bluuebunny/crossref_metadata_2025_split huggingface dataset:
A force-compensated compliant MEMS-amplifier with electrostatic anti-springs
Authors: Schmitt Philip , Hoffmann Martin 
Published: June 2023

AbstractIn this paper, an electrostatic compliant mechanical amplifier intended for force-compensated displacement amplification in MEMS sensor applications is described. Usually, mechanical transformers that enhance a small input displacement into a large output displacement generate large forces at the input of the transformer. The microsystem proposed here allows for the reduction and compensation of the input stiffness of the amplifier and any mechanical components connected to it while providing a constant amplification ratio at the same time. The amplifying mechanism features bidirectional electrostatic anti-springs enabling the control of the stiffness by applying a constant DC voltage. The electrode design of the anti-springs and its influence on the force-displacement characteristic, the side instability and the maximal displacement are studied through analytical approaches and supported by FEA and by experiments. Based on the derived models, a compliant electromechanical amplifier is developed, featuring an amplification ratio of 50. For this amplifier the initial input stiffness of 422 N/m could be reduced to 6.8 N/m by applying a voltage of 100 V. As an additional application, we show how the amplifier can be used as a mechanical force sensor with tuneable sensitivity, where the forces at the input are transformed into large output displacements. Through experiments, we show how the sensitivity can be adjusted and increased by a factor of 25 by applying a voltage at the anti-springs.
Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine
Authors: Khanra Sourav , Reddy Preethi , Giménez-Palomo Anna , Park Chun Hui J. , Panizzutti Bruna , McCallum Madeleine , Arumugham Shyam Sundar , Umesh Shreekantiah , Debnath Monojit , Das Basudeb , Venkatasubramanian Ganesan , Ashton Melanie , Turner Alyna , Dean Olivia M. , Walder Ken , Vieta Eduard , Yatham Lakshmi N. , Pacchiarotti Isabella , Reddy Y. C. Janardhan , Goyal Nishant , Kesavan Muralidharan , Colomer Lluc , Berk Michael , Kim Jee Hyun 
Published: June 2023

AbstractBipolar disorder’s core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression–mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine’s potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine’s demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.
Appearance of tuft cells during prostate cancer progression
Authors: Vlajic Katarina , Pennington Kluger Hannah , Bie Wenjun , Merrill Bradley J. , Nonn Larisa , Kajdacsy-Balla Andre , Tyner Angela L. 
Published: June 2023

AbstractTuft cells are chemosensory epithelial cells that increase in number following infection or injury to robustly activate the innate immune response to alleviate or promote disease. Recent studies of castration resistant prostate cancer and its subtype, neuroendocrine prostate cancer, revealed Pou2f3+ populations in mouse models. The transcription factor Pou2f3 is a master regulator of the tuft cell lineage. We show that tuft cells are upregulated early during prostate cancer development, and their numbers increase with progression. Cancer-associated tuft cells in the mouse prostate express DCLK1, COX1, COX2, while human tuft cells express COX1. Mouse and human tuft cells exhibit strong activation of signaling pathways including EGFR and SRC-family kinases. While DCLK1 is a mouse tuft cell marker, it is not present in human prostate tuft cells. Tuft cells that appear in mouse models of prostate cancer display genotype-specific tuft cell gene expression signatures. Using bioinformatic analysis tools and publicly available datasets, we characterized prostate tuft cells in aggressive disease and highlighted differences between tuft cell populations. Our findings indicate that tuft cells contribute to the prostate cancer microenvironment and may promote development of more advanced disease. Further research is needed to understand contributions of tuft cells to prostate cancer progression.
Metabolism-related brain morphology accelerates aging and predicts neurodegenerative diseases and stroke: a UK Biobank study
Authors: Shen Chenye , Liu Chaoqiang , Qiu Anqi 
Published: June 2023

