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Article
| Open AccessDe novo generation of multi-target compounds using deep generative chemistry
Polypharmacology drugs are compounds designed to inhibit multiple protein targets. Here, authors use recent advances in AI to rapidly generate polypharmacology compounds against any pair of protein targets, experimentally validating numerous compounds targeting MEK1 and mTOR.
- Brenton P. Munson
- , Michael Chen
- & Trey Ideker
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Article
| Open AccessArabidopsis α-Aurora kinase plays a role in cytokinesis through regulating MAP65-3 association with microtubules at phragmoplast midzone
Arabidopsis α-Aurora kinase regulates plant cytokinesis by phosphorylating the microtubule-associated protein MAP65-3, which controls the dynamic organization of the phragmoplast structure essential for cytokinesis completion.
- Xingguang Deng
- , Yu Xiao
- & Honghui Lin
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Article
| Open AccessActive site remodeling in tumor-relevant IDH1 mutants drives distinct kinetic features and potential resistance mechanisms
Here the authors show mutants of isocitrate dehydrogenase 1 (IDH1), an enzyme implicated in various cancers, have distinct catalytic and structural features that drive their ability to generate an oncometabolite.
- Matthew Mealka
- , Nicole A. Sierra
- & Christal D. Sohl
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Article
| Open AccessBERNN: Enhancing classification of Liquid Chromatography Mass Spectrometry data with batch effect removal neural networks
Liquid Chromatography Mass Spectrometry (LC-MS) is a powerful method for profiling biological samples. Here, the authors have developed a suit of Batch Effect Removal Neural Networks (BERNN) to remove batch effects in large LC-MS experiments to maximize sample classification between conditions.
- Simon J. Pelletier
- , Mickaël Leclercq
- & Arnaud Droit
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Article
| Open AccessIn vivo genome editing via CRISPR/Cas9-mediated homology-independent targeted integration for Bietti crystalline corneoretinal dystrophy treatment
Bietti crystalline corneoretinal dystrophy (BCD) is an autosomal recessive chorioretinal degenerative disease without approved therapeutic drug. Here, the authors show a promising CRISPR/Cas9 mediated homology-independent targeted integration therapy in patient derived cells and humanized mice carrying BCD mutations.
- Xiang Meng
- , Ruixuan Jia
- & Liping Yang
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Article
| Open AccessGenetic influence on within-person longitudinal change in anthropometric traits in the UK Biobank
The availability of longitudinal data in large biobanks is increasing. Here, using data from the UK Biobank, the authors develop and apply analytical approaches to quantify genetic contributions to change over time for traits like height and weight.
- Kathryn E. Kemper
- , Julia Sidorenko
- & Peter M. Visscher
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Article
| Open AccessPlatform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis
SAMHD1 is a regulator of dNTP homeostasis and an HIV restriction factor. The authors use time-resolved cryo-EM to visualise dynamic conformational changes that drive the catalytic cycle and allosteric regulation of this multi-subunit enzyme.
- Oliver J. Acton
- , Devon Sheppard
- & Ian A. Taylor
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Article
| Open AccessTargeted delivery of the probiotic Saccharomyces boulardii to the extracellular matrix enhances gut residence time and recovery in murine colitis
In this study, the authors engineered a targeted Saccharomyces boulardii probiotic yeast platform, showing it exhibits high adherence to extracellular matrix proteins, resulting in longer gut residence, higher colon concentrations, and enhanced recovery in murine colitis.
- Mairead K. Heavey
- , Anthony Hazelton
- & Juliane Nguyen
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Article
| Open AccessAn adeno-associated virus variant enabling efficient ocular-directed gene delivery across species
In non-human primates, rAAVs are delivered through suprachoroidal injection at a high dose to achieve optimal efficacy. Here, the authors present a novel AAV capsid (AAVv128) that significantly improved the transduction efficiency in photoreceptor and retinal pigment epithelial cells across species.
- Shuang Luo
- , Hao Jiang
- & Xun Sun
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Article
| Open AccessBiosynthetic production of anticoagulant heparin polysaccharides through metabolic and sulfotransferases engineering strategies
Microbial heparin bioproduction is hampered by the difficulty of recombinant expression of active heparan sulfate N-deacetylase/N-sulfotransferase. Here, the authors solve the problem by developing a cellular system-based semisynthetic strategy and achieve the production of active heparin by engineered E. coli.
