bluuebunny/crossref_metadata_2025 huggingface dataset:
White Matter Alterations in Depressive Disorder
Authors: He Enling , Liu Min , Gong Sizhu , Fu Xiyao , Han Yue , Deng Fang
Published: May 2022

Depressive disorder is the most prevalent affective disorder today. Depressive disorder has been linked to changes in the white matter. White matter changes in depressive disorder could be a result of impaired cerebral blood flow (CBF) and CBF self-regulation, impaired blood-brain barrier function, inflammatory factors, genes and environmental factors. Additionally, white matter changes in patients with depression are associated with clinical variables such as differential diagnosis, severity, treatment effect, and efficacy assessment. This review discusses the characteristics, possible mechanisms, clinical relevance, and potential treatment of white matter alterations caused by depressive disorders.
Oxygen Desaturation Is Associated With Fibrocyte Activation via Epidermal Growth Factor Receptor/Hypoxia-Inducible Factor-1α Axis in Chronic Obstructive Pulmonary Disease
Authors: Wang Chun-Hua , Lo Chun-Yu , Huang Hung-Yu , Wang Tsai-Yu , Weng Chih-Ming , Chen Chih-Jung , Huang Yu-Chen , Chung Fu-Tsai , Lin Chang-Wei , Chung Kian Fan , Kuo Han-Pin
Published: May 2022

Fibrocytes are bloodborne mesenchymal progenitors which accumulate and differentiate at the disease site. We investigated whether hypoxemia activates fibrocytes, accelerating airflow limitation and exercise intolerance in chronic obstructive pulmonary disease (COPD) patients. Flow cytometry was used to determine collagen I+/CD45+ fibrocytes and α-smooth muscle actin+ differentiating fibrocytes within peripheral blood and cultured cells, as well as the expression of CXC chemokine receptor 4 (CXCR4), epidermal growth factor receptor (EGFR), connective tissue growth factor (CTGF) and hypoxia-inducible factor (HIF)-1α. Fibrocytes in lung specimens were identified by confocal microscopy. Compared to non-desaturators, COPD desaturators (peripheral blood oxygen saturation ≤88% during exercise) had greater number of fibrocytes in peripheral blood and lung specimens, paralleled with faster yearly lung function decline and a 6-minute walk distance. Fibrocytes from desaturators expressed more EGFR, CXCR4, CTGF, and HIF-1α, with a higher capacity of proliferation and myofibroblastic differentiation. Hypoxia (5% oxygen) increased the expression of EGFR, CXCR4, CTGF, and HIF-1α, the number and differentiation in fibrocytes. These effects were attenuated by EGFR inhibitor gefitinib, HIF-1α gene silencing, and anti-CTGF antibody. These data elucidate that hypoxemia triggers fibrocyte activation through the EGFR/HIF-1α axis, aggravating airflow obstruction in COPD.
Analysis of a miR-148a Targetome in B Cell Central Tolerance
Authors: Ma Fengge , Zhan Yating , Bartolomé-Cabrero Rocío , Ying Wei , Asano Masahide , Huang Zhe , Xiao Changchun , González-Martín Alicia
Published: May 2022

A microRNA (miRNA) often regulates the expression of hundreds of target genes. A fundamental question in the field of miRNA research is whether a miRNA exerts its biological function through regulating a small number of key targets or through small changes in the expression of hundreds of target genes. We addressed this issue by performing functional analysis of target genes regulated by miR-148a. We previously identified miR-148a as a critical regulator of B cell central tolerance and found 119 target genes that may mediate its function. We selected 4 of them for validation and demonstrated a regulatory role for Bim, Pten, and Gadd45a in this process. In this study, we performed functional analysis of the other miR-148a target genes in in vitro and in vivo models of B cell central tolerance. Our results show that those additional target genes play a minimal role, if any, in miR-148a-mediated control of B cell central tolerance, suggesting that the function of miRNAs is mediated by a few key target genes. These findings have advanced our understanding of molecular mechanisms underlying miRNA regulation of gene expression and B cell central tolerance.
Loss of CD11b Accelerates Lupus Nephritis in Lyn-Deficient Mice Without Disrupting Glomerular Leukocyte Trafficking
Authors: Gottschalk Timothy A. , Hall Pamela , Tsantikos Evelyn , L’Estrange-Stranieri Elan , Hickey Michael J. , Hibbs Margaret L.
Published: May 2022

Systemic lupus erythematosus (SLE) is a complex, heterogeneous autoimmune disease. A common manifestation, lupus nephritis, arises from immune complex deposition in the kidney microvasculature promoting leukocyte activation and infiltration, which triggers glomerular damage and renal dysfunction. CD11b is a leukocyte integrin mainly expressed on myeloid cells, and aside from its well-ascribed roles in leukocyte trafficking and phagocytosis, it can also suppress cytokine production and autoreactivity. Genome-wide association studies have identified loss-of-function polymorphisms in the CD11b-encoding gene ITGAM that are strongly associated with SLE and lupus nephritis; however, it is not known whether these polymorphisms act alone to induce disease or in concert with other risk alleles. Herein we show using Itgam-/- mice that loss of CD11b led to mild inflammatory traits, which were insufficient to trigger autoimmunity or glomerulonephritis. However, deficiency of CD11b in autoimmune-prone Lyn-deficient mice (Lyn-/-Itgam-/-) accelerated lupus-like disease, driving early-onset immune cell dysregulation, autoantibody production and glomerulonephritis, impacting survival. Migration of leukocytes to the kidney in Lyn-/- mice was unhindered by lack of CD11b. Indeed, kidney inflammatory macrophages were further enriched, neutrophil retention in glomerular capillaries was increased and kidney inflammatory cytokine responses were enhanced in Lyn-/-Itgam-/- mice. These findings indicate that ITGAM is a non-monogenic autoimmune susceptibility gene, with loss of functional CD11b exacerbating disease without impeding glomerular leukocyte trafficking when in conjunction with other pre-disposing genetic mutations. This highlights a primarily protective role for CD11b in restraining inflammation and autoimmune disease and provides a potential therapeutic avenue for lupus treatment.
Top-Down and Bottom-Up Control in the Galápagos Upwelling System
Authors: Brandt Margarita , Silva-Romero Isabel , Fernández-Garnica David , Agudo-Adriani Esteban , Bove Colleen B. , Bruno John F.
Published: May 2022

