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| Open AccessClinically used broad-spectrum antibiotics compromise inflammatory monocyte-dependent antibacterial defense in the lung
Authors utilise a murine model of infection to provide mechanistic insight into how antimicrobial therapy may be a predisposing risk factor for hospital-acquired pneumonia. They show that antibiotic-induced microbiota perturbations compromise inflammatory monocytes and thereby impair antibacterial defence.
- Patrick J. Dörner
- , Harithaa Anandakumar
- & Bastian Opitz
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Article
| Open AccessThe CHK1 inhibitor prexasertib in BRCA wild-type platinum-resistant recurrent high-grade serous ovarian carcinoma: a phase 2 trial
ATR/CHK1 pathway inhibitors represent a therapeutic option for platinum-resistant high-grade serous ovarian carcinoma (HGSOC). Here the authors report the results of a phase 2 clinical study of the CHK1 inhibitor prexasertib in patients with BRCA wild-type platinum-resistant HGSOC with or without biopsiable disease.
- Elena Giudice
- , Tzu-Ting Huang
- & Jung-Min Lee
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Article
| Open AccessAdjuvant nivolumab, capecitabine or the combination in patients with residual triple-negative breast cancer: the OXEL randomized phase II study
Post-neoadjuvant treatment options for patients with triple-negative breast cancer (TNBC) include the chemo-drug capecitabine but also immune checkpoint inhibitors. Here the authors report the results of a phase II study of adjuvant nivolumab, capecitabine or the combination in patients with residual TNBC.
- Filipa Lynce
- , Candace Mainor
- & Claudine Isaacs
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Article
| Open AccessThe effects of genetic and modifiable risk factors on brain regions vulnerable to ageing and disease
A network of brain regions degenerates earlier in aging. Here the authors show that, this network is most vulnerable to diabetes, traffic-related pollution and alcohol consumption in terms of risk factors for dementia, and associated with the XG blood group genes.
- Jordi Manuello
- , Joosung Min
- & Gwenaëlle Douaud
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Article
| Open AccessS100A8/A9 as a prognostic biomarker with causal effects for post-acute myocardial infarction heart failure
Heart failure is the most prevalent complication of acute myocardial infarction. Here, the authors show that circulating S100A8/A9 is a robust predictor and potentially causal medicator for heart failure post-acute myocardial infarction, as such could serve as a promising drug target for cardioprotection.
- Jie Ma
- , Yang Li
- & Yulin Li
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Article
| Open AccessPolygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis
Colitis is one of the most common immune-related adverse events in patients with cancer treated with immune checkpoint inhibitors. Here the authors show that a polygenic risk score for ulcerative colitis can predict immune checkpoint inhibitor-mediated colitis in patients with cancer.
- Pooja Middha
- , Rohit Thummalapalli
- & Elad Ziv
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Article
| Open AccessThe genetic architecture of multimodal human brain age
The biological basis of brain aging is not well understood, but it has implications for human health. Here, the authors explore the genetic basis of human brain aging, finding genetic variants, genes and potential causal relationships with disease.
- Junhao Wen
- , Bingxin Zhao
- & Christos Davatzikos
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Article
| Open AccessOutcome differences by sex in oncology clinical trials
The role of sex differences in response to cancer therapy remains unclear but this could be improved by reporting sex comparisons of outcomes in clinical trials. Here, the authors characterise the sex outcome comparisons in 89,221 interventional trials, finding that while comparisons were rare, important insights could be obtained.
- Ashwin V. Kammula
- , Alejandro A. Schäffer
- & Eytan Ruppin
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Article
| Open AccessLong-term effects of Omicron BA.2 breakthrough infection on immunity-metabolism balance: a 6-month prospective study
Here the authors study recovery from mild to moderate Omicron breakthrough infection at six months post infection. Serum proteomics, PBMC single-cell transcriptomics and clinical parameters indicate slow recovery with coagulation abnormalities and an imbalance of the immune response and metabolism remaining.
- Yanhua Li
- , Shijie Qin
- & George Fu Gao
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Article
| Open AccessElevated blood remnant cholesterol and triglycerides are causally related to the risks of cardiometabolic multimorbidity
Dysmetabolism of triglyceride-rich lipoproteins is considered a shared risk factor for cardiometabolic diseases, but their associations with cardiometabolic multimorbidity have not been fully understood. Here, the authors show that elevated levels of remnant cholesterol and triglycerides were observationally and genetically associated with a higher risk of cardiometabolic multimorbidity.
