bluuebunny/crossref_metadata_2025 huggingface dataset:
Two-Dimensional Profile Simulation Model for Five-Axis CNC Machining with Bull-Nose Cutter
Authors: Dong Jieshi , Chang Zhiyong , Chen Peng , He Jinming , Wan Neng
Published: August 2022

Surface topography is closely related to fatigue strength and mating accuracy of workpieces. The profile method is widely adopted to evaluate surface topography. In the present study, a 2D profile simulation model of five-axis CNC machining with a bull-nose cutter is proposed to predict the surface topography of a machined workpiece. To this end, a simplified scallop model is established by analyzing the geometry and motion of the bull-nose cutter. Then, the principles of the 2D profile simulation model for plane and free-form surfaces are described to provide the basis for building 2D profile simulation models. After that, 2D profiles are obtained directly from CL data, tool parameters, and workpiece design models, and an algorithm is proposed to obtain 2D profiles. Finally, the proposed algorithm is verified by different machining experiments on plane and free-form surfaces. The results show that the simulation and measurement results are in good agreement. The proposed simulation model for five-axis CNC machining with a bull-nose cutter can be effectively applied to simulate 2D profiles of plane and free-form surfaces. The present study is expected to provide a reference for optimizing process parameters.
Efficient Gene Transfection by Electroporation—In Vitro and In Silico Study of Pulse Parameters
Authors: Potočnik Tjaša , Sachdev Shaurya , Polajžer Tamara , Maček Lebar Alenka , Miklavčič Damijan
Published: August 2022

Gene electrotransfer (GET) is a widely used method for nucleic acids’ delivery into cells. We explored, evaluated, and demonstrated the potential use of different pulse durations for introducing plasmid DNA (pDNA) into cells in vitro and compared the efficiency and dynamics of transgene expression after GET. We performed experiments on cell suspensions of 1306 fibroblasts and C2C12 myoblasts with four ranges of pulse durations (nanosecond, high frequency bipolar (HF-BP), and micro- and millisecond). Six different concentrations of pDNA encoding green fluorescent protein were used. We show that GET can be achieved with nanosecond pulses with a low pulse repetition rate (10 Hz). The GET’s efficiency depends on the pDNA concentration and cell line. Time dynamics of transgene expression are comparable between millisecond, microsecond, HF-BP, and nanosecond pulses but depend greatly on cell line. Lastly, based on the data obtained in the experiments of pDNA concentration effect on GET the model of the probability of pDNA and cell membrane contact during GET was developed. The model shows that pDNA migration is dominated by diffusion for nanosecond and HF-BP pulses and by electrophoresis for micro- and millisecond pulses. Modeling results can provide valuable guidance for further experiments and interpretations of the results obtained by various pulse protocols.
Unsupervised Classification of Human Activity with Hidden Semi-Markov Models
Authors: Cavallo Francesca Romana , Toumazou Christofer , Nikolic Konstantin
Published: August 2022

The modern sedentary lifestyle is negatively influencing human health, and the current guidelines recommend at least 150 min of moderate activity per week. However, the challenge is how to measure human activity in a practical way. While accelerometers are the most common tools to measure activity, current activity classification methods require calibration studies or labelled datasets—requirements that slow the research progress. Therefore, there is a pressing need to classify and quantify human activity efficiently. In this work, we propose an unsupervised approach to classify activities from accelerometer data using hidden semi-Markov models. We tune and infer the model parameters on accelerometer data from the UK Biobank and select the optimal model based on features used and informativeness of the prior. The best model achieves an average correlation of 0.4 between the inferred activities and the reference ones, with the overall physical activity obtaining a correlation of 0.8. Additionally, to prove the clinical significance of the method, we validate it by performing a linear regression between the inferred activities and anthropometric measures such as BMI and waist circumference. We show that for a sedentary behaviour and total physical activity, the proposed method achieves comparable regression coefficients to the reference labelled dataset. Moreover, the proposed method achieves a good agreement with a labelled dataset for daily time spent in a sedentary behaviour and total physical activity. The unsupervised nature of the method allows for a data-driven classification that does not require calibration studies or labelled datasets and can thus facilitate both clinical research as well as lifestyle recommendations.
Radiological Atmospheric Risk Modelling of NORM Repositories in Hungary
Authors: Csordás Anita , Shahrokhi Amin , Tóth Gergely , Kovács Tibor
Published: August 2022