Increased standing macroalgal biomass in upwelling zones is generally assumed to be the result of higher nutrient flux due to upwelled waters. However, other factors can strongly impact macroalgal communities. For example, herbivory and temperature, via their effects on primary producers and the metabolic demands of consumers, can also influence macroalgal biomass and productivity, respectively. We assessed the effects of nutrient availability, temperature, and herbivory on macroalgal biomass on a subtidal nearshore rocky reef in the Galápagos Islands. We manipulated nutrient availability and herbivory in field experiments performed in two seasons: the first during a cool, upwelling season, and the second during a warm, non-upwelling season. Excluding macro-herbivores had a clear effect on standing macroalgal biomass, independent of season or nutrient availability. However, we found different interactive effects of nutrients and macro-herbivores between the two seasons. During the cool season, macroalgal biomass was significantly higher in herbivore exclusions than in open areas under ambient nutrient conditions. However, when nutrients were added, macroalgal biomass was not significantly different across all herbivore treatments, which suggests reduced top-down control of herbivores (hence a greater standing algal biomass) in open areas. In the warm season, macroalgal biomass was significantly higher in herbivore exclusions compared to open treatments, both with and without nutrient addition. Furthermore, biomass reached 11X in herbivore exclusions with nutrient additions, which hints nutrient limitation only during warm, low-upwelling conditions. Overall, our results support the hypothesis that macro-herbivores reduce macroalgal biomass in this system and suggest that nutrient availability, but not temperature, modulate herbivory.
Temperature Across Vegetation Canopy-Water-Soil Interfaces Is Modulated by Hydroperiod and Extreme Weather in Coastal Wetlands
Authors: Zhao Xiaochen , Rivera-Monroy Victor H. , Li Chunyan , Vargas-Lopez Ivan A. , Rohli Robert V. , Xue Z. George , Castañeda-Moya Edward , Coronado-Molina Carlos
Published: May 2022

Environmental temperature is a widely used variable to describe weather and climate conditions. The use of temperature anomalies to identify variations in climate and weather systems makes temperature a key variable to evaluate not only climate variability but also shifts in ecosystem structural and functional properties. In contrast to terrestrial ecosystems, the assessment of regional temperature anomalies in coastal wetlands is more complex since the local temperature is modulated by hydrology and weather. Thus, it is unknown how the regional free-air temperature (TFree) is coupled to local temperature anomalies, which can vary across interfaces among vegetation canopy, water, and soil that modify the wetland microclimate regime. Here, we investigated the temperature differences (offsets) at those three interfaces in mangrove-saltmarsh ecotones in coastal Louisiana and South Florida in the northern Gulf of Mexico (2017–2019). We found that the canopy offset (range: 0.2–1.6°C) between TFree and below-canopy temperature (TCanopy) was caused by the canopy buffering effect. The similar offset values in both Louisiana and Florida underscore the role of vegetation in regulating near-ground energy fluxes. Overall, the inundation depth did not influence soil temperature (TSoil). The interaction between frequency and duration of inundation, however, significantly modulated TSoil given the presence of water on the wetland soil surface, thus attenuating any short- or long-term changes in the TCanopy and TFree. Extreme weather events—including cold fronts and tropical cyclones—induced high defoliation and weakened canopy buffering, resulting in long-term changes in canopy or soil offsets. These results highlight the need to measure simultaneously the interaction between ecological and climatic processes to reduce uncertainty when modeling macro- and microclimate in coastal areas under a changing climate, especially given the current local temperature anomalies data scarcity. This work advances the coupling of Earth system models to climate models to forecast regional and global climate change and variability along coastal areas.
Contrasting Life Traits of Sympatric Calanus glacialis and C. finmarchicus in a Warming Arctic Revealed by a Year-Round Study in Isfjorden, Svalbard
Authors: Hatlebakk Maja , Kosobokova Ksenia , Daase Malin , Søreide Janne E.
Published: May 2022

