bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuromorphic device based on silicon nanosheets
Authors: Wang Chenhao , Xu Xinyi , Pi Xiaodong , Butala Mark D. , Huang Wen , Yin Lei , Peng Wenbing , Ali Munir , Bodepudi Srikrishna Chanakya , Qiao Xvsheng , Xu Yang , Sun Wei , Yang Deren
Published: September 2022

Silicon is vital for its high abundance, vast production, and perfect compatibility with the well-established CMOS processing industry. Recently, artificially stacked layered 2D structures have gained tremendous attention via fine-tuning properties for electronic devices. This article presents neuromorphic devices based on silicon nanosheets that are chemically exfoliated and surface-modified, enabling self-assembly into hierarchical stacking structures. The device functionality can be switched between a unipolar memristor and a feasibly reset-able synaptic device. The memory function of the device is based on the charge storage in the partially oxidized SiNS stacks followed by the discharge activated by the electric field at the Au-Si Schottky interface, as verified in both experimental and theoretical means. This work further inspired elegant neuromorphic computation models for digit recognition and noise filtration. Ultimately, it brings silicon - the most established semiconductor - back to the forefront for next-generation computations.
In vivo adenine base editing reverts C282Y and improves iron metabolism in hemochromatosis mice
Authors: Rovai Alice , Chung BoMee , Hu Qingluan , Hook Sebastian , Yuan Qinggong , Kempf Tibor , Schmidt Florian , Grimm Dirk , Talbot Steven R. , Steinbrück Lars , Götting Jasper , Bohne Jens , Krooss Simon A. , Ott Michael
Published: September 2022

Hemochromatosis is one of the most common inherited metabolic diseases among white populations and predominantly originates from a homozygous C282Y mutation in the HFE gene. The G > A transition at position c.845 of the gene causes misfolding of the HFE protein, ultimately resulting in its absence at the cell membrane. Consequently, the lack of interaction with the transferrin receptors 1 and 2 leads to systemic iron overload. We screened potential gRNAs in a highly precise cell culture assay and applied an AAV8 split-vector expressing the adenine base editor ABE7.10 and our candidate gRNA in 129-Hfetm.1.1Nca mice. Here we show that a single injection of our therapeutic vector leads to a gene correction rate of >10% and improved iron metabolism in the liver. Our study presents a proof-of-concept for a targeted gene correction therapy for one of the most frequent hereditary diseases affecting humans.
Neutralization of hepatitis B virus with vaccine-escape mutations by hepatitis B vaccine with large-HBs antigen
Authors: Washizaki Ayaka , Murayama Asako , Murata Megumi , Kiyohara Tomoko , Yato Keigo , Yamada Norie , Aly Hussein Hassan , Tanaka Tomohisa , Moriishi Kohji , Nishitsuji Hironori , Shimotohno Kunitada , Goh Yasumasa , Ishii Ken J. , Yotsuyanagi Hiroshi , Muramatsu Masamichi , Ishii Koji , Takahashi Yoshimasa , Suzuki Ryosuke , Akari Hirofumi , Kato Takanobu
Published: September 2022

Although the current hepatitis B (HB) vaccine comprising small-HBs antigen (Ag) is potent and safe, attenuated prophylaxis against hepatitis B virus (HBV) with vaccine-escape mutations (VEMs) has been reported. We investigate an HB vaccine consisting of large-HBsAg that overcomes the shortcomings of the current HB vaccine. Yeast-derived large-HBsAg is immunized into rhesus macaques, and the neutralizing activities of the induced antibodies are compared with those of the current HB vaccine. Although the antibodies induced by the current HB vaccine cannot prevent HBV infection with VEMs, the large-HBsAg vaccine-induced antibodies neutralize those infections. The HBV genotypes that exhibited attenuated neutralization via these vaccines are different. Here, we show that the HB vaccine consisting of large-HBsAg is useful to compensate for the shortcomings of the current HB vaccine. The combined use of these HB vaccines may induce antibodies that can neutralize HBV strains with VEMs or multiple HBV genotypes.
Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1
Authors: Lobanov Sergey V. , McAllister Branduff , McDade-Kumar Mia , Landwehrmeyer G. Bernhard , Orth Michael , Rosser Anne E. ,   REGISTRY Investigators of the European Huntington’s disease network, Paulsen Jane S. ,   PREDICT-HD Investigators of the Huntington Study Group, Lee Jong-Min , MacDonald Marcy E. , Gusella James F. , Long Jeffrey D. , Ryten Mina , Williams Nigel M. , Holmans Peter , Massey Thomas H. , Jones Lesley
Published: September 2022

Huntington’s disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington’s disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. We developed a method for calling perfect and imperfect repeats from exome-sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington’s disease via regression analysis. We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1 × 10−9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD.
Diagnostic differentiation between asthma and COPD in primary care using lung function testing
Authors: Bouwens Jelle D. M. , Bischoff Erik W. M. A. , in ’t Veen Johannes C. C. M. , Schermer Tjard R.
Published: September 2022