AbstractsMetabolic syndrome (MetS) is characterized by a constellation of metabolic risk factors, including obesity, hypertriglyceridemia, low high-density lipoprotein (HDL) levels, hypertension, and hyperglycemia, and is associated with stroke and neurodegenerative diseases. This study capitalized on brain structural images and clinical data from the UK Biobank and explored the associations of brain morphology with MetS and brain aging due to MetS. Cortical surface area, thickness, and subcortical volumes were assessed using FreeSurfer. Linear regression was used to examine associations of brain morphology with five MetS components and the MetS severity in a metabolic aging group (N = 23,676, age 62.8 ± 7.5 years). Partial least squares (PLS) were employed to predict brain age using MetS-associated brain morphology. The five MetS components and MetS severity were associated with increased cortical surface area and decreased thickness, particularly in the frontal, temporal, and sensorimotor cortex, and reduced volumes in the basal ganglia. Obesity best explained the variation of brain morphology. Moreover, participants with the most severe MetS had brain age 1-year older than those without MetS. Brain age in patients with stroke (N = 1042), dementia (N = 83), Parkinson’s (N = 107), and multiple sclerosis (N = 235) was greater than that in the metabolic aging group. The obesity-related brain morphology had the leading discriminative power. Therefore, the MetS-related brain morphological model can be used for risk assessment of stroke and neurodegenerative diseases. Our findings suggested that prioritizing adjusting obesity among the five metabolic components may be more helpful for improving brain health in aging populations.
Psychological resilience mediates the protective role of default-mode network functional connectivity against COVID-19 vicarious traumatization
Authors: Liu Xiqin , Zhao Yajun , Suo Xueling , Zhang Xun , Pan Nanfang , Kemp Graham J. , Gong Qiyong , Wang Song 
Published: June 2023

AbstractVicarious traumatization (VT), a negative reaction to witnessing others’ trauma, has been experienced by some people during the COVID-19 pandemic, and can lead to mental health problems. This study aimed to identify functional brain markers of COVID-specific VT and explore the psychological mechanism underlying the brain-VT link. One hundred healthy participants underwent resting-state functional magnetic resonance imaging before the pandemic (October 2019–January 2020) and completed VT measurement during the pandemic (February–April 2020). Whole-brain correlation analysis based on global functional connectivity density (FCD) mapping revealed that VT was negatively correlated with FCD in the right inferior temporal gyrus (ITG) (i.e., the lower FCD in ITG, the worse the VT), identified by mapping onto known large-scale networks as part of the default-mode network (DMN). Resting-state functional connectivity (RSFC) analysis using ITG as seed found that VT was predicted by lower functional connectivity between ITG and other DMN regions including left medial prefrontal cortex, left orbitofrontal cortex, right superior frontal gyrus, right inferior parietal lobule and bilateral precuneus (i.e., the lower the ITG-DMN connectivity, the worse the VT). Mediation analyses suggested that psychological resilience served as a mediator in these associations of ITG FCD and ITG-DMN RSFC with VT. Our results provide novel evidence on the brain basis of VT and emphasize psychological resilience as an important link from DMN functional connectivity to COVID-specific-VT. This may facilitate public health interventions by helping identify individuals at risk of stress- and trauma-related psychopathologies.
Efficacy evaluation of chimeric antigen receptor-modified human peritoneal macrophages in the treatment of gastric cancer
Authors: Dong Xuhui , Fan Jiqiang , Xie Wangxu , Wu Xiang , Wei Jia , He Zhonglei , Wang Wenxin , Wang Xueting , Shen Pingping , Bei Yuncheng 
Published: June 2023

Abstract
Background
Gastric cancer is one of the most common cancers. Peritoneal carcinomatosis (PC) appears to be the most common pattern of recurrence, and more than half of the GC patients eventually die from PC. Novel strategies for the management of patients with PC are urgently needed. Recently, rapid progress has been made in adoptive transfer therapy by using macrophages as the effector cells due to their capabilities of phagocytosis, antigen presentation, and high penetration. Here, we generated a novel macrophage-based therapy and investigated anti-tumoral effects on GC and potential toxicity.

Methods
We developed a novel Chimeric Antigen Receptor-Macrophage (CAR-M) based on genetically modifying human peritoneal macrophages (PMs), expressing a HER2-FcεR1γ-CAR (HF-CAR). We tested HF-CAR macrophages in a variety of GC models in vitro and in vivo.

