bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessment of soil erosion risk in a semi-arid climate watershed using SWAT model: case of Tata basin, South-East of Morocco
Authors: Echogdali F. Z. , Boutaleb S. , Taia S. , Ouchchen M. , Id-Belqas M. , Kpan R. B. , Abioui M. , Aswathi J. , Sajinkumar K. S.
Published: April 2022

Increased sedimentation is the main problem that affects dam efficiency by reducing storage capacity. Planning for dam construction and maintenance requires design strategies that heavily depend on integrated basin models, properly identifying principal sediment origins within the watershed and qualifying the sediment production rate. In this research work, the physically-based watershed SWAT model, defined as the Soil and Water Assessment Tool, was used to estimate the rate of sediment production for future dams in the Tata basin, located in southeast Morocco. The model was calibrated and tested for uncertainty by the employment of the algorithm Sequential Uncertainty Fitting-2. The outputs were used for assessing critical sediment source areas. Calibration and validation of the model were performed by monthly data. The values for Nash–Sutcliffe efficiency coefficient, Percent bias coefficient and determination coefficient (R2), respectively, during the calibration period 1990–1998 (0.96, −13% and 0.96) and the validation period 1999–2006 (0.77, + 11% and 0.93) indicate the accordance with the results obtained for the measured flow and the simulated flow values. The annual sediment yield of the Tata basin extends from 0 to 11 t/ha/y with a mean of 2.3 t/ha/y. The spatial distribution of these sediments varies from upstream to downstream. The downstream basin generated more sediment to the river per unit area, though it was less than the total amount of the basin for the upstream area. This variation is influenced by the increased downstream surface runoff and also by other characteristics of the basin such as slope and lithology. The low erosion places correspond to areas with lithological formations that are more resistant to erosion.
Characterization of antimicrobial use and co-infections among hospitalized patients with COVID-19: a prospective observational cohort study
Authors: Lingscheid Tilman , Lippert Lena J. , Hillus David , Kruis Tassilo , Thibeault Charlotte , Helbig Elisa T. , Tober-Lau Pinkus , Pfäfflin Frieder , Müller-Redetzky Holger , Witzenrath Martin , Zoller Thomas , Uhrig Alexander , Opitz Bastian , Suttorp Norbert , Kramer Tobias S. , Sander Leif E. , Stegemann Miriam S. , Kurth Florian
Published: April 2022

Purpose

To investigate antimicrobial use and primary and nosocomial infections in hospitalized COVID-19 patients to provide data for guidance of antimicrobial therapy.

Methods

Prospective observational cohort study conducted at Charité–Universitätsmedizin Berlin, including patients hospitalized with SARS-CoV-2-infection between March and November 2020.

Results

309 patients were included, 231 directly admitted and 78 transferred from other centres. Antimicrobial therapy was initiated in 62/231 (26.8%) of directly admitted and in 44/78 (56.4%) of transferred patients. The rate of microbiologically confirmed primary co-infections was 4.8% (11/231). Although elevated in most COVID-19 patients, C-reactive protein and procalcitonin levels were higher in patients with primary co-infections than in those without (median CRP 110 mg/l, IQR 51–222 vs. 36, IQR 11–101, respectively; p < 0.0001). Nosocomial bloodstream and respiratory infections occurred in 47/309 (15.2%) and 91/309 (29.4%) of patients, respectively, and were associated with need for invasive mechanical ventilation (OR 45.6 95%CI 13.7–151.8 and 104.6 95%CI 41.5–263.5, respectively), extracorporeal membrane oxygenation (OR 14.3 95%CI 6.5–31.5 and 16.5 95%CI 6.5–41.6, respectively), and haemodialysis (OR 31.4 95%CI 13.9–71.2 and OR 22.3 95%CI 11.2–44.2, respectively). The event of any nosocomial infection was significantly associated with in-hospital death (33/99 (33.3%) with nosocomial infection vs. 23/210 (10.9%) without, OR 4.1 95%CI 2.2–7.3).

Conclusions

Primary co-infections are rare, yet antimicrobial use was frequent, mostly based on clinical worsening and elevated inflammation markers without clear evidence for co-infection. More reliable diagnostic prospects may help to reduce overtreatment. Rates of nosocomial infections are substantial in severely ill patients on organ support and associated with worse patient outcome.
From additive to transport noise in 2D fluid dynamics
Authors: Flandoli Franco , Pappalettera Umberto
Published: April 2022

Additive noise in Partial Differential equations, in particular those of fluid mechanics, has relatively natural motivations. The aim of this work is showing that suitable multiscale arguments lead rigorously, from a model of fluid with additive noise, to transport type noise. The arguments apply both to small-scale random perturbations of the fluid acting on a large-scale passive scalar and to the action of the former on the large scales of the fluid itself. Our approach consists in studying the (stochastic) characteristics associated to small-scale random perturbations of the fluid, here modelled by stochastic 2D Euler equations with additive noise, and their convergence in the infinite scale separation limit.
Fit for Work and Life—an eight-week program for improvement of functionality and quality of life
Authors: Pausch Kunigunde , Blanke Katrin , Niederberger Verena , Egli Sarah , Rufer Michael , Ajdacic-Gross Vladeta , Olbrich Sebastian , Müller Mario
Published: April 2022

Background

The current two-stage study focused on work integration and quality of life of patients in an acute psychiatric day care unit. There is evidence that a longer absence from work due to illness negatively affects job retention, life satisfaction and clinical prognosis. Furthermore, there are individual supportive methods that proved to be effective in work integration. We therefore developed a specific group program Fit for Work and Life (FWL) for patients in an acute psychiatric day care unit focusing on work integration in the first labor market (in contrast to work in institutions for people with disabilities/second labor market).