- Jian-Qun Deng
- , Yi Li
- & Ju-Zheng Sheng
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Article
| Open AccessAn oxylipin signal confers protection against antifungal echinocandins in pathogenic aspergilli
Echinocandins are antifungal drugs that inhibit hyphal growth and induce lysis of hyphal tip compartments in pathogenic Aspergillus species. Here, Calise et al. show that echinocandins induce production of a fungal oxylipin signal, thus triggering hyphal growth changes that reduce hyphal tip lysis and confer echinocandin tolerance.
- Dante G. Calise
- , Sung Chul Park
- & Nancy P. Keller
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Article
| Open AccessMutation characteristics and molecular evolution of ovarian metastasis from gastric cancer and potential biomarkers for paclitaxel treatment
‘Gastric cancer metastasis to the ovary is difficult to treat and is not fully understood. Here, the authors characterized mutations in a cohort of matched primary and metastatic disease, and found mutations, including in CLDN18, could predict treatment response to paclitaxel.
- Pengfei Yu
- , Can Hu
- & Xiangdong Cheng
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Article
| Open AccessTargeting adipocyte ESRRA promotes osteogenesis and vascular formation in adipocyte-rich bone marrow
Excessive bone marrow adipocytes accumulation is involved in bone deterioration. Here, the authors show that adipocyte ESRRA abrogation promotes osteogenesis and vascular formation in adipocyte-rich bone marrow via oppositely regulating the expression and secretion of leptin and SPP1.
- Tongling Huang
- , Zhaocheng Lu
- & Min Guan
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Article
| Open AccessGiant organelle vesicles to uncover intracellular membrane mechanics and plasticity
The biophysical properties of cellular organelles are difficult to study directly. Here, the authors generate and characterize osmotically-expanded giant vesicles of several organelles, which maintain some of their functional properties.
- Alexandre Santinho
- , Maxime Carpentier
- & Abdou Rachid Thiam
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Article
| Open AccessArabidopsis SBT5.2 and SBT1.7 subtilases mediate C-terminal cleavage of flg22 epitope from bacterial flagellin
Plants initiate specific defense responses by recognizing flg22 peptide epitope derived from flagellin, the major structural protein of the bacterial flagellum. Here, the authors identified two plant subtilases, SBT5.2 and SBT1.7, as specific proteases responsible for cleaving the peptide epitope.
- Sayaka Matsui
- , Saki Noda
- & Yoshikatsu Matsubayashi
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Article
| Open AccessIL-17C is a driver of damaging inflammation during Neisseria gonorrhoeae infection of human Fallopian tube
In pelvic inflammatory disease, host immune responses to Neisseria gonorrhoeae damage Fallopian tube tissue and cause infertility. Here, Garcia et al. show that the cytokine IL-17C induces inflammatory responses, and peptidoglycan fragments reduce transcripts related to tissue integrity.
- Erin M. Garcia
- , Jonathan D. Lenz
- & Joseph P. Dillard
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Article
| Open AccessDiet-omics in the
S tudy ofU rban andR uralC rohn diseaseE volution (SOURCE) cohortExposures rather than genetics likely contribute to the worldwide increased prevalence of Crohn Disease (CD). Here, the authors constructed the Study Of Urban and Rural Crohn disease Evolution (SOURCE), a multicenter and multi-omics cross-sectional study, to identify that time spent by rural residents in urban environments is linked with changes in gut microbial composition and metabolomics, which mirrored those seen in CD. Reviewer recognition:
- Tzipi Braun
- , Rui Feng
- & Yael Haberman
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Article
| Open AccessOzone as an environmental driver of influenza
Temperature and absolute humidity are associated with influenza activity, and recent data from Hong Kong have suggested ozone as an additional environmental driver. Here, the authors investigate the relationship between ozone and influenza transmission using surveillance data from the USA and find evidence for an inhibitory effect.
- Fang Guo
- , Pei Zhang
- & Linwei Tian
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Article
| Open AccessGenetic association of inflammatory marker GlycA with lung function and respiratory diseases
Here, the authors observed significant genetic correlation of GlycA with lung function, asthma and COPD and identified ten shared loci revealing potential shared biological mechanisms involving ubiquitination and Wnt/β-catenin signaling.