Asthma and COPD are defined as different disease entities, but in practice patients often show features of both diseases making it challenging for primary care clinicians to establish a correct diagnosis. We aimed to establish the added value of spirometry and more advanced lung function measurements to differentiate between asthma and COPD. A cross-sectional study in 10 Dutch general practices was performed. 532 subjects were extensively screened on respiratory symptoms and lung function. Two chest physicians assessed if asthma or COPD was present. Using multivariable logistic regression analysis we assessed the ability of three scenarios (i.e. only patient history; diagnostics available to primary care; diagnostics available only to secondary care) to differentiate between the two conditions. Receiver operator characteristics (ROC) curves and area under the curve (AUC) were calculated for each scenario, with the chest physicians’ assessment as golden standard. Results showed that 84 subjects were diagnosed with asthma, 138 with COPD, and 310 with no chronic respiratory disease. In the scenario including only patient history items, ROC characteristics of the model showed an AUC of 0.84 (95% CI 0.78–0.89) for differentiation between asthma and COPD. When adding diagnostics available to primary care (i.e., pre- and postbronchodilator spirometry) AUC increased to 0.89 (95% CI 0.84–0.93; p = 0.020). When adding more advanced secondary care diagnostic tests AUC remained 0.89 (95% CI 0.85–0.94; p = 0.967). We conclude that primary care clinicians’ ability to differentiate between asthma and COPD is enhanced by spirometry testing. More advanced diagnostic tests used in hospital care settings do not seem to provide a better overall diagnostic differentiation between asthma and COPD in primary care patients.
Long-term cardiac pathology in individuals with mild initial COVID-19 illness
Authors: Puntmann Valentina O. , Martin Simon , Shchendrygina Anastasia , Hoffmann Jedrzej , Ka Mame Madjiguène , Giokoglu Eleni , Vanchin Byambasuren , Holm Niels , Karyou Argyro , Laux Gerald S. , Arendt Christophe , De Leuw Philipp , Zacharowski Kai , Khodamoradi Yascha , Vehreschild Maria J. G. T. , Rohde Gernot , Zeiher Andreas M. , Vogl Thomas J. , Schwenke Carsten , Nagel Eike
Published: September 2022

Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77–177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274–383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness.
Genome-wide association analysis to delineate high-quality SNPs for seed micronutrient density in chickpea (Cicer arietinum L.)
Authors: Fayaz Humara , Tyagi Sandhya , Wani Aijaz A. , Pandey Renu , Akhtar Sabina , Bhat Mohd Ashraf , Chitikineni Annapurna , Varshney Rajeev Kumar , Thudi Mahendar , Kumar Upendra , Mir Reyazul Rouf
Published: September 2022

Chickpea is the most important nutrient-rich grain legume crop in the world. A diverse core set of 147 chickpea genotypes was genotyped with a Axiom(®)50K CicerSNP array and trait phenotyped in two different environments for four seed micronutrients (Zn, Cu, Fe and Mn). The trait data and high-throughput 50K SNP genotypic data were used for the genome-wide association study (GWAS). The study led to the discovery of genes/QTLs for seed Zn, Cu, Fe and Mn, concentrations in chickpea. The analysis of seed micronutrient data revealed significant differences for all four micronutrient concentrations (P ≤ 0.05). The mean concentrations of seed Zn, Cu, Fe and Mn pooled over the 2 years were 45.9 ppm, 63.8 ppm 146.1 ppm, and 27.0 ppm, respectively. The analysis of results led to the identification of 35 SNPs significantly associated with seed Zn, Cu, Fe and Mn concentrations. Among these 35 marker-trait associations (MTAs), 5 were stable (consistently identified in different environments), 6 were major (explaining more than 15% of the phenotypic variation for an individual trait) and 3 were both major and stable MTAs. A set of 6 MTAs, MTAs (3 for Mn, 2 for Fe, and 1 for Cu) reported by us during the present study have been also reported in the same/almost same genomic regions in earlier studies and therefore declared as validated MTAs. The stable, major and validated MTAs identified during the present study will prove useful in future chickpea molecular breeding programs aimed at enhancing the seed nutrient density of chickpea.
Potential of ESBL-producing Escherichia coli selection in bovine feces after intramammary administration of first generation cephalosporins using in vitro experiments
Authors: Speksnijder David C. , Hopman Nonke E. M. , Kusters Nina E. , Timmerman Arjen , Swinkels Jantijn M. , Penterman Pleun A. A. , Krömker Volker , Bradley Andrew J. , Botteldoorn Nadine , Gehring Ronette , Zomer Aldert L.
Published: September 2022

Selection and spread of Extended Spectrum Beta-Lactamase (ESBL) -producing Enterobacteriaceae within animal production systems and potential spillover to humans is a major concern. Intramammary treatment of dairy cows with first-generation cephalosporins is a common practice and potentially selects for ESBL-producing Enterobacteriaceae, although it is unknown whether this really occurs in the bovine fecal environment. We aimed to study the potential effects of intramammary application of cephapirin (CP) and cefalonium (CL) to select for ESBL-producing Escherichia coli in the intestinal content of treated dairy cows and in manure slurry, using in vitro competition experiments with ESBL and non-ESBL E. coli isolates. No selection of ESBL-producing E. coli was observed at or below concentrations of 0.8 µg/ml and 4.0 µg/ml in bovine feces for CP and CL, respectively, and at or below 8.0 µg/ml and 4.0 µg/ml, respectively, in manure slurry. We calculated that the maximum concentration of CP and CL after intramammary treatment with commercial products will not exceed 0.29 µg/ml in feces and 0.03 µg/ml in manure slurry. Therefore, the results of this study did not find evidence supporting the selection of ESBL-producing E. coli in bovine feces or in manure slurry after intramammary use of commercial CP or CL-containing products.
A cross-sectional study of clinical, dermoscopic, histopathological, and molecular patterns of scalp melanoma in patients with or without androgenetic alopecia
Authors: Porto Ana Carolina , Pinto Blumetti Tatiana , Calsavara Vinícius Fernando , Tardin Torrezan Giovana , Andrade de Paula Cláudia Alessandra , Lellis Rute , Pedreira Duprat Neto João , Carraro Dirce Maria , Casagrande Tavoloni Braga J.
Published: September 2022