Methods

Between 2018 and 2020, 62 patients (intervention group; IG) were enrolled in an 8‑week prospective job integration program and compared to 74 patients (control group; CG) who received treatment as usual (partly retrospective survey). Patients of both groups held a job when entering treatment. Main outcome was defined as their working status 4 weeks after the end of treatment as well as self-reported life satisfaction.

Results

At the end of treatment (i.e. the week prior to discharge), the IG participants reported higher overall life satisfaction as well as higher health-, self- and living condition-related satisfaction than controls. Functional and clinical improvement during treatment was linked to subsequently returning to work. Functional improvement was further linked to higher life satisfaction. Mediational analysis revealed an indirect path from functional improvement on life satisfaction via working status, i.e. the higher functional improvement during treatment, the higher the chance of successfully returning to work, which in turn increased life satisfaction.

Conclusion

Our findings suggest that programs such as FWL are useful interventions for employed patients to improve reintegration into work and life and to help to increase life satisfaction.
Anti-Parkinsonian Therapy: Strategies for Crossing the Blood–Brain Barrier and Nano-Biological Effects of Nanomaterials
Authors: Cheng Guowang , Liu Yujing , Ma Rui , Cheng Guopan , Guan Yucheng , Chen Xiaojia , Wu Zhenfeng , Chen Tongkai
Published: April 2022

Parkinson’s disease (PD), a neurodegenerative disease that shows a high incidence in older individuals, is becoming increasingly prevalent. Unfortunately, there is no clinical cure for PD, and novel anti-PD drugs are therefore urgently required. However, the selective permeability of the blood–brain barrier (BBB) poses a huge challenge in the development of such drugs. Fortunately, through strategies based on the physiological characteristics of the BBB and other modifications, including enhancement of BBB permeability, nanotechnology can offer a solution to this problem and facilitate drug delivery across the BBB. Although nanomaterials are often used as carriers for PD treatment, their biological activity is ignored. Several studies in recent years have shown that nanomaterials can improve PD symptoms via their own nano-bio effects. In this review, we first summarize the physiological features of the BBB and then discuss the design of appropriate brain-targeted delivery nanoplatforms for PD treatment. Subsequently, we highlight the emerging strategies for crossing the BBB and the development of novel nanomaterials with anti-PD nano-biological effects. Finally, we discuss the current challenges in nanomaterial-based PD treatment and the future trends in this field. Our review emphasizes the clinical value of nanotechnology in PD treatment based on recent patents and could guide researchers working in this area in the future.
Biochar-induced changes in the soil diazotroph community abundance and structure in a peanut field trial
Authors: Chen Kun , Li Na , Zhang Shiyu , Liu Ning , Yang Jinfeng , Zhan Xiumei , Han Xiaori
Published: April 2022

Biological nitrogen fixation (BNF) can help replenish available nitrogen (N) in cropland and reduce the use of chemical N fertilizers, with diazotrophs playing an important role. However, the response of diazotroph community and BNF activity in biochar amendment soil, especially in the deep soil horizon, are poorly understood. In this study, soil samples were collected from topsoil (0–20 cm) and subsoil (20–40 cm) in the field experiment (established in 2013) comprising treatments with no chemical fertilizer (CK), chemical fertilizer (NPK), biochar (BC), and biochar plus chemical fertilizers (BNPK). Here, we investigated the diazotroph community using real-time PCR and high-throughput sequencing of the nifH gene, and assessed the soil N2 fixation rate (RNfix) using acetylene reduction assay (ARA). Results showed that in the topsoil, the treatments with biochar significantly increased nifH gene copies and RNfix, which was consistent with the increased soil organic matter (SOM), total carbon-to-nitrogen ratio (C/N), dissolved organic carbon (DOC) and pH. In the subsoil, applying chemical fertilizers (NPK) strongly decreased RNfix, but had no effect on diazotroph abundance; in contrast, biochar application (BC) had no effect on RNfix, but suppressed the growth of bacteria and diazotrophs while increasing the abundance of Rhizobiales order. Diazotroph and bacterial gene copies were significantly and positively correlated in both top- and sub-soil, and they were mainly influenced by SOM and total nitrogen (TN). In addition, soil nitrate nitrogen (NO3−–N) was the major factor in shaping the vertical stratification of diazotroph community structure. Although nifH gene abundance was significantly correlated with RNfix in the topsoil, the structure equation modeling (SEM) showed the highest correlation between diazotroph community structure and RNfix. Hence, we suggested that soil carbon and nitrogen sources were the key factors correlated with changes in the vertical pattern of diazotroph abundance. Biochar induced the dominant diazotroph community succession and increased soil carbon content and pH, which contributed to the BNF activity. Changes in the BNF activity were driven by the variation in diazotroph community structure.
Autonomy and the social dilemma of online manipulative behavior
Authors: Botes Marietjie
Published: April 2022

