bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Plasmodium falciparum Rh5 invasion protein complex reveals an excess of rare variant mutations
Authors: Ndwiga Leonard , Osoti Victor , Ochwedo Kevin Omondi , Wamae Kevin , Bejon Philip , Rayner Julian C. , Githinji George , Ochola-Oyier Lynette Isabella 
Published: June 2021

Abstract
Background
The invasion of the red blood cells by Plasmodium falciparum merozoites involves the interplay of several proteins that are also targets for vaccine development. The proteins PfRh5-PfRipr-PfCyRPA-Pfp113 assemble into a complex at the apical end of the merozoite and are together essential for erythrocyte invasion. They have also been shown to induce neutralizing antibodies and appear to be less polymorphic than other invasion-associated proteins, making them high priority blood-stage vaccine candidates. Using available whole genome sequencing data (WGS) and new capillary sequencing data (CS), this study describes the genetic polymorphism in the Rh5 complex in P. falciparum isolates obtained from Kilifi, Kenya.

Methods
162 samples collected in 2013 and 2014 were genotyped by capillary sequencing (CS) and re-analysed WGS from 68 culture-adapted P. falciparum samples obtained from a drug trial conducted from 2005 to 2007. The frequency of polymorphisms in the merozoite invasion proteins, PfRh5, PfRipr, PfCyRPA and PfP113 were examined and where possible polymorphisms co-occurring in the same isolates.

Results
From a total 70 variants, including 2 indels, 19 SNPs [27.1%] were identified by both CS and WGS, while an additional 15 [21.4%] and 36 [51.4%] SNPs were identified only by either CS or WGS, respectively. All the SNPs identified by CS were non-synonymous, whereas WGS identified 8 synonymous and 47 non-synonymous SNPs. CS identified indels in repeat regions in the p113 gene in codons 275 and 859 that were not identified in the WGS data. The minor allele frequencies of the SNPs ranged between 0.7 and 34.9% for WGS and 1.1–29.6% for CS. Collectively, 12 high frequency SNPs (> 5%) were identified: four in Rh5 codon 147, 148, 203 and 429, two in p113 at codons 7 and 267 and six in Ripr codons 190, 259, 524, 985, 1003 and 1039.

Conclusion
This study reveals that the majority of the polymorphisms are rare variants and confirms a low level of genetic polymorphisms in all proteins within the Rh5 complex.
Novel CD44-targeting and pH/redox-dual-stimuli-responsive core–shell nanoparticles loading triptolide combats breast cancer growth and lung metastasis
Authors: Shi Jinfeng , Ren Yali , Ma Jiaqi , Luo Xi , Li Jiaxin , Wu Yihan , Gu Huan , Fu Chaomei , Cao Zhixing , Zhang Jinming 
Published: June 2021

Abstract
Background
The toxicity and inefficient delivery of triptolide (TPL) in tumor therapy have greatly limited the clinical application. Thus, we fabricated a CD44-targeting and tumor microenvironment pH/redox-sensitive nanosystem composed of hyaluronic acid-vitamin E succinate and poly (β-amino esters) (PBAEss) polymers to enhance the TPL-mediated suppression of breast cancer proliferation and lung metastasis.

Results
The generated TPL nanoparticles (NPs) had high drug loading efficiency (94.93% ± 2.1%) and a desirable average size (191 nm). Mediated by the PBAEss core, TPL/NPs displayed a pH/redox-dual-stimuli-responsive drug release profile in vitro. Based on the hyaluronic acid coating, TPL/NPs exhibited selective tumor cellular uptake and high tumor tissue accumulation capacity by targeting CD44. Consequently, TPL/NPs induced higher suppression of cell proliferation, blockage of proapoptotic and cell cycle activities, and strong inhibition of cell migration and invasion than that induced by free TPL in MCF-7 and MDA-MB-231 cells. Importantly, TPL/NPs also showed higher efficacy in shrinking tumor size and blocking lung metastasis with decreased systemic toxicity in a 4T1 breast cancer mouse model at an equivalent or lower TPL dosage compared with that of free TPL. Histological immunofluorescence and immunohistochemical analyses in tumor and lung tissue revealed that TPL/NPs induced a high level of apoptosis and suppressed expression of matrix metalloproteinases, which contributed to inhibiting tumor growth and pulmonary metastasis.

Conclusion
Collectively, our results demonstrate that TPL/NPs, which combine tumor active targeting and pH/redox-responsive drug release with proapoptotic and antimobility effects, represent a promising candidate in halting breast cancer progression and metastasis while minimizing systemic toxicity.

Graphic Abstract
Fe-doped chrysotile nanotubes containing siRNAs to silence SPAG5 to treat bladder cancer
Authors: Liu Jianye , Zhang Yi , Zeng Hongliang , Wang Long , Zhang Qun , Wu Pei , Liu Xiaoming , Xie Hongyi , Xiang Wei , Liu Biao , Liu Jiahao , Liu Xuewen , Xie Jianfei , Tang Jin , Long Zhi , He Leye , Xiao Mengqing , Xiang Liang , Cao Ke 
Published: June 2021

Abstract
Background
For certain human cancers, sperm associated antigen 5 (SPAG5) exerts important functions for their development and progression. However, whether RNA interference (RNAi) targeting SPAG5 has antitumor effects has not been determined clinically.

Results
The results indicated that Fe-doped chrysotile nanotubes (FeSiNTs) with a relatively uniform outer diameter (15–25 nm) and inner diameter (7–8 nm), and a length of several hundred nanometers, which delivered an siRNA against the SPAG5 oncogene (siSPAG5) efficiently. The nanomaterials were designed to prolong the half-life of siSPAG5 in blood, increase tumor cell-specific uptake, and maximize the efficiency of SPAG5 silencing. In vitro, FeSiNTs carrying siSPAG5 inhibited the growth, migration, and invasion of bladder cancer cells. In vivo, the FeSiNTs inhibited growth and metastasis in three models of bladder tumors (a tail vein