The human population is continuously exposed to natural radionuclides in environmental elements. The concentration of these nuclides is usually low, but different technological processes and activities can concentrate them in products, by-products, or wastes. These activities are, for example, coal mining, fertilizer production, ore mining, metal production, etc. These materials are labelled as NORM (Naturally Occurring Radioactive Material). The most common method of disposal for NORMs is deposition in different types of depositories. The long-term effects of these depositories on the environment and on human health are hard to estimate. The aim of the study is to assess radiation risk from the five selected NORM depositories (Ajka coal ash, Ajka red mud, Almásfüzitő red mud, Zalatárnok drilling mud, and Úrkút manganese residue) for members of the public and biota. The radionuclide concentrations were determined by HPGe gamma-spectrometry. The measured concentration was between 31 Bq/kg and 1997 Bq/kg for Ra-226, between 33 Bq/kg and 283 Bq/kg for Th-232, and between 48 Bq/kg and 607 Bq/kg for K-40. The dose estimation was investigated using RESRAD-ONSITE and RESRAD BIOTA, which are computer codes developed by the Argonne National Laboratory (USA). RESRAD-ONSITE can estimate the radiation risk from the radionuclides in the contaminated sites. The highest dose was observed in the case of the Ajka coal ash depository–without cover (12.38 mSv/y), and the lowest was in the case of Zalatárnok (0.53 mSv/y). The most significant contributors to the population dose are the uptakes through plants and external pathways, which account for more than 80% of the total dose on average. RESRAD-BIOTA code was used to estimate the radiation exposure of terrestrial organisms (plants and animals). During this work, the values of sum ratio factor (SRF), biota concentration guide (BCG), external dose, internal dose, and total dose were determined.
Climatology of Different Classifications of Tropical Cyclones Landfalling in Guangdong Province of China during 1951–2020
Authors: Zhang Shuqin , Zheng Yanzhu , Liu Chunlei , Huang Zhefan , Weng Hanwei , Xu Jianjun , Tu Shifei
Published: August 2022

The climatology of different classifications (based on the intensity at the landfall time) of tropical cyclones (TCs) making landfall in Guangdong Province of China during 1951–2020 (70 years) is investigated using the best track data from the China Meteorological Administration and ERA5 reanalysis data. There were 234 TCs making landfall in Guangdong Province, with more severe tropical storms (STSs, 30.8%) and typhoons (TYs, 27.3%), and less tropical depressions (TDs, 19.7%) and tropical storms (TSs, 22.2%) during the past 70 years. The frequency of the landfall TCs had a significant interannual oscillation of 2–5 years. Landfall TCs generated over the western North Pacific (WNP) were usually more and stronger than those generated over the South China Sea (SCS). The TCs generated over the WNP had longer lifetime duration and shorter on-land duration than those generated over the SCS. TCs making landfall in western Guangdong were the most, followed by central Guangdong and eastern Guangdong. The composite analysis using TC-relative coordinates indicated that the precipitation of different classifications of TCs making landfall in Guangdong Province was asymmetric, which was stronger in the south of the TC center. The position of the maximum precipitation showed a cyclonic rotation around the TC center with increasing TC intensity. Generally, the vertical velocity, moisture flux, warm core, and vertical wind shear enhanced with the increasing landfall TC intensity. The vertical velocity and moisture flux of different classifications of TCs also showed an asymmetric structure related to the distribution of TC precipitation. TSs, STSs, and TYs had a double warm-core configuration. The precipitation of the TDs and TSs usually occurred over the down-shear of average vertical wind shear, those of the STSs and TYs over the left-of-shear.
Numerical Simulation of a Typical Convective Precipitation and Its Cloud Microphysical Process in the Yushu Area, Based on the WRF Model
Authors: He Minghao , Zhang Shaobo , Yang Xianyu , Yin Shucheng
Published: August 2022

Cloud microphysical processes significantly impact the time variation and intensity of precipitation. However, due to the high altitude of the Tibetan Plateau (TP) and the lack of observational data, the understanding of cloud microphysical processes on the TP is relatively insufficient, affecting the accuracy of precipitation simulations around the TP. To further reveal the characteristics of convective precipitation and cloud microphysical structure over the TP, the mesoscale numerical model, WRF, and various observational data were used to simulate and evaluate typical convective precipitation in the Yushu area, which was recorded from 11 to 12 August 2020. The results showed that the combination of the Lin scheme in the WRF model could effectively reproduce this case’s characteristics and evolution process. In the simulation process, the particles of each phase were distributed at different altitudes, and their mass and density over time reflected the characteristics of surface precipitation changes. Among the particles mentioned above, rainwater contributed the most to the initiation and growth of graupel particles. Further research established that the initiation of graupel was mainly affected by the freezing effect of rainwater and cloud ice, while the growth of graupel was influenced primarily by the collision of graupel particles and rainwater. On the whole, from the evolution characteristics of microphysical processes over time, it was found that the ice phase process plays an essential role in this typical convective precipitation.
The Effects of Consuming Amino Acids L-Arginine, L-Citrulline (and Their Combination) as a Beverage or Powder, on Athletic and Physical Performance: A Systematic Review
Authors: Nyawose Siphamandla , Naidoo Rowena , Naumovski Nenad , McKune Andrew J.
Published: August 2022

Consumption of amino acids L-arginine (L-Arg) and L-citrulline (L-Cit) are purported to increase nitric oxide (NO) production and improve physical performance. Clinical trials have shown relatively more favorable outcomes than not after supplementing with L-Cit and combined L-Arg and L-Cit. However, in most studies, other active ingredients such as malate were included in the supplement. Therefore, the aim of this study was to determine the efficacy of consuming standalone L-Arg, L-Cit, and their combination (in the form of powder or beverage) on blood NO level and physical performance markers. A systematic review was undertaken following PRISMA 2020 guidelines (PROSPERO: CRD42021287530). Four electronic databases (PubMed, Ebscohost, Science Direct, and Google scholar) were used. An acute dose of 0.075 g/kg of L-Arg or 6 g L-Arg had no significant increase in NO biomarkers and physical performance markers (p > 0.05). Consumption of 2.4 to 6 g/day of L-Cit over 7 to 16 days significantly increased NO level and physical performance markers (p < 0.05). Combined L-Arg and L-Cit supplementation significantly increased circulating NO, improved performance, and reduced feelings of exertion (p < 0.05). Standalone L-Cit and combined L-Arg with L-Cit consumed over several days effectively increases circulating NO and improves physical performance and feelings of exertion in recreationally active and well-trained athletes.
The Effects of Tamoxifen on Tolerogenic Cells in Cancer
Authors: Mohd Idris Ros Akmal , Mussa Ali , Ahmad Suhana , Al-Hatamleh Mohammad A. I. , Hassan Rosline , Tengku Din Tengku Ahmad Damitri Al Astani , Wan Abdul Rahman Wan Faiziah , Lazim Norhafiza Mat , Boer Jennifer C. , Plebanski Magdalena , Mohamud Rohimah
Published: August 2022