Persuasive online technologies were initially designed and used to gain insights into the online behavior of individuals to personalize advertising campaigns in an effort to influence people and convince them to buy certain products. But recently, these technologies have blurred the lines and morphed into technologies that covertly and gradually manipulate people into attaining a goal that is predetermined by the algorithm and disregards the decision-making rights of the individual. This may lead to people exercising decisions that do not align with their personal values and beliefs, and rob them of their autonomy—an ethical principle, in the absence of which the application of these technologies may be unethical. However, not all technologies that are persuasive are necessarily manipulative which require the careful consideration of a couple of elements to determine whether or not technologies are manipulative and ultimately whether their application is ethical or not. In this article, we analyze the ethical principle of autonomy and unpack the underlying elements of this ethical principle which must be considered to determine whether the application of a technology is ethical or not in the context of it being persuasive or manipulative.
Maternal high salt-diet increases offspring's blood pressure with dysfunction of NO/PKGI signaling pathway in heart tissue
Authors: Huang Minshan , Li Xiuying , Ren Luwen , Huang Lin , Pan Jiahong , Yao Jinlin , Du Lili , Chen Dunjin , Chen Jingsi
Published: April 2022

Background

High salt-diets have become significant threats to human health, resulting in hypertension and cardiovascular diseases. Hypertensive disorders during pregnancy are complicated, since the maternal cardiovascular system undergoes extensive physiological changes during pregnancy. High-salt diets during pregnancy can disturb the intrauterine environment and negatively affect fetal development. Therefore, we explored how high-salt diets during pregnancy could affect the offspring.

Methods

Rats were divided into three groups and fed with low, normal, and high salt diets. The offspring were separated into three groups after weaning based on dietary salt concentration. The blood pressure and urine protein content of both dams and offspring were measured. To evaluate cardiac function, we used Masson staining and immunodetection to confirm the fibrosis status. Finally, we extracted protein from cardiac tissue to test the expression levels of the Nitric Oxide (NO)/cGMP-dependent protein kinase I (PKGI) pathway and the angiotensin receptor.

Results

High-salt diets increased blood pressure, and offspring previously exposed to high-salt environments were predisposed to hypertension. High-salt diets were also found to induce cardiac fibrosis and exacerbate fibrosis in offspring and alter the epithelial-mesenchymal transition (EMT). Under these conditions, the NO/PKGI pathway was activated in cardiac tissue and the type-1angiotensin II receptor (AT1R) was upregulated, though the type-2 angiotensin II receptor (AT2R) had the opposite effect.

Conclusion

High-salt diets induce high blood pressure and increase predisposition to hypertension in offspring. They are accompanied by cardiac fibrosis, which could be caused by the activation of NO/PKGI and upregulation of AT1R.
Beta-Thalassemia major with Gaucher disease
Authors: Ibrahimi Mohammad Akbar , Hakimi Turyalai , Halimi Sultan Ahmad
Published: April 2022

ABSTRACT

Introduction and importance:

β-thalassemia major is an inherited disorder resulting from mutation or deletion of the beta-globin gene, causing a reduced beta-globin chain of hemoglobin. Gaucher's disease (GD) is a type of lysosomal storage disorder resulting from the deficiency of the glucocerebrosidase enzyme or storage of glucocerebrosides in the tissues. Coexistence of these two entities is very rare. The importance of reporting this case is that both medical conditions have overlapping clinical manifestations and the diagnosis of one will be mistaken for the other.

Case presentation:

A 12-year-old child was brought to our pediatric department with complaints of abdominal distension, anemia, hepatosplenomegaly, and iron overload due to frequent blood transfusions. Initially, anemia and iron overload were treated with blood transfusion and iron chelation therapy along with management of congestive heart failure (CHF) followed by splenectomy. The patient's follow-up result was favorable.

Clinical discussion:

β-thalassemia major is a genetic disorder that is prevalent in South Asian nations. GD, or lysosomal storage disease, is a rare medical condition requiring enzyme replacement therapy. Coexistence of both disorders is mostly missed where genetic screening is not available. β-thalassemia major is blood transfusion (BT) dependent, and the frequency of BT directly justifies the decision for splenectomy due to splenomegaly and iron overload.

Conclusion:

Our report highlights the similarities of Beta thalassemia major and GD due to overlapping clinical manifestations, therefore this is wise to do all relevant clinical investigations for the purpose of definite diagnosis and proper treatment of both medical conditions.

Highlights
Extreme Exospheric Dynamics at Charon: Implications for the Red Spot
Authors: Teolis Ben , Raut Ujjwal , Kammer Joshua A. , Gimar Caleb J. , Howett Carly J. A. , Gladstone G. Randall , Retherford Kurt D.
Published: April 2022

Charon's exosphere may exhibit extreme seasonal dynamics, with centuries of quiescence punctuated by short lived (∼4 earth years) exospheric surges near the equinoxes, as spring sunrise bi‐annually drives frozen methane off the polar night zones. Charon's pole‐centric red spot has been proposed to be the product of Ly‐α photolysis of frozen methane into refractory hydrocarbon “tholins”, but the role of exospheric dynamics in the red material's formation has not been investigated. We show with exospheric modeling that methane “polar‐swap”, in which exospheric CH4 sublimated from the spring polar zone is rapidly re‐frozen onto the autumn hemisphere, deposits ∼30 μm polar frosts too thick for Ly‐α light to penetrate. Ethane, the primary methane photoproduct under these conditions, may unlike methane remain frozen decades after polar sunrise under solar wind exposure. Solar wind radiolysis of polar ethane frost synthesizes higher‐order refractories that may contribute to the coloration of Charon's polar zones.
Complex Patterns of Mantle Flow in Eastern SE Asian Subduction Zones Inferred From P‐Wave Anisotropic Tomography
Authors: Wei Wei , Zhao Dapeng , Yu Weiqian , Shi Yaolin
Published: April 2022