- Yanjun Guo
- , Quanhong Liu
- & Weihong Chen
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Article
| Open AccessA multicenter proof-of-concept study on deep learning-based intraoperative discrimination of primary central nervous system lymphoma
Correct diagnosis of primary central nervous system lymphoma is key in determining treatment, however, this depends on pathology analysis. Here, the authors develop a deep learning method to diagnose primary nervous system lymphoma from stained whole-slide images.
- Xinke Zhang
- , Zihan Zhao
- & Muyan Cai
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Article
| Open AccessA statistical resolution measure of fluorescence microscopy with finite photons
Abbe’s diffraction limit has been a defining concept for microscopy. With finite photon, photon noise remains one essential factor yet to be considered in the theoretical resolution limit. Here, the authors introduced information-based resolution limit allowing for photon-considered resolution assessment of various microscopy and super-resolution modalities.
- Yilun Li
- & Fang Huang
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Article
| Open AccessA human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations
Copy number alterations in stem cells impair neural crest differentiation and set the stage for neuroblastoma-like traits and tumours. This study hints at early tumourigenesis mechanisms and finds developmental gene signatures linked to prognosis.
- Ingrid M. Saldana-Guerrero
- , Luis F. Montano-Gutierrez
- & Florian Halbritter
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Article
| Open AccessAdjuvant-dependent impact of inactivated SARS-CoV-2 vaccines during heterologous infection by a SARS-related coronavirus
Here, Dillard and Taft-Benz et al. show in a female mouse model how different adjuvants affect inactivated vaccine-mediated protection against homologous SARS-CoV-2 and heterologous SARS-CoV-1-like coronaviruses. They find that an aluminum hydroxide-adjuvanted vaccine can increase risk of adverse outcomes during heterologous infection.
- Jacob A. Dillard
- , Sharon A. Taft-Benz
- & Mark T. Heise
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Article
| Open AccessDiscovery of immunotherapy targets for pediatric solid and brain tumors by exon-level expression
CAR T cell immunotherapy for paediatric solid and brain tumours is constrained by the availability of targetable antigens. Here, the authors investigate the landscape of cancer-specific exons as potential targets by analysing 1,532 RNAseq datasets from 16 types of paediatric solid and brain tumours.
- Timothy I. Shaw
- , Jessica Wagner
- & Stephen Gottschalk
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Article
| Open AccessPrimordial germ cell DNA demethylation and development require DNA translesion synthesis
Here the authors show that DNA translesion synthesis affects primordial germ cell DNA demethylation and plays a role in the development of embryonic germ cells.
- Pranay Shah
- , Ross Hill
- & Gerry P. Crossan
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Article
| Open AccessCD74 supports accumulation and function of regulatory T cells in tumors
CD74, the MHC class II invariant chain, was thought to be mainly expressed by antigen presenting cells. Here the authors report that CD74 is overexpressed by human tumor infiltrating regulatory T cells (Tregs) and that its loss affects Treg accumulation and function in tumors.
- Elisa Bonnin
- , Maria Rodrigo Riestra
- & Eliane Piaggio
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Article
| Open AccessSynthetic BZLF1-targeted transcriptional activator for efficient lytic induction therapy against EBV-associated epithelial cancers
EBV (Epstein-Barr virus)-targeted therapy is limited by efficient agents inducing lytic cycle in cancer cells. Here they report a transcriptional activator incorporated into lipid nanoparticles that could specifically activate endogenous BZLF1 and induce lytic reactivation in EBV-positive cancer cells thereby suppress tumor progression.
- Man Wu
- , Pok Man Hau
- & Kwok-Wai Lo
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Article
| Open AccessAcinar to β-like cell conversion through inhibition of focal adhesion kinase
A cure for diabetes could entail an effective cell replacement therapy through generation of new insulinproducing cells. In this study, we show that inhibition of focal adhesion kinase activity results in transdifferentiation of a subset of peri-islet acinar cells into functional insulin producing β-like cells.
- Shakti Dahiya
- , Mohamed Saleh
- & Farzad Esni
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Article
| Open AccessThe DEAD-box RNA helicase PfDOZI imposes opposing actions on RNA metabolism in Plasmodium falciparum
Min and colleagues study post-transcriptional regulation in the malaria parasite. They describe opposing actions of the DDX6-family RNA helicase complex on the decay and protection of specific mRNA targets during development and stress conditions.