Tamoxifen (TAM) is the most prescribed selective estrogen receptor modulator (SERM) to treat hormone-receptor-positive breast cancer patients and has been used for more than 20 years. Its role as a hormone therapy is well established; however, the potential role in modulating tolerogenic cells needs to be better clarified. Infiltrating tumor-microenvironment-regulatory T cells (TME-Tregs) are important as they serve a suppressive function through the transcription factor Forkhead box P3 (Foxp3). Abundant studies have suggested that Foxp3 regulates the expression of several genes (CTLA-4, PD-1, LAG-3, TIM-3, TIGIT, TNFR2) involved in carcinogenesis to utilize its tumor suppressor function through knockout models. TAM is indirectly concomitant via the Cre/loxP system by allowing nuclear translocation of the fusion protein, excision of the floxed STOP cassette and heritable expression of encoding fluorescent protein in a cohort of cells that express Foxp3. Moreover, TAM administration in breast cancer treatment has shown its effects directly through MDSCs by the enrichment of its leukocyte populations, such as NK and NKT cells, while it impairs the differentiation and activation of DCs. However, the fundamental mechanisms of the reduction of this pool by TAM are unknown. Here, we review the vital effects of TAM on Tregs for a precise mechanistic understanding of cancer immunotherapies.
Putative Protein Discovery from Microalgal Genomes as a Synthetic Biology Protein Library for Heavy Metal Bio-Removal
Authors: Uttarotai Toungporn , Mukjang Nilita , Chaisoung Natcha , Pathom-Aree Wasu , Pekkoh Jeeraporn , Pumas Chayakorn , Sattayawat Pachara
Published: August 2022

Synthetic biology is a principle that aims to create new biological systems with particular functions or to redesign the existing ones through bioengineering. Therefore, this principle is often utilized as a tool to put the knowledge learned to practical use in actual fields. However, there is still a great deal of information remaining to be found, and this limits the possible utilization of synthetic biology, particularly on the topic that is the focus of the present work—heavy metal bio-removal. In this work, we aim to construct a comprehensive library of putative proteins that might support heavy metal bio-removal. Hypothetical proteins were discovered from Chlorella and Scenedesmus genomes and extensively annotated. The protein structures of these putative proteins were also modeled through Alphafold2. Although a portion of this workflow has previously been demonstrated to annotate hypothetical proteins from whole genome sequences, the adaptation of such steps is yet to be done for library construction purposes. We also demonstrated further downstream steps that allow a more accurate function prediction of the hypothetical proteins by subjecting the models generated to structure-based annotation. In conclusion, a total of 72 newly discovered putative proteins were annotated with ready-to-use predicted structures available for further investigation.
Neuraminidases—Key Players in the Inflammatory Response after Pathophysiological Cardiac Stress and Potential New Therapeutic Targets in Cardiac Disease
Authors: Heimerl Maren , Gausepohl Thomas , Mueller Julia H. , Ricke-Hoch Melanie
Published: August 2022

Glycoproteins and glycolipids on the cell surfaces of vertebrates and higher invertebrates contain α-keto acid sugars called sialic acids, terminally attached to their glycan structures. The actual level of sialylation, regulated through enzymatic removal of the latter ones by NEU enzymes, highly affects protein-protein, cell-matrix and cell-cell interactions. Thus, their regulatory features affect a large number of different cell types, including those of the immune system. Research regarding NEUs within heart and vessels provides new insights of their involvement in the development of cardiovascular pathologies and identifies mechanisms on how inhibiting NEU enzymes can have a beneficial effect on cardiac remodelling and on a number of different cardiac diseases including CMs and atherosclerosis. In this regard, a multitude of clinical studies demonstrated the potential of N-acetylneuraminic acid (Neu5Ac) to serve as a biomarker following cardiac diseases. Anti-influenza drugs i.e., zanamivir and oseltamivir are viral NEU inhibitors, thus, they block the enzymatic activity of NEUs. When considering the improvement in cardiac function in several different cardiac disease animal models, which results from NEU reduction, the inhibition of NEU enzymes provides a new potential therapeutic treatment strategy to treat cardiac inflammatory pathologies, and thus, administrate cardioprotection.
The Crystal Structure of the Defense Conferring Rice Protein OsJAC1 Reveals a Carbohydrate Binding Site on the Dirigent-like Domain
Authors: Huwa Nikolai , Weiergräber Oliver H. , Fejzagić Alexander V. , Kirsch Christian , Schaffrath Ulrich , Classen Thomas
Published: August 2022