We determine 3‐D isotropic and anisotropic P‐wave velocity models beneath eastern SE Asia by inverting a large number of P‐wave arrival times selected from the ISC‐EHB database. Our results reveal detailed structures of the subducting South China Sea (SCS), Negros, Molucca Sea, Philippine Sea, and Banda slabs, the previously subducted Proto‐SCS slab and remnants of other paleo slabs, showing long‐lived subductions of these oceanic slabs in eastern SE Asia. There is an obvious change in the subduction angle of the SCS slab at 18°N along the Manila trench. We suggest that the relatively low dip angle of the SCS slab to the south of 18°N was caused by subduction of an extinct mid‐ocean ridge, and a slab tear is possibly formed at 18°N. This feature is supported by the resolved fast velocity directions (FVDs) of P‐wave azimuthal anisotropy in the mantle wedge, which show that 3‐D toroidal mantle flow may develop around the southern part of the SCS slab. Trench‐normal FVDs are revealed in the deeper mantle wedge of the Sangihe subduction zone, which are associated with the deep subduction and stagnancy of the Molucca Sea slab. A nearly trench‐parallel FVD is observed beneath the Molucca Sea slab, which may be caused by trench‐parallel extension due to the retreating slab or reflect subslab mantle flow associated with the double‐sided subduction. The subducting Banda slab exhibits a curved feature, which greatly affects the flow pattern in the mantle wedge.
Longitudinal body mass index trajectories at preschool age: children with rapid growth have differential composition of the gut microbiota in the first year of life
Authors: Reyna Myrtha E. , Petersen Charisse , Dai Darlene L. Y. , Dai Ruixue , Becker Allan B. , Azad Meghan B. , Miliku Kozeta , Lefebvre Diana L. , Moraes Theo J. , Mandhane Piushkumar J. , Boutin Rozlyn C. T. , Finlay B. Brett , Simons Elinor , Kozyrskyj Anita L. , Lou Wendy , Turvey Stuart E. , Subbarao Padmaja
Published: April 2022

Background/Objective

The steep rise in childhood obesity has emerged as a worldwide public health problem. The first 4 years of life are a critical window where long-term developmental patterns of body mass index (BMI) are established and a critical period for microbiota maturation. Understanding how the early-life microbiota relate to preschool growth may be useful for identifying preventive interventions for childhood obesity. We aim to investigate whether longitudinal shifts within the bacterial community between 3 months and 1 year of life are associated with preschool BMI z-score trajectories.

Methods

BMI trajectories from birth to 5 years of age were identified using group-based trajectory modeling in 3059 children. Their association with familial and environmental factors were analyzed. Infant gut microbiota at 3 months and 1 year was defined by 16S RNA sequencing and changes in diversity and composition within each BMIz trajectory were analyzed.

Results

Four BMIz trajectories were identified: low stable, normative, high stable, and rapid growth. Infants in the rapid growth trajectory were less likely to have been breastfed, and gained less microbiota diversity in the first year of life. Relative abundance of Akkermansia increased with age in children with stable growth, but decreased in those with rapid growth, abundance of Ruminococcus and Clostridium at 1 year were elevated in children with rapid growth. Children who were breastfed at 6 months had increased levels of Sutterella, and decreased levels of Ruminococcus and Clostridium.

Conclusion

This study provides new insights into the relationship between the gut microbiota in infancy and patterns of growth in a cohort of preschool Canadian children. We highlight that rapid growth since birth is associated with bacteria shown in animal models to have a causative role in weight gain. Our findings support a novel avenue of research targeted on tangible interventions to reduce childhood obesity.
Validation of a small molecule inhibitor of PDE6D-RAS interaction with favorable anti-leukemic effects
Authors: Canovas Nunes Sara , De Vita Serena , Anighoro Andrew , Autelitano François , Beaumont Edward , Klingbeil Pamela , McGuinness Meaghan , Duvert Beatrice , Harris Chad , Yang Lu , Pokharel Sheela Pangeni , Chen Chun-Wei , Ermann Monika , Williams David A. , Xu Haiming
Published: April 2022

RAS mutations prevalent in high-risk leukemia have been linked to relapse and chemotherapy resistance. Efforts to directly target RAS proteins have been largely unsuccessful. However, since RAS-mediated transformation is dependent on signaling through the RAS-related C3 botulinum toxin substrate (RAC) small GTPase, we hypothesized that targeting RAC may be an effective therapeutic approach in RAS mutated tumors. Here we describe multiple small molecules capable of inhibiting RAC activation in acute lymphoblastic leukemia cell lines. One of these, DW0254, also demonstrates promising anti-leukemic activity in RAS-mutated cells. Using chemical proteomics and biophysical methods, we identified the hydrophobic pocket of phosphodiester 6 subunit delta (PDE6D), a known RAS chaperone, as a target for this compound. Inhibition of RAS localization to the plasma membrane upon DW0254 treatment is associated with RAC inhibition through a phosphatidylinositol-3-kinase/AKT-dependent mechanism. Our findings provide new insights into the importance of PDE6D-mediated transport for RAS-dependent RAC activation and leukemic cell survival.
Mesenchymal stem cell-derived exosomal microRNA-182-5p alleviates myocardial ischemia/reperfusion injury by targeting GSDMD in mice
Authors: Yue Rongchuan , Lu Shengzhong , Luo Yu , Zeng Jing , Liang Hao , Qin Dan , Wang Xiaobo , Wang Tao , Pu Jun , Hu Houxiang
Published: April 2022