The calanoid copepod Calanus glacialis dominates the mesozooplankton biomass in the Arctic shelf seas, but its smaller North Atlantic sibling Calanus finmarchicus is expanding northwards and may potentially replace it if the climate continues to warm. Here we studied the population structure, overwintering strategies, gonad maturation and egg production of C. glacialis and C. finmarchicus over a period of 15 consecutive months in a high-Arctic fjord with sub-Arctic ocean climate and no sea ice formation in winter. The relative proportions of C. glacialis and C. finmarchicus varied throughout the study period, but with an overall dominance of C. glacialis. The overwintering population of C. glacialis was dominated by copepodite stage CIV (74%) while C. finmarchicus overwintered mainly as CV (65%), reflecting a primarily two- and one-year life cycle, respectively. Adult males and females of C. glacialis appeared as early as October with a peak during December-January, two months earlier than in C. finmarchicus, with a corresponding one-month earlier peak in recruitment for C. glacialis. While C. glacialis reproduced prior to the bloom with egg production peaking during the bloom, C. finmarchicus started egg laying during the bloom and continued to reproduce throughout the summer. Seasonal changes in the population structure suggest that C. finmarchicus born early in spring are able to develop to CV during summer and overwinter successfully, while offspring born later in the season do most likely not reach the CV overwintering stage. The ability to reproduce early and the flexibility to alter between 1- and 2-year life cycles give C. glacialis an advantage over C. finmarchicus in high-Arctic unpredictable environments with short-pulsed primary production regimes. Our data indicate that C. glacialis and C. finmarchicus occupy similar environmental niches, but different timing in reproduction reduces the competition. If sea temperatures remain within their temperature-tolerance ranges, both C. glacialis and C. finmarchicus seem to benefit from warming due to accelerating growth and higher survival of the recruits as long as C. glacialis has access to a colder refuge by descending to deeper depths.
Pressure Mapping Using Nanocomposite-Enhanced Foam and Machine Learning
Authors: Quqa Said , Shu Yening , Li Sijia , Loh Kenneth J.
Published: May 2022

Pressure mapping has garnered considerable interest in the healthcare and robotic industries. Low-cost and large-area compliant devices, as well as fast and effective computational algorithms, have been proposed in the last few years to facilitate distributed pressure sensing. One approach is to use electrical impedance tomography (EIT) to reconstruct the contact pressure distribution of piezoresistive materials. While tremendous success has been demonstrated, conventional algorithms may be unsuitable for real-time monitoring due to its computational demand and runtime. Moreover, the low resolution of reconstructed images is a well-known issue related to the regularization strategies typically employed for traditional EIT methods. Therefore, in this study, two different supervised machine learning (ML) approaches, namely, radial basis function networks and deep neural networks, were employed to efficiently solve the inverse EIT problem and improve the resolution of reconstructed pressure maps. The demonstration of high-resolution pressure mapping, specifically, for identifying pressure hotspots, was achieved using a carbon nanotube-based thin film integrated with foam.
A Monolithic CMOS-MEMS Reconfigurable/Tunable Capacitive Accelerometer with Integrated Sensing Circuits
Authors: Chiu Yi , Lin Cheng-Yen , Hong Hao-Chiao
Published: May 2022

MEMS accelerometers have been widely used in various applications with a wide range of signal levels and bandwidth. Therefore it is desired to have a sensor whose characteristics such as sensitivity and bandwidth can be reconfigured/tuned depending on specific applications. This paper presents a reconfigurable/tunable z-axis accelerometer whose mechanical resonant frequency, sensitivity and sensing bandwidth can be tuned by the electrostatic spring softening effect. The proposed accelerometer was designed using a commercial 0.35 μm CMOS foundry service. The tuning electrodes were implemented in the metal and polysilicon layers in the standard CMOS process. An on-chip chopper stabilized readout circuit was designed to convert the capacitance signal to a voltage readout. The sensing structure was released by post-CMOS wet metal etching. Measurement results showed the proposed accelerometer had a sensitivity of 12 mV/g in the range of 0–5 g. The sensitivity and bandwidth tuning ranges are 50% and 18%, respectively, for an applied tuning voltage of 25 V. The demonstrated device is the first reconfigurable/tunable CMOS-MEMS accelerometer in the literature to our best knowledge.
Application of Quantitative Magnetic Resonance Imaging in the Diagnosis of Autism in Children
Authors: Tang Shilong , Nie Lisha , Liu Xianfan , Chen Zhuo , Zhou Yu , Pan Zhengxia , He Ling
Published: May 2022

Objective

To explore the application of quantitative magnetic resonance imaging in the diagnosis of autism in children.

Methods

Sixty autistic children aged 2–3 years and 60 age- and sex-matched healthy children participated in the study. All the children were scanned using head MRI conventional sequences, 3D-T1, diffusion kurtosis imaging (DKI), enhanced T2*- weighted magnetic resonance angiography (ESWAN) and 3D-pseudo continuous Arterial Spin-Labeled (3D-pcASL) sequences. The quantitative susceptibility mapping (QSM), cerebral blood flow (CBF), and brain microstructure of each brain area were compared between the groups, and correlations were analyzed.

Results

The iron content and cerebral blood flow in the frontal lobe, temporal lobe, hippocampus, caudate nucleus, substantia nigra, and red nucleus of the study group were lower than those in the corresponding brain areas of the control group (P < 0.05). The mean kurtosis (MK), radial kurtosis (RK), and axial kurtosis (AK) values of the frontal lobe, temporal lobe, putamen, hippocampus, caudate nucleus, substantia nigra, and red nucleus in the study group were lower than those of the corresponding brain areas in the control group (P < 0.05). The mean diffusivity (MD) and fractional anisotropy of kurtosis (FAK) values of the frontal lobe, temporal lobe and hippocampus in the control group were lower than those in the corresponding brain areas in the study group (P < 0.05). The values of CBF, QSM, and DKI in frontal lobe, temporal lobe and hippocampus could distinguish ASD children (AUC > 0.5, P < 0.05), among which multimodal technology (QSM, CBF, DKI) had the highest AUC (0.917) and DKI had the lowest AUC (0.642).