Pesticides are routinely used to prevent severe losses in agriculture. This practice is under debate because of its potential negative environmental impact and selection of resistances in pathogens. Therefore, the development of disease resistant plants is mandatory. It was shown that the rice (Oryza sativa) protein OsJAC1 enhances resistance against different bacterial and fungal plant pathogens in rice, barley, and wheat. Recently we reported possible carbohydrate interaction partners for both domains of OsJAC1 (a jacalin-related lectin (JRL) and a dirigent (DIR) domain), however, a mechanistic understanding of its function is still lacking. Here, we report crystal structures for both individual domains and the complex of galactobiose with the DIR domain, which revealed a new carbohydrate binding motif for DIR proteins. Docking studies of the two domains led to a model of the full-length protein. Our findings offer insights into structure and binding properties of OsJAC1 and its possible function in pathogen resistance.
Advancing Our Understanding of the Chronically Denervated Schwann Cell: A Potential Therapeutic Target?
Authors: McMorrow Liam A. , Kosalko Adrian , Robinson Daniel , Saiani Alberto , Reid Adam J.
Published: August 2022

Outcomes for patients following major peripheral nerve injury are extremely poor. Despite advanced microsurgical techniques, the recovery of function is limited by an inherently slow rate of axonal regeneration. In particular, a time-dependent deterioration in the ability of the distal stump to support axonal growth is a major determinant to the failure of reinnervation. Schwann cells (SC) are crucial in the orchestration of nerve regeneration; their plasticity permits the adoption of a repair phenotype following nerve injury. The repair SC modulates the initial immune response, directs myelin clearance, provides neurotrophic support and remodels the distal nerve. These functions are critical for regeneration; yet the repair phenotype is unstable in the setting of chronic denervation. This phenotypic instability accounts for the deteriorating regenerative support offered by the distal nerve stump. Over the past 10 years, our understanding of the cellular machinery behind this repair phenotype, in particular the role of c-Jun, has increased exponentially, creating opportunities for therapeutic intervention. This review will cover the activation of the repair phenotype in SC, the effects of chronic denervation on SC and current strategies to ‘hack’ these cellular pathways toward supporting more prolonged periods of neural regeneration.
An Interpretable Machine-Learning Algorithm to Predict Disordered Protein Phase Separation Based on Biophysical Interactions
Authors: Cai Hao , Vernon Robert M. , Forman-Kay Julie D.
Published: August 2022

Protein phase separation is increasingly understood to be an important mechanism of biological organization and biomaterial formation. Intrinsically disordered protein regions (IDRs) are often significant drivers of protein phase separation. A number of protein phase-separation-prediction algorithms are available, with many being specific for particular classes of proteins and others providing results that are not amenable to the interpretation of the contributing biophysical interactions. Here, we describe LLPhyScore, a new predictor of IDR-driven phase separation, based on a broad set of physical interactions or features. LLPhyScore uses sequence-based statistics from the RCSB PDB database of folded structures for these interactions, and is trained on a manually curated set of phase-separation-driving proteins with different negative training sets including the PDB and human proteome. Competitive training for a variety of physical chemical interactions shows the greatest contribution of solvent contacts, disorder, hydrogen bonds, pi–pi contacts, and kinked beta-structures to the score, with electrostatics, cation–pi contacts, and the absence of a helical secondary structure also contributing. LLPhyScore has strong phase-separation-prediction recall statistics and enables a breakdown of the contribution from each physical feature to a sequence’s phase-separation propensity, while recognizing the interdependence of many of these features. The tool should be a valuable resource for guiding experiments and providing hypotheses for protein function in normal and pathological states, as well as for understanding how specificity emerges in defining individual biomolecular condensates.
Cutting-Edge AI Technologies Meet Precision Medicine to Improve Cancer Care
Authors: Lin Peng-Chan , Tsai Yi-Shan , Yeh Yu-Min , Shen Meng-Ru
Published: August 2022

To provide precision medicine for better cancer care, researchers must work on clinical patient data, such as electronic medical records, physiological measurements, biochemistry, computerized tomography scans, digital pathology, and the genetic landscape of cancer tissue. To interpret big biodata in cancer genomics, an operational flow based on artificial intelligence (AI) models and medical management platforms with high-performance computing must be set up for precision cancer genomics in clinical practice. To work in the fast-evolving fields of patient care, clinical diagnostics, and therapeutic services, clinicians must understand the fundamentals of the AI tool approach. Therefore, the present article covers the following four themes: (i) computational prediction of pathogenic variants of cancer susceptibility genes; (ii) AI model for mutational analysis; (iii) single-cell genomics and computational biology; (iv) text mining for identifying gene targets in cancer; and (v) the NVIDIA graphics processing units, DRAGEN field programmable gate arrays systems and AI medical cloud platforms in clinical next-generation sequencing laboratories. Based on AI medical platforms and visualization, large amounts of clinical biodata can be rapidly copied and understood using an AI pipeline. The use of innovative AI technologies can deliver more accurate and rapid cancer therapy targets.
GRP78, a Novel Host Factor for SARS-CoV-2: The Emerging Roles in COVID-19 Related to Metabolic Risk Factors
Authors: Shin Jihoon , Toyoda Shinichiro , Fukuhara Atsunori , Shimomura Iichiro
Published: August 2022

