bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors Associated With Coverage of Health Insurance Among Women in Malawi
Authors: Chauluka Margaret , Uzochukwu Benjamin S. C. , Chinkhumba Jobiba
Published: May 2022

Introduction

Access to healthcare for the vulnerable groups including women has long been a theme encouraged worldwide from the first general assembly on health to the current sustainable development goals. Despite many countries having a free public healthcare system, there are inequalities in access to care and significant out-of-pocket spending, pushing most women into poverty against the principles of universal health coverage. Coverage of Malawian women with health insurance is poor; thus, there is limited cushioning and high risk of poverty, as women bear costs of care as primary caregivers. There is need to explore determinants of coverage of health insurance among women in Malawi to inform health policy.

Methodology

This study was quantitative in nature, using cross-sectional secondary data from the 2015 to 2016 Malawi Demographic and Health Survey involving women aged between 15 and 49 years. We assessed factors associated with insurance coverage by comparing women with and without insurance schemes using binary logistic regression. Analysis was done using STATA statistical package version 13.

Results

The analysis included a total of 24,562 women with a mean age of 28 SD (9.3). Of these cases, 1.5% had health insurance. High education attainment, occupation, and wealth were significantly associated with health insurance ownership, with all having p-values of < 0.01. On the other hand, a woman's residence, marital status, and who heads a household were not associated with ownership of health insurance significantly.

Conclusion

Education, occupation, and wealth have a key role in influencing a woman's choice in owning health insurance. This informs policymakers and health insurance providers on how best to approach women's health financing and factors to target in social security programs and health insurance products that speak to women's needs and capacity.
Fault-Aware Adversary Attack Analyses and Enhancement for RRAM-Based Neuromorphic Accelerator
Authors: Shang Liuting , Jung Sungyong , Li Fengjun , Pan Chenyun
Published: May 2022

Neural networks have been widely deployed in sensor networks and IoT systems due to the advance in lightweight design and edge computing as well as emerging energy-efficient neuromorphic accelerators. However, adversary attack has raised a major threat against neural networks, which can be further enhanced by leveraging the natural hard faults in the neuromorphic accelerator that is based on resistive random access memory (RRAM). In this paper, we perform a comprehensive fault-aware attack analysis method for RRAM-based accelerators by considering five attack models based on a wide range of device- and circuit-level nonideal properties. The research on nonideal properties takes into account detailed hardware situations and provides a more accurate perspective on security. Compared to the existing adversary attack strategy that only leverages the natural fault, we propose an initiative attack based on two soft fault injection methods, which do not require a high-precision laboratory environment. In addition, an optimized fault-aware adversary algorithm is also proposed to enhance the attack effectiveness. The simulation results of an MNIST dataset on a classic convolutional neural network have shown that the proposed fault-aware adversary attack models and algorithms achieve a significant improvement in the attacking image classification.
Renal Pseudoaneurysms after Flexible Ureteroscopy and Holmium Laser Lithotripsy: A Case Report
Authors: Deng Xin-xi , Zhang Wensheng , Fu Delai , Fu Bin
Published: May 2022

Background

Flexible ureteroscopy (FURS) and holmium laser lithotripsy is considered one of the most minimally invasive and safe surgical methods for the treatment of renal calculi. Renal pseudoaneurysm is a rare complication after FURS holmium laser lithotripsy. We report a case of renal pseudoaneurysm after FURS and holmium laser lithotripsy and review the relevant literature to analyze the possible etiology and summarize the treatment.

Case presentation

A 29-year-old male with a 2-year history of diabetes was admitted to the hospital because of right back pain for 5 days. A doppler ultrasound demonstrated bilateral renal calculi with bilateral mild hydronephrosis. The patient underwent one-stage right FURS and holmium laser lithotripsy and bilateral ureteral stent implantation. The urine was clear on the second day after the operation, and he was discharged from the hospital. Due to severe gross hematuria, he had to be hospitalized 28 days after the operation. A CT scan showed multiple blood clots in the right renal pelvis and bladder. An emergency blood transfusion and removal of the bladder blood clots and bilateral double J tubes were performed. His urine was clear for one week, and he was discharged from the hospital. He was hospitalized again 47 days after the operation because of fever and hematuria. A CT scan demonstrated blood clots in the bladder and right renal pelvis. Angiography showed a pseudoaneurysm in a small branch of the right renal artery, and hematuria stopped after selective renal artery embolization with microcoils.

Conclusion

FURS and holmium laser lithotripsy is safe, but we should be aware of the possibility of renal artery pseudoaneurysms (RAP). Through careful operation during the surgery, avoiding kidney injury, reducing intrarenal pressure and controlling the time of operation may prevent the occurrence of this complication. Vascular embolization is the first choice for the treatment of pseudoaneurysms.
Role of Female Research at the Asociacion Mexicana de Cirugia General Annual Meeting: A Retrospective Analysis From 2013 to 2019
Authors: Mejía-Fernández Lorelí , Romero-Hernández Fernanda , López-Ruiz Ana , Lopez-Verdugo Fidel , Sanchez-Garcia Jorge , Martinez-Ordaz Jose L. , Moreno-Paquentin Eduardo , Lopez-Gavito Elena
Published: May 2022

Background

Academic surgery has been a traditionally male-dominated field. Female contribution remains challenging. In Mexico, there is no published evidence regarding gender disparity in academic surgery. We aimed to analyze the female role in clinical research submitted to the Asociación Mexicana de Cirugía General (AMCG).