- Yimin Zhao
- , Zhenhuang Zhuang
- & Tao Huang
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Article
| Open AccessGenomic malaria surveillance of antenatal care users detects reduced transmission following elimination interventions in Mozambique
Routine sampling of pregnant women at first antenatal care (ANC) visits could be used for malaria surveillance. Here, the authors compare the genetic structure of Plasmodium falciparum parasite populations between samples from first ANC users and children from the community in Mozambique, and show that it can inform about changes in transmission beyond epidemiological data.
- Nanna Brokhattingen
- , Glória Matambisso
- & Alfredo Mayor
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Article
| Open AccessProinflammatory polarization of engineered heat-inducible macrophages reprogram the tumor immune microenvironment during cancer immunotherapy
Alternatively activated macrophages have a pivotal role in resolving inflammation but in the tumour microenvironment they are immunosuppressive. Here author show that adoptively transferred engineered macrophages harbouring a heat-inducible genetic switch can resist the polarizing effect of the tumour microenvironment, and do not only remain pro-inflammatory themselves but also re-polarise the endogenous macrophages upon controlled warming with a purpose-made device.
- Yanan Xue
- , Xiaojie Yan
- & Yuan Ping
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Article
| Open AccessInhalation of ACE2-expressing lung exosomes provides prophylactic protection against SARS-CoV-2
Inhibiting SARS-CoV-2 interaction with ACE2 is a promising antiviral strategy. Here, the authors show that exosomes derived from human lung spheroid cells expressing hACE2 accumulate in the lung following prophylactic inhalation to bind and neutralize SARS-CoV-2 and protect mice from SARS-CoV-2-induced disease.
- Zhenzhen Wang
- , Shiqi Hu
- & Ke Cheng
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Article
| Open AccessNeoadjuvant chemo-immunotherapy with camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced squamous cell carcinoma of the head and neck: a pilot phase II trial
Neoadjuvant chemo-immunotherapy represents a therapeutic option for resectable head and neck squamous cell carcinoma (HNSCC). Here the authors report the results of a phase II trial of neoadjuvant camrelizumab plus nab-paclitaxel and cisplatin in resectable locally advanced HNSCC.
- Di Wu
- , Yong Li
- & Xuekui Liu
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Article
| Open AccessImpact of vaccination on the association of COVID-19 with cardiovascular diseases: An OpenSAFELY cohort study
SARS-CoV-2 infection is associated with an increased risk of arterial and venous thrombotic events. Here, the authors investigate the degree to which this association is modified by virus variant and vaccination using electronic health record data for ~18 million adults in England.
- Genevieve I. Cezard
- , Rachel E. Denholm
- & Venexia Walker
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Article
| Open AccessTissue engineered vascular grafts are resistant to the formation of dystrophic calcification
Advancements in congenital heart surgery stress the need for durable biomaterials. Here, the authors compare tissue-engineered vascular grafts (TEVGs) with traditional polytetrafluoroethylene grafts, revealing TEVGs’ superior durability and reduced calcification, promising improved long-term success for surgeries.
- Mackenzie E. Turner
- , Kevin M. Blum
- & Christopher K. Breuer
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Article
| Open AccessDrivers and impact of the early silent invasion of SARS-CoV-2 Alpha
The SARS-CoV-2 Alpha variant of concern emerged in the UK in late 2020 but spread internationally before it was detected. Here, the authors reconstruct the dynamics of dissemination of this variant out of the UK by combining extent of genomic sequencing, travel volume, and local epidemic dynamics in a Bayesian model.
- Benjamin Faucher
- , Chiara E. Sabbatini
- & Chiara Poletto
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| Open AccessTargeting P2Y14R protects against necroptosis of intestinal epithelial cells through PKA/CREB/RIPK1 axis in ulcerative colitis
P2Y14R regulates necroptosis of intestinal epithelial cells though PKA/CREB/RIPK1 axis in the pathogenesis of ulcerative colitis (UC). Targeting P2Y14R with a small molecule inhibitor improves dextran sulfate sodium-induced UC in mice, suggesting P2Y14R as a promising target for treatment of UC.
- Chunxiao Liu
- , Hui Wang
- & Qinghua Hu
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Article
| Open AccessA phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss
Pharmacological inhibition of gamma-secretase induced partial recovery of hearing in animal models. Here, the authors present the safety and efficacy results and key learnings of the First in Human Phase I/IIa study of a gamma-secretase inhibitor in patients with acquired Hearing Loss.