Conclusion

Quantitative magnetic resonance imaging (including QSM, 3D-pcASL, and DKI) can detect abnormalities in the iron content, cerebral blood flow and brain microstructure in young autistic children, multimodal technology (QSM, CBF, DKI) could be considered as the first choice of imaging diagnostic technology.

Clinical Trial Registration

[http://www.chictr.org.cn/searchprojen.aspx], identifier [ChiCTR2000029699].
The Efficacy and Safety of Pirfenidone Combined With Immunosuppressant Therapy in Connective Tissue Disease-Associated Interstitial Lung Disease: A 24-Week Prospective Controlled Cohort Study
Authors: Wang Jiaqi , Wang Xiao , Qi Xiaoyan , Sun Zhijian , Zhang Tao , Cui Yi , Shu Qiang
Published: May 2022

Objective

Interstitial lung disease (ILD) is a common manifestation of connective tissue disease (CTD) that manifests as several subtypes with significant differences in prognosis. It is necessary to evaluate the efficacy and safety of pirfenidone (PFD) combined with immunosuppressant (IS) in the treatment of CTD-ILD.

Methods

A total of 111 patients with CTD-ILD were enrolled, including those with systemic sclerosis (SSc), inflammatory myopathy (IIM), rheumatoid arthritis (RA), and other CTDs (such as systemic lupus erythematosus, primary Sjogren's syndrome, and undifferentiated CTD). After evaluation of the high-resolution computed tomography (HRCT), pulmonary function (PF), and basic disease activity, patients either were or were not prescribed PFD and were followed up regularly for 24 weeks.

Results

After 24 weeks of treatment, predicted forced vital capacity (FVC%) in the SSc-PFD group had improved by 6.60%, whereas this value was 0.55% in patients with SSc-no-PFD. The elevation in FVC% was also significant in IIM-PFD over the IIM-no-PFD controls (7.50 vs. 1.00%). The predicted diffusing capacity for carbon monoxide (DLCo%) of RA-PFD was enhanced by 7.40%, whereas that of RA-no-PFD decreased by 5.50%. When performing a subtype analysis of HRCT images, the change in FVC% among patients with SSc with a tendency toward usual interstitial pneumonia (UIP) was higher in those given PFD (SSc-PFD-UIP) than the no-PFD group (8.05 vs. −3.20%). However, in IIM patients with a non-UIP tendency, PFD displayed better therapeutic effects than the control (10.50 vs. 1.00%). DLCo% improved significantly in patients with the PFD-treated RA-non-UIP subtype compared with the patients with no-PFD (10.40 vs. −4.45%). Dichotomizing the patients around a baseline FVC% or DLCo% value of 70%, the PFD arm had a more improved FVC% than the no-PFD arm within the high-baseline-FVC% subgroups of patients with SSc and IIM (6.60 vs. 0.10%, 6.30 vs. 1.10%). In patients with RA-PFD, DLCo% showed a significant increase in the subgroup with low baseline DLCo% compared to that in patients with RA-no-PFD (7.40 vs. −6.60%).

Conclusion

The response of PF to PFD varied between CTD-ILD subsets. Patients with SSc and IIM showed obvious improvements in FVC%, especially patients with SSc-UIP and IIM-non-UIP. In RA, the subsets of patients with non-UIP and a lower baseline DLCo% most benefited from PFD.
A Two-Stage Bedside Intubation Method to Improve Success Rate of Post-pyloric Placement of Spiral Nasoenteric Tubes in Critically Ill Patients: A Multi-Center, Prospective Study
Authors: Xu Jing , Li Sinian , Chen Xiangyin , Tan Bo , Chen Shenglong , Hu Bei , Nie Zhiqiang , Ye Heng , Sun Cheng , Chi Ruibin , Chen Chunbo
Published: May 2022

Backgrounds

Prokinetic agents could improve the success rate of post-pyloric placement of self-propelled spiral nasoenteric tubes (NETs), and bedside blind technique might apply as a rescue therapy subsequent to spontaneous transpyloric migration failure. The objective of this study was to investigated the validity and safety of these two bedside intubation methods as a sequential procedure for post-pyloric placement of spiral NETs in critically ill patients.

Methods

The multicenter, prospective study was conducted in intensive care units of four tertiary hospitals (June 2020 to January 2021). Eligible patients received self-propelled spiral NET placements, promoted by prokinetic agents (Stage 1). An abdominal X-ray performed 24 h post-intubation confirmed the position of the tube tip. Patients with a failed transpyloric migration entered Stage 2, where beside blind intubation was conducted (reconfirmed by X-ray). The primary end point was the overall success rate of post-pyloric placement.

Results

The overall success rate of post-pyloric placement of the spiral NET was 91.1% (73.4% in the third portion of the duodenum [D3] or beyond). The total adverse event rate was 21.0%, without any serious adverse events. In Stage 1, 55.6% of participants achieved transpyloric migration, of these, 44.4% migrated to D3 or beyond. The median time from decision to intubate to the initiation of enteral nutrition (EN) was 25 h. In Stage 2, 83.0% of patients had successful post-pyloric intubation (67.9% in D3 or beyond). The median time from decision to EN initiation after the two-stage process was 36 h.

Conclusions

Prokinetic agents-assisted self-propelled intubation and remedial bedside blind technique as a sequential procedure for post-pyloric placement of spiral NETs were effective and safe, and this two-stage process did not affect the implementation of early EN in critically ill patients.