Methods

Retrospective study evaluating abstracts submitted to AMCG annual meetings from 2013 to 2019. Categorical variables were compared using χ2 test. Univariate logistic regression was performed to calculate odds ratios (OR) followed by a log-binomial logistic regression model to obtain the adjusted relative risk (aRR) for acceptance as an oral presentation.

Results

Overall, 7,439 abstracts were analyzed of which 24.2% were submitted by females. Female-submitted abstracts increased from 22.5% to 25.3% during 2013–2019 (p = 0.15). The proportion of 47 abstracts submitted by females was higher in the resident group (27.7% vs. 18.8%; p < 0.001). The percentage of females’ abstracts selected for oral presentation was less than the percentage of males’ 49 abstracts selected for presentation (9% vs. 11.5%; p = 0.002). Females’ abstracts submitted have a 50 23.5% decreased chance of being selected for oral presentation (OR = 0.765, CI 95%, 0.639–0.917, 51 p = 0.003). However, after adjusting for research type and trainee status, the gender of the oral 52 presenting author showed no association (aRR = 0.95, CI 95%, 0.8–1.1, p = 0.56).

Conclusion

In Mexico, the female role in academic surgery is still limited. These results should 55 encourage professors and program directors to identify and address factors contributing to gender 56 disparities.
The Role of Histopathology as a Complementary Diagnostic Tool in the Monitoring of Bovine Tuberculosis
Authors: Larenas-Muñoz Fernanda , Sánchez-Carvajal José M. , Galán-Relaño Ángela , Ruedas-Torres Inés , Vera-Salmoral Eduardo , Gómez-Gascón Lidia , Maldonado Alfonso , Carrasco Librado , Tarradas Carmen , Luque Inmaculada , Rodríguez-Gómez Irene M. , Gómez-Laguna Jaime
Published: May 2022

The diagnosis of bovine tuberculosis (bTB) is based on the single intradermal tuberculin test (SIT), interferon gamma, and compulsory slaughter of reactor animals. Culture and PCR from fresh tissue are regarded as gold standard techniques for post-mortem confirmation, with the former being time-consuming and presenting moderate to low sensitivity and the latter presenting promising results. Histopathology has the advantage to identify and categorize lesions in both reactor and non-reactor animals. Therefore, this study aims to highlight the role of histopathology in the systematic diagnosis of bTB to shorten the time to disclose positive animals. Blood (212) and lymph node (681) samples were collected for serological, bacteriological, and histopathological analyses from a total of 230 cattle subjected to the Spanish bTB eradication program. Seventy-one lymph nodes and 59 cattle yielded a positive result to bacteriology, with 59 lymph nodes and 48 cattle presenting a positive result in real-time PCR from fresh tissue. Roughly 19% (40/212) of sera samples gave a positive result to ELISA. Tuberculosis-like lesions (TBLs) were observed in 11.9% (81/681) of the lymph nodes and 30.9% (71/230) of cattle. Noteworthy, TBLs were evidenced in 18 out of 83 SIT− and real-time PCR and bacteriology negative animals, with 11/18 disclosing a positive result to Ziehl-Neelsen technique and two of them to ddPCR from paraffin blocks targeting IS6110. Six out of these 11 ZN+ corresponded with mesenteric LN and were confirmed positive to paratuberculosis. Histopathology yielded a sensitivity of 91.3% (CI95 83.2–99.4%) and a specificity of 84.4% (CI95 78.6–89.3%) with good agreement (κ = 0.626) when compared with real-time PCR. Our results confirm that histopathology allows a rapid confirmation of real-time PCR and bacteriology, emphasizing its contribution to bTB control and monitoring.
Short Communication: Efficacy of Two Commercial Disinfectants on Paenibacillus larvae Spores
Authors: Kiriamburi Joseph , Muturi Jamleck , Mugweru Julius , Forsgren Eva , Nilsson Anna
Published: May 2022

Paenibacillus larvae is a spore-forming bacterium causing American foulbrood (AFB) in honey bee larvae. The remains of a diseased larva contains billions of extremely resilient P. larvae spores viable for decades. Burning clinically symptomatic colonies is widely considered the only workable strategy to prevent further spread of the disease, and the management practices used for decontamination requires high concentrations of chemicals or special equipment. The aim of this study was to test and compare the biocidal effect of two commercially available disinfectants, “Disinfection for beekeeping” and Virkon S on P. larvae. The two products were applied to P. larvae spores in suspension as well as inoculated on two common beehive materials, wood and Styrofoam. “Disinfection for beekeeping” had a 100 % biocidal effect on P. larvae spores in suspension compared to 87.0–88.6% for Virkon S which, however, had a significantly better effect on P. larvae on Styrofoam. The two disinfectants had similar effect on infected wood material.
Enhancing Dynamic Bandwidth of Amplified Piezoelectric Actuators by a Hybrid Lever and Bridge-Type Compliant Mechanism
Authors: Ling Mingxiang , Yuan Lei , Luo Zhihong , Huang Tao , Zhang Xianmin
Published: May 2022