Scalp melanoma (SM) has a worse prognosis than melanoma in other locations likely because of late diagnosis due to hair coverage, difficulties in interpreting dermoscopy findings, and its unique molecular profile. We aimed to describe the clinical, histopathological, molecular, and dermoscopic patterns of SM and its relation to androgenetic alopecia/elastosis at the tumor site. Through a retrospective cross-sectional study, we identified all SM diagnosed at the A.C.Camargo Cancer Center between 2008 and 2018. In all, 48 SM were analyzed: 45.8% of which exhibited moderate/severe androgenetic alopecia and 54.1% exhibited elastosis. Androgenetic alopecia/elastosis at the site of the SM was associated with older age (p < 0.001), chronic sun damage (p < 0.001), lentigo maligna subtype (p = 0.029), and photodamaged dermoscopic pattern (p < 0.001). Additionally, 41 cases were evaluated with a 14-gene panel: 53.7% displayed mutations and 46.3% were wild-type. BRAF mutations were most common (77%), with BRAF V600K being more frequent (50%) than BRAF V600E (31.2%). The NF1 gene was evaluated in 40 samples, of which 20% exhibited mutations. SM presents differently in areas covered by hair compared to in areas with androgenetic alopecia. Patients without alopecia may have higher Breslow thickness due to late diagnosis because of hair concealment. The high frequency of detrimental mutations can also explain the poor prognosis of SM.
Measurement of focal light spot at single-photon level with silicon photomultipliers
Authors: Yang Yaxian , Zhang Guoqing , Zhang Chen , Cao Xinyue , Liu Lina , Li Lianbi , Han Xiaoxiang
Published: September 2022

Focal spot (light spot) at single-photon level have important applications in many fields. This report demonstrates a method for measuring focal spot size at the single-photon level indirectly. This method utilizes Silicon Photomultiplier (SiPM) as the single-photon sensitive detectors, combined with a nano-positioning stage. The approach involves one- or two-dimensional space scanning and a deconvolution operation, which enable evaluations of the size and spatial distribution of the focal spot formed by a single-photon-level pulsed laser. The results indicate that the average full width at half maximum of the focal spot is about 0.657 μm, which is close to the nominal resolution of the objective lens of the microscope (i.e. 0.42 μm). The proposed method has two key advantages: (1) it can measure focal spot at the single-photon level, and (2) the focal spot can easily be aligned with the detector because the array area of the Geiger mode avalanche photodiode (Gm-APD) cells in SiPM is usually on the order of square millimeter, and there is no need to put an optical slit, knife edge, or pinhole in front of the detector. The method described herein is applicable in weak focal spot detection related fields.
Complete chloroplast genome sequence of Lens ervoides and comparison to Lens culinaris
Authors: Tayşi Nurbanu , Kaymaz Yasin , Ateş Duygu , Sari Hatice , Toker Cengiz , Tanyolaç M. Bahattin
Published: September 2022

Lens is a member of the Papilionoideae subfamily of Fabaceae and is generally used as a source of vegetable protein as part of human diets in many regions worldwide. Chloroplast (cp) genomes are highly active genetic components of plants and can be utilized as molecular markers for various purposes. As one of the wild lentil species, the Lens ervoides cp genome has been sequenced for the first time in this study using next-generation sequencing. The de novo assembly of the cp genome resulted in a single 122,722 bp sequence as two separate coexisting structural haplotypes with similar lengths. Results indicated that the cp genome of L. ervoides belongs to the inverted repeat lacking clade. Several noteworthy divergences within the coding regions were observed in ndhB, ndhF, rbcL, rpoC2, and ycf2 genes. Analysis of relative synonymous codon usage showed that certain genes, psbN, psaI, psbI, psbE, psbK, petD, and ndhC, preferred using biased codons more often and therefore might have elevated expression and translation efficiencies. Overall, this study exhibited the divergence level between the wild-type and cultured lentil cp genomes and pointed to certain regions that can be utilized as distinction markers for various goals.
Optical thin film coated organic nonlinear crystal for efficient terahertz wave generation
Authors: Uchida Hirohisa , Kawauchi Tetsuya , Otake Gemma , Koyama Chisa , Takeya Kei , Tripathi Saroj R.
Published: September 2022