Results
HF-CAR-PMs specifically targeted HER2-expressed GC, and harboured the FcεR1γ moieties to trigger engulfment. Intraperitoneal administration of HF-CAR-PMs significantly facilitated the HER2-positive tumour regression in PC mouse model and prolonged the overall survival rate. In addition, the combined use of oxaliplatin and HF-CAR-PMs exhibited significantly augment anti-tumour activity and survival benefit.

Conclusions
HF-CAR-PMs could represent an exciting therapeutic option for patients with HER2-positive GC cancer, which should be tested in carefully designed clinical trials.
Blocking tri-methylguanosine synthase 1 (TGS1) stops anchorage-independent growth of canine sarcomas
Authors: Zucko Dora , Boris-Lawrie Kathleen 
Published: June 2023

AbstractTri methylguanosine synthase 1 (TGS1) is the enzyme that hyper methylates the hallmark 7-methyl-guanosine cap (m7G-cap) appended to the transcription start site of RNAs. The m7G-cap and the eIF4E-cap binding protein guide canonical cap-dependent translation of mRNAs, whereas hyper methylated cap, m2,2,7G-cap (TMG) lacks adequate eIF4E affinity and licenses entry into a different translation initiation pathway. The potential role for TGS1 and TMG-capped mRNA in neoplastic growth is unknown. Canine sarcoma has high translational value to the human disease. Cumulative downregulation of protein synthesis in osteosarcoma OSCA-40 was achieved cooperatively by siTGS1 and Torin-1. Torin-1 inhibited the proliferation of three canine sarcoma explants in a reversible manner that was eliminated by siRNA-downregulation of TGS1. TGS1 failure prevented the anchorage-independent growth of osteo- and hemangio-sarcomas and curtailed sarcoma recovery from mTOR inhibition. RNA immunoprecipitation studies identified TMG-capped mRNAs encoding TGS1, DHX9 and JUND. TMG-tgs1 transcripts were downregulated by leptomycin B and TGS1 failure was compensated by eIF4E mRNP-dependent tgs1 mRNA translation affected by mTOR. The evidence documents TMG-capped mRNAs are hallmarks of the investigated neoplasms and synergy between TGS1 specialized translation and canonical translation is involved in sarcoma recovery from mTOR inhibition. Therapeutic targeting of TGS1 activity in cancer is ripe for future exploration.
Biallelic FBXW7 knockout induces AKAP8-mediated DNA damage in neighbouring wildtype cells
Authors: Chan Dedrick Kok Hong , Mandal Amit , Hester Svenja , Yu Zhanru , Higgins Geoff Stuart , Kessler Benedikt Mathias , Fischer Roman , Buczacki Simon James Alexander 
Published: June 2023

AbstractColorectal cancer possesses marked intratumoral heterogeneity. While subclonal interactions between Vogelstein driver mutations have been extensively studied, less is known about competitive or cooperative effects between subclonal populations with other cancer driver mutations. FBXW7 is a cancer driver mutation which is present in close to 17% of colorectal cancer cells. In this study, we generated isogenic FBXW7 mutant cells using CRISPR-Cas9. We identified an upregulation of oxidative phosphorylation and DNA damage in FBXW7 mutant cells, which surprisingly proliferated at a decreased rate compared to wildtype cells. To determine subclonal interactions, wildtype and mutant FBXW7 cells were cocultured using a Transwell system. Wildtype cells cocultured with FBXW7 mutant cells similarly developed DNA damage which was not observed when wildtype cells were co-cultured with other wildtype cells, suggesting that FBXW7 mutant cells were inducing DNA damage in neighbouring wildtype cells. Using mass spectrometry, we identified AKAP8 as being secreted by FBXW7 mutant cells into the coculture media. Furthermore, overexpression of AKAP8 in wildtype cells recapitulated the DNA damage phenotype observed during coculture, while co-culture of wildtype cells with double mutant FBXW7−/−/AKAP8−/− cells abrogated the DNA damage phenotype. Here, we describe a hitherto unknown phenomenon of AKAP8-mediated DNA damage from FBXW7 mutant to neighbouring wildtype cells. Our findings demonstrate the importance of elucidating the local effect of cancer driver mutations between subclonal populations.
MicroRNA-375 restrains the progression of lung squamous cell carcinoma by modulating the ERK pathway via UBE3A-mediated DUSP1 degradation
Authors: Gan Junqing , Zhang Yu , Liu Shan , Mu Guannan , Zhao Juan , Jiang Wei , Li Jiade , Li Qi , Wu Yangjiazi , Wang Xinling , Che Dehai , Li Xiaomei , Huang Xiaoyi , Meng Qingwei 
Published: June 2023