Trial Registration

Chinese Clinical Trial Registry, ChiCTR1900026381. Registered on 6 October 2019.
A Prognostic Signature Consisting of Pyroptosis-Related Genes and SCAF11 for Predicting Immune Response in Breast Cancer
Authors: Chu Ling , Yi Qiaoli , Yan Yuanliang , Peng Jinwu , Li Zhilan , Jiang Feng , He Qingchun , Ouyang Lingzi , Wu Shangjun , Fu Chencheng , Liu Ying , Xu Zhijie
Published: May 2022

Pyroptosis, characterized as an inflammasome-mediated cell death pathway, may be participated in tumorigenesis and progression. However, the underlying molecular function and mechanism of pyroptosis in BRCA remain unclear. In our study, we aimed to develop a prognostic signature in BRCA based on pyroptosis-associated genes. Data was downloaded from TCGA database, and then we screened 760 female BRCA samples and 104 normal breast tissues as the training set. Seven pyroptosis-related genes (CASP9, GPX4, IL18, NLRC4, SCAF11, TIRAP, and TNF) were identified as the pyroptosis-related prognostic model for BRCA using LASSO Cox regression. We subsequently tested the prognostic value of pyroptosis-associated gene signature in a validation set, GSE 20685. Time-dependent receiver operating characteristic analysis demonstrated the credible predictive capacity of this pyroptosis-associated gene signature. The area under the curves were 0.806 at 3 years, 0.787 at 5 years, 0.775 at 8 years, and 0.793 at 10 years in the training set, and 0.824 at 5 years, 0.808 at 8 years, and 0.790 at 10 years in the validation set. Furthermore, there are currently few data on SCAF11 regulating pyroptosis. To clarify this issue, we performed integrative bioinformatics and experimental analysis. Knocking down SCAF11 possessed an anti-cancer effect in terms of inhibiting cell viability and suppressing colony-formation in in-vitro functional assays. Meanwhile, the biological functions of SCAF11 in BRCA were further validated with several algorithms, such as Xiantao tool, LinkedOmics, GEPIA2, and TISIDB. These findings indicated that the expression of SCAF11 was significantly correlated with diverse tumor-infiltrating lymphocytes (TILs), including T central memory cell (Tcm), and type 2 T helper cell (Th2), etc. Functional enrichment analysis suggested that co-expression genes of SCAF11 primarily participated in inflammation and immune-related signaling pathways, such as oxidative phosphorylation, antimicrobial humoral response, and immunoglobulin complex. Moreover, SCAF11 expression was positively correlated with several immune checkpoints, including PD-L1, B7H3, and PDCD1LG2. Taken together, this study uncovered that pyroptosis-associated gene signature might be applied as an effective independent predictor in patients with BRCA. The pyroptosis-related gene SCAF11 might play potential roles in the regulation of immune microenvironment in BRCA.
A Baseline Study of Oxygen Saturation in Parafoveal Vessels Using Visible Light Optical Coherence Tomography
Authors: Wang Jingyu , Song Weiye , Sadlak Natalie , Fiorello Marissa G. , Desai Manishi , Yi Ji
Published: May 2022

The retinal macula is at the center of our visual field, and thus pathological damage in the macula significantly impacts an individual's quality of life. The parafoveal vessels form the inner retina provide oxygen perfusion, and the measurement of parafoveal oxygen saturation (sO2) can evaluate macular metabolism and provide pathophysiological insight. In this paper, for the first time, we present a baseline study of microvascular oxygen saturation (sO2) in perifoveal macular region using visible light optical coherence tomography (VIS-OCT) on normal eyes. The arterial and venous sO2 from all eyes was 92.1 ± 7.1 (vol %) and 48.4 ± 5.0 (vol %) (mean ± SD), respectively. Arteriovenous sO2 difference was 43.8 ± 9.5 (vol %). Marginal correlation was found between venous sO2 and intraocular pressure (IOP) among eyes. No significant correlation was found between sO2 and vessel topological features, including length, diameter, and distance to fovea. This baseline study could serve as a benchmark for the future sO2 investigation of retinal macular pathologies.
The Release of 24 h Infravesical Obstruction in Mice: Changes in Molecular, Morphological, and Functional Parameters for 14-Day Observation
Authors: Lu Yutao , Manson Scott R. , de Araujo Isabela Bastos Binotti Abreu , Austin Paul F. , Djurhuus Jens C. , Olsen L. Henning , Nørregaard Rikke
Published: May 2022

Bladder outlet obstruction (BOO) induces bladder dysfunction and altered bladder architecture. Irrespective of the release of the obstruction, persistent bladder dysfunction severely affects the quality of life. A better understanding of the repair process offers an opportunity to enhance postintervention management. We subsequently evaluated the postobstructive repair process in mice subjected to 24 h BOO followed by release. Male and female mice bladders were obstructed for 24 h by placing a clip around the bladder neck. After the release of obstruction, the mice were studied for 3, 7, and 14 days to observe the bladder repair process over time. Voiding frequency and volume were recorded using the voiding spot assay, and the transcutaneous glomerular filtration rate (tGFR) was measured. Fibrogenesis and associated gene expressions and altered protein levels were evaluated in the bladder using histology, quantatative polymerase chain reaction (qPCR), and Western blot analyses. Bladder wall thickness was increased in both genders over time but occurred later in female mice. Moreover, collagen deposition in the smooth muscle layer increased over time in both genders. Male mice showed a decreased average voided volume at 3 days post release, while female mice showed no significant change during the time course. Fibrosis-related molecular events, including upregulation of fibronectin (FN) protein and Collagen-3 (Col-3) mRNA expression, were transient and normalized again at 14 days in both genders. Transforming growth factor-β (TGF-β) and bone morphogenic protein (BMP)-7 mRNA expressions were upregulated at 14 days post release in both genders. Transcutaneous GFR remained normal during the time course. Release of 24 h BOO initiated a bladder remodeling process. The animal model enables a wide range of experiments to study bladder remodeling, and gender differences offer potential targets for understanding bladder fibrosis and adaptation with BOO.
Mutations in degP and spoT Genes Mediate Response to Fermentation Stress in Thermally Adapted Strains of Acetic Acid Bacterium Komagataeibacter medellinensis NBRC 3288
Authors: Kataoka Naoya , Matsutani Minenosuke , Matsumoto Nami , Oda Misuzu , Mizumachi Yuki , Ito Kohei , Tanaka Shuhei , Kanesaki Yu , Yakushi Toshiharu , Matsushita Kazunobu
Published: May 2022