The outbreak of coronavirus disease 19 (COVID-19), caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in an unprecedented amount of infection cases and deaths, leading to the global health crisis. Despite many research efforts, our understanding of COVID-19 remains elusive. Recent studies have suggested that cell surface glucose-regulated protein 78 (GRP78) acts as a host co-receptor for SARS-CoV-2 infection and is related to COVID-19 risks, such as older age, obesity, and diabetes. Given its significance in a wide range of biological processes, such as protein homeostasis and cellular signaling, GRP78 might also play an important role in various stages of the viral life cycle and pathology of SARS-CoV-2. In this perspective, we explore the emerging and potential roles of GRP78 in SARS-CoV-2 infection. Additionally, we discuss the association with COVID-19 risks and symptoms. We hope this review article will be helpful to understand COVID-19 pathology and promote attention and study of GRP78 from many clinical and basic research fields.
Electrochemical Biosensors for Circulating Tumor DNA Detection
Authors: Wang Ke , Peng Zhijia , Lin Xiaogang , Nian Weiqi , Zheng Xiaodong , Wu Jayne
Published: August 2022

Early diagnosis and treatment have always been highly desired in the fight against cancer, and detection of circulating tumor DNA (ctDNA) has recently been touted as highly promising for early cancer-screening. Consequently, the detection of ctDNA in liquid biopsy is gaining much attention in the field of tumor diagnosis and treatment, which has also attracted research interest from industry. However, it is difficult to achieve low-cost, real-time, and portable measurement of ctDNA in traditional gene-detection technology. Electrochemical biosensors have become a highly promising solution to ctDNA detection due to their unique advantages such as high sensitivity, high specificity, low cost, and good portability. Therefore, this review aims to discuss the latest developments in biosensors for minimally invasive, rapid, and real-time ctDNA detection. Various ctDNA sensors are reviewed with respect to their choices of receptor probes, designs of electrodes, detection strategies, preparation of samples, and figures of merit, sorted by type of electrode surface recognition elements. The development of biosensors for the Internet of Things, point-of-care testing, big data, and big health is analyzed, with a focus on their portable, real-time, and non-destructive characteristics.
A Co-Printed Nanoslit Surface Plasmon Resonance Structure in Microfluidic Device for LMP-1 Detection
Authors: Lo Shu-Cheng , Li Shao-Sian , Yang Wen-Fai , Wu Kuang-Chong , Wei Pei-Kuen , Sheen Horn-Jiunn , Fan Yu-Jui
Published: August 2022

This paper reports a novel micro/nanostructure co-hot embossing technique. Gold-capped nanostructures were used as localized surface plasmon resonance (SPR) sensors and were integrated into a microfluidic channel. The advantage of the co-hot embossing technique is that the SPR sensors do not need to be aligned with the microfluidic channel while bonding to it. The integrated SPR sensor and microfluidic channel were first characterized, and the sensitivity of the SPR sensor to the refractive index was found using different concentrations of glycerol solutions. The SPR sensor was also used to quantify latent membrane protein (LMP-1) when modifying anti-LMP-1 at the surface of the SPR sensor. Different concentrations of LMP-1 samples were used to build a calibration curve.
Beneficial Influence of Exendin-4 on Specific Organs and Mechanisms Favourable for the Elderly with Concomitant Obstructive Lung Diseases
Authors: Figat Magdalena , Kardas Grzegorz , Kuna Piotr , Panek Michał
Published: August 2022

Exendin-4 (Ex-4), better known in its synthetic form and used clinically as exenatide, currently applied in the treatment of diabetes, induces a beneficial impact on nerve cells, and shows promising effects in obstructive lung diseases. At an advanced age, the development of the neurodegenerative process of brain tissue is masked by numerous concomitant diseases. The initial latent phase of neurodegenerative disease results in occurrence of manifestations at an advanced stage. To protect the brain and to simultaneously ensure proper treatment of common coexisting conditions in late life, such as diabetes, chronic obstructive pulmonary disease, or asthma, a pleiotropic medication should be chosen. Molecular mechanisms of Ex-4 exert neuroprotective effects or lead to secondary neurogenesis. Additionally, Ex-4 plays an important role in anti-inflammatory actions which are necessary both in the case of asthma and Parkinson’s disease. Specific receptors in the lungs also reduce the secretion of surfactants, which decreases the risk of exacerbation in chronic obstructive lung disease. In a great number of patients suffering from diabetes, asthma, or chronic lung disease, there is a great potential for both treatment of the main condition and protection against brain neurodegeneration.
Novel Targeted Therapies for T-Cell Malignancies
Authors: Tesio Melania
Published: August 2022

T-cell malignancies comprise a heterogeneous group of cancers resulting from the clonal expansion of T-cells at different developmental stages [...]
Characteristics, Treatments, and Survival of Uveal Melanoma: A Comparison between Chinese and American Cohorts
Authors: Luo Jingting , Zhang Chengkai , Yang Yuhang , Xiu Jingying , Zhao Hanqing , Liang Chuqiao , Feng Zhaoxun , Chen Yuning , Liu Yueming , Li Yang , Wei Wenbin
Published: August 2022