In the process of terahertz (THz) wave generation via optical rectification of infrared femtosecond pulses in a non-linear optical crystal, the power of terahertz wave is directly proportional to the square of the optical pump power. Therefore, high power terahertz wave can be generated using a high power femtosecond laser provided that the crystal has both high laser induced damage threshold and optical non-linear coefficient. However, a significant amount of pump power is lost in this process due to the Fresnel’s reflection at the air-crystal boundary. In this paper, we numerically and experimentally demonstrate that the coat of optical thin film called Cytop on the 4-N, N-dimethylamino-4’-N’-methyl-stilbazolium tosylate (DAST) crystal effectively reduces the reflection loss of pump power, thereby increasing the THz wave emission efficiency of the DAST crystal. We found that the average power of THz wave emitted by the thin film coated crystal is about 28% higher than the THz power emitted by the uncoated crystal when an equal amount of laser power is used. The thin film coated DAST crystals can be used not only in terahertz measurement systems but also in optical devices such as modulators and waveguides.
Single-base resolution methylomes of somatic embryogenesis in Theobroma cacao L. reveal epigenome modifications associated with somatic embryo abnormalities
Authors: Garcia Claudia , Furtado de Almeida Alex-Alan , Costa Marcio , Britto Dahyana , Correa Fabio , Mangabeira Pedro , Silva Lidiane , Silva Jose , Royaert Stefan , Marelli Jean-Philippe
Published: September 2022

Propagation by somatic embryogenesis in Theobroma cacao has some issues to be solved, as many morphologically abnormal somatic embryos that do not germinate into plants are frequently observed, thus hampering plant production on a commercial scale. For the first time the methylome landscape of T. cacao somatic embryogenesis was examined, using whole-genome bisulfite sequencing technique, with the aim to understand the epigenetic basis of somatic embryo abnormalities. We identified 873 differentially methylated genes (DMGs) in the CpG context between zygotic embryos, normal and abnormal somatic embryos, with important roles in development, programmed cell death, oxidative stress, and hypoxia induction, which can help to explain the morphological abnormalities of somatic embryos. We also identified the role of ethylene and its precursor 1-aminocyclopropane-1-carboxylate in several biological processes, such as hypoxia induction, cell differentiation and cell polarity, that could be associated to the development of abnormal somatic embryos. The biological processes and the hypothesis of ethylene and its precursor involvement in the somatic embryo abnormalities in cacao are discussed.
Uncertainty propagation in pore water chemical composition calculation using surrogate models
Authors: Sochala Pierre , Chiaberge Christophe , Claret Francis , Tournassat Christophe
Published: September 2022

Performance assessment in deep geological nuclear waste repository systems necessitates an extended knowledge of the pore water chemical conditions prevailing in host-rock formations. In the last two decades, important progress has been made in the experimental characterization and thermodynamic modeling of pore water speciation, but the influence of experimental artifacts and uncertainties of thermodynamic input parameters are seldom evaluated. In this respect, we conducted an uncertainty propagation study in a reference geochemical model describing the pore water chemistry of the Callovian-Oxfordian clay formation. Nineteen model input parameters were perturbed, including those associated to experimental characterization (leached anions, exchanged cations, cation exchange selectivity coefficients) and those associated to generic thermodynamic databases (solubilities). A set of 13 quantities of interest were studied by the use of polynomial chaos expansions built non-intrusively with a least-squares forward stepwise regression approach. Training and validation sets of simulations were carried out using the geochemical speciation code PHREEQC. The statistical results explored the marginal distribution of each quantity of interest, their bivariate correlations as well as their global sensitivity indices. The influence of the assumed distributions for input parameters uncertainties was evaluated by considering two parametric domain sizes.
Assessing wastewater-based epidemiology for the prediction of SARS-CoV-2 incidence in Catalonia
Authors: Joseph-Duran Bernat , Serra-Compte Albert , Sàrrias Miquel , Gonzalez Susana , López Daniel , Prats Clara , Català Martí , Alvarez-Lacalle Enric , Alonso Sergio , Arnaldos Marina
Published: September 2022

While wastewater-based epidemiology has proven a useful tool for epidemiological surveillance during the COVID-19 pandemic, few quantitative models comparing virus concentrations in wastewater samples and cumulative incidence have been established. In this work, a simple mathematical model relating virus concentration and cumulative incidence for full contagion waves was developed. The model was then used for short-term forecasting and compared to a local linear model. Both scenarios were tested using a dataset composed of samples from 32 wastewater treatment plants and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) incidence data covering the corresponding geographical areas during a 7-month period, including two contagion waves. A population-averaged dataset was also developed to model and predict the incidence over the full geography. Overall, the mathematical model based on wastewater data showed a good correlation with cumulative cases and allowed us to anticipate SARS-CoV-2 incidence in one week, which is of special relevance in situations where the epidemiological monitoring system cannot be fully implemented.
Real-world effectiveness of anti-interleukin-23 antibodies in chronic plaque-type psoriasis of patients from the Austrian Psoriasis Registry (PsoRA)
Authors: Graier T. , Weger W. , Jonak C. , Sator P. , Zikeli C. , Prillinger K. , Sassmann C. , Gruber B. , Saxinger W. , Ratzinger G. , Painsi C. , Mlynek A. , Häring N. , Sadoghi B. , Trattner H. , Müllegger R. , Quehenberger F. , Salmhofer W. , Wolf Peter
Published: September 2022