- Hui Min
- , Xiaoying Liang
- & Liwang Cui
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Article
| Open AccessAnnoSpat annotates cell types and quantifies cellular arrangements from spatial proteomics
Annotation of cell types and quantification of their relative localization in tissues remain challenging. Here, the authors present AnnoSpat (Annotator and Spatial Pattern Finder), a computational tool that can automatically identify cell types and quantify cell-cell proximity relationships.
- Aanchal Mongia
- , Fatema Tuz Zohora
- & Robert B. Faryabi
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Article
| Open AccessA non-image-forming visual circuit mediates the innate fear of heights in male mice
The neural basis underlying fear of heights is not well understood. Here the authors identify, in mice, a subcortical route for innate fear of heights, bypassing the primary visual cortex.
- Wei Shang
- , Shuangyi Xie
- & Xiao-Bing Yuan
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Article
| Open AccessFocal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer
Remaining drug-tolerant persistent (DTP) cancer cells limit the efficacy of targeted therapy in EGFR, ALK and KRAS mutant non-small cell lung cancer (NSCLC). Here, the authors show that focal adhesion kinase (FAK)-YAP signalling supports DTP cells promoting residual disease and targeting this pathway improved tumour response in NSCLC preclinical models.
- Franziska Haderk
- , Yu-Ting Chou
- & Trever G. Bivona
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Article
| Open AccessLncRNA-LncDACH1 mediated phenotypic switching of smooth muscle cells during neointimal hyperplasia in male arteriovenous fistulas
Arteriovenous fistulas are the most common vascular access points for hemodialysis, but they have a high incidence of postoperative dysfunction, mainly due to excessive neointimal hyperplasia. Here, the author shows that LncDACH1 regulates NIH through the HSP90/ SRPK1/ AKT signaling axis.
- Zhaozheng Li
- , Yao Zhao
- & Jundong Jiao
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Article
| Open AccessCell-penetrating protein-recognizing polymeric nanoparticles through dynamic covalent chemistry and double imprinting
Molecular recognition of proteins is essential for achieving their biological functions but it is challenging to prepare selective protein-binding materials. Here the authors report a method that combines dynamic covalent chemistry and double molecular imprinting to construct protein-recognizing nanoparticles capable of specific inhibition of protein–protein interactions.
- Avijit Ghosh
- , Mansi Sharma
- & Yan Zhao
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Matters Arising
| Open AccessReassessing data quality underlying the recently updated floristic map of the world
- Hong Qian
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Matters Arising
| Open AccessReply to: Reassessing data quality underlying the recently updated floristic map of the world
- Yunpeng Liu
- , Xiaoting Xu
- & Zhiheng Wang
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Article
| Open AccessSynthetic intrinsically disordered protein fusion tags that enhance protein solubility
Insoluble protein expression continues to be a bottleneck for biotechnology. Here, Chilkoti and colleagues report a method for generating and identifying hypersoluble intrinsically disordered protein fusion tags to improve soluble protein expression and rescue protein function.
- Nicholas C. Tang
- , Jonathan C. Su
- & Ashutosh Chilkoti
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Article
| Open AccessGlobally occurring pelagiphage infections create ribosome-deprived cells
SAR11 bacteria and their phages are abundant in the oceans. Here the authors quantify the number of phage-infected SAR11 cells using microscopy techniques and discover phage-infected cells without any detectable ribosomes. They hypothesize that ribosomal RNA may be used for the synthesis of phage genomes.
- Jan D. Brüwer
- , Chandni Sidhu
- & Bernhard M. Fuchs
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Article
| Open AccessHPK1 citron homology domain regulates phosphorylation of SLP76 and modulates kinase domain interaction dynamics
In this work, the authors unveil a mechanism where the Citron homology domain regulates HPK1’s kinase domain, shedding light on the relationship between HPK1’s structure and function. This enhances our understanding of HPK1, an intracellular target for cancer immunotherapy and provides a direction for immuno-oncology drug discovery.
