but not lymphatics, since a lymphatic endothelial-specific targeting strategy did not result in TLS formation, and involves loss of arterial specification and concomitant acquisition of a high endothelial cell phenotype, as shown by transcriptional analysis of kidney endothelial cells. This indicates a so far unrecognized role for vascular endothelial cells and Notch signaling in TLS initiation.
Anti-drude metal of bosons
Authors: Masella Guido , Prokof’ev Nikolay V. , Pupillo Guido
Published: April 2022

In the absence of frustration, interacting bosons in their ground state in one or two dimensions exist either in the superfluid or insulating phases. Superfluidity corresponds to frictionless flow of the matter field, and in optical conductivity is revealed through a distinct δ-functional peak at zero frequency with the amplitude known as the Drude weight. This characteristic low-frequency feature is instead absent in insulating phases, defined by zero static optical conductivity. Here we demonstrate that bosonic particles in disordered one dimensional chains can also exist in a conducting, non-superfluid, phase when their hopping is of the dipolar type, often viewed as short-ranged in one dimension. This phase is characterized by finite static optical conductivity, followed by a broad anti-Drude peak at finite frequencies. Off-diagonal correlations are also unconventional: they feature an integrable algebraic decay for arbitrarily large values of disorder. These results do not fit the description of any known quantum phase, and strongly suggest the existence of an unusual conducting state of bosonic matter in the ground state.
Low complexity RGG-motif sequence is required for Processing body (P-body) disassembly
Authors: Roy Raju , Das Gitartha , Kuttanda Ishwarya Achappa , Bhatter Nupur , Rajyaguru Purusharth I.
Published: April 2022

P-bodies are conserved mRNP complexes that are implicated in determining mRNA fate by affecting translation and mRNA decay. In this report, we identify RGG-motif containing translation repressor protein Sbp1 as a disassembly factor of P-bodies since disassembly of P-bodies is defective in Δsbp1. RGG-motif is necessary and sufficient to rescue the PB disassembly defect in Δsbp1. Binding studies using purified proteins revealed that Sbp1 physically interacts with Edc3 and Sbp1-Edc3 interaction competes with Edc3-Edc3 interaction. Purified Edc3 forms assemblies, promoted by the presence of RNA and NADH and the addition of purified Sbp1, but not the RGG-deletion mutant, leads to significantly decreased Edc3 assemblies. We further note that the aggregates of human EWSR1 protein, implicated in neurodegeneration, are more persistent in the absence of Sbp1 and overexpression of EWSR1 in Δsbp1 leads to a growth defect. Taken together, our observations suggest a role of Sbp1 in disassembly, which could apply to disease-relevant heterologous protein-aggregates.
Insulin action and resistance are dependent on a GSK3β-FBXW7-ERRα transcriptional axis
Authors: Xia Hui , Scholtes Charlotte , Dufour Catherine R. , Ouellet Carlo , Ghahremani Majid , Giguère Vincent
Published: April 2022

Insulin resistance, a harbinger of the metabolic syndrome, is a state of compromised hormonal response resulting from the dysregulation of a wide range of insulin-controlled cellular processes. However, how insulin affects cellular energy metabolism via long-term transcriptional regulation and whether boosting mitochondrial function alleviates insulin resistance remains to be elucidated. Herein we reveal that insulin directly enhances the activity of the nuclear receptor ERRα via a GSK3β/FBXW7 signaling axis. Liver-specific deletion of GSK3β or FBXW7 and mice harboring mutations of ERRα phosphosites (ERRα3SA) co-targeted by GSK3β/FBXW7 result in accumulated ERRα proteins that no longer respond to fluctuating insulin levels. ERRα3SA mice display reprogrammed liver and muscle transcriptomes, resulting in compromised energy homeostasis and reduced insulin sensitivity despite improved mitochondrial function. This crossroad of insulin signaling and transcriptional control by a nuclear receptor offers a framework to better understand the complex cellular processes contributing to the development of insulin resistance.
Cavβ1 regulates T cell expansion and apoptosis independently of voltage-gated Ca2+ channel function
Authors: Erdogmus Serap , Concepcion Axel R. , Yamashita Megumi , Sidhu Ikjot , Tao Anthony Y. , Li Wenyi , Rocha Pedro P. , Huang Bonnie , Garippa Ralph , Lee Boram , Lee Amy , Hell Johannes W. , Lewis Richard S. , Prakriya Murali , Feske Stefan
Published: April 2022