- Anne G. M. Schilder
- , Stephan Wolpert
- & Athanasios G. Bibas
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Article
| Open AccessEffect of gut microbiome modulation on muscle function and cognition: the PROMOTe randomised controlled trial
Here, the authors present the results of the PROMOTe trial, reporting improved cognition with prebiotic vs placebo in twins over 60 years old, probing that remote trials are feasible in older adults, and suggesting that the gut microbiota may represent a therapeutic target for age-associated morbidity.
- Mary Ni Lochlainn
- , Ruth C. E. Bowyer
- & Claire J. Steves
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Article
| Open AccessApplying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis
People who experience optic neuritis, a cause of potentially serious sudden vision loss, have up to a 50% chance of ultimately being diagnosed with multiple sclerosis. Here, the authors find that genetic information combined with age and sex helps predict risk of future diagnosis of multiple sclerosis.
- Pavel Loginovic
- , Feiyi Wang
- & Tasanee Braithwaite
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Article
| Open AccessA framework for evaluating clinical artificial intelligence systems without ground-truth annotations
Estimating the performance of clinical AI systems on data in the wild is complicated by distribution shift and the absence of ground-truth annotations. Here, we introduce SUDO, a framework for more reliably evaluating AI systems on data in the wild.
- Dani Kiyasseh
- , Aaron Cohen
- & Nicholas Altieri
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Article
| Open AccessMetabolomic profiles of sleep-disordered breathing are associated with hypertension and diabetes mellitus development
Sleep-disordered breathing (SDB) is a prevalent disorder linked to higher cardiovascular disease risk. Here, the authors show that summary scores reflecting SDB metabolite signatures are associated with increased risks for incident hypertension and diabetes, potentially useful in guiding risk stratification.
- Ying Zhang
- , Bing Yu
- & Tamar Sofer
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Article
| Open AccessMulti-night cortico-basal recordings reveal mechanisms of NREM slow-wave suppression and spontaneous awakenings in Parkinson’s disease
Using at-home intracranial DBS recordings in PD participants, the authors found subcortical beta has an inverse effect on cortical slow-wave in NREM sleep, rises before awakenings and found >88% accuracy in NREM vs Wake classification in brief 5 s epochs.
- Md Fahim Anjum
- , Clay Smyth
- & Simon Little
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Article
| Open AccessPersistence in risk and effect of COVID-19 vaccination on long-term health consequences after SARS-CoV-2 infection
The long-term health consequences of COVID-19 infection are not fully understood. In this retrospective cohort study from Hong Kong, the authors describe changes in the risk of various clinical outcomes including all-cause mortality for one year following COVID-19 infection and how they vary by vaccination status.
- Ivan Chun Hang Lam
- , Ran Zhang
- & Eric Yuk Fai Wan
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Article
| Open AccessNAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice
Circulating monocytes contribute to the transition to pain chronicity but the molecular events that cause their deployment are still unclear. Using a mouse model of hyperalgesic priming, here the authors show that blood monocytes contribute to the emergence of chronic pain via a mechanism that requires a transient disruption of NAAA-regulated lipid signaling.
- Yannick Fotio
- , Alex Mabou Tagne
- & Daniele Piomelli
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Article
| Open AccessPrior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection
Flavivirus infection or vaccination can induce cross-reactive immune responses. Here, the authors show how previous immunization with the tick-borne encephalitis virus vaccine affects the immune response to the yellow fever vaccine, suggesting that the yellow fever vaccine virus conceals epitopes shared with other flaviviruses in flavivirus-naive but not flavivirus-pre-exposed individuals.
- Antonio Santos-Peral
- , Fabian Luppa
- & Simon Rothenfusser
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Article
| Open AccessRandomized controlled trial of molnupiravir SARS-CoV-2 viral and antibody response in at-risk adult outpatients
In this clinical trial, the authors show that a 5-day molnupiravir treatment reduces SARS-CoV-2 viral load in at-risk outpatients by day 5 but mostly fails to clear virus, leads to lower spike antibody response by day 14 and higher virus mutation rates.
- Joseph F. Standing
- , Laura Buggiotti
- & Francis Yongblah
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Article
| Open AccessAdjuvant dendritic cell therapy in stage IIIB/C melanoma: the MIND-DC randomized phase III trial
Immunotherapy using dendritic cell (DC)-based vaccination has been exploited in the clinic for cancer treatment. Here the authors report the results of a randomized, placebo-controlled, phase 3 trial of adjuvant blood-derived DC cell-based therapy in patients with stage IIIB and IIIC melanoma.