Recent evidence indicates that exosomes derived from mesenchymal stem cells (MSCs) confer protective effects against myocardial ischemia/reperfusion (I/R) injury. Exosomes are carriers of potentially protective endogenous molecules, including microRNAs (miRNAs/miRs). The current study set out to test the effects of transferring miR-182-5p from MSC-derived exosomes into myocardial cells on myocardial I/R injury. First, an I/R mouse model was developed by left anterior descending coronary artery occlusion, and myocardial cells were exposed to hypoxia/reoxygenation (H/R) for in vitro I/R model establishment. Loss- and gain-of-function experiments of miR-182-5p and GSDMD were conducted to explore the effects of miR-182-5p via MSC-derived exosomes on cell pyroptosis and viability. GSDMD was robustly expressed in I/R-injured myocardial tissues and H/R-exposed myocardial cells. GSDMD upregulation promoted H/R-induced myocardial cell pyroptosis and reduced viability, corresponding to increased lactate dehydrogenase release, reactive oxygen species production, and pyroptosis. A luciferase assay demonstrated GSDMD as a target of miR-182-5p. In addition, exosomal miR-182-5p was found to diminish GSDMD-dependent cell pyroptosis and inflammation induced by H/R. Furthermore, MSC-derived exosomes carrying miR-182-5p improved cardiac function and reduced myocardial infarction, accompanied with reduced inflammation and cell pyroptosis in vivo. Taken together, our findings suggest a cardioprotective effect of exosomal miR-182-5p against myocardial I/R injury, shedding light on an attractive therapeutic strategy.
SNORD1C maintains stemness and 5-FU resistance by activation of Wnt signaling pathway in colorectal cancer
Authors: Liu Yonghui , Zhao Chengwen , Wang Guihua , Chen Jing , Ju Shaoqing , Huang Jianfei , Wang Xudong
Published: April 2022

Small nucleolar RNAs (snoRNAs) are a class of non-coding RNAs that play indispensable roles in cancers, including colorectal cancer (CRC). However, the role of SNORD1C in CRC is unclear. In the current study, SNORD1C expression was measured in CRC tissues using quantitative real-time PCR. A series of in vivo and in vitro experiments were performed to examine the functional role of SNORD1C in CRC. Quantitative real-time PCR, western blotting, sphere formation assay, and chemotherapy resistance analysis were conducted to illustrate the SNORD1C molecular mechanism. SNORD1C was upregulated in CRC and that high SNORD1C expression was related to poor prognosis. After knocking down SNORD1C in CRC cell lines, cell proliferation, colony formation, cell migration, and invasion were alleviated, while apoptosis was increased. Transcriptional RNA-sequencing analysis revealed that following SNORD1C knockdown, β-catenin was downregulated, as was the transcription factor TCF7, which inhibited the Wnt/β-catenin pathway. Meanwhile, levels of the stem cell-related factors were reduced, diminishing cell stemness and tumorigenesis. Our findings suggest that SNORD1C functions via the Wnt/β-catenin pathway to enhance cancer cell stemness in CRC and could be a predictive biomarker for the prognosis ad aggressiveness of this malignancy. Additionally, targeting SNORD1C may be a novel therapeutic strategy for CRC.
Persistent ferroptosis promotes cervical squamous intraepithelial lesion development and oncogenesis by regulating KRAS expression in patients with high risk-HPV infection
Authors: Wang Tianming , Gong Min , Cao Yuting , Zhao Chengcheng , Lu Yingfei , Zhou Yu , Yao Shasha , Chen Jianquan , Zhao Chun , Ju Rong
Published: April 2022

Cervical squamous cell carcinoma (CSCC) is a type of female cancer that affects millions of families worldwide. Human papillomavirus (HPV) infection is the main reason for CSCC formation, and squamous intraepithelial lesions (SILs) induced by high-risk HPV (HR-HPV) infection are considered precancerous lesions. A previous study reported that HPV-infected cancer cells were able to counteract lipid peroxidation for survival. Recent research has reported that ferroptosis acts in an iron-dependent lipid peroxidation manner to kill cancer cells, and it is proposed as a new approach for female cancer therapy. Here, we investigated the role of ferroptosis throughout SIL development into CSCC. We found that ferroptosis occurred in SIL, but anti-ferroptosis emerged in CSCC. Our data further indicated that an antiferroptotic effect was formed in response to persistent ferroptosis and then promoted oncogenesis. Altogether, we provide novel insight into ferroptosis in cervical SIL development and suggest a potential therapeutic target for the treatment of CSCC.
CDP-ribitol prodrug treatment ameliorates ISPD-deficient muscular dystrophy mouse model
Authors: Tokuoka Hideki , Imae Rieko , Nakashima Hitomi , Manya Hiroshi , Masuda Chiaki , Hoshino Shunsuke , Kobayashi Kazuhiro , Lefeber Dirk J. , Matsumoto Riki , Okada Takashi , Endo Tamao , Kanagawa Motoi , Toda Tatsushi
Published: April 2022