TCR stimulation triggers Ca2+ signals that are critical for T cell function and immunity. Several pore-forming α and auxiliary β subunits of voltage-gated Ca2+ channels (VGCC) were reported in T cells, but their mechanism of activation remains elusive and their contribution to Ca2+ signaling in T cells is controversial. We here identify CaVβ1, encoded by Cacnb1, as a regulator of T cell function. Cacnb1 deletion enhances apoptosis and impairs the clonal expansion of T cells after lymphocytic choriomeningitis virus (LCMV) infection. By contrast, Cacnb1 is dispensable for T cell proliferation, cytokine production and Ca2+ signaling. Using patch clamp electrophysiology and Ca2+ recordings, we are unable to detect voltage-gated Ca2+ currents or Ca2+ influx in human and mouse T cells upon depolarization with or without prior TCR stimulation. mRNAs of several VGCC α1 subunits are detectable in human (CaV3.3, CaV3.2) and mouse (CaV2.1) T cells, but they lack transcription of many 5’ exons, likely resulting in N-terminally truncated and non-functional proteins. Our findings demonstrate that although CaVβ1 regulates T cell function, these effects are independent of VGCC channel activity.
Structure, gating, and pharmacology of human CaV3.3 channel
Authors: He Lingli , Yu Zhuoya , Geng Ze , Huang Zhuo , Zhang Changjiang , Dong Yanli , Gao Yiwei , Wang Yuhang , Chen Qihao , Sun Le , Ma Xinyue , Huang Bo , Wang Xiaoqun , Zhao Yan
Published: April 2022

The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type CaV3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. CaV3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type CaV channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the CaV3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders.
Achieving gas pressure-dependent luminescence from an AIEgen-based metal-organic framework
Authors: Li Zhijia , Jiang Feilong , Yu Muxin , Li Shengchang , Chen Lian , Hong Maochun
Published: April 2022

Materials exhibiting aggregation-induced emission (AIE) behaviour enable strong emission in solid state and can respond to various external stimuli, which may facilitate the development of materials for optical sensing, bioimaging or optoelectronic devices. Herein, we use an AIE luminogen 2’,5’-diphenyl-[1,1’:4’,1”-terphenyl]-4,4”-dicarboxylic acid as the ligand to prepare an AIEgen-based MOF (metal-organic framework) named FJI-H31. FJI-H31 exhibits bright luminescence under ambient conditions (under air and at room temperature), but almost no emission is observed under vacuum. Our investigation shows that the emission intensity displays a smooth and reversible enhancement with increased gas pressure, which may be attributed to the restriction of intramolecular motion brought by structural deformation under pressure stimulus. Unlike most pressure-responsive MOFs, the luminescence reverts to its original state once gas pressure recovers. By virtue of its unique optical properties, a luminescent MOF with sensing ability of gas-pressure is realized.
Anisotropy-driven quantum criticality in an intermediate valence system
Authors: Grbić Mihael S. , O’Farrell Eoin C. T. , Matsumoto Yosuke , Kuga Kentaro , Brando Manuel , Küchler Robert , Nevidomskyy Andriy H. , Yoshida Makoto , Sakakibara Toshiro , Kono Yohei , Shimura Yasuyuki , Sutherland Michael L. , Takigawa Masashi , Nakatsuji Satoru
Published: April 2022

Intermetallic compounds containing f-electron elements have been prototypical materials for investigating strong electron correlations and quantum criticality (QC). Their heavy fermion ground state evoked by the magnetic f-electrons is susceptible to the onset of quantum phases, such as magnetism or superconductivity, due to the enhanced effective mass (m*) and a corresponding decrease of the Fermi temperature. However, the presence of f-electron valence fluctuations to a non-magnetic state is regarded an anathema to QC, as it usually generates a paramagnetic Fermi-liquid state with quasiparticles of moderate m*. Such systems are typically isotropic, with a characteristic energy scale T0 of the order of hundreds of kelvins that require large magnetic fields or pressures to promote a valence or magnetic instability. Here we show the discovery of a quantum critical behaviour and a Lifshitz transition under low magnetic field in an intermediate valence compound α-YbAlB4. The QC origin is attributed to the anisotropic hybridization between the conduction and localized f-electrons. These findings suggest a new route to bypass the large valence energy scale in developing the QC.
Communication-efficient federated learning via knowledge distillation
Authors: Wu Chuhan , Wu Fangzhao , Lyu Lingjuan , Huang Yongfeng , Xie Xing
Published: April 2022

Federated learning is a privacy-preserving machine learning technique to train intelligent models from decentralized data, which enables exploiting private data by communicating local model updates in each iteration of model learning rather than the raw data. However, model updates can be extremely large if they contain numerous parameters, and many rounds of communication are needed for model training. The huge communication cost in federated learning leads to heavy overheads on clients and high environmental burdens. Here, we present a federated learning method named FedKD that is both communication-efficient and effective, based on adaptive mutual knowledge distillation and dynamic gradient compression techniques. FedKD is validated on three different scenarios that need privacy protection, showing that it maximally can reduce 94.89% of communication cost and achieve competitive results with centralized model learning. FedKD provides a potential to efficiently deploy privacy-preserving intelligent systems in many scenarios, such as intelligent healthcare and personalization.
Boron encapsulated in a liposome can be used for combinational neutron capture therapy
Authors: Li Jiyuan , Sun Qi , Lu Chuanjie , Xiao Han , Guo Zhibin , Duan Dongban , Zhang Zizhu , Liu Tong , Liu Zhibo
Published: April 2022