- Kalijn F. Bol
- , Gerty Schreibelt
- & I. Jolanda M. de Vries
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Article
| Open AccessImmune signature of Chlamydia vaccine CTH522/CAF®01 translates from mouse-to-human and induces durable protection in mice
Authors present a comparative immunological characterisation of Chlamydia vaccine, CTH522/CAF®01, in mice and humans. Findings suggest the mouse to be a good predictor of human immunity to the Chlamydia vaccine CTH522/CAF®01, and long-lasting protection in the mouse further supports the development of this promising vaccine candidate.
- Anja W. Olsen
- , Ida Rosenkrands
- & Frank Follmann
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Article
| Open AccessConcordance of randomised controlled trials for artificial intelligence interventions with the CONSORT-AI reporting guidelines
The CONSORT-AI extension was developed to provide specific guidance for randomised controlled trials involving Artificial Intelligence (AI) interventions. Here, the authors show that since publication of CONSORT-AI, several AI-specific considerations remain systematically underreported.
- Alexander P. L. Martindale
- , Benjamin Ng
- & Xiaoxuan Liu
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Matters Arising
| Open AccessDaylight saving time and mortality—proceed with caution
- Elizabeth B. Klerman
- , Matthew D. Weaver
- & Karin G. Johnson
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Article
| Open AccessData encoding for healthcare data democratization and information leakage prevention
Healthcare data democratization is often hampered by privacy constraints governing the sensitive healthcare data. Here, the authors show that encoding healthcare data could be a potential solution for achieving healthcare democratization within the context of deep learning.
- Anshul Thakur
- , Tingting Zhu
- & David A. Clifton
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Article
| Open AccessWASH interventions and child diarrhea at the interface of climate and socioeconomic position in Bangladesh
Household water, sanitation, and handwashing (WASH) interventions can reduce diarrhoea-related morbidity in young children. Here, the authors report findings from a pre-specified secondary analysis of a cluster-randomised trial assessing how WASH impacts vary by socioeconomic position and season.
- Pearl Anne Ante-Testard
- , Francois Rerolle
- & Benjamin F. Arnold
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Article
| Open AccessBiomimetic computer-to-brain communication enhancing naturalistic touch sensations via peripheral nerve stimulation
Loss of communication between the brain and the body severely impacts the sensorimotor abilities of disabled individuals. Here, the authors design and test a neuroscience-driven framework for advancing bionic devices that leverages biomimetic stimulation to induce physiologically plausible information flow in animals and enhances patient performance with neuroprostheses.
- Giacomo Valle
- , Natalija Katic Secerovic
- & Stanisa Raspopovic
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Article
| Open AccessClinical and biomarker results from a phase II trial of combined cabozantinib and durvalumab in patients with chemotherapy-refractory colorectal cancer (CRC): CAMILLA CRC cohort
CAMILLA is a basket trial evaluating cabozantinib plus the ICI durvalumab in chemorefractory gastrointestinal cancer. Here, the authors present the result of the phase II in the colorectal cohort.
- Anwaar Saeed
- , Robin Park
- & Azhar Saeed
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Article
| Open AccessGenome-wide screens identify SEL1L as an intracellular rheostat controlling collagen turnover
Mechanisms regulating collagen clearance may be useful for treating fibrosis. Here, the authors conducted functional genome-wide screens and found that collagen biosynthesis directly regulates collagen clearance via a noncanonical function of SEL1L.
- Michael J. Podolsky
- , Benjamin Kheyfets
- & Kamran Atabai
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Article
| Open AccessMolecular co-assembled strategy tuning protein conformation for cartilage regeneration
The assembly of oligopeptide and polypeptide molecules can reconstruct various ordered advanced structures. Here the authors develop a “molecular velcro”-inspired amphiphilic supramolecular co-assembly strategy, which improves the mechanical strength and cartilaginous regeneration efficiency through conformation transition.
- Chengkun Zhao
- , Xing Li
- & Yong Sun
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Article
| Open AccessDemographic and Clinical Factors Associated With SARS-CoV-2 Spike 1 Antibody Response Among Vaccinated US Adults: the C4R Study
The antibody response to COVID-19 vaccines varies among individuals. Here the authors find that older age, male sex, smoking, higher BMI, vaccine type, and certain comorbidities are associated with lower anti-S1 antibody levels after COVID-19 vaccinations, indicating that certain groups might benefit from higher frequency or doses of vaccination.