Ongoing interests in high-speed precision actuation continuously sparks great attention on developing fast amplified piezoelectric actuators (APAs) with compliant mechanisms. A new type of APA with enhanced resonance frequency is herein reported based on a hybrid compliant amplifying mechanism. A two-stage displacement flexure amplifier is proposed by synthesizing the lever-type and semi bridge-type compliant mechanisms in a compact configuration, promising to a well tradeoff between the displacement amplification ratio and dynamic bandwidth. The static and dynamic performances are experimentally evaluated. The resonance frequency of 2.1 kHz, displacement amplification ratio of 6, and step response time of around 0.4 ms are realized with a compact size of 50 mm × 44 mm × 7 mm. Another contribution of this paper is to develop a comprehensive two-port dynamic stiffness model to predict the static and dynamic behaviors of the compliant amplifier. The modeling approach presented here differs from previous studies in that it enables the traditional transfer matrix method to formulate both the kinetostatics and dynamics of compliant mechanisms including serial-parallel branches and rigid bodies.
Development of a Parallel Dual-Stage Compliant Nanopositioning System
Authors: Yang Xu , Ji Lichao , Shang Ying , Zhu Wule , Li Shizhen
Published: May 2022

This paper presents a novel parallel dual-stage compliant nanopositioning system (PDCNS), aimed at nanoscale positioning for microscale manipulation. In the developed PDCNS, the coarse stage actuated by the voice coil motor and the fine stage driven by the piezoelectric actuator are integrated in a parallel manner by a specially devised A-shaped compliant mechanism, which leads to many excellent performances, such as good resolution and large stroke and broadband. To enhance the closed-loop-positioning capability of the proposed PDCNS, a double-servo cooperative control (DSCC) strategy is specially constructed. The performance of the proposed PDCNS is evaluated by analytical model, finite element analysis, and experimental research. Results show that the first-order resonance frequency of the designed A-shaped compliant mechanism can reach 99.7 Hz. Combined with the designed DSCC, the developed PDCNS prototype is demonstrated to provide a stroke of 1.49 mm and a positioning resolution of ≤50 nm.
A Modal Interpretation for Aeroelastic Stability Enhancement of Mistuned Bladed Disks
Authors: Liu Xin , Fan Yu , Li Lin , Yu Xiaoping
Published: May 2022

Understanding the mechanism of the aeroelastic stability improvement induced by mistuning is essential for the design of bladed disks in aero-engines. In this paper, a quantitative interpretation is given. It starts by projecting the mistuned aeroelastic modes into the space spanned by the tuned modes. In this way, the mistuned aeroelastic damping can be expressed by the superposition of the tuned damping. Closed-form expressions are found, providing clear interpretations of several frequently reported trends in the literature. Further, a prediction approach is proposed, where the analysis of aeroelastic coupling only needs to be performed once, and it is decoupled from the analysis of the mistuning effect. The advantages are two-fold. First, the design of the mistuning pattern is accelerated. Second, this allows one to introduce more accurate data or models of aeroelastic damping. An empirical bladed disk with NASA-ROTOR37 profile is used as an example, and the alternate, wave, and random patterns are considered.
The Use of Bacteriophages in Biotechnology and Recent Insights into Proteomics
Authors: Abril Ana G. , Carrera Mónica , Notario Vicente , Sánchez-Pérez Ángeles , Villa Tomás G.
Published: May 2022

Phages have certain features, such as their ability to form protein–protein interactions, that make them good candidates for use in a variety of beneficial applications, such as in human or animal health, industry, food science, food safety, and agriculture. It is essential to identify and characterize the proteins produced by particular phages in order to use these viruses in a variety of functional processes, such as bacterial detection, as vehicles for drug delivery, in vaccine development, and to combat multidrug resistant bacterial infections. Furthermore, phages can also play a major role in the design of a variety of cheap and stable sensors as well as in diagnostic assays that can either specifically identify specific compounds or detect bacteria. This article reviews recently developed phage-based techniques, such as the use of recombinant tempered phages, phage display and phage amplification-based detection. It also encompasses the application of phages as capture elements, biosensors and bioreceptors, with a special emphasis on novel bacteriophage-based mass spectrometry (MS) applications.
Antimicrobial Resistance Profile by Metagenomic and Metatranscriptomic Approach in Clinical Practice: Opportunity and Challenge
Authors: Waskito Langgeng Agung , Rezkitha Yudith Annisa Ayu , Vilaichone Ratha-korn , Wibawa I Dewa Nyoman , Mustika Syifa , Sugihartono Titong , Miftahussurur Muhammad
Published: May 2022

The burden of bacterial resistance to antibiotics affects several key sectors in the world, including healthcare, the government, and the economic sector. Resistant bacterial infection is associated with prolonged hospital stays, direct costs, and costs due to loss of productivity, which will cause policy makers to adjust their policies. Current widely performed procedures for the identification of antibiotic-resistant bacteria rely on culture-based methodology. However, some resistance determinants, such as free-floating DNA of resistance genes, are outside the bacterial genome, which could be potentially transferred under antibiotic exposure. Metagenomic and metatranscriptomic approaches to profiling antibiotic resistance offer several advantages to overcome the limitations of the culture-based approach. These methodologies enhance the probability of detecting resistance determinant genes inside and outside the bacterial genome and novel resistance genes yet pose inherent challenges in availability, validity, expert usability, and cost. Despite these challenges, such molecular-based and bioinformatics technologies offer an exquisite advantage in improving clinicians’ diagnoses and the management of resistant infectious diseases in humans. This review provides a comprehensive overview of next-generation sequencing technologies, metagenomics, and metatranscriptomics in assessing antimicrobial resistance profiles.
Antioxidant and Anticancer Functions of Protein Acyltransferase DHHC3
Authors: Sharma Chandan , Hemler Martin E.
Published: May 2022