Boron neutron capture therapy (BNCT) is an attractive approach to treat invasive malignant tumours due to binary heavy-particle irradiation, but its clinical applications have been hindered by boron delivery agents with low in vivo stability, poor biocompatibility, and limited application of combinational modalities. Here, we report boronsome, a carboranyl-phosphatidylcholine based liposome for combinational BNCT and chemotherapy. Theoretical simulations and experimental approaches illustrate high stability of boronsome. Then positron emission tomography (PET) imaging with Cu-64 labelled boronsome reveals high-specific tumour accumulation and long retention with a clear irradiation background. In particular, we show the suppression of tumour growth treated with boronsome with neutron irradiation and therapeutic outcomes are further improved by encapsulation of chemotherapy drugs, especially with PARP1 inhibitors. In sum, boronsome may be an efficient agent for concurrent chemoradiotherapy with theranostic properties against malignancies.
Multilayered regulations of alternative splicing, NMD, and protein stability control temporal induction and tissue-specific expression of TRIM46 during axon formation
Authors: Vuong John K. , Ergin Volkan , Chen Liang , Zheng Sika
Published: April 2022

The gene regulation underlying axon formation and its exclusiveness to neurons remains elusive. TRIM46 is postulated to determine axonal fate. We show Trim46 mRNA is expressed before axonogenesis, but TRIM46 protein level is inhibited by alternative splicing of two cassette exons coupled separately to stability controls of Trim46 mRNA and proteins, effectively inducing functional knockout of TRIM46 proteins. Exon 8 inclusion causes nonsense-mediated mRNA decay of Trim46 transcripts. PTBP2-mediated exon 10 skipping produces transcripts encoding unstable TRIM46 proteins. During axonogenesis, transcriptional activation, decreased exon 8 inclusion, and enhanced exon 10 inclusion converge to increase TRIM46 proteins, leading to its neural-specific expression. Genetic deletion of these exons alters TRIM46 protein levels and shows TRIM46 is instructive though not always required for AnkG localization nor a determinant of AnkG density. Therefore, two concurrently but independently regulated alternative exons orchestrate the temporal induction and tissue-specific expression of TRIM46 proteins to mediate axon formation.
Genomic and transcriptomic analysis of a library of small cell lung cancer patient-derived xenografts
Authors: Caeser Rebecca , Egger Jacklynn V. , Chavan Shweta , Socci Nicholas D. , Jones Caitlin Byrne , Kombak Faruk Erdem , Asher Marina , Roehrl Michael H. , Shah Nisargbhai S. , Allaj Viola , Manoj Parvathy , Tischfield Sam E. , Kulick Amanda , Meneses Maximiliano , Iacobuzio-Donahue Christine A. , Lai W. Victoria , Bhanot Umeshkumar , Baine Marina K. , Rekhtman Natasha , Hollmann Travis J. , de Stanchina Elisa , Poirier John T. , Rudin Charles M. , Sen Triparna
Published: April 2022

Access to clinically relevant small cell lung cancer (SCLC) tissue is limited because surgical resection is rare in metastatic SCLC. Patient-derived xenografts (PDX) and circulating tumor cell-derived xenografts (CDX) have emerged as valuable tools to characterize SCLC. Here, we present a resource of 46 extensively annotated PDX/CDX models derived from 33 patients with SCLC. We perform multi-omic analyses, using targeted tumor next-generation sequencing, RNA-sequencing, and immunohistochemistry to deconvolute the mutational landscapes, global expression profiles, and molecular subtypes of these SCLC models. SCLC subtypes characterized by transcriptional regulators, ASCL1, NEUROD1 and POU2F3 are confirmed in this cohort. A subset of SCLC clinical specimens, including matched PDX/CDX and clinical specimen pairs, confirm that the primary features and genomic and proteomic landscapes of the tumors of origin are preserved in the derivative PDX models. This resource provides a powerful system to study SCLC biology.
Anisotropic nanocrystal superlattices overcoming intrinsic light outcoupling efficiency limit in perovskite quantum dot light-emitting diodes
Authors: Kumar Sudhir , Marcato Tommaso , Krumeich Frank , Li Yen-Ting , Chiu Yu-Cheng , Shih Chih-Jen
Published: April 2022

Quantum dot (QD) light-emitting diodes (LEDs) are emerging as one of the most promising candidates for next-generation displays. However, their intrinsic light outcoupling efficiency remains considerably lower than the organic counterpart, because it is not yet possible to control the transition-dipole-moment (TDM) orientation in QD solids at device level. Here, using the colloidal lead halide perovskite anisotropic nanocrystals (ANCs) as a model system, we report a directed self-assembly approach to form the anisotropic nanocrystal superlattices (ANSLs). Emission polarization in individual ANCs rescales the radiation from horizontal and vertical transition dipoles, effectively resulting in preferentially horizontal TDM orientation. Based on the emissive thin films comprised of ANSLs, we demonstrate an enhanced ratio of horizontal dipole up to 0.75, enhancing the theoretical light outcoupling efficiency of greater than 30%. Our optimized single-junction QD LEDs showed peak external quantum efficiency of up to 24.96%, comparable to state-of-the-art organic LEDs.
Installation of synergistic binding sites onto porous organic polymers for efficient removal of perfluorooctanoic acid
Authors: Liu Xiongli , Zhu Changjia , Yin Jun , Li Jixin , Zhang Zhiyuan , Li Jinli , Shui Feng , You Zifeng , Shi Zhan , Li Baiyan , Bu Xian-He , Nafady Ayman , Ma Shengqian
Published: April 2022