An acetic acid bacterium, Komagataeibacter medellinensis NBRC 3288, was adapted to higher growth temperatures through an experimental evolution approach in acetic acid fermentation conditions, in which the cells grew under high concentrations of ethanol and acetic acid. The thermally adapted strains were shown to exhibit significantly increased growth and fermentation ability, compared to the wild strain, at higher temperatures. Although the wild cells were largely elongated and exhibited a rough cell surface, the adapted strains repressed the elongation and exhibited a smaller cell size and a smoother cell surface than the wild strain. Among the adapted strains, the ITO-1 strain isolated during the initial rounds of adaptation was shown to have three indel mutations in the genes gyrB, degP, and spoT. Among these, two dispensable genes, degP and spoT, were further examined in this study. Rough cell surface morphology related to degP mutation suggested that membrane vesicle-like structures were increased on the cell surface of the wild-type strain but repressed in the ITO-1 strain under high-temperature acetic acid fermentation conditions. The ΔdegP strain could not grow at higher temperatures and accumulated a large amount of membrane vesicles in the culture supernatant when grown even at 30°C, suggesting that the degP mutation is involved in cell surface stability. As the spoT gene of ITO-1 lost a 3′-end of 424 bp, which includes one (Act-4) of the possible two regulatory domains (TGS and Act-4), two spoT mutant strains were created: one (ΔTGSAct) with a drug cassette in between the 5′-half catalytic domain and 3′-half regulatory domains of the gene, and the other (ΔAct-4) in between TGS and Act-4 domains of the regulatory domain. These spoT mutants exhibited different growth responses; ΔTGSAct grew better in both the fermentation and non-fermentation conditions, whereas ΔAct-4 did only under fermentation conditions, such as ITO-1 at higher temperatures. We suggest that cell elongation and/or cell size are largely related to these spoT mutations, which may be involved in fermentation stress and thermotolerance.
Inhibition of Virulence Gene Expression in Salmonella Dublin, Escherichia coli F5 and Clostridium perfringens Associated With Neonatal Calf Diarrhea by Factors Produced by Lactic Acid Bacteria During Fermentation of Cow Milk
Authors: Liu Gang , Kragh Martin Laage , Aabo Søren , Jensen Annette Nygaard , Olsen John Elmerdahl
Published: May 2022

Diarrhea is a major health problem in neonatal and young calves worldwide. It can be caused by a variety of infectious agents, including the bacteria Salmonella enterica serovar Dublin (S. Dublin), enterotoxigenic Escherichia coli (ETEC), and Clostridium perfringens. Preventive alternatives to antibiotic treatment should be identified. As a first step toward this, the aim of the current study was to examine whether cell-free supernatants from cow milk fermented by lactic acid bacteria affects virulence-gene expression in strains of S. Dublin, ETEC E. coli F5 and C. perfringens. pH-neutralized, cell-free, spent medium of milk (nCFSM) fermented by 61 different lactic acid bacteria (LAB) and non-LAB starter cultures belonging to 17 genera was assayed for their effect on expression of important virulence factors (S. Dublin hilA, ssrB, ssaG, flhD, prgI, fliC; ETEC E. coli F5 fanC, estA, fim41a; C. perfringens cpa), when the bacteria were grown in the nCFSM. Screening was done using either a promoter-reporter expression system or RT-qPCR. nCFSM from Bifidobacterium longum BL-15955 and Limosilactobacillus reuteri LR-33016 downregulated the expression of fanC, fim41a and estA genes in the four tested ETEC E. coli F5 strains without affecting their growth, while mainly B. longum BL-15955 downregulated expression of cpa in the four tested strains of C. perfringens. nCFSM from the mixed cultures; NU-TRISH® BY-Mild (Lactobacillus delbrueckii subsp. bulgaricus, Streptococcus thermophilus and Bifidobacterium BL-15954) and COMBO4 (Lactobacillus delbrueckii subsp. bulgaricus and Streptococcus thermophilus), as well as Lactobacillus helveticus CNRZ32 downregulated the tested virulence genes in the three tested strains of S. Dublin. To enable possible downregulation of the expression of virulence genes in all three target bacteria simultaneously, nCFSM was prepared from NU-TRISH® By-Mild in combination with B. longum BL-15955 (i.e. a four-strain combination). The nCFSM from this combination downregulated the virulence genes expression in all the three species. In the future, NU-TRISH® By-Mild and B. longum BL-15955 in combination could potentially be used for prevention of neonatal calf diarrhea caused by S. Dublin, E. coli F5, and C. perfringens, reducing the need for antimicrobial treatment, however, field studies are needed to prove that.
Post-Translational Modification of GPX4 is a Promising Target for Treating Ferroptosis-Related Diseases
Authors: Cui Can , Yang Fei , Li Qian
Published: May 2022