Ribitol-phosphate modification is crucial for the functional maturation of α-dystroglycan. Its dysfunction is associated with muscular dystrophy, cardiomyopathy, and central nervous system abnormalities; however, no effective treatments are currently available for diseases caused by ribitol-phosphate defects. In this study, we demonstrate that prodrug treatments can ameliorate muscular dystrophy caused by defects in isoprenoid synthase domain containing (ISPD), which encodes an enzyme that synthesizes CDP-ribitol, a donor substrate for ribitol-phosphate modification. We generated skeletal muscle-selective Ispd conditional knockout mice, leading to a pathogenic reduction in CDP-ribitol levels, abnormal glycosylation of α-dystroglycan, and severe muscular dystrophy. Adeno-associated virus-mediated gene replacement experiments suggested that the recovery of CDP-ribitol levels rescues the ISPD-deficient pathology. As a prodrug treatment strategy, we developed a series of membrane-permeable CDP-ribitol derivatives, among which tetraacetylated CDP-ribitol ameliorated the dystrophic pathology. In addition, the prodrug successfully rescued abnormal α-dystroglycan glycosylation in patient fibroblasts. Consequently, our findings provide proof-of-concept for supplementation therapy with CDP-ribitol and could accelerate the development of therapeutic agents for muscular dystrophy and other diseases caused by glycosylation defects.
Non-metallic T2-MRI agents based on conjugated polymers
Authors: Lin Qinrui , Yang Yuhong , Shao Zhengzhong
Published: April 2022

Developing non-metallic contrast agents of clinically applied magnetic resonance imaging (MRI) is an alternative strategy to reduce the toxicity of heavy metal elements in current MRI agents. These non-metallic MRI agents usually generate contrasts by unpaired electrons, which are prone to be deactivated by in vivo radical scavenging pathways. Since the unpaired electrons in conjugated polymers exhibit satisfying stability for in vivo imaging, developing conjugated polymers based MRI agents may solve the in vivo stability problem of current non-metallic agents. However, MRI-active properties have not been reported in existing conjugated polymers yet. Herein we report on MRI-active conjugated polymer nanoparticles based on polypyrrole (PPy), which can be used for in vivo imaging. Our method not only introduce a kind of non-metallic MRI agents but extends the applications of conjugated polymers from optical imagings to MRI.
Proteolysis of adaptor protein Mmr1 during budding is necessary for mitochondrial homeostasis in Saccharomyces cerevisiae
Authors: Obara Keisuke , Yoshikawa Taku , Yamaguchi Ryu , Kuwata Keiko , Nakatsukasa Kunio , Nishimura Kohei , Kamura Takumi
Published: April 2022

In yeast, mitochondria are passed on to daughter cells via the actin cable, motor protein Myo2, and adaptor protein Mmr1. They are released from the actin-myosin machinery after reaching the daughter cells. We report that Mmr1 is rapidly degraded by the ubiquitin-proteasome system in Saccharomyces cerevisiae. Redundant ubiquitin ligases Dma1 and Dma2 are responsible for Mmr1 ubiquitination. Dma1/2-mediated Mmr1 ubiquitination requires phosphorylation, most likely at S414 residue by Ste20 and Cla4. These kinases are mostly localized to the growing bud and nearly absent from mother cells, ensuring phosphorylation and ubiquitination of Mmr1 after the mitochondria enter the growing bud. In dma1Δ dma2Δ cells, transported mitochondria are first stacked at the bud-tip and then pulled back to the bud-neck. Stacked mitochondria in dma1Δ dma2Δ cells exhibit abnormal morphology, elevated respiratory activity, and increased level of reactive oxygen species, along with hypersensitivity to oxidative stresses. Collectively, spatiotemporally-regulated Mmr1 turnover guarantees mitochondrial homeostasis.
Differences in RNA polymerase II complexes and their interactions with surrounding chromatin on human and cytomegalovirus genomes
Authors: Spector Benjamin M. , Parida Mrutyunjaya , Li Ming , Ball Christopher B. , Meier Jeffery L. , Luse Donal S. , Price David H.
Published: April 2022

Interactions of the RNA polymerase II (Pol II) preinitiation complex (PIC) and paused early elongation complexes with the first downstream (+1) nucleosome are thought to be functionally important. However, current methods are limited for investigating these relationships, both for cellular chromatin and the human cytomegalovirus (HCMV) genome. Digestion with human DNA fragmentation factor (DFF) before immunoprecipitation (DFF-ChIP) precisely revealed both similarities and major differences in PICs driven by TBP on the host genome in comparison with PICs driven by TBP or the viral-specific, late initiation factor UL87 on the viral genome. Host PICs and paused Pol II complexes are frequently found in contact with the +1 nucleosome and paused Pol II can also be found in a complex involved in the initial invasion of the +1 nucleosome. In contrast, viral transcription complexes have very limited nucleosomal interactions, reflecting a relative lack of chromatinization of transcriptionally active regions of HCMV genomes.
Inactivation of various variant types of SARS-CoV-2 by indoor-light-sensitive TiO2-based photocatalyst
Authors: Nakano Ryuichi , Yamaguchi Akira , Sunada Kayano , Nagai Takeshi , Nakano Akiyo , Suzuki Yuki , Yano Hisakazu , Ishiguro Hitoshi , Miyauchi Masahiro
Published: April 2022

Photocatalysts are promising materials for solid-state antiviral coatings to protect against the spread of pandemic coronavirus disease (COVID-19). This paper reports that copper oxide nanoclusters grafted with titanium dioxide (CuxO/TiO2) inactivated the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, including its Delta variant, even under dark condition, and further inactivated it under illumination with a white fluorescent bulb. To investigate its inactivation mechanism, the denaturation of spike proteins of SARS-CoV-2 was examined by sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS-PAGE) and enzyme-linked immunosorbent assay (ELISA). In addition to spike proteins, fragmentation of ribonucleic acids in SARS-CoV-2 was investigated by real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR). As a result, both spike proteins and RNAs in the SARS-CoV-2 virus were damaged by the CuxO/TiO2 photocatalyst even under dark condition and were further damaged under white fluorescent bulb illumination. Based on the present antiviral mechanism, the CuxO/TiO2 photocatalyst will be effective in inactivating other potential mutant strains of SARS-CoV-2. The CuxO/TiO2 photocatalyst can thus be used to reduce the infectious risk of COVID-19 in an indoor environment, where light illumination is turned on during the day and off during the night.
Rear 4-min Schirmer test, a modified indicator of Schirmer test in diagnosing dry eye
Authors: Wang Xin , Fan Xiaojing , Wu Yaying , Mou Yujie , Min Jinjin , Jin Xiuming
Published: April 2022