Herein, we report a strategy to construct highly efficient perfluorooctanoic acid (PFOA) adsorbents by installing synergistic electrostatic/hydrophobic sites onto porous organic polymers (POPs). The constructed model material of PAF-1-NDMB (NDMB = N,N-dimethyl-butylamine) demonstrates an exceptionally high PFOA uptake capacity over 2000 mg g−1, which is 14.8 times enhancement compared with its parent material of PAF-1. And it is 32.0 and 24.1 times higher than benchmark materials of DFB-CDP (β-cyclodextrin (β-CD)-based polymer network) and activated carbon under the same conditions. Furthermore, PAF-1-NDMB exhibits the highest k2 value of 24,000 g mg−1 h−1 among all reported PFOA sorbents. And it can remove 99.99% PFOA from 1000 ppb to <70 ppt within 2 min, which is lower than the advisory level of Environmental Protection Agency of United States. This work thus not only provides a generic approach for constructing PFOA adsorbents, but also develops POPs as a platform for PFOA capture.
Controlling forward and backward rotary molecular motion on demand
Authors: Pfeifer L. , Crespi S. , van der Meulen P. , Kemmink J. , Scheek R. M. , Hilbers M. F. , Buma W. J. , Feringa B. L.
Published: April 2022

Synthetic molecular machines hold tremendous potential to revolutionize chemical and materials sciences. Their autonomous motion controlled by external stimuli allows to develop smart materials whose properties can be adapted on command. For the realisation of more complex molecular machines, it is crucial to design building blocks whose properties can be controlled by multiple orthogonal stimuli. A major challenge is to reversibly switch from forward to backward and again forward light-driven rotary motion using external stimuli. Here we report a push-pull substituted photo-responsive overcrowded alkene whose function can be toggled between that of a unidirectional 2nd generation rotary motor and a molecular switch depending on its protonation and the polarity of its environment. With its simplicity in design, easy preparation, outstanding stability and orthogonal control of distinct forward and backward motions, we believe that the present concept paves the way for creating more advanced molecular machines.
Secondary structure RNA elements control the cleavage activity of DICER
Authors: Nguyen Trung Duc , Trinh Tam Anh , Bao Sheng , Nguyen Tuan Anh
Published: April 2022

The accurate and efficient cleavage of shRNAs and pre-miRNAs by DICER is crucial for their gene-silencing activity. Here, we conduct high-throughput DICER cleavage assays for more than ~20,000 different shRNAs and show the comprehensive cleavage activities of DICER on these sequences. We discover a single-nucleotide bulge (22-bulge), which facilitates the cleavage activity of DICER on shRNAs and human pre-miRNAs. As a result, this 22-bulge enhances the gene-silencing activity of shRNAs and the accuracy of miRNA biogenesis. In addition, various single-nucleotide polymorphism-edited 22-bulges are found to govern the cleavage sites of DICER on pre-miRNAs and thereby control their functions. Finally, we identify the single cleavage of DICER and reveal its molecular mechanism. Our findings improve the understanding of the DICER cleavage mechanism, provide a foundation for the design of accurate and efficient shRNAs for gene-silencing, and indicate the function of bulges in regulating miRNA biogenesis.
Perylenetetracarboxylic acid nanosheets with internal electric fields and anisotropic charge migration for photocatalytic hydrogen evolution
Authors: Guo Yan , Zhou Qixin , Nan Jun , Shi Wenxin , Cui Fuyi , Zhu Yongfa
Published: April 2022

Highly efficient hydrogen evolution reactions carried out via photocatalysis using solar light remain a formidable challenge. Herein, perylenetetracarboxylic acid nanosheets with a monolayer thickness of ~1.5 nm were synthesized and shown to be active hydrogen evolution photocatalysts with production rates of 118.9 mmol g−1h−1.The carboxyl groups increased the intensity of the internal electric fields of perylenetetracarboxylic acid from the perylene center to the carboxyl border by 10.3 times to promote charge-carrier separation. The photogenerated electrons and holes migrated to the edge and plane, respectively, to weaken charge-carrier recombination. Moreover, the perylenetetracarboxylic acid reduction potential increases from −0.47 V to −1.13 V due to the decreased molecular conjugation and enhances the reduction ability. In addition, the carboxyl groups created hydrophilic sites. This work provides a strategy to engineer the molecular structures of future efficient photocatalysts.
Electrically tunable collective motion of dissipative solitons in chiral nematic films
Authors: Shen Yuan , Dierking Ingo
Published: April 2022