Silencing of DHHC3, an acyltransferase enzyme in the DHHC family, extensively upregulates oxidative stress (OS). Substrates for DHHC3-mediated palmitoylation include several antioxidant proteins and many other redox regulatory proteins. This helps to explain why DHHC3 ablation upregulates OS. DHHC3 also plays a key role in cancer. DHHC3 ablation leads to diminished xenograft growth of multiple cancer cell types, along with diminished metastasis. Furthermore, DHHC3 protein is upregulated on malignant/metastatic cancer samples, and upregulated gene expression correlates with diminished patient survival in several human cancers. Decreased primary tumor growth due to DHHC3 ablation may be partly explained by an elevated OS → senescence → innate immune cell recruitment mechanism. Elevated OS due to DHHC3 ablation may also contribute to adaptive anticancer immunity and impair tumor metastasis. In addition, DHHC3 ablation disrupts antioxidant protection mechanisms, thus enhancing the efficacy of OS-inducing anticancer drugs. A major focus has thus far been on OS regulation by DHHC3. However, remaining to be studied are multiple DHHC3 substrates that may affect tumor behavior independent of OS. Nonetheless, the currently established properties of DHHC3 make it an attractive candidate for therapeutic targeting in situations in which antioxidant protections need to be downmodulated, and also in cancer.
Properties of Spatially Indirect Excitons in Nanowire Arrays
Authors: Pyrkov Vladimir N. , Burlakov Victor M.
Published: May 2022

This paper deals with the excitons formed by electrons and holes located in different, closely placed semiconducting nanowires (spatially indirect excitons). We calculated the charge densities and the binding energies of the excitons for different nanowire diameters D and distances h between the nanowires. Together with the estimated exciton lifetimes, these results suggest that at certain h and D, the spatially indirect excitons in the nanowire arrays may have the potential to serve as information-processing units. Possible ways of exciton generation in the nanowire arrays are discussed.
A Note on the Reverse Order Law for g-Inverse of Operator Product
Authors: Qin Yingying , Xiong Zhiping
Published: May 2022

The generalized inverse has many important applications in aspects of the theoretical research of matrices and statistics. One of the core problems of the generalized inverse is finding the necessary and sufficient conditions of the reverse order laws for the generalized inverse of the operator product. In this paper, we study the reverse order law for the g-inverse of an operator product T1T2T3 using the technique of matrix form of bounded linear operators. In particular, some necessary and sufficient conditions for the inclusion T3{1}T2{1}T1{1}⊆(T1T2T3){1} is presented. Moreover, some finite dimensional results are extended to infinite dimensional settings.
A Two-Stage Multi-Criteria Supplier Selection Model for Sustainable Automotive Supply Chain under Uncertainty
Authors: Dang Thanh-Tuan , Nguyen Ngoc-Ai-Thy , Nguyen Van-Thanh-Tien , Dang Le-Thanh-Hieu
Published: May 2022

Sustainable supplier selection (SSS) is gaining popularity as a practical method to supply chain sustainability among academics and practitioners. However, in addition to balancing economic, social, and environmental factors, the emergence of the COVID-19 pandemic has affected the selection of long-term suppliers to ensure sustainable supply chains, recover better from the pandemic and effectively respond to any future unprecedented crises. The purpose of this study is to assess and choose a possible supplier based on their capability to adapt to the COVID-19 epidemic in a sustainable manner. For this assessment, a framework based on multi-criteria decision making (MCDM) is provided that integrates spherical fuzzy Analytical Hierarchical Process (SF-AHP) and grey Complex Proportional Assessment (G-COPRAS), in which spherical fuzzy sets and grey numbers are used to express the ambiguous linguistic evaluation statements of experts. In the first stage, the evaluation criteria system is identified through a literature review and experts’ opinions. The SF-AHP is then used to determine the criteria weights. Finally, the G-COPRAS method is utilized to select sustainable suppliers. A case study in the automotive industry in Vietnam is presented to demonstrate the proposed approach’s effectiveness. From the SF-AHP findings, “quality”, “use of personal protective equipment”, “cost/price”, “safety and health practices and wellbeing of suppliers”, and “economic recovery programs” have been ranked as the five most important criteria. From G-COPRAS analysis, THACO Parts (Supplier 02) is the best supplier. A sensitivity study was also conducted to verify the robustness of the proposed model, in which the priority rankings of the best suppliers are very similar. For long-term development and increased competitiveness, industrial businesses must stress the integration of response mechanisms during SSS implementation in the COVID-19 epidemic, according to the findings. This will result in significant cost and resource savings, as well as reduced environmental consequences and a long-term supply chain, independent of the crisis.
Knowledge Modelling and Learning through Cognitive Networks
Authors: Stella Massimo , Kenett Yoed N.
Published: May 2022

Knowledge modelling is a growing field at the fringe of computer science, psychology and network science [...]
RoFDT: Identification of Drug–Target Interactions from Protein Sequence and Drug Molecular Structure Using Rotation Forest
Authors: Wang Ying , Wang Lei , Wong Leon , Zhao Bowei , Su Xiaorui , Li Yang , You Zhuhong
Published: May 2022