This study aims to investigate the reliability and efficacy of rear 4-min Schirmer test, as a supplement indicator, in assessing tear secretion and diagnosing dry eye. 180 participants were enrolled in this study. Schirmer test I without anaesthesia was performed once on both eyes to determine the value of normal Schirmer test. The values of tear secretion were recorded at each minute. Other examinations included the following: the ocular surface disease index (OSDI), the standard patient evaluation of eye dryness (SPEED), fluorescein stain, tear film break-up time (BUT), and Meibomian gland (MG) secretion grading. The participants were divided into dry eye (DE) group and non-dry eye (ND) group. The values of the 2-min Schirmer test, rear 3-min Schirmer test, rear 4-min Schirmer test, and 5-min Schirmer test were 5.36 ± 4.63, 5.57 ± 2.11, 7.21 ± 4.13, and 10.93 ± 6.30, respectively, in the DE group. These indicators were 8.25 ± 6.80, 2.73 ± 2.31, 7.36 ± 3.42, and 11.84 ± 6.16, respectively, in the ND group. The rear 4-min Schirmer test had a significant correlation with OSDI and SPEED in the DE group (r =  − 0.242/ − 0.183) and in the ND group (r =  − 0.316/ − 0.373). Meanwhile, the rear 4-min Schirmer test had a stronger connection with fBUT (r = 0.159) and MG secretion (r =  − 0.162) in the DE group and also had higher accuracy in diagnosing severe DE and borderline DE. In conclusion, the rear 4-min Schirmer test may be a supplement indicator in assessing tear secretion and diagnosing DE.
A new principle of pulse detection based on terahertz wave plethysmography
Authors: Rong Yu , Theofanopoulos Panagiotis C. , Trichopoulos Georgios C. , Bliss Daniel W.
Published: April 2022

This study presents findings in the terahertz (THz) frequency spectrum for non-contact cardiac sensing applications. Cardiac pulse information is simultaneously extracted using THz waves based on the established principles in electronics and optics. The first fundamental principle is micro-Doppler motion effect. This motion based method, primarily using coherent phase information from the radar receiver, has been widely exploited in microwave frequency bands and has recently found popularity in millimeter waves (mmWave) for breathe rate and heart rate detection. The second fundamental principle is reflectance based optical measurement using infrared or visible light. The variation in the light reflection is proportional to the volumetric change of the heart, often referred as photoplethysmography (PPG). Herein, we introduce the concept of terahertz-wave-plethysmography (TPG), which detects blood volume changes in the upper dermis tissue layer by measuring the reflectance of THz waves, similar to the existing remote PPG (rPPG) principle. The TPG principle is justified by scientific deduction, electromagnetic wave simulations and carefully designed experimental demonstrations. Additionally, pulse measurements from various peripheral body parts of interest (BOI), palm, inner elbow, temple, fingertip and forehead, are demonstrated using a wideband THz sensing system developed by the Terahertz Electronics Lab at Arizona State University, Tempe. Among the BOIs under test, it is found that the measurements from forehead BOI gives the best accuracy with mean heart rate (HR) estimation error 1.51 beats per minute (BPM) and standard deviation 1.08 BPM. The results validate the feasibility of TPG for direct pulse monitoring. A comparative study on pulse sensitivity is conducted between TPG and rPPG. The results indicate that the TPG contains more pulsatile information from the forehead BOI than that in the rPPG signals in regular office lighting condition and thus generate better heart rate estimation statistic in the form of empirical cumulative distribution function of HR estimation error. Last but not least, TPG penetrability test for covered skin is demonstrated using two types of garment materials commonly used in daily life.
HiIDDD: a high-throughput imaging pipeline for the quantitative detection of DNA damage in primary human immune cells
Authors: Gallant Kelsey , Bektas Arsun , Kaileh Mary , Lustig Ana , Ferrucci Luigi , Pegoraro Gianluca , Misteli Tom
Published: April 2022

DNA damage is a prominent biomarker for numerous diseases, including cancer, as well as for the aging process. Detection of DNA damage routinely relies on traditional microscopy or cytometric methods. However, these techniques are typically of limited throughput and are not ideally suited for large-scale longitudinal and population studies that require analysis of large sample sets. We have developed HiIDDD (High-throughput Immune cell DNA Damage Detection), a robust, quantitative and single-cell assay that measures DNA damage by high-throughput imaging using the two major DNA damage markers 53BP1 and $$\upgamma$$
γ
-H2AX. We demonstrate sensitive detection with low inter-assay variability of DNA damage in various types of freshly isolated and cryopreserved primary human immune cells, including CD4 + and CD8 + T cells, B cells and monocytes. As proof of principle, we demonstrate parallel batch processing of several immune cell types from multiple donors. We find common patterns of DNA damage in multiple immune cell types of donors of varying ages, suggesting that immune cell properties are specific to individuals. These results establish a novel high-throughput assay for the evaluation of DNA damage in large-scale studies.
An activation specific anti-Mac-1 designed ankyrin repeat protein improves survival in a mouse model of acute lung injury
Authors: Siegel Patrick M. , Przewosnik Anne-Sophie , Wrobel Jan , Heidt Timo , Moser Martin , Peter Karlheinz , Bode Christoph , Diehl Philipp , Bojti István
Published: April 2022