From the motion of fish and birds, to migrating herds of ungulates, collective motion has attracted people for centuries. Active soft matter exhibits a plethora of emergent dynamic behaviors that mimic those of biological systems. Here we introduce an active system composed of dynamic dissipative solitons, i.e. directrons, which mimics the collective motion of living systems. Although the directrons are inanimate, artificial particle-like solitonic field configurations, they locally align their motions like their biological counterparts. Driven by external electric fields, hundreds of directrons are generated in a chiral nematic film. They start with random motions but self-organize into flocks and synchronize their motions. The directron flocks exhibit rich dynamic behaviors and induce population density fluctuations far larger than those in thermal equilibrium systems. They exhibit “turbulent” swimming patterns manifested by transient vortices and jets. They even distinguish topological defects, heading towards defects of positive topological strength and avoiding negative ones.
Integrated photonic metasystem for image classifications at telecommunication wavelength
Authors: Wang Zi , Chang Lorry , Wang Feifan , Li Tiantian , Gu Tingyi
Published: April 2022

Miniaturized image classifiers are potential for revolutionizing their applications in optical communication, autonomous vehicles, and healthcare. With subwavelength structure enabled directional diffraction and dispersion engineering, the light propagation through multi-layer metasurfaces achieves wavelength-selective image recognitions on a silicon photonic platform at telecommunication wavelength. The metasystems implement high-throughput vector-by-matrix multiplications, enabled by near 103 nanoscale phase shifters as weight elements within 0.135 mm2 footprints. The diffraction manifested computing capability incorporates the fabrication and measurement related phase fluctuations, and thus the pre-trained metasystem can handle uncertainties in inputs without post-tuning. Here we demonstrate three functional metasystems: a 15-pixel spatial pattern classifier that reaches near 90% accuracy with femtosecond inputs, a multi-channel wavelength demultiplexer, and a hyperspectral image classifier. The diffractive metasystem provides an alternative machine learning architecture for photonic integrated circuits, with densely integrated phase shifters, spatially multiplexed throughput, and data processing capabilities.
An analysis of neuroscience and psychiatry papers published from 2009 and 2019 outlines opportunities for increasing discovery of sex differences
Authors: Rechlin Rebecca K. , Splinter Tallinn F. L. , Hodges Travis E. , Albert Arianne Y. , Galea Liisa A. M.
Published: April 2022

Sex differences exist in many neurological and psychiatric diseases, but these have not always been addressed adequately in research. In order to address this, it is necessary to consider how sex is incorporated into the design (e.g. using a balanced design) and into the analyses (e.g. using sex as a covariate) in the published literature. We surveyed papers published in 2009 and 2019 across six journals in neuroscience and psychiatry. In this sample, we find a 30% increase in the percentage of papers reporting studies that included both sexes in 2019 compared with 2009. Despite this increase, in 2019 only 19% of papers in the sample reported using an optimal design for discovery of possible sex differences, and only 5% of the papers reported studies that analysed sex as a discovery variable. We conclude that progress to date has not been sufficient to address the importance of sex differences in research for discovery and therapeutic potential for neurological and psychiatric disease.
A pan-tissue DNA-methylation epigenetic clock based on deep learning
Authors: de Lima Camillo Lucas Paulo , Lapierre Louis R. , Singh Ritambhara
Published: April 2022

Several age predictors based on DNA methylation, dubbed epigenetic clocks, have been created in recent years, with the vast majority based on regularized linear regression. This study explores the improvement in the performance and interpretation of epigenetic clocks using deep learning. First, we gathered 142 publicly available data sets from several human tissues to develop AltumAge, a neural network framework that is a highly accurate and precise age predictor. Compared to ElasticNet, AltumAge performs better for within-data set and cross-data set age prediction, being particularly more generalizable in older ages and new tissue types. We then used deep learning interpretation methods to learn which methylation sites contributed to the final model predictions. We observe that while most important CpG sites are linearly related to age, some highly-interacting CpG sites can influence the relevance of such relationships. Using chromatin annotations, we show that the CpG sites with the highest contribution to the model predictions were related to gene regulatory regions in the genome, including proximity to CTCF binding sites. We also found age-related KEGG pathways for genes containing these CpG sites. Lastly, we performed downstream analyses of AltumAge to explore its applicability and compare its age acceleration with Horvath’s 2013 model. We show that our neural network approach predicts higher age acceleration for tumors, for cells that exhibit age-related changes in vitro, such as immune and mitochondrial dysfunction, and for samples from patients with multiple sclerosis, type 2 diabetes, and HIV, among other conditions. Altogether, our neural network approach provides significant improvement and flexibility compared to current epigenetic clocks for both performance and model interpretability.
Activity gradient driven mass transport in molten fluoride salt medium
Authors: Falconer Cody , Elbakhshwan Mohamed , Doniger William , Weinstein Matthew , Sridharan Kumar , Couet Adrien
Published: April 2022