Uveal melanoma (UM) is the most common intraocular malignant carcinoma. This study aimed to compare the clinical features, treatment modalities, and prognosis of UM patients in China with those in America over a 15-year period. In the study, 4088 American patients with primary UM from the Surveillance, Epidemiology, and End Results (SEER) database and 1508 Chinese patients from Tongren-ophthalmology Research Association of Clinical Evaluation (TRACE) were included. Univariable and multivariable analyses were performed to determine prognostic factors and propensity score matching (PSM) and sensitivity analyses were applied to adjust for confounders and identify independent prognostic factors. Chinese patients were diagnosed at a younger age (mean ± SD, 47.3 ± 12.5 years vs. 59.7 ± 14.8 years) and tumors at diagnosis were larger (diameter: 12.0 ± 3.54 mm vs. 11.3 ± 8.27 mm; thickness: 7.13 ± 3.28 mm vs. 4.91 ± 3.01 mm). Chinese patients were more likely to undergo brachytherapy than American patients. Chinese patients had better overall survival than American patients while no significant differences exhibited after adjusting for age through PSM. In conclusion, compared with American patients, Chinese patients had younger onset age, larger tumors at diagnosis and better prognosis, mainly because of their younger age.
Significance of Dermoscopy in Association with Clinical Features in Differentiation of Basal Cell Carcinoma and Benign Trichoblastic Tumours
Authors: Sławińska Martyna , Płaszczyńska Anna , Lakomy Joanna , Pastuszak Krzysztof , Biernat Wojciech , Sikorska Monika , Nowicki Roman J. , Sobjanek Michał
Published: August 2022

Background: Although basal cell carcinoma (BCC) can, in the majority of cases, be diagnosed based on clinical and dermoscopic assessment, a potential overlap with benign adnexal skin tumours seems to exist, including trichoblastic tumours (TT). Methods: Retrospective analysis of clinical and dermoscopic features of benign TT and BCC cases was performed to develop a diagnostic algorithm with a potential utility in clinical practice. Results: In the study, 502 histopathologically confirmed BCC cases were compared with 61 TT (including 44 TB (72.13%), 10 TE (16.39%) and 7 DTE (11.48%]). Patients in the BCC group were statistically older (mean age was 71.4 vs. 64.4 years, respectively; p = 0.009). BCC presented generally as larger tumours (mean tumour size 11.0 vs. 8.2 mm for the TT group; p = 0.001) and was more frequently associated with clinically visible ulceration (59.4% vs. 19.7%, respectively; p < 0.001). Comparison of lesion morphology, clinically visible pigmentation, and anatomical location did not show significant differences between the analysed groups. Dermoscopically visible ulceration was significantly more common in the BCC group compared to the TT group (52.2% vs. 14.8%; p < 0.0001). Pigmented structures, specifically brown dots and brown globules, were significantly more prevalent in the TT group (32.8% vs. 11.4%; p = 0.0001 and 29.5% vs. 8.2%; p <0.0001). Similarly, TT more commonly than BCC showed the presence of cloudy/starry milia-like cysts (26.2% vs. 11.6%; p = 0.0031) and yellow globules (16.4% vs. 7.2%; p = 0.033). Conclusions: Despite differences in frequency of clinical and dermoscopic features between BCC and TT in the studied group, differential diagnosis based on these variables is not reliable. Histopathological examination remains a diagnostic gold standard in differentiation of BCC and TT.
Recent Advances and Challenges in Cancer Immunotherapy
Authors: Peterson Chelsea , Denlinger Nathan , Yang Yiping
Published: August 2022

Cancer immunotherapy has revolutionized the field of oncology in recent years. Harnessing the immune system to treat cancer has led to a large growth in the number of novel immunotherapeutic strategies, including immune checkpoint inhibition, chimeric antigen receptor T-cell therapy and cancer vaccination. In this review, we will discuss the current landscape of immuno-oncology research, with a focus on elements that influence immunotherapeutic outcomes. We will also highlight recent advances in basic aspects of tumor immunology, in particular, the role of the immunosuppressive cells within the tumor microenvironment in regulating antitumor immunity. Lastly, we will discuss how the understanding of basic tumor immunology can lead to the development of new immunotherapeutic strategies.
Multi-Omic Analysis of Two Common P53 Mutations: Proteins Regulated by Mutated P53 as Potential Targets for Immunotherapy
Authors: Vadakekolathu Jayakumar , Boocock David J. , Pandey Kirti , Guinn Barbara-ann , Legrand Antoine , Miles Amanda K. , Coveney Clare , Ayala Rochelle , Purcell Anthony W. , McArdle Stephanie E.
Published: August 2022

The p53 protein is mutated in more than 50% of human cancers. Mutated p53 proteins not only lose their normal function but often acquire novel oncogenic functions, a phenomenon termed mutant p53 gain-of-function. Mutant p53 has been shown to affect the transcription of a range of genes, as well as protein–protein interactions with transcription factors and other effectors; however, no one has intensively investigated and identified these proteins, or their MHC presented epitopes, from the viewpoint of their ability to act as targets for immunotherapeutic interventions. We investigated the molecular changes that occurred after the TP53 null osteosarcoma cells, SaOS-2, were transfected with one of two conformational p53-mutants, either R175H or R273H. We then examined the phenotypic and functional changes using macroscopic observations, proliferation, gene expression and proteomics alongside immunopeptidome profiling of peptide antigen presentation in the context of major histocompatibility complex (MHC) class I molecules. We identified several candidate proteins in both TP53 mutant cell lines with differential expression when compared to the TP53 null vector control, SaOS-V. Quantitative SWATH proteomics combined with immune-peptidome analysis of the class-I eluted peptides identified several epitopes presented on pMHC and in silico analysis shortlisted which antigens were expressed in a range of cancerous but not adjacent healthy tissues. Out of all the candidates, KLC1 and TOP2A showed high levels of expression in every tumor type examined. From these proteins, three A2 and four pan HLA-A epitopes were identified in both R175H and R273H from TOP2A. We have now provided a short list of future immunotherapy targets for the treatment of cancers harboring mutated TP53.
Skin-Aging Pigmentation: Who Is the Real Enemy?
Authors: Kim Jin Cheol , Park Tae Jun , Kang Hee Young
Published: August 2022