With the introduction of the latest class of biologic drugs targeting interleukin (IL)-23p19, three new, highly effective drugs can be used for the treatment of chronic plaque psoriasis. However, poorer skin improvement as well as higher rates of serious adverse events have been reported for patients under real-world conditions (outside clinical trials). This accounts especially for patients who have already been treated with biologic drugs. We therefore aimed to determine effectiveness and safety of IL-23p19 inhibitors in real-world patients by analysing data from the Psoriasis Registry Austria (PsoRA) in this observational, retrospective, multicentre cohort study. Data for 197 patients (52.3% biologic-non-naïve), who were treated with anti-IL-23p19 antibodies (127 guselkumab, 55 risankizumab and 15 tildrakizumab) for at least 3 months, were eligible for analysis. In general, biologic-non-naïve patients displayed a less favourable response to anti-IL-23 treatment as compared to biologic-naïve patients. However, after correction for previous biologic exposure, few differences in PASI improvement were detected among biologic-naïve and -non-naïve patients treated with different IL-23p19 inhibitors. This indicates that treatment effectiveness is not related to the class of the previously administered therapy in biologic-non-naïve patients. Therefore, IL-23p19 inhibitors represent a promising treatment alternative for patients who have not responded to previous biologics. However, as with other biologic agents (including IL-17 inhibitors), we did not observe an entirely satisfactory treatment response (i.e. PASI < 3 and/or PASI 75) to anti-IL-23 treatment in one out of four to five patients. Adverse events (mainly non-severe infections) were observed in 23 (11.7%) patients with no major differences regarding the administered IL-23 inhibitor or previous biologic exposure.
Gender specific somatic symptom burden and mortality risk in the general population
Authors: Atasoy Seryan , Hausteiner-Wiehle Constanze , Sattel Heribert , Johar Hamimatunnisa , Roenneberg Casper , Peters Annette , Ladwig Karl-Heinz , Henningsen Peter
Published: September 2022

Gender specific all-cause mortality risk associated with ahighsomatic symptom burden (SSB) in a population-based cohort was investigated. The study population included 5679 women and 5861 men aged 25–74 years from the population-based MONICA/KORA Cohort. SSB was assessed following the Somatic Symptom Scale-8 and categorized asvery high(≥ 95th percentile),high(60–95th percentile),moderate(30–60th percentile), andlow(≤ 30th percentile). The impact of SSB on all-cause mortality risk within a mean follow-up period of 22.6 years (SD 7.1; 267,278 person years) was estimated by gender-specific Cox regression models adjusted for sociodemographic, lifestyle, somatic and psychosocial risk factors, as well as pre-existing medical conditions. Approximately 5.7% of men and 7.3% of women hadvery highSSB. During follow-up, 3638 (30.6%) mortality cases were observed. Men with avery-highSSB had 48% increased relative risk of mortality in comparison to men with alowSSB after adjustment for concurrent risk factors (1.48, 95% CI 1.20–1.81,p< .0001), corresponding to 2% increased risk of mortality for each 1-point increment in SSB (1.02; 95% CI 1.01–1.03;p= 0.03). In contrast, women with avery highSSB had a 22% lower risk of mortality (0.78, 95% CI 0.61–1.00,p= 0.05) and women withhighSSB had an 18% lower risk of mortality (0.82; 95% CI 0.68–0.98,p= 0.03) following adjustment for concurrent risk factors. The current findings indicate that an increasing SSB is an independent risk factor for mortality in men but not in women, pointing in the direction of critical gender differences in the management of SSB, including women’s earlier health care utilization than men.
Changes of macrophage and CD4+ T cell in inflammatory response in type 1 diabetic mice
Authors: Li Chenhao , Gao Qingyuan , Jiang Hao , Liu Chengrun , Du Yujun , Li Lisha
Published: September 2022

Immune cells play an important role in the development of inflammation in type 1 diabetes mellitus, so we want to explore the changes of CD4+T cells and macrophages in vivo, which can provide an experimental basis for immunotherapy based on CD4+T cells and macrophages. The intraperitoneal injection of streptozocin was used to induce a type 1 diabetes mellitus mouse model; the blood glucose, body weight, and the expression of inflammatory factors in the kidney were measured. Immunohistochemistry was applied to determine and analyze the infiltration of CD4+T cells and macrophages in the spleen, pancreas, and kidney. The subtypes of macrophages in the kidney and CD4+T cells in the spleen were analyzed by flow cytometry. Our study suggests that CD4+T cells and macrophages increase, while the inflammatory immune response system is activated in the development of T1DM. CD4+T cells positively correlated with macrophages in the pancreas and kidney of T1DM. CD4+T cells turn to pro-inflammatory subtypes in the spleen of T1DM, while macrophages turn to pro-inflammatory subtypes in the kidney of T1DM. Therefore, regulation of CD4+T cells and macrophages may be a potential target for T1DM and kidney complications.
Distinct histone H3 modification profiles correlate with aggressive characteristics of salivary gland neoplasms
Authors: Lam-Ubol Aroonwan , Phattarataratip Ekarat
Published: September 2022