As the basis for screening drug candidates, the identification of drug–target interactions (DTIs) plays a crucial role in the innovative drugs research. However, due to the inherent constraints of small-scale and time-consuming wet experiments, DTI recognition is usually difficult to carry out. In the present study, we developed a computational approach called RoFDT to predict DTIs by combining feature-weighted Rotation Forest (FwRF) with a protein sequence. In particular, we first encode protein sequences as numerical matrices by Position-Specific Score Matrix (PSSM), then extract their features utilize Pseudo Position-Specific Score Matrix (PsePSSM) and combine them with drug structure information-molecular fingerprints and finally feed them into the FwRF classifier and validate the performance of RoFDT on Enzyme, GPCR, Ion Channel and Nuclear Receptor datasets. In the above dataset, RoFDT achieved 91.68%, 84.72%, 88.11% and 78.33% accuracy, respectively. RoFDT shows excellent performance in comparison with support vector machine models and previous superior approaches. Furthermore, 7 of the top 10 DTIs with RoFDT estimate scores were proven by the relevant database. These results demonstrate that RoFDT can be employed to a powerful predictive approach for DTIs to provide theoretical support for innovative drug discovery.
Tensiomyography Allows to Discriminate between Injured and Non-Injured Biceps Femoris Muscle
Authors: Đorđević Srđan , Rozman Sergej , Zupet Petra , Dopsaj Milivoj , Maffulli Nicola
Published: May 2022

The hamstring muscle group is the most frequently injured muscle group in non-contact muscle injuries in sports involving high-speed running. A total of 84% of hamstring injuries affect the biceps femoris (BF) muscle. Clinical assessments and magnetic resonance imaging (MRI) are routinely used for diagnosis and plan management. MRI-negative scans for clinically diagnosed hamstring injuries range from 14% to 45%. We tested the hypothesis that the functional differences between injured and non-injured BF assessed by tensiomyography can be used for diagnostic and classification purposes. We compared an injured group of 53 international-level soccer players and sprinters with 53 non-injured international-level soccer players and sprinters of both sexes. Comparing the injured vs. non-injured athletes and the left vs. right side in all of the athletes, we used the percentage of absolute differences in the BF contraction time (Tc) to classify non-injured and injured BF muscles. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) and the precision–recall curve (PRC) were used to measure the classification accuracy and to identify cut-off limits using the Tc differences. There was a very high ROC AUC value of 0.981 (SE = 0.009, p < 0.000), with 98.11% of the injured muscles being correctly classified (cut-off point 12.50% on Tc differences), and an AUPRC value of 0.981, with association classification criteria at >9.87. Tensiomyography has a high predictive ability to discriminate between injured and non-injured BF non-invasively and functionally.
Lympho-Hematopoietic Microenvironments and Fish Immune System
Authors: Zapata Agustín G.
Published: May 2022

In the last 50 years information on the fish immune system has increased importantly, particularly that on species of marked commercial interest (i.e., salmonids, cods, catfish, sea breams), that occupy a key position in the vertebrate phylogenetical tree (i.e., Agnatha, Chondrichtyes, lungfish) or represent consolidated experimental models, such as zebrafish or medaka. However, most obtained information was based on genetic sequence analysis with little or no information on the cellular basis of the immune responses. Although jawed fish contain a thymus and lympho-hematopoietic organs equivalents to mammalian bone marrow, few studies have accounted for the presumptive relationships between the organization of these cell microenvironments and the known immune capabilities of the fish immune system. In the current review, we analyze this topic providing information on: (1) The origins of T and B lymphopoiesis in Agnatha and jawed fish; (2) the remarkable organization of the thymus of teleost fish; (3) the occurrence of numerous, apparently unrelated organs housing lympho-hematopoietic progenitors and, presumably, B lymphopoiesis; (4) the existence of fish immunological memory in the absence of germinal centers.
Clade-Specific Alterations within the HIV-1 Capsid Protein with Implications for Nuclear Translocation
Authors: Dick Alexej , Meuser Megan E. , Cocklin Simon
Published: May 2022

The HIV-1 capsid (CA) protein has emerged as an attractive therapeutic target. However, all inhibitor designs and structural analyses for this essential HIV-1 protein have focused on the clade B HIV-1 (NL4-3) variant. This study creates, overproduces, purifies, and characterizes the CA proteins from clade A1, A2, B, C, and D isolates. These new CA constructs represent novel reagents that can be used in future CA-targeted inhibitor design and to investigate CA proteins’ structural and biochemical properties from genetically diverse HIV-1 subtypes. Moreover, we used surface plasmon resonance (SPR) spectrometry and computational modeling to examine inter-clade differences in CA assembly and binding of PF-74, CPSF-6, and NUP-153. Interestingly, we found that HIV-1 CA from clade A1 does not bind to NUP-153, suggesting that the import of CA core structures through the nuclear pore complex may be altered for viruses from this clade. Overall, we have demonstrated that in silico generated models of the HIV-1 CA protein from clades other than the prototypically used clade B have utility in understanding and predicting biology and antiviral drug design and mechanism of action.
Dopamine Modulates the Processing of Food Odour in the Ventral Striatum
Authors: Rampin Olivier , Saint Albin Deliot Audrey , Ouali Christian , Burguet Jasmine , Gry Elisa , Champeil Potokar Gaelle , Jérôme Nathalie , Davidenko Olga , Darcel Nicolas , Bombail Vincent , Andrey Philippe , Denis Isabelle
Published: May 2022