AbstractMiRNA-375 has been reported to play critical roles in a variety of cancers. To unravel its biological roles, especially its specific mechanisms of action in lung squamous cell carcinoma (LUSC), LUSC tissue microarrays and miRNAscope were performed to identify the miR-375 expression. Associations with clinicopathologic features, survival, and the prognostic value of miR-375 in LUSC were clarified in a retrospective study of 90 pairs of LUSC tissues. In vitro and in vivo gain- and loss-of-function assays were conducted to validate the effects and mechanism of miR-375 in LUSC. The mechanism responsible for interactions was verified by dual-luciferase reporter gene assay, immunoprecipitation (IP) analysis, immunofluorescence (IF) assay and ubiquitination assay. We found that miR-375 had higher expression in noncancerous adjacent tissues than in LUSC tissues. Clinicopathologic analyses showed that miR-375 expression was correlated with pathologic stage and was an independent predictor of overall survival (OS) for LUSC. MiR-375, as a tumor inhibitor, inhibited proliferation and metastasis while promoting apoptosis of LUSC cells. Mechanistic research indicated that miR-375 targeted ubiquitin-protein ligase E3A (UBE3A), which in turn promoted the activity of the ERK signaling pathway via ubiquitin-mediated dual-specificity protein phosphatase 1 (DUSP1) degradation. Collectively, we propose a novel mechanism of tumorigenesis and metastasis of LUSC via the miR-375/UBE3A/DUSP1/ERK axis, which could potentially facilitate new strategies for the treatment of LUSC.
Long-term effects of SARS-CoV-2 infection on human brain and memory
Authors: Ding Qiulu , Zhao HanJun 
Published: June 2023

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have caused several waves of outbreaks. From the ancestral strain to Omicron variant, SARS-CoV-2 has evolved with the high transmissibility and increased immune escape against vaccines. Because of the multiple basic amino acids in the S1-S2 junction of spike protein, the widespread distribution of angiotensin-converting enzyme 2 (ACE2) receptor in human body and the high transmissibility, SARS-CoV-2 can infect multiple organs and has led to over 0.7 billion infectious cases. Studies showed that SARS-CoV-2 infection can cause more than 10% patients with the Long-COVID syndrome, including pathological changes in brains. This review mainly provides the molecular foundations for understanding the mechanism of SARS-CoV-2 invading human brain and the molecular basis of SARS-CoV-2 infection interfering with human brain and memory, which are associated with the immune dysfunction, syncytia-induced cell death, the persistence of SARS-CoV-2 infection, microclots and biopsychosocial aspects. We also discuss the strategies for reducing the Long-COVID syndrome. Further studies and analysis of shared researches will allow for further clarity regarding the long-term health consequences.
Single-cell transcriptomics uncovers EGFR signaling-mediated gastric progenitor cell differentiation in stomach homeostasis
Authors: Takada Hitomi , Sasagawa Yohei , Yoshimura Mika , Tanaka Kaori , Iwayama Yoshimi , Hayashi Tetsutaro , Isomura-Matoba Ayako , Nikaido Itoshi , Kurisaki Akira 
Published: June 2023