Post-translational modification of histones is the crucial event that affect many tumor-specific traits. A diverse type of histone modifications had been reported in different cancers with prognostic implications. This study aimed to examine the degree of histone H3 modifications in salivary gland neoplasms and their associations with tumor pathologic characteristics and proliferative activity. The expression of H3K9Ac, H3K18Ac, H3K9Me3 and Ki-67 in 70 specimens of salivary gland neoplasms, consisting of 30 mucoepidermoid carcinoma (MEC), 20 adenoid cystic carcinoma (ACC) and 20 pleomorphic adenoma (PA), were investigated immunohistochemically. The immunohistochemical scoring of 3 histone modification types and Ki-67 labeling index were determined. Overall, MEC demonstrated elevated H3K9Ac level compared with benign PA. Increased H3K9Me3 in MEC was positively correlated with small nest invasion at tumor front, advanced pathologic grade, and elevated proliferative index. In addition, the significant upregulation of all 3 types of histone H3 modification was noted in solid subtype of ACC and associated with increased cell proliferation. This study indicates that salivary gland neoplasms differentially acquire distinct patterns of histone H3 modification, which impact prognostically relevant cancer phenotypes. The hyperacetylation and methylation of histone H3 could be underpinning the prognostically worsen solid type of ACC, and the trimethylation of H3K9 may be involved in aggressive characteristics of MEC.
Compellingly high SARS-CoV-2 susceptibility of Golden Syrian hamsters suggests multiple zoonotic infections of pet hamsters during the COVID-19 pandemic
Authors: Blaurock Claudia , Breithaupt Angele , Weber Saskia , Wylezich Claudia , Keller Markus , Mohl Björn-Patrick , Görlich Dirk , Groschup Martin H. , Sadeghi Balal , Höper Dirk , Mettenleiter Thomas C. , Balkema-Buschmann Anne
Published: September 2022

Golden Syrian hamsters (Mesocricetus auratus) are used as a research model for severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Millions of Golden Syrian hamsters are also kept as pets in close contact to humans. To determine the minimum infective dose (MID) for assessing the zoonotic transmission risk, and to define the optimal infection dose for experimental studies, we orotracheally inoculated hamsters with SARS-CoV-2 doses from 1 * 105 to 1 * 10−4 tissue culture infectious dose 50 (TCID50). Body weight and virus shedding were monitored daily. 1 * 10−3 TCID50 was defined as the MID, and this was still sufficient to induce virus shedding at levels up to 102.75 TCID50/ml, equaling the estimated MID for humans. Virological and histological data revealed 1 * 102 TCID50 as the optimal dose for experimental infections. This compelling high susceptibility leading to productive infections in Golden Syrian hamsters must be considered as a potential source of SARS-CoV-2 infection for humans that come into close contact with pet hamsters.
Loneliness and diurnal cortisol levels during COVID-19 lockdown: the roles of living situation, relationship status and relationship quality
Authors: Hopf Dora , Schneider Ekaterina , Aguilar-Raab Corina , Scheele Dirk , Morr Mitjan , Klein Thomas , Ditzen Beate , Eckstein Monika
Published: September 2022

Loneliness and social isolation have become increasing concerns during COVID-19 lockdown through neuroendocrine stress-reactions, physical and mental health problems. We investigated living situation, relationship status and quality as potential moderators for trait and state loneliness and salivary cortisol levels (hormonal stress-responses) in healthy adults during the first lockdown in Germany. N = 1242 participants (mean age = 36.32, 78% female) filled out an online questionnaire on demographics, trait loneliness and relationship quality. Next, N = 247 (mean age = 32.6, 70% female) completed ecological momentary assessment (EMA), collecting twelve saliva samples on 2 days and simultaneously reporting their momentary loneliness levels. Divorced/widowed showed highest trait loneliness, followed by singles and partnerships. The latter displayed lower momentary loneliness and cortisol levels compared to singles. Relationship satisfaction significantly reduced loneliness levels in participants with a partner and those who were living apart from their partner reported loneliness levels similar to singles living alone. Living alone was associated with higher loneliness levels. Hierarchical linear models revealed a significant cross-level interaction between relationship status and momentary loneliness in predicting cortisol. The results imply that widowhood, being single, living alone and low relationship quality represent risk factors for loneliness and having a partner buffers neuroendocrine stress responses during lockdown.
The moderating effect of physical activity on the association between screen-based behaviors and chronic diseases
Authors: Araujo Raphael H. O. , Werneck André O. , Barboza Luciana L. , Silva Ellen C. M. , Silva Danilo R.
Published: September 2022

We analyzed the associations of screen-based behaviors with obesity, hypertension, and diabetes, and the moderation of different physical activity (PA) domains in these associations. We used data from the 2019 Brazilian National Health Survey, including data from 80,940 adults (mean age of 32.6 years). TV viewing, other screens (PC, tablet, and cell phone), PA domains (leisure-time, occupational, and transport) were collected via interview. Logistic regression models were used. There was a dose–response association of higher TV viewing with diabetes. Within the groups with medium and higher time spent on other screens, those with < 150 min/week in leisure-time PA increased the odds for obesity [1–2.9 h/day: OR = 1.18 (1.01, 1.39)] and hypertension [1–2.9 h/day: OR = 1.29 (1.08, 1.53); ≥ 6 h/day: OR = 1.47 (1.03, 2.09)]. Likewise, among the participants who spent ≥ 6 h/day of TV viewing, those with < 150 min/week of occupational PA presented higher odds for hypertension [OR = 1.61 (1.03, 2.53)]. In the group with higher use of other screens, < 150 min per week of occupational PA was associated with lower odds for obesity [1–2.9 h/day: OR = 0.81 (0.68, 0.97)] and hypertension [≥ 6 h/day: OR = 0.65 (0.44, 0.98)]. In conclusion, the associations of other screens with obesity and hypertension were strongest among those without leisure-time PA, while the moderator role of occupational PA was not clear.
1D solitons in cubic-quintic fractional nonlinear Schrödinger model
Authors: Stephanovich V. A. , Olchawa W. , Kirichenko E. V. , Dugaev V. K.
Published: September 2022