Food odour is a potent stimulus of food intake. Odour coding in the brain occurs in synergy or competition with other sensory information and internal signals. For eliciting feeding behaviour, food odour coding has to gain signification through enrichment with additional labelling in the brain. Since the ventral striatum, at the crossroads of olfactory and reward pathways, receives a rich dopaminergic innervation, we hypothesized that dopamine plays a role in food odour information processing in the ventral striatum. Using single neurones recordings in anesthetised rats, we show that some ventral striatum neurones respond to food odour. This neuronal network displays a variety of responses (excitation, inhibition, rhythmic activity in phase with respiration). The localization of recorded neurones in a 3-dimensional brain model suggests the spatial segregation of this food-odour responsive population. Using local field potentials recordings, we found that the neural population response to food odour was characterized by an increase of power in the beta-band frequency. This response was modulated by dopamine, as evidenced by its depression following administration of the dopaminergic D1 and D2 antagonists SCH23390 and raclopride. Our results suggest that dopamine improves food odour processing in the ventral striatum.
Butyrate Inhibits Colorectal Cancer Cell Proliferation through Autophagy Degradation of β-Catenin Regardless of APC and β-Catenin Mutational Status
Authors: Garavaglia Beatrice , Vallino Letizia , Ferraresi Alessandra , Esposito Andrea , Salwa Amreen , Vidoni Chiara , Gentilli Sergio , Isidoro Ciro
Published: May 2022

Colorectal cancer (CRC) pathogenesis is mainly driven by alterations in WNT signaling, which results in altered transcriptional activity of β-Catenin. Mutations in APC (Adenomatous Polyposis Coli) are reflected in β-Catenin hyperactivation and loss of proliferation control. Certain intestinal bacteria metabolites have shown the ability to limit CRC cell proliferation and CRC pathogenesis. Here, we investigated the molecular mechanism underlying the anti-proliferative activity of butyrate, a microbiota-derived short chain fatty acid, in two CRC cell lines, namely HCT116 and SW620, which bear a mutation in β-Catenin and APC, respectively. In particular, we focused on autophagy, a lysosome-dependent degradation pathway, which was shown to control intestinal tissue homeostasis. Butyrate reduced CRC cell proliferation, as witnessed by the downregulation of proliferation markers. TCGA bioinformatic transcriptomic analysis of CTNNB1 (β-Catenin) gene correlation in CRC patients showed that β-Catenin negatively correlates with the autophagy gene ATG4D. In CRC cells, regardless of the mutational state of APC or β-Catenin genes, butyrate caused the autophagy-mediated degradation of β-Catenin; thus, preventing its transcriptional activity. Autophagy gene silencing restored β-Catenin levels, allowing it to translocate into the nucleus to promote the expression of downstream genes associated with cancer cell proliferation. CRC-affected patients show driver mutations in the WNT pathway; thus, targeting its crucial effector may be a promising therapeutic strategy in CRC treatment; for instance, by using ad hoc probiotics that stimulate autophagy.
Abnormal Prefrontal Functional Connectivity Is Associated with Inflexible Information Processing in Patients with Autism Spectrum Disorder (ASD): An fNIRS Study
Authors: Chan Melody , Chan Ming-Chung , Lai Oscar , Krishnamurthy Karthikeyan , Han Yvonne
Published: May 2022

Individuals with autism spectrum disorder (ASD) are characterized by impairments in flexibly acquiring and maintaining new information, as well as in applying learned information for problem solving. However, the neural mechanism underpinning such impairments remains unclear. This study investigated the flexibility in the acquisition and application of visual information in ASD (aged 14–21) when they performed the Wisconsin Card Sorting Test (WCST). Behavioral data including response accuracy and latency, and prefrontal hemodynamic data measured by functional near-infrared spectroscopy (fNIRS), were collected when individuals performed WCST. Canonical general linear model and functional connectivity analyses were performed to examine the prefrontal activation and synchronization patterns, respectively. Results showed that although ASD individuals (n = 29) achieved comparable accuracy rates when compared with age- and intelligence quotient (IQ)-matched typically developing (TD; n = 26) individuals (F1,53 = 3.15, p = 0.082), ASD individuals needed significantly more time to acquire and apply WCST card sorting rules (F1,53 = 17.92, p < 0.001). Moreover, ASD individuals showed significantly lower prefrontal functional connectivity than TD individuals during WCST (F1,42 = 9.99, p = 0.003). The hypoconnectivity in ASD individuals was highly significant in the right lateral PFC in the acquisition condition (p = 0.005) and in the bilateral lateral PFC in the application condition (ps = 0.006). Furthermore, slower WCST reaction time was correlated with lower bilateral lateral PFC functional connectivity only in the application condition (ps = 0.003) but not the acquisition condition. Impairment in information acquisition and application is evident in ASD individuals and is mediated by processing speed, which is associated with lower functional connectivity in the bilateral lateral PFC when these individuals apply learned rules to solve novel problems.
Risk of Adverse Pregnancy Outcomes in Young Women with Thyroid Cancer: A Systematic Review and Meta-Analysis
Authors: Moon Shinje , Yi Ka Hee , Park Young Joo
Published: May 2022