Skin aging is induced and sustained by chronological aging and photoaging. Aging skin pigmentation such as mottled pigmentation (senile lentigo) and melasma are typical signs of photoaging. The skin, like other human organs, undergoes cellular senescence, and senescent cells in the skin increase with age. The crosstalk between melanocytes as pigmentary cells and other adjacent types of aged skin cells such as senescent fibroblasts play a role in skin-aging pigmentation. In this review, we provide an overview of cellular senescence during the skin-aging process. The discussion also includes cellular senescence related to skin-aging pigmentation and the therapeutic potential of regulating the senescence process.
Centella asiatica-Derived Endothelial Paracrine Restores Epithelial Barrier Dysfunction in Radiation-Induced Enteritis
Authors: Kwak Seo Young , Jang Won Il , Lee Seung Bum , Kim Min-Jung , Park Sunhoo , Cho Sang Sik , Kim Hyewon , Lee Sun-Joo , Shim Sehwan , Jang Hyosun
Published: August 2022

Radiation-induced enteritis is frequently observed following radiotherapy for cancer or occurs due to radiation exposure in a nuclear accident. The loss of the epithelial integrity leads to ‘leaky gut’, so recovery of damaged epithelium is an important strategy in therapeutic trials. Centella asiatica (CA), a traditional herbal medicine, is widely used for wound healing by protecting against endothelial damage. In this study, we investigated the radio-mitigating effect of CA, focusing on the crosstalk between endothelial and epithelial cells. CA treatment relieved radiation-induced endothelial dysfunction and mitigated radiation-induced enteritis. In particular, treatment of the conditioned media from CA-treated irradiated endothelial cells recovered radiation-induced epithelial barrier damage. We also determined that epidermal growth factor (EGF) is a critical factor secreted by CA-treated irradiated endothelial cells. Treatment with EGF effectively improved the radiation-induced epithelial barrier dysfunction. We also identified the therapeutic effects of CA-induced endothelial paracrine in a radiation-induced enteritis mouse model with epithelial barrier restoration. Otherwise, CA treatment did not show radioprotective effects on colorectal tumors in vivo. We showed therapeutic effects of CA on radiation-induced enteritis, with the recovery of endothelial and epithelial dysfunction. Thus, our findings suggest that CA is an effective radio-mitigator against radiation-induced enteritis.
A Genomic BSAseq Approach for the Characterization of QTLs Underlying Resistance to Fusarium oxysporum in Eggplant
Authors: Tassone Maria Rosaria , Bagnaresi Paolo , Desiderio Francesca , Bassolino Laura , Barchi Lorenzo , Florio Francesco Elia , Sunseri Francesco , Sirangelo Tiziana Maria , Rotino Giuseppe Leonardo , Toppino Laura
Published: August 2022

Eggplant (Solanum melongena L.), similar to many other crops, suffers from soil-borne diseases, including Fusarium oxysporum f. sp. melongenae (Fom), causing wilting and heavy yield loss. To date, the genetic factors underlying plant responses to Fom are not well known. We previously developed a Recombinant Inbred Lines (RILs) population using as a female parent the fully resistant line ‘305E40’ and as a male parent the partially resistant line ‘67/3’. The fully resistant trait to Fom was introgressed from the allied species S. aethiopicum. In this work, the RIL population was assessed for the responses to Fom and by using a genomic mapping approach, two major QTLs on chromosomes CH02 and CH11 were identified, associated with the full and partial resistance trait to Fom, respectively. A targeted BSAseq procedure in which Illumina reads bulks of RILs grouped according to their resistance score was aligned to the appropriate reference genomes highlighted differentially enriched regions between resistant/susceptible progeny in the genomic regions underlying both QTLs. The characterization of such regions allowed us to identify the most reliable candidate genes for the two resistance traits. With the aim of revealing exclusive species-specific contigs and scaffolds inherited from the allied species and thus associated with the full resistance trait, a draft de-novo assembly of available Illumina sequences of the ‘305E40’ parent was developed to better resolve the non-recombining genomic region on its CH02 carrying the introgressed Fom resistance locus from S. aethiopicum.
Single-Cell and Bulk RNA Sequencing Reveal Malignant Epithelial Cell Heterogeneity and Prognosis Signatures in Gastric Carcinoma
Authors: Huang Zhihong , Wu Chao , Liu Xinkui , Lu Shan , You Leiming , Guo Fengying , Stalin Antony , Zhang Jingyuan , Zhang Fanqin , Wu Zhishan , Tan Yingying , Fan Xiaotian , Huang Jiaqi , Zhai Yiyan , Shi Rui , Chen Meilin , Wu Chunfang , Li Huiying , Wu Jiarui
Published: August 2022