We examine the properties of a soliton solution of the fractional Schrö dinger equation with cubic-quintic nonlinearity. Using analytical (variational) and numerical arguments, we have shown that the substitution of the ordinary Laplacian in the Schrödinger equation by its fractional counterpart with Lévy index $$\alpha$$
α
permits to stabilize the soliton texture in the wide range of its parameters (nonlinearity coefficients and $$\alpha$$
α
) values. Our studies of $$\omega (N)$$

ω
(
N
)

dependence ($$\omega$$
ω
is soliton frequency and N its norm) permit to acquire the regions of existence and stability of the fractional soliton solution. For that we use famous Vakhitov-Kolokolov (VK) criterion. The variational results are confirmed by numerical solution of a one-dimensional cubic-quintic nonlinear Schrödinger equation. Direct numerical simulations of the linear stability problem of soliton texture gives the same soliton stability boundary as within variational method. Thus we confirm that simple variational approach combined with VK criterion gives reliable information about soliton structure and stability in our model. Our results may be relevant to both optical solitons and Bose-Einstein condensates in cold atomic gases.
Analysis of flow rate and pressure in syringe-based wound irrigation using Bernoulli's equation
Authors: Lee Hanna , Lee Ye-kyung , Park Ji-Yun , Han Jeong-won
Published: September 2022

The objective of this study was to examine the dependence of the pressure level in the wound area on the height of the syringe needle from the wound, the gauge of the needle, and the flow rate using the Bernoulli equation. This study was the control-volume analysis using the Bernoulli equation. At a given height of the syringe needle from the wound, the gauge of the syringe needle was fixed, and the pressure in the wound area, which depended on the flow rate of the irrigation solution discharged from the tip of the needle, was calculated according to the Bernoulli equation and the definition of the flow rate. At a constant flow rate of the irrigation solution, the velocity of the irrigation solution discharged through the syringe needle decreased (7.80 → 0.80) with an increase in the diameter of the needle (18G → 14G). At a constant inner diameter of the needle, the velocity of the irrigation solution increased with a reduction in the flow rate of the solution. As the velocity of the irrigation solution increased, the pressure in the wound area increased. As the height of the syringe needle from the wound area increased, the pressure in the wound area increased. In order to maintain the pressure of 8–15 psi when nurses perform syringe-based irrigation, it is necessary to set the flow rate of the cleaning solution from 3.5 cc/s to less than 4.8 cc/s for 19G. In addition, 20G maintains the flow rate of the solution at 2.6 cc/s or more and less than 3.5 cc/s, 22G maintains the flow rate of solution at 1.3 cc/s or more and less than 1.8 cc/s, and 25G maintains the flow rate of solution at 0.5 cc/s. This study provides nurses with a reference for the flow rate at which syringe-based irrigation can be performed while maintaining the appropriate pressure based on fluid dynamics, which can be used as the basis for wound nursing standards.
Phenol-soluble modulin α and β display divergent roles in mice with staphylococcal septic arthritis
Authors: Hu Zhicheng , Kopparapu Pradeep Kumar , Ebner Patrick , Mohammad Majd , Lind Simon , Jarneborn Anders , Dahlgren Claes , Schultz Michelle , Deshmukh Meghshree , Pullerits Rille , Nega Mulugeta , Nguyen Minh-Thu , Fei Ying , Forsman Huamei , Götz Friedrich , Jin Tao
Published: September 2022

Phenol-soluble modulin α (PSMα) is identified as potent virulence factors in Staphylococcus aureus (S. aureus) infections. Very little is known about the role of PSMβ which belongs to the same toxin family. Here we compared the role of PSMs in S. aureus-induced septic arthritis in a murine model using three isogenic S. aureus strains differing in the expression of PSMs (Newman, Δpsmα, and Δpsmβ). The effects of PSMs on neutrophil NADPH-oxidase activity were determined in vitro. We show that the PSMα activates neutrophils via the formyl peptide receptor (FPR) 2 and reduces their NADPH-oxidase activity in response to the phorbol ester PMA. Despite being a poor neutrophil activator, PSMβ has the ability to reduce the neutrophil activating effect of PSMα and to partly reverse the effect of PSMα on the neutrophil response to PMA. Mice infected with S. aureus lacking PSMα had better weight development and lower bacterial burden in the kidneys compared to mice infected with the parental strain, whereas mice infected with bacteria lacking PSMβ strain developed more severe septic arthritis accompanied with higher IL-6 and KC. We conclude that PSMα and PSMβ play distinct roles in septic arthritis: PSMα aggravates systemic infection, whereas PSMβ protects arthritis development.
Clonal dynamics underlying the skewed CD4/CD8 ratio of mouse thymocytes revealed by TCR-independent barcoding
Authors: Iwanami Norimasa , Petersen Malte , Diekhoff Dagmar , Boehm Thomas
Published: September 2022