Glutathione peroxidase 4 (GPX4) is one of the most important antioxidant enzymes. As the key regulator of ferroptosis, GPX4 has attracted considerable attention in the fields of cancer, cardiovascular, and neuroscience research in the past 10 years. How to regulate GPX4 activity has become a hot topic nowadays. GPX4 protein level is regulated transcriptionally by transcription factor SP2 or Nrf2. GPX4 activity can be upregulated by supplementing intracellular selenium or glutathione, and also be inhibited by ferroptosis inducers such as ML162 and RSL3. These regulatory mechanisms of GPX4 level/activity have already shown a great potential for treating ferroptosis-related diseases in preclinical studies, especially in cancer cells. Until recently, research show that GPX4 can undergo post-translational modifications (PTMs), such as ubiquitination, succination, phosphorylation, and glycosylation. PTMs of GPX4 affect the protein level/activity of GPX4, indicating that modifying these processes can be a potential therapy for treating ferroptosis-related diseases. This article summarizes the protein characteristics, enzyme properties, and PTMs of GPX4. It also provides a hypothetical idea for treating ferroptosis-related diseases by targeting the PTMs of GPX4.
Autophagy Regulation Influences β-Amyloid Toxicity in Transgenic Caenorhabditis elegans
Authors: Lin Hongru , Gao Yehui , Zhang Chen , Ma Botian , Wu Mengchen , Cui Xianghuan , Wang Hongbing
Published: May 2022

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized by the accumulation of amyloid-beta (Aβ) proteins in the form of plaques that cause a proteostasis imbalance in the brain. Several studies have identified autophagy deficits in both AD patients and AD animal models. Here, we used transgenic Caenorhabditis elegans to study the relationship between autophagy flux and Aβ. We labeled autophagosomes with an advanced fluorescence reporter system, and used this to observe that human Aβ expression caused autophagosome accumulation in C. elegans muscle. The autophagy-related drugs chloroquine and 3-MA were employed to investigate the relationship between changes in autophagic flux and the toxicity of Aβ expression. We found that reducing autophagosome accumulation delayed Aβ-induced paralysis in the CL4176 strain of C. elegans, and alleviated Aβ-induced toxicity, thus having a neuroprotective effect. Finally, we used RNA-sequencing and proteomics to identify genes whose expression was affected by Aβ aggregation in C. elegans. We identified a series of enriched autophagy-related signal pathways, suggesting that autophagosome accumulation impairs Aβ protein homeostasis in nematodes. Thus, maintaining normal autophagy levels appears to be important in repairing the protein homeostasis imbalance caused by Aβ expression.
Distinct Subdivisions in the Transition Between Telencephalon and Hypothalamus Produce Otp and Sim1 Cells for the Extended Amygdala in Sauropsids
Authors: Metwalli Alek H. , Abellán Antonio , Freixes Júlia , Pross Alessandra , Desfilis Ester , Medina Loreta
Published: May 2022

Based on the coexpression of the transcription factors Foxg1 and Otp, we recently identified in the mouse a new radial embryonic division named the telencephalon-opto-hypothalamic (TOH) domain that produces the vast majority of glutamatergic neurons found in the medial extended amygdala. To know whether a similar division exists in other amniotes, we carried out double labeling of Foxg1 and Otp in embryonic brain sections of two species of sauropsids, the domestic chicken (Gallus gallus domesticus), and the long-tailed lacertid lizard (Psammodromus algirus). Since in mice Otp overlaps with the transcription factor Sim1, we also analyzed the coexpression of Foxg1 and Sim1 and compared it to the glutamatergic cell marker VGLUT2. Our results showed that the TOH domain is also present in sauropsids and produces subpopulations of Otp/Foxg1 and Sim1/Foxg1 cells for the medial extended amygdala. In addition, we found Sim1/Foxg1 cells that invade the central extended amygdala, and other Otp and Sim1 cells not coexpressing Foxg1 that invade the extended and the pallial amygdala. These different Otp and Sim1 cell subpopulations, with or without Foxg1, are likely glutamatergic. Our results highlight the complex divisional organization of telencephalon-hypothalamic transition, which contributes to the heterogeneity of amygdalar cells. In addition, our results open new venues to study further the amygdalar cells derived from different divisions around this transition zone and their relationship to other cells derived from the pallium or the subpallium.
The Neural Circuit Architecture of Social Hierarchy in Rodents and Primates
Authors: Ferreira-Fernandes Emanuel , Peça João
Published: May 2022

Social status is recognized as a major determinant of social behavior and health among animals; however, the neural circuits supporting the formation and navigation of social hierarchies remain under extensive research. Available evidence suggests the prefrontal cortex is a keystone in this circuit, but upstream and downstream candidates are progressively emerging. In this review, we compare and integrate findings from rodent and primate studies to create a model of the neural and cellular networks supporting social hierarchies, both from a macro (i.e., circuits) to a micro-scale perspective (microcircuits and synapses). We start by summarizing the literature on the prefrontal cortex and other relevant brain regions to expand the current “prefrontal-centric” view of social hierarchy behaviors. Based on connectivity data we also discuss candidate regions that might inspire further investigation, as well as the caveats and strategies that have been used to further our understanding of the biological substrates underpinning social hierarchy and dominance.
A Novel Device of Reaching, Grasping, and Retrieving Task for Head-Fixed Mice
Authors: Manita Satoshi , Ikezoe Koji , Kitamura Kazuo
Published: May 2022