Gastric carcinoma (GC) heterogeneity represents a major barrier to accurate diagnosis and treatment. Here, we established a comprehensive single-cell transcriptional atlas to identify the cellular heterogeneity in malignant epithelial cells of GC using single-cell RNA sequencing (scRNA-seq). A total of 49,994 cells from nine patients with paired primary tumor and normal tissues were analyzed by multiple strategies. This study focused on the malignant epithelial cells, which were divided into three subtypes, including pit mucous cells, chief cells, and gastric and intestinal cells. The trajectory analysis results suggest that the differentiation of the three subtypes could be from the pit mucous cells to the chief cells and then to the gastric and intestinal cells. Lauren’s histopathology of GC might originate from various subtypes of malignant epithelial cells. The functional enrichment analysis results show that the three subtypes focused on different biological processes (BP) and pathways related to tumor development. In addition, we generated and validated the prognostic signatures for predicting the OS in GC patients by combining the scRNA-seq and bulk RNA sequencing (bulk RNA-seq) datasets. Overall, our study provides a resource for understanding the heterogeneity of GC that will contribute to accurate diagnosis and prognosis.
Dynamin-Independent Mechanisms of Endocytosis and Receptor Trafficking
Authors: Gundu Chayanika , Arruri Vijay Kumar , Yadav Poonam , Navik Umashanker , Kumar Ashutosh , Amalkar Veda Sudhir , Vikram Ajit , Gaddam Ravinder Reddy
Published: August 2022

Endocytosis is a fundamental mechanism by which cells perform housekeeping functions. It occurs via a variety of mechanisms and involves many regulatory proteins. The GTPase dynamin acts as a “molecular scissor” to form endocytic vesicles and is a critical regulator among the proteins involved in endocytosis. Some GTPases (e.g., Cdc42, arf6, RhoA), membrane proteins (e.g., flotillins, tetraspanins), and secondary messengers (e.g., calcium) mediate dynamin-independent endocytosis. These pathways may be convergent, as multiple pathways exist in a single cell. However, what determines the specific path of endocytosis is complex and challenging to comprehend. This review summarizes the mechanisms of dynamin-independent endocytosis, the involvement of microRNAs, and factors that contribute to the cellular decision about the specific route of endocytosis.
“The Peer Educator Is the Game-Changer of My Life”: Perceptions of Adolescents Living with HIV in DR Congo on Involving Peer Educators in the Process of HIV Disclosure
Authors: Kitetele Faustin Nd. , Lelo Gilbert M. , Akele Cathy E. , Lelo Patricia V. M. , Mafuta Eric M. , Tylleskär Thorkild , Kashala-Abotnes Espérance
Published: August 2022

Several approaches to the disclosure of HIV status to children and adolescents have been described. Each of these places particular emphasis on the role of parents and health care workers (HCWs) to mitigate the impact of disclosure on the adolescent without exploring the possible roles that other individuals might play in the process of disclosure. This article assesses the perceptions of adolescents living with HIV (ALHIV) about disclosure done by parents, guardians, HCWs, peer educators in the role of peer supporters, accidentally or by self-discovery, and the subsequent effects of disclosure method on their mental health. We used a qualitative study to conduct semi-structured interviews with 73 ALHIV at the Kalembelembe Paediatric Hospital, in DR Congo disclosed to by parents, guardians, HCWs, and/or peer educators, respectively, or disclosed to accidentally or by self-discovery. Microsoft Excel analysis matrix was used to organize the qualitative data. The majority of ALHIV whose disclosure involved a peer educator unanimously acknowledged the important role of the peer in accepting their HIV status, in their ART adherence, and their development of self-esteem. However, most ALHIV disclosed without involving peers declared that they had accepted their situation after a relatively long period followed by contact with the peer and integration in the self-support group. We found that the peer approach is the game-changer of the HIV status disclosure process that would allow ALHIV to accept their HIV status with minimum distress, it builds resilience, and allows them to adhere to treatment.
Changing Epidemiology of Acute Viral Respiratory Infections in Hospitalized Children: The Post-Lockdown Effect
Authors: Maglione Marco , Pascarella Antonia , Botti Chiara , Ricci Giuseppe , Morelli Fiorella , Camelia Fabiana , Micillo Alberto , Calì Camilla , Savoia Fabio , Tipo Vincenzo , Giannattasio Antonietta
Published: August 2022

Several reports highlighted how public health measures aimed at limiting severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) circulation have likely contributed to reducing the circulation of other respiratory viruses, particularly during the first year of the COVID-19 pandemic. We evaluated the epidemiology of acute respiratory infections in a large cohort of hospitalized children during the third year of the pandemic (2021–2022). We retrospectively analyzed data from the health records of children (<14 years) hospitalized for acute respiratory infections between 1 July 2021 and 31 March 2022. A total of 1763 respiratory panels were collected. Overall, 1269 (72%) panels hadpositive results for at least one pathogen. Most positive panels (53.8%) belonged to patients aged 1–12 months. The most detected pathogen was respiratory syncytial virus (RSV) (57.8% of positive panels). The RSV peak occurred in November 2021. Nine hundred and forty-five (74.5%) panels were positive for one pathogen while three hundred and twenty-four (25.5%) showed multiple infections. Patients with multiple infections were significantly older than those with a single infection. The 2021–2022 peak of RSV infection in Italy occurred earlier than in the previous pre-pandemic seasons. A high number of children have been hospitalized because of acute viral infections also due to less aggressive viruses.