The acute respiratory distress syndrome (ARDS) is a life-threatening clinical condition. The number of ARDS cases has risen dramatically recently but specific treatment options are limited. ARDS is associated with an overshooting inflammatory response and neutrophils play a central role in its pathogenesis. Neutrophils express the integrin Mac-1 on their surface which adopts a resting and activated conformation depending on leukocyte activation. The aim of this study was to investigate the anti-inflammatory effects of the unique activation-specific anti-Mac-1 DARPin ‘F7’ in a mouse model of ARDS. ARDS was induced by intratracheal lipopolysaccharide (LPS) instillation and the acute (day 1–4) and chronic phase (day 5–10) were studied. After expression and purification, F7, a control DARPin and PBS, were applied daily via the intraperitoneal route. Survival and weight loss were recorded. Histological analysis of lung sections, flow cytometric leukocyte analysis of blood and bronchioalveolar lavage (BALF) were performed. Moreover, protein concentration and cytokine levels were determined in the BALF. Treatment with F7 improved survival and reduced weight loss significantly compared to treatment with the control DARPin or PBS. Neutrophil count in the BALF and peripheral blood were significantly reduced in mice treated with F7. Histology revealed significantly reduced pulmonary inflammation in the F7 treated group. Treatment with DARPin F7 inhibited neutrophil accumulation, reduced signs of local and systemic inflammation and improved survival in a mouse model of ARDS. F7 may be a novel anti-inflammatory drug candidate for the treatment of severe ARDS.
Combined effects of nucleotide-binding domain-like receptor protein 3 polymorphisms and environmental metals exposure on chronic kidney disease
Authors: Hsueh Yu-Mei , Chen Wei-Jen , Lin Ying-Chin , Huang Ya-Li , Shiue Horng-Sheng , Lin Yuh-Feng , Hsieh Ru-Lan , Chen Hsi-Hsien
Published: April 2022

Chronic inflammation is the cause of chronic kidney disease (CKD). The nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome plays a vital role in the inflammation process and is associated with the regulatory effects of NLRP3 gene polymorphisms. This study evaluated the association between NLRP3 gene polymorphisms and CKD, and further explored whether the association of environmental metals with CKD varied by the NLRP3 genotypes. A total of 218 CKD patients and 427 age- and sex-matched healthy controls were recruited in this clinic-based case–control study. Patients were identified as having CKD if their estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 and stage 3–5 for at least 3 months. We examined the genotypes of fifteen common ssingle-nucleotide polymorphisms in NLRP3 genes. Concentrations of total urinary arsenic were examined by summing of urinary inorganic arsenic species. Concentrations of selenium, cadmium, and lead were measured from blood samples. Associations between NLRP3 polymorphisms, environmental metals exposure, and CKD were evaluated using multivariable logistic regression while controlling for confounders. We observed that the odds of carrying NLRP3 rs4925650 GA/AA genotypes, NLRP3 rs1539019 CA/AA genotypes, and NLRP3 rs10157379 CT/TT genotypes were significantly higher among CKD cases compared to controls, with the adjusted odds ratio (95% confidence interval) were 1.54 (1.01–2.36), 1.56 (1.04–2.33), and 1.59 (1.05–2.38), respectively. The significant multiplicative interactions were identified between high levels of blood lead and NLRP3 rs4925650 GA/AA genotypes; high levels of blood cadmium or low levels of plasma selenium and the NLRP3 haplotype (rs4925648, rs4925650, rs12048215, and rs10754555) C-A-A-C multiplicatively interacted to increase the risk of CKD. Our results imply that NLRP3 polymorphisms may play an important role in the development of environmental metals exposure related CKD.
Dynamics of laser-induced tunable focusing in silicon
Authors: Shabairou Nadav , Tiferet Maor , Zalevsky Zeev , Sinvani Moshe
Published: April 2022

We report here on focusing of a probe IR (λ = 1.55 μm) laser beam in silicon. The focusing is done by a second pump laser beam, at λ = 0.775 μm and 30 ps pulse width, with a donut shape that is launched collinearly and simultaneously (with some delay time) with the IR beam pulse. The pump beam pulse is absorbed in the silicon and creates, temporally, a free charge carriers (FCCs) donut pattern in the silicon. Following the plasma dispersion effect, the donut FCCs shapes a complex index of refraction pattern in the silicon that serves as a sort of dynamic GRIN lens for the probe beam due to the diffusion of the FCCs towards the donut center. This lens can be tuned to its focal point by the pump-probe delay time to reduce the point spread function (PSF) of the IR probe beam. We start seeing the focusing of the probe beam at pump-probe delay time of $$\mathrm{\Delta t }\approx 100\mathrm{ ps}$$

Δ
t

≈
100
ps

. The best focusing (results in PSF $$< 2\mathrm{ \mu m}$$

<
2

μ
m

) was observed at $$\mathrm{\Delta t}\approx 350\mathrm{ ps}$$

Δ
t

≈
350
ps

and it slowly degrades before the FCCs full recombination at $$\mathrm{\Delta t }\sim 12\mathrm{ ns}$$

Δ
t

∼
12
ns

. We propose this beam shaping method to overcome the diffraction resolution limit in silicon microscopy on and deep under the silicon surface dependent on the pump wavelength and the pulse width. We also proposed this technique for direct measurement of the FCCs dynamics.