The molten salt-cooled reactor concept has garnered significant interest and one of the current challenges limiting the deployment of these reactor concepts is the complex corrosion phenomenon observed in molten salt environments. One of these phenomena is activity gradient mass transport, which has been shown to affect dissimilar materials submerged in the same salt medium even when best efforts have been made to electrically isolate dissimilar materials from one another. This mechanism while shown experimentally, has not been predictively studied through a modeling approach. In this study, activity gradients in several 316L-X materials systems have been modeled and the mass transport predicted by the model has been confirmed through static isothermal corrosion testing in a molten fluoride salt medium.
Space-efficient binary optimization for variational quantum computing
Authors: Glos Adam , Krawiec Aleksandra , Zimborás Zoltán
Published: April 2022

In the era of Noisy Intermediate-Scale Quantum (NISQ) computers it is crucial to design quantum algorithms which do not require many qubits or deep circuits. Unfortunately, most of the well-known quantum algorithms are too demanding to be run on currently available quantum devices. Moreover, even the state-of-the-art algorithms developed for the NISQ era often suffer from high space complexity requirements for particular problem classes. In this paper, we show that it is possible to greatly reduce the number of qubits needed for the Travelling Salesman Problem (TSP), a paradigmatic optimization task, at the cost of having deeper variational circuits. While the focus is on this particular problem, we claim that the approach can be generalized for other problems where the standard bit-encoding is highly inefficient. Finally, we also propose encoding schemes which smoothly interpolate between the qubit-efficient and the circuit depth-efficient models. All the proposed encodings have the same volume up to polylogarithmic factors and remain efficient to implement within the Quantum Approximate Optimization Algorithm framework.
Functional stratification of cancer drugs through integrated network similarity
Authors: Unsal-Beyge Seyma , Tuncbag Nurcan
Published: April 2022

Drugs not only perturb their immediate protein targets but also modulate multiple signaling pathways. In this study, we explored networks modulated by several drugs across multiple cancer cell lines by integrating their targets with transcriptomic and phosphoproteomic data. As a result, we obtained 236 reconstructed networks covering five cell lines and 70 drugs. A rigorous topological and pathway analysis showed that chemically and functionally different drugs may modulate overlapping networks. Additionally, we revealed a set of tumor-specific hidden pathways with the help of drug network models that are not detectable from the initial data. The difference in the target selectivity of the drugs leads to disjoint networks despite sharing a similar mechanism of action, e.g., HDAC inhibitors. We also used the reconstructed network models to study potential drug combinations based on the topological separation and found literature evidence for a set of drug pairs. Overall, network-level exploration of drug-modulated pathways and their deep comparison may potentially help optimize treatment strategies and suggest new drug combinations.
Measles-based Zika vaccine induces long-term immunity and requires NS1 antibodies to protect the female reproductive tract
Authors: Kurup Drishya , Wirblich Christoph , Lambert Rachael , Diba Leila Zabihi , Leiby Benjamin E. , Schnell Matthias J.
Published: April 2022

Zika virus (ZIKV) can cause devastating effects in the unborn fetus of pregnant women. To develop a candidate vaccine that can protect human fetuses, we generated a panel of live measles vaccine (MV) vectors expressing ZIKV-E and -NS1. Our MV-based ZIKV-E vaccine, MV-E2, protected mice from the non-lethal Zika Asian strain (PRVABC59) and the lethal African strain (MR766) challenge. Despite 100% survival of the MV-E2 mice, however, complete viral clearance was not achieved in the brain and reproductive tract of the lethally challenged mice. We then tested MV-based vaccines that expressed E and NS1 together or separately in two different vaccines. We observed complete clearance of ZIKV from the female reproductive tract and complete fetal protection in the lethal African challenge model in animals that received the dual antigen vaccines. Additionally, MV-E2 and MV-NS1, when administered together, induced durable plasma cell responses. Our findings suggest that NS1 antibodies are required to enhance the protection of ZIKV-E antibodies in the female reproductive tract.
Monitoring of radioactive cesium in wild boars captured inside the difficult-to-return zone in Fukushima Prefecture over a 5-year period
Authors: Saito Rie , Kumada Reiko , Inami Kenji , Kanda Kousuke , Kabeya Masahiko , Tamaoki Masanori , Nemoto Yui
Published: April 2022

Following the Fukushima Daiichi Nuclear Power Plant accident in 2011, tissue samples from wild boar (Sus scrofa) outside the evacuation zone (difficult-to-return zone, DRZ) tended to show high activity concentrations of cesium-137 (137Cs). Understanding the 137Cs dynamics of wild boar populations inside the DRZ is necessary because they affect 137Cs dynamics and wild boar management in areas outside the DRZ. Since few detailed, long-term studies have been conducted inside the DRZ, we measured 137Cs activity concentrations in 221 wild boar muscle samples obtained from wild boar caught inside the DRZ and surrounding areas over a 5-year period. Our results showed that the 137Cs activity concentration in wild boar from inside the DRZ were higher than those in wild boar outside this zone. No significant difference was observed between muscle and soil 137Cs levels, but significant correlations were observed between muscle 137Cs activity concentrations and body length and body weight in the low-activity-concentration season, but not between all seasons and the high-activity-concentration seasons. It is considered that the size effects observed during the low-activity-concentration season may be due to factors related to metabolism and changes in food habit. This is the first long-term survey of 137Cs in wild boar inside the DRZ.
Environmental induced transgenerational inheritance impacts systems epigenetics in disease etiology
Authors: Beck Daniel , Nilsson Eric E. , Ben Maamar Millissia , Skinner Michael K.
Published: April 2022