This meta-analysis investigated whether thyroidectomy or radioactive iodine treatment (RAIT) in patients with differentiated thyroid cancer (DTC) was associated with an increase in adverse pregnancy outcomes, such as miscarriage, preterm delivery, and congenital malformations. A total of 22 articles (5 case-control and 17 case series studies) from 1262 studies identified through a literature search in the PubMed and EMBASE databases from inception up to 13 September 2021 were included. In patients with DTC who underwent thyroidectomy, the event rates for miscarriage, preterm labor, and congenital anomalies were 0.07 (95% confidence interval [CI], 0.05–0.11; 17 studies), 0.07 (95% CI, 0.05–0.09; 14 studies), and 0.03 (95% CI, 0.02–0.06; 17 studies), respectively. These results are similar to those previously reported in the general population. The risk of miscarriage or abortion was increased in patients with DTC when compared with controls without DTC (odds ratio [OR], 1.80; 95% CI, 1.28–2.53; I2 = 33%; 3 studies), while the OR values for preterm labor and the presence of congenital anomalies were 1.22 (95% CI, 0.90–1.66; I2 = 62%; five studies) and 0.73 (95% CI, 0.39–1.38; I2 = 0%; two studies) respectively, which showed no statistical significance. A subgroup analysis of patients with DTC according to RAIT revealed that the risk of miscarriage, preterm labor, or congenital anomalies was not increased in the RAIT group when compared with patients without RAIT. The results of this meta-analysis suggest that thyroid cancer treatment, including RAIT, is not associated with an increased risk of adverse pregnancy outcomes, including miscarriage, preterm labor, and congenital anomalies.
Large-Scale Chromatin Rearrangements in Cancer
Authors: Yamaguchi Kosuke , Chen Xiaoying , Oji Asami , Hiratani Ichiro , Defossez Pierre-Antoine
Published: May 2022

Epigenetic abnormalities are extremely widespread in cancer. Some of them are mere consequences of transformation, but some actively contribute to cancer initiation and progression; they provide powerful new biological markers, as well as new targets for therapies. In this review, we examine the recent literature and focus on one particular aspect of epigenome deregulation: large-scale chromatin changes, causing global changes of DNA methylation or histone modifications. After a brief overview of the one-dimension (1D) and three-dimension (3D) epigenome in healthy cells and of its homeostasis mechanisms, we use selected examples to describe how many different events (mutations, changes in metabolism, and infections) can cause profound changes to the epigenome and fuel cancer. We then present the consequences for therapies and briefly discuss the role of single-cell approaches for the future progress of the field.
Safety and Efficacy of Crizotinib in Combination with Temozolomide and Radiotherapy in Patients with Newly Diagnosed Glioblastoma: Phase Ib GEINO 1402 Trial
Authors: Martínez-García María , Velasco Guillermo , Pineda Estela , Gil-Gil Miguel , Alameda Francesc , Capellades Jaume , Martín-Soberón Mari Cruz , López-Valero Israel , Tovar Ambel Elena , Foro Palmira , Taus Álvaro , Arumi Montserrat , Hernández-Laín Aurelio , Sepúlveda-Sánchez Juan Manuel
Published: May 2022

Background: MET-signaling and midkine (ALK ligand) promote glioma cell maintenance and resistance against anticancer therapies. ALK and c-MET inhibition with crizotinib have a preclinical therapeutic rationale to be tested in newly diagnosed GBM. Methods: Eligible patients received crizotinib with standard radiotherapy (RT)/temozolomide (TMZ) followed by maintenance with crizotinib. The primary objective was to determine the recommended phase 2 dose (RP2D) in a 3 + 3 dose escalation (DE) strategy and safety evaluation in the expansion cohort (EC). Secondary objectives included progression-free (PFS) and overall survival (OS) and exploratory biomarker analysis. Results: The study enrolled 38 patients. The median age was 52 years (33–76), 44% were male, 44% were MGMT methylated, and three patients had IDH1/2 mutation. In DE, DLTs were reported in 1/6 in the second cohort (250 mg/QD), declaring 250 mg/QD of crizotinib as the RP2D for the EC. In the EC, 9/25 patients (32%) presented grade ≥3 adverse events. The median follow up was 18.7 months (m) and the median PFS was 10.7 m (95% CI, 7.7–13.8), with a 6 m PFS and 12 m PFS of 71.5% and 38.8%, respectively. At the time of this analysis, 1 died without progression and 24 had progressed. The median OS was 22.6 m (95% CI, 14.1–31.1) with a 24 m OS of 44.5%. Molecular biomarkers showed no correlation with efficacy. Conclusions: The addition of crizotinib to standard RT and TMZ for newly diagnosed GBM was safe and the efficacy was encouraging, warranting prospective validation in an adequately powered, randomized controlled study.
Proton Pump Inhibitors Enhance the Antitumor Effect of Chemotherapy for Esophageal Squamous Cell Carcinoma
Authors: Matsumura Shinya , Ishikawa Takeshi , Yoshida Juichiro , Morita Ryuichi , Sakakida Tomoki , Endo Yuki , Doi Toshifumi , Hirose Ryohei , Inoue Ken , Dohi Osamu , Yoshida Naohisa , Uchiyama Kazuhiko , Takagi Tomohisa , Konishi Hideyuki , Yasui Kohichiroh , Naito Yuji , Itoh Yoshito
Published: May 2022