- John S. Kim
- , Yifei Sun
- & Elizabeth C. Oelsner
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Article
| Open AccessVascular network-inspired fluidic system (VasFluidics) with spatially functionalizable membranous walls
Functional features in the spatiotemporal regulation of blood chemistry are not much explored. Here authors show vascular network-inspired fluidics, functionalizable for different region-specific trans-wall transport to regulate fluids over space and time.
- Yafeng Yu
- , Yi Pan
- & Ho Cheung Shum
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Article
| Open AccessTGF-β blockade drives a transitional effector phenotype in T cells reversing SIV latency and decreasing SIV reservoirs in vivo
Treatment with the clinical stage TGF-β inhibitor galunisertib promotes latency reversal of HIV/SIV. Here, using a treatment regimen similar to the one tested in clinical trials, the authors show how galunisertib affects immune cell function, increases SIV reactivation, and reduces the viral reservoir in macaques.
- Jinhee Kim
- , Deepanwita Bose
- & Elena Martinelli
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Article
| Open AccessThe molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma
The application of fibroblast growth factor receptor (FGFR)−2 selective tyrosine kinase inhibitors (TKIs) in cholangiocarcinoma (CCA) with FGFR2 fusions has been reported to lead to mutations in the kinase domain of FGFR2.
Here, the authors report that non-selective TKI, lenvatinib may be an alternative in case of insurmountable side effects to specific FGFR inhibitors or to overcome and delay the development of resistance mediating FGFR2 mutations.
- Stephan Spahn
- , Fabian Kleinhenz
- & Michael Bitzer
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Article
| Open AccessHeterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage
Hepatocytes regenerate the liver after injury, however, the tissue repair mechanisms have been little explored. Here, the authors show that midlobular and pericentral hepatocytes increase their number and size in response to chemical, physical, and viral insults facilitating liver regeneration.
- Inmaculada Ruz-Maldonado
- , John T. Gonzalez
- & Carlos Fernández-Hernando
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Article
| Open AccessChildren born after assisted reproduction more commonly carry a mitochondrial genotype associating with low birthweight
Assisted reproduction increases low birthweight risk in children. This study finds a mitochondrial DNA genotype that is more common in ART children, associates to birthweight and that is linked to maternal ageing and to ovarian stimulation.
- Joke Mertens
- , Florence Belva
- & Claudia Spits
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Article
| Open AccessEfficacy and safety of using auditory-motor entrainment to improve walking after stroke: a multi-site randomized controlled trial of InTandemTM
Post-stroke walking impairment is a significant public health concern. Here, the authors perform an interventional, randomized controlled trial evaluating the efficacy and safety of InTandem™, an autonomous neurorehabilitation system utilizing auditory-motor entrainment to improve walking after stroke.
- Louis N. Awad
- , Arun Jayaraman
- & Sabrina R. Taylor
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Article
| Open AccessDisease clusters subsequent to anxiety and stress-related disorders and their genetic determinants
In this study, the authors found five disease clusters associated with a prior diagnosis of anxiety/stress-related disorders, and identified several underlying genetic components. These findings may aid mechanistic exploration and risk management for health decline among those patients.
- Xin Han
- , Qing Shen
- & Huan Song
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Article
| Open AccessA clinically applicable connectivity signature for glioblastoma includes the tumor network driver CHI3L1
In glioblastoma (GBM), tumour microtubes (TM) connect tumour cells to a broader cellular network, with roles in tumour progression and therapy resistance. Here, the authors combine a dye uptake method in GBM xenograft models with subsequent scRNA-seq to infer a TM connectivity signature, finding CHI3L1 as a marker of connectivity.
- Ling Hai
- , Dirk C. Hoffmann
- & Tobias Kessler
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Article
| Open AccessSmith-specific regulatory T cells halt the progression of lupus nephritis
Antigen specific regulatory T cells (Treg) play key roles in the peripheral tolerance to suppress autoreactive immune cells and represent potential avenue for therapeutic intervention. Here the authors identify Smith specific Treg and engineer Treg based cell therapy showing suppression of inflammation in a murine model of lupus nephritis.
- Peter J. Eggenhuizen
- , Rachel M. Y. Cheong
- & Joshua D. Ooi
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Article
| Open AccessThe impact of reproductive factors on the metabolic profile of females from menarche to menopause
Here, the authors explore the relation between age at menarche, parity and age at natural menopause with 249 metabolic traits in over 65,000 UK Biobank to explore whether reproductive factors are likely to impact females’ metabolic profile later in life.
- Gemma L. Clayton
- , Maria Carolina Borges
- & Deborah A. Lawlor