AbstractDefects in gastric progenitor cell differentiation are associated with various gastric disorders, including atrophic gastritis, intestinal metaplasia, and gastric cancer. However, the mechanisms underlying the multilineage differentiation of gastric progenitor cells during healthy homeostasis remain poorly understood. Here, using a single-cell RNA sequencing method, Quartz-Seq2, we analyzed the gene expression dynamics of progenitor cell differentiation toward pit cell, neck cell, and parietal cell lineages in healthy adult mouse corpus tissues. Enrichment analysis of pseudotime-dependent genes and a gastric organoid assay revealed that EGFR-ERK signaling promotes pit cell differentiation, whereas NF-κB signaling maintains gastric progenitor cells in an undifferentiated state. In addition, pharmacological inhibition of EGFR in vivo resulted in a decreased number of pit cells. Although activation of EGFR signaling in gastric progenitor cells has been suggested as one of the major inducers of gastric cancers, our findings unexpectedly identified that EGFR signaling exerts a differentiation-promoting function, not a mitogenic function, in normal gastric homeostasis.
A single centre prospective study of three device-assisted therapies for Parkinson’s disease
Authors: Morales-Briceño Hugo , Ha Ainhi D. , Chiang Han-Lin , Tai Yicheng , Chang Florence C. F. , Tsui David S. , Griffith Jane , Galea Donna , Kim Samuel D. , Cruse Belinda , Mahant Neil , Fung Victor S. C. 
Published: June 2023

AbstractComparative studies assessing outcomes with the three device-assisted therapies could help to individualise treatment for patients living with Parkinson’s disease. We designed a single-centre non-randomised prospective observational study assessing the quality of life (QoL), motor and non-motor outcomes at 6 and 12-months in patients treated with subcutaneous apomorphine continuous 16-hours infusion (APO), levodopa-carbidopa intestinal gel (LCIG) or subthalamic nucleus deep brain stimulation (STN-DBS). In this study, 66 patients were included (13 APO; 19 LCIG; 34 STN-DBS). At baseline, cognitive, non-motor and motor scores were significantly less severe in the STN-DBS group, whereas the LCIG group had a longer disease duration and higher non-motor scores. In the APO group, there were no statistically significant changes in non-motor, motor and QoL scales. The LCIG group had significant changes in QoL and motor scales that were significant after multiple comparison analysis at 6 and 12-months. The STN-DBS group showed improvement in QoL scores and non-motor and motor scores at 6 and 12-months after multiple comparison analysis. In this real-life prospective study, device-assisted therapies showed differences in their effects on QoL and motor and non-motor function at 12-months. However, there were also differences in baseline characteristics of the patient groups that were not based on pre-determined selection criteria. Differences in characteristics of patients offered and/or treatment with different device-assisted therapies may reflect within-centre biases that may, in turn, influence perceptions of treatment efficacy or outcomes. Treatment centres should be aware of this potential confounder when assessing and offering device-assisted treatment options to their patients and potential baseline differences need to be taken into consideration when comparing the results of non-randomised studies.
Predictive value of abbreviated olfactory tests in prodromal Parkinson disease
Authors: Vaswani Pavan A. , Morley James F. , Jennings Danna , Siderowf Andrew , Marek Kenneth ,   the PARS Investigators, Seibyl John , Stern Matthew , Russell David , Sethi Kapil , Frank Samuel , Simuni Tanya , Hauser Robert , Ravina Bernard , Richards Irene , Liang Grace , Adler Charles , Saunders-Pullman Rachel , Evatt Marian L. , Lai Eugene , Subramanian Indu , Hogarth Penelope , Chung Kathryn 
Published: June 2023

AbstractThere is disagreement in the literature whether olfaction may show specific impairments in Parkinson Disease (PD) and if olfactory tests comprised of selected odors could be more specific for diagnosis. We sought to validate previously proposed subsets of the University of Pennsylvania Smell Identification Test (UPSIT) odors for predicting conversion to PD in an independent, prodromal cohort. Conversion to PD was assessed in 229 participants in the Parkinson At Risk Study who completed baseline olfactory testing with the UPSIT and up to 12 years of clinical and imaging evaluations. No commercially available or proposed subset performed better than the full 40-item UPSIT. The proposed “PD-specific” subsets also did not perform better than expected by chance. We did not find evidence for selective olfactory impairment in Parkinson disease. Shorter odor identification tests, including commercially available 10–12 item tests, may have utility for ease of use and cost, but not for superior predictive value.