- Avantika S. Chitre
- , Ping Wu
- & Weiru Wang
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Article
| Open AccessThe complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation
The amino acid transporter complex LAT1-4F2hc is considered a major drug target for many cancers. Here, the authors apply native mass spectrometry-based approaches to decode a complete LAT1-4F2hc assembly. To do this, they connect post-translational modification and endogenous phospholipid binding to super-dimerization, function and localisation of LAT1-4F2hc.
- Di Wu
- , Renhong Yan
- & Carol V. Robinson
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Article
| Open AccessEndogenous clock-mediated regulation of intracellular oxygen dynamics is essential for diazotrophic growth of unicellular cyanobacteria
The authors investigate the circadian clock in a unicellular diazotrophic cyanobacterium. They demonstrate the role of the clock in regulating intracellular oxygen dynamics, a necessity to accommodate nitrogen fixation in an oxygen-producing cell.
- Anindita Bandyopadhyay
- , Annesha Sengupta
- & Himadri B. Pakrasi
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Article
| Open AccessDisease related changes in ATAC-seq of iPSC-derived motor neuron lines from ALS patients and controls
Amyotrophic Lateral Sclerosis (ALS) is highly heritable but the mechanisms of sporadic ALS are not fully understood. In this study, the authors identify drivers of variation and disease-relevant changes in the epigenomic profile of iPSC-derived motor neuron lines generated from ALS patients and healthy controls as part of the Answer ALS program.
- Stanislav Tsitkov
- , Kelsey Valentine
- & Ernest Fraenkel
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Article
| Open AccessMultiplexed representation of others in the hippocampal CA1 subfield of female mice
How the position of conspecifics is represented in the brain is not fully understood. Here authors show that the position of conspecifics is represented relative to self-position in the hippocampus of female mice, which is modulated by context and identity and improved through learning.
- Xiang Zhang
- , Qichen Cao
- & Chenglin Miao
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Article
| Open AccessRegulatory sequence-based discovery of anti-defense genes in archaeal viruses
Little is known about how archaeal viruses counteract host immunity. Here, the authors leverage a viral gene regulatory feature to predict 354 potential anti-defense genes and experimentally validate a CRISPR-Cas I-A inhibitor and an inhibitor of a toxin-antitoxin system.
- Yuvaraj Bhoobalan-Chitty
- , Shuanshuan Xu
- & Xu Peng
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Article
| Open AccessTiming the evolution of phosphorus-cycling enzymes through geological time using phylogenomics
Phosphorus is an essential nutrient which may have influenced Earth’s early biosphere. This study interrogates genomic records, finding potentially phosphate depleted conditions toward the end of the Archean when enzymes for scavenging reduced phosphorus compounds spread throughout the tree of life.
- Joanne S. Boden
- , Juntao Zhong
- & Eva E. Stüeken
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Article
| Open AccessAnomalous dynamics of a passive droplet in active turbulence
The fluctuating dynamics of a passive object suspended in an active fluid can provide fundamental insight into the fundamental non-equilibrium behavior of the fluid. Singh and Chaudhuri theoretically investigate the dynamics of a passive deformable droplet in active nematic turbulence and show how the motion of the droplet is influenced by the interplay of spatial correlations of the flow and the size of the droplet.
- Chamkor Singh
- & Abhishek Chaudhuri
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Article
| Open AccessMultimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions
Please let us know if there are any inaccuracies: ‘Esophageal squamous cell carcinoma is most commonly detected at a late stage, which limits survival and treatment options. Here, the authors utilise whole genome bisulfite sequencing to create a cfDNA framework to detect cfDNA methylation, copy number variants and fragmentation.
- Jiaqi Liu
- , Lijun Dai
- & Zhihua Liu
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Article
| Open AccessUsing genome and transcriptome data from African-ancestry female participants to identify putative breast cancer susceptibility genes
Here, the authors integrate genomic and transcriptomic data obtained from African-ancestry female participants and identify six genes associated with breast cancer risk which provides biological insights into this common cancer in an underrepresented population.
- Jie Ping
- , Guochong Jia
- & Wei Zheng
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Article
| Open AccessA sparse quantized hopfield network for online-continual memory
Brains and neuromorphic systems learn with local learning rules in online-continual learning scenarios. Designing neural networks that learn effectively under these conditions is challenging. The authors introduce a neural network that implements an effective, principled approach to local, online-continual learning on associative memory tasks.
- Nicholas Alonso
- & Jeffrey L. Krichmar
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