T cell differentiation in the thymus generates CD4+helper and cytotoxic CD8+cells as the two principal T cell lineages. Curiously, at the end of this complex selection process, CD4+cells invariably outnumber CD8+cells. Here, we examine the dynamics of repertoire formation and the emergence of the skewed CD4/CD8 ratio using high-resolution endogenous CRISPR/Cas9 barcoding that indelibly marks immature T cells at the DN2/DN3 pre-TCR stage. In wild-type mice, greater clone size of CD4+cells and an intrinsically greater probability of Tcr β clonotypes for pMHCII interactions are major contributors to the skewed CD4/CD8 ratio. Clonal perturbations of thymocyte differentiation following the precocious expression of a rearranged iNKT invariant TCR α chain are due to loss of Tcr β clonotypes from the CD4 lineage-committed pre-selection repertoire. The present barcoding scheme offers a novel means to examine the clonal dynamics of lymphocyte differentiation orthogonal to that using TCR clonotypes.
CPEB2 m6A methylation regulates blood–tumor barrier permeability by regulating splicing factor SRSF5 stability
Authors: Zhang Mengyang , Yang Chunqing , Ruan Xuelei , Liu Xiaobai , Wang Di , Liu Libo , Shao Lianqi , Wang Ping , Dong Weiwei , Xue Yixue
Published: September 2022

The blood–tumor barrier (BTB) contributes to poor therapeutic efficacy by limiting drug uptake; therefore, elevating BTB permeability is essential for glioma treatment. Here, we prepared astrocyte microvascular endothelial cells (ECs) and glioma microvascular ECs (GECs) as in vitro blood–brain barrier (BBB) and BTB models. Upregulation of METTL3 and IGF2BP3 in GECs increased the stability ofCPEB2mRNA through its m6A methylation. CPEB2 bound to and increasedSRSF5mRNA stability, which promoted the ETS1 exon inclusion. P51-ETS1 promoted the expression of ZO-1, occludin, and claudin-5 transcriptionally, thus regulating BTB permeability. Subsequent in vivo knockdown of these molecules in glioblastoma xenograft mice elevated BTB permeability, promoted doxorubicin penetration, and improved glioma-specific chemotherapeutic effects. These results provide a theoretical and experimental basis for epigenetic regulation of the BTB, as well as insight into comprehensive glioma treatment.
Endogenous oxytocin exerts anti-nociceptive and anti-inflammatory effects in rats
Authors: Nishimura Haruki , Yoshimura Mitsuhiro , Shimizu Makiko , Sanada Kenya , Sonoda Satomi , Nishimura Kazuaki , Baba Kazuhiko , Ikeda Naofumi , Motojima Yasuhito , Maruyama Takashi , Nonaka Yuki , Baba Ryoko , Onaka Tatsushi , Horishita Takafumi , Morimoto Hiroyuki , Yoshida Yasuhiro , Kawasaki Makoto , Sakai Akinori , Muratani Masafumi , Conway-Campbell Becky , Lightman Stafford , Ueta Yoichi
Published: September 2022

Oxytocin is involved in pain transmission, although the detailed mechanism is not fully understood. Here, we generate a transgenic rat line that expresses human muscarinic acetylcholine receptors (hM3Dq) and mCherry in oxytocin neurons. We report that clozapine-N-oxide (CNO) treatment of our oxytocin-hM3Dq-mCherry rats exclusively activates oxytocin neurons within the supraoptic and paraventricular nuclei, leading to activation of neurons in the locus coeruleus (LC) and dorsal raphe nucleus (DR), and differential gene expression in GABA-ergic neurons in the L5 spinal dorsal horn. Hyperalgesia, which is robustly exacerbated in experimental pain models, is significantly attenuated after CNO injection. The analgesic effects of CNO are ablated by co-treatment with oxytocin receptor antagonist. Endogenous oxytocin also exerts anti-inflammatory effects via activation of the hypothalamus-pituitary-adrenal axis. Moreover, inhibition of mast cell degranulation is found to be involved in the response. Taken together, our results suggest that oxytocin may exert anti-nociceptive and anti-inflammatory effects via both neuronal and humoral pathways.
The impact of protozoa addition on the survivability of Bacillus inoculants and soil microbiome dynamics
Authors: Mawarda Panji Cahya , Le Roux Xavier , Acosta Melissa Uribe , van Elsas Jan Dirk , Salles Joana Falcão
Published: September 2022

Protists’ selective predation of bacterial cells is an important regulator of soil microbiomes, which might influence the success of bacterial releases in soils. For instance, the survival and activity of introduced bacteria can be affected by selective grazing on resident communities or the inoculant, but this remains poorly understood. Here, we investigated the impact of the introduction in the soil of two protozoa species, Rosculus terrestris ECOP02 and/or Cerocomonas lenta ECOP01, on the survival of the inoculants Bacillus mycoides M2E15 (BM) or B. pumilus ECOB02 (BP). We also evaluated the impact of bacterial inoculation with or without protozoan addition on the abundance and diversity of native soil bacterial and protist communities. While the addition of both protozoa decreased the survival of BM, their presence contrarily increased the BP abundance. Protists’ selective predation governs the establishment of these bacterial inoculants via modifying the soil microbiome structure and the total bacterial abundance. In the BP experiment, the presence of the introduced protozoa altered the soil community structures and decreased soil bacterial abundance at the end of the experiment, favouring the invader survival. Meanwhile, the introduced protozoa did not modify the soil community structures in the BM experiment and reduced the BM + Protozoa inoculants’ effect on total soil bacterial abundance. Our study reinforces the view that, provided added protozoa do not feed preferentially on bacterial inoculants, their predatory behaviour can be used to steer the soil microbiome to improve the success of bacterial inoculations by reducing resource competition with the resident soil microbial communities.