Environmental toxicants have been shown to promote the epigenetic transgenerational inheritance of disease through exposure specific epigenetic alterations in the germline. The current study examines the actions of hydrocarbon jet fuel, dioxin, pesticides (permethrin and methoxychlor), plastics, and herbicides (glyphosate and atrazine) in the promotion of transgenerational disease in the great grand-offspring rats that correlates with specific disease associated differential DNA methylation regions (DMRs). The transgenerational disease observed was similar for all exposures and includes pathologies of the kidney, prostate, and testis, pubertal abnormalities, and obesity. The disease specific DMRs in sperm were exposure specific for each pathology with negligible overlap. Therefore, for each disease the DMRs and associated genes were distinct for each exposure generational lineage. Observations suggest a large number of DMRs and associated genes are involved in a specific pathology, and various environmental exposures influence unique subsets of DMRs and genes to promote the transgenerational developmental origins of disease susceptibility later in life. A novel multiscale systems biology basis of disease etiology is proposed involving an integration of environmental epigenetics, genetics and generational toxicology.
Naloxone’s dose-dependent displacement of [11C]carfentanil and duration of receptor occupancy in the rat brain
Authors: Kang Yeona , O’Conor Kelly A. , Kelleher Andrew C. , Ramsey Joseph , Bakhoda Abolghasem , Eisenberg Seth M. , Zhao Wenjing , Stodden Tyler , Pearson Torben D. , Guo Min , Brown Nina , Liow Jeih-San , Fowler Joanna S. , Kim Sung Won , Volkow Nora D.
Published: April 2022

The continuous rise in opioid overdoses in the United States is predominantly driven by very potent synthetic opioids, mostly fentanyl and its derivatives (fentanyls). Although naloxone (NLX) has been shown to effectively reverse overdoses by conventional opioids, there may be a need for higher or repeated doses of NLX to revert overdoses from highly potent fentanyls. Here, we used positron emission tomography (PET) to assess NLX’s dose-dependence on both its rate of displacement of [11C]carfentanil ([11C]CFN) binding and its duration of mu opioid receptor (MOR) occupancy in the male rat brain. We showed that clinically relevant doses of intravenously (IV) administered NLX (0.035 mg/kg, Human Equivalent Dose (HED) 0.4 mg; 0.17 mg/kg, HED 2 mg) rapidly displaced the specific binding of [11C]CFN in the thalamus in a dose-dependent manner. Brain MOR occupancy by IV NLX was greater than 90% at 5 min after NLX administration for both doses, but at 27.3 min after 0.035 mg/kg dose and at 85 min after 0.17 mg/kg NLX, only 50% occupancy remained. This indicates that the duration of NLX occupancy at MORs is short-lived. Overall, these results show that clinically relevant doses of IV NLX can promptly displace fentanyls at brain MORs, but repeated or higher NLX doses may be required to prevent re-narcotization following overdoses with long-acting fentanyls.
Hybridized sine cosine algorithm with convolutional neural networks dropout regularization application
Authors: Bacanin Nebojsa , Zivkovic Miodrag , Al-Turjman Fadi , Venkatachalam K. , Trojovský Pavel , Strumberger Ivana , Bezdan Timea
Published: April 2022

Deep learning has recently been utilized with great success in a large number of diverse application domains, such as visual and face recognition, natural language processing, speech recognition, and handwriting identification. Convolutional neural networks, that belong to the deep learning models, are a subtype of artificial neural networks, which are inspired by the complex structure of the human brain and are often used for image classification tasks. One of the biggest challenges in all deep neural networks is the overfitting issue, which happens when the model performs well on the training data, but fails to make accurate predictions for the new data that is fed into the model. Several regularization methods have been introduced to prevent the overfitting problem. In the research presented in this manuscript, the overfitting challenge was tackled by selecting a proper value for the regularization parameter dropout by utilizing a swarm intelligence approach. Notwithstanding that the swarm algorithms have already been successfully applied to this domain, according to the available literature survey, their potential is still not fully investigated. Finding the optimal value of dropout is a challenging and time-consuming task if it is performed manually. Therefore, this research proposes an automated framework based on the hybridized sine cosine algorithm for tackling this major deep learning issue. The first experiment was conducted over four benchmark datasets: MNIST, CIFAR10, Semeion, and UPS, while the second experiment was performed on the brain tumor magnetic resonance imaging classification task. The obtained experimental results are compared to those generated by several similar approaches. The overall experimental results indicate that the proposed method outperforms other state-of-the-art methods included in the comparative analysis in terms of classification error and accuracy.
Chimeric bacteriocin S5-PmnH engineered by domain swapping efficiently controls Pseudomonas aeruginosa infection in murine keratitis and lung models
Authors: Paškevičius Šarūnas , Dapkutė Viktorija , Misiūnas Audrius , Balzaris Modestas , Thommes Pia , Sattar Abdul , Gleba Yuri , Ražanskienė Aušra
Published: April 2022