Background: Vacuolar ATPase (V-ATPase) is involved in cancer development. The use of proton pump inhibitors (PPIs) as V-ATPase inhibitors has been reported to enhance the effectiveness of chemotherapy in certain cancers. This study aimed to evaluate the effect of PPIs on chemotherapy for esophageal cancer. Methods: To investigate the effects of PPIs on esophageal cancer cells, human KYSE50 and 70 cells were plated and 3 PPIs (lansoprazole, esomeprazole, vonoprazan) were added at various concentrations with 5-Fluorouracil (5-FU) to the corresponding cells for a cell viability assay. To investigate the effects of PPI treatment on patients undergoing 5-FU-based therapy in the clinical setting, we retrospectively analyzed the clinical outcomes and chemotherapy-related adverse events in 40 esophageal cancer patients who received 5-FU chemotherapy in our hospital between May 2013 and April 2017. Results: In the viability assays, all PPIs significantly enhanced the cytotoxic effect of 5-FU on the two esophageal cancer cell lines. In the clinical study, PPI-treated patients showed better overall survival (OS) than patients managed without PPI treatment. A multivariate analysis revealed that PPI treatment was independently associated with OS (p = 0.009, HR, 0.33; 95% CI, 0.12–0.76). Conclusions: PPI treatment may safely enhance chemosensitivity in esophageal cancer patients.
Computational Screening of Anti-Cancer Drugs Identifies a New BRCA Independent Gene Expression Signature to Predict Breast Cancer Sensitivity to Cisplatin
Authors: Berthelet Jean , Foroutan Momeneh , Bhuva Dharmesh D. , Whitfield Holly J. , El-Saafin Farrah , Cursons Joseph , Serrano Antonin , Merdas Michal , Lim Elgene , Charafe-Jauffret Emmanuelle , Ginestier Christophe , Ernst Matthias , Hollande Frédéric , Anderson Robin L. , Pal Bhupinder , Yeo Belinda , Davis Melissa J. , Merino Delphine
Published: May 2022

The development of therapies that target specific disease subtypes has dramatically improved outcomes for patients with breast cancer. However, survival gains have not been uniform across patients, even within a given molecular subtype. Large collections of publicly available drug screening data matched with transcriptomic measurements have facilitated the development of computational models that predict response to therapy. Here, we generated a series of predictive gene signatures to estimate the sensitivity of breast cancer samples to 90 drugs, comprising FDA-approved drugs or compounds in early development. To achieve this, we used a cell line-based drug screen with matched transcriptomic data to derive in silico models that we validated in large independent datasets obtained from cell lines and patient-derived xenograft (PDX) models. Robust computational signatures were obtained for 28 drugs and used to predict drug efficacy in a set of PDX models. We found that our signature for cisplatin can be used to identify tumors that are likely to respond to this drug, even in absence of the BRCA-1 mutation routinely used to select patients for platinum-based therapies. This clinically relevant observation was confirmed in multiple PDXs. Our study foreshadows an effective delivery approach for precision medicine.
Secondary Malignancy Risk Following Proton vs. X-ray Radiotherapy of Thymic Epithelial Tumors: A Comparative Modeling Study of Thoracic Organ-Specific Cancer Risk
Authors: König Laila , Hörner-Rieber Juliane , Forsthoefel Matthew , Haering Peter , Meixner Eva , Eichkorn Tanja , Krämer Anna , Mielke Thomas , Tonndorf-Martini Eric , Haefner Matthias F. , Debus Jürgen , Lischalk Jonathan W.
Published: May 2022

Background: Proton beam radiotherapy (PBT) offers physical dose advantages that might reduce the risk for secondary malignancies (SM). The aim of the current study is to calculate the risk for SM after X-ray-based 3D conformal (3DCRT) radiotherapy, intensity-modulated radiotherapy (IMRT), and active pencil beam scanned proton therapy (PBS) in patients treated for thymic malignancies. Methods: Comparative treatment plans for each of the different treatment modalities were generated for 17 patients. The risk for radiation-induced SM was estimated using two distinct prediction models—the Dasu and the Schneider model. Results: The total and fatal SM risks estimated using the Dasu model demonstrated significant reductions with the use of PBS relative to both 3DCRT and IMRT for all independent thoracic organs analyzed with the exception of the thyroid gland (p ≤ 0.001). SM rates per 10,000 patients per year per Gy evaluated using the Schneider model also resulted in significant reductions with the use of PBS relative to 3DCRT and IMRT for the lungs, breasts, and esophagus (p ≤ 0.001). Conclusions: PBS achieved superior sparing of relevant OARs compared to 3DCRT and IMRT, leading to a lower risk for radiation-induced SM. PBS should therefore be considered in patients diagnosed with thymic malignancies, particularly young female patients.
Genome-Wide Association Study Suggests the Variant rs7551288*A within the DHCR24 Gene Is Associated with Poor Overall Survival in Melanoma Patients
Authors: Pflugfelder Annette , Yong Xuan Ling Hilary , Jagirdar Kasturee , Eigentler Thomas K. , Soyer H. Peter , Sturm Richard A. , Flatz Lukas , Duffy David L.
Published: May 2022

Melanoma incidence rates are high among individuals with fair skin and multiple naevi. Established prognostic factors are tumour specific, and less is known about prognostic host factors. A total of 556 stage I to stage IV melanoma patients from Germany with phenotypic and disease-specific data were analysed; 64 of these patients died of melanoma after a median follow-up time of 8 years. Germline DNA was assessed by the HumanCoreExome BeadChip and data of 356,384 common polymorphisms distributed over all 23 chromosomes were used for a genome-wide analysis. A suggestive genome-wide significant association of the intronic allele rs7551288*A with diminished melanoma-specific survival was detected (p = 2 × 10−6). The frequency of rs7551288*A was 0.43 and was not associated with melanoma risk, hair and eye colour, tanning and total naevus count. Cox regression multivariate analyses revealed a 5.31-fold increased risk of melanoma-specific death for patients with the rs7551288 A/A genotype, independent of tumour thickness, ulceration and stage of disease at diagnoses. The variant rs7551288 belongs to the DHCR24 gene, which encodes Seladin-1, an enzyme involved in the biosynthesis of cholesterol. Further investigations are needed to confirm this genetic variant as a novel prognostic biomarker and to explore whether specific treatment strategies for melanoma patients might be derived from it.