Reaching, grasping, and retrieving movements are essential to our daily lives and are common in many mammalian species. To understand the mechanism for controlling this movement at the neural circuit level, it is necessary to observe the activity of individual neurons involved in the movement. For stable electrophysiological or optical recordings of neural activity in a behaving animal, head fixation effectively minimizes motion artifacts. Here, we developed a new device that allows mice to perform reaching, grasping, and retrieving movements during head fixation. In this method, agar cubes were presented as target objects in front of water-restricted mice, and the mice were able to reach, grasp, and retrieve them with their forelimb. The agar cubes were supplied by a custom-made automatic dispenser, which uses a microcontroller to control the two motors to push out the agar cubes. This agar presentation system supplied approximately 20 agar cubes in consecutive trials. We confirmed that each agar cube could be presented to the mouse with an average weight of 55 ± 3 mg and positional accuracy of less than 1 mm. Using this system, we showed that head-fixed mice could perform reaching, grasping, and retrieving tasks after 1 week of training. When the agar cube was placed near the mice, they could grasp it with a high success rate without extensive training. On the other hand, when the agar cube was presented far from the mice, the success rate was initially low and increased with subsequent test sessions. Furthermore, we showed that activity in the primary motor cortex is required for reaching movements in this task. Therefore, our system can be used to study neural circuit mechanisms for the control and learning of reaching, grasping, and retrieving movements under head-fixed conditions.
Using a Network Physiology Approach to Prescribe Exercise for Exercise Oncology
Authors: Thomas Gwendolyn A.
Published: May 2022

Current American College of Sports Medicine (ACSM) exercise guidelines for exercise oncology survivors are generic one-size fits all recommendations, which assume ideal or prototypic health and fitness state in order to prescribe. Individualization is based on the objective evaluation of the patient’s baseline physiological status based on a linear dose response relationship of endpoints. This is only a partial snapshot of both the acute and chronic responses exercise can provide. Each acute exercise session represents a unique challenge to whole-body homeostasis and complex acute and adaptive responses occur at the cellular and systemic levels. Additionally, external factors must be considered when prescribing exercise. Network physiology views the human organism in terms of physiological and organ systems, each with structural organization and functional complexity. This organizational approach leads to complex, transient, fluctuating and nonlinear output dynamics which should be utilized in exercise prescription across health states. Targeting health outcomes requires a multi-system approach as change doesn’t happen in only one system at a time or in one direction Utilizing a multi-system or person-centered approach, allows for targeting and personalization and understands and targets non-linear dynamics of change. Therefore, the aims of this review are to propose a paradigm shift towards a Network Physiology approach for exercise prescription for cancer survivors. Cancer treatment affects multiple systems that interact to create symptoms and disruptions across these and therefore, prescribing exercise utilizing both external daily factors and internal physiological networks is of the highest order.
Risk Assessment of Cnm-Positive Streptococcus mutans in Stroke Survivors (RAMESSES): Protocol for a Multicenter Prospective Cohort Study
Authors: Hosoki Satoshi , Hattori Yorito , Saito Satoshi , Takegami Misa , Tonomura Shuichi , Yamamoto Yumi , Ikeda Shuhei , Hosomi Naohisa , Oishi Naoya , Morita Yoshiaki , Miyamoto Yoshihiro , Nomura Ryota , Nakano Kazuhiko , Ihara Masafumi
Published: May 2022

Introduction

The role of commensal microbiota in systemic diseases, including brain diseases, has attracted increasing attention. Oral infectious diseases, such as dental caries and periodontitis, are also involved in cerebrovascular diseases and cognitive impairment. Cerebral microbleeds (CMBs) and intracerebral hemorrhage due to small vessel disease (SVD), are presumably associated with a high risk of vascular cognitive impairment and stroke. We previously reported that Streptococcus mutans (S. mutans, the main pathogen of dental caries), harboring the cnm gene that encodes the collagen-binding protein Cnm, is associated with the development of hypertensive intracerebral hemorrhage and aggravation of CMBs. We also proposed a mechanism by which the circulating Cnm-expressing S. mutans causes intracerebral hemorrhage or CMBs; it binds to denuded basement membranes mainly composed of collagen IV through damaged tight junctions or it directly invades endothelial cells, resulting in blood-brain barrier injury. In November 2018, we initiated a multicenter, prospective cohort study (RAMESSES: Risk Assessment of Cnm-positive S. mutans in Stroke Survivors; UMIN Clinical Trials Registry: UMIN000045559) to explore the longitudinal association between Cnm-positive S. mutans and CMBs with comprehensive dental findings, which should determine the effect of Cnm-positive S. mutans in the oral cavity on the risk of CMB development and cognitive decline.

Methods

Fifteen domestic institutes will be enlisted to enroll 230 patients who have at least one CMB in the deep brain area and develop a stroke within the past year. The prevalence of Cnm-positive S. mutans based on oral specimens and dental hygiene will be examined. The primary outcome is the number of newly developed deep CMBs. The secondary outcomes include the new development of lobar, subtentorial, or any type of CMBs; symptomatic intracerebral hemorrhage or ischemic stroke; changes in cognitive function or frailty; major bleeding; all-cause mortality; and antibody titers against periodontal pathogens. The observation period will be 2 years.

Discussion

The 2-year longitudinal prospective cohort study is expected to establish the role of Cnm-positive S. mutans in SVD including CMBs and intracerebral hemorrhage from the perspective of the “brain-oral axis” and provide guidance for novel prophylactic strategies against Cnm-positive S. mutans-induced SVD.