Rampant rise of multidrug resistant strains among Gram-negative bacteria has necessitated investigation of alternative antimicrobial agents with novel modes of action including antimicrobial proteins such as bacteriocins. The main hurdle in the clinical development of bacteriocin biologics is their narrow specificity and limited strain activity spectrum. Genome mining of bacteria for broadly active bacteriocins have identified a number of promising candidates but attempts to improve these natural multidomain proteins further, for example by combining domains of different origin, have so far met with limited success. We have found that domain swapping of Pseudomonas bacteriocins of porin type, when carried out between phylogenetically related molecules with similar mechanism of activity, allows the generation of highly active molecules with broader spectrum of activity, for example by abolishing strain resistance due to the presence of immunity proteins. The most broadly active chimera engineered in this study, S5-PmnH, exhibits excellent control of Pseudomonas aeruginosa infection in validated murine keratitis and lung infection models.
Efficient CRISPR/Cas9-mediated genome modification of the glassy-winged sharpshooter Homalodisca vitripennis (Germar)
Authors: de Souza Pacheco Inaiara , Doss Anna-Louise A. , Vindiola Beatriz G. , Brown Dylan J. , Ettinger Cassandra L. , Stajich Jason E. , Redak Richard A. , Walling Linda L. , Atkinson Peter W.
Published: April 2022

CRISPR/Cas9 technology enables the extension of genetic techniques into insect pests previously refractory to genetic analysis. We report the establishment of genetic analysis in the glassy-winged sharpshooter (GWSS), Homalodisca vitripennis, which is a significant leafhopper pest of agriculture in California. We use a novel and simple approach of embryo microinjection in situ on the host plant and obtain high frequency mutagenesis, in excess of 55%, of the cinnabar and white eye pigmentation loci. Through pair matings, we obtained 100% transmission of w and cn alleles to the G3 generation and also established that both genes are located on autosomes. Our analysis of wing phenotype revealed an unexpected discovery of the participation of pteridine pigments in wing and wing-vein coloration, indicating a role for these pigments beyond eye color. We used amplicon sequencing to examine the extent of off-target mutagenesis in adults arising from injected eggs, which was found to be negligible or non-existent. Our data show that GWSS can be easily developed as a genetic model system for the Hemiptera, enabling the study of traits that contribute to the success of invasive pests and vectors of plant pathogens. This will facilitate novel genetic control strategies.
Cationic vacancies as defects in honeycomb lattices with modular symmetries
Authors: Kanyolo Godwill Mbiti , Masese Titus
Published: April 2022

Layered materials tend to exhibit intriguing crystalline symmetries and topological characteristics based on their two dimensional (2D) geometries and defects. We consider the diffusion dynamics of positively charged ions (cations) localized in honeycomb lattices within layered materials when an external electric field, non-trivial topologies, curvatures and cationic vacancies are present. The unit (primitive) cell of the honeycomb lattice is characterized by two generators,$$J_1, J_2 \in \mathrm{SL}_2({\mathbb {Z}})$$J1,J2∈SL2(Z)of modular symmetries in the special linear group with integer entries, corresponding to discrete re-scaling and rotations respectively. Moreover, applying a 2D conformal metric in an idealized model, we can consistently treat cationic vacancies as topological defects in an emergent manifold. The framework can be utilized to elucidate the molecular dynamics of the cations in exemplar honeycomb layered frameworks and the role of quantum geometry and topological defects not only in the diffusion process such as prediction of conductance peaks during cationic (de-)intercalation process, but also pseudo-spin and pseudo-magnetic field degrees of freedom on the cationic honeycomb lattice responsible for bilayers.
Removal of mercury(II) from aqueous solution by partially reduced graphene oxide
Authors: Tene Talia , Arias Arias Fabian , Guevara Marco , Nuñez Adriana , Villamagua Luis , Tapia Carlos , Pisarra Michele , Torres F. Javier , Caputi Lorenzo S. , Vacacela Gomez Cristian
Published: April 2022

Mercury (Hg(II)) has been classified as a pollutant and its removal from aqueous sources is considered a priority for public health as well as ecosystem protection policies. Oxidized graphenes have attracted vast interest in water purification and wastewater treatment. In this report, a partially reduced graphene oxide is proposed as a pristine adsorbent material for Hg(II) removal. The proposed material exhibits a high saturation Hg(II) uptake capacity of 110.21 mg g−1, and can effectively reduce the Hg(II) concentration from 150 mg L−1 to concentrations smaller than 40 mg L−1, with an efficiency of about 75% within 20 min. The adsorption of Hg(II) on reduced graphene oxide shows a mixed physisorption–chemisorption process. Density functional theory calculations confirm that Hg atom adsorbs preferentially on clean zones rather than locations containing oxygen functional groups. The present work, therefore, presents new findings for Hg(II) adsorbent materials based on partially reduced graphene oxide, providing a new perspective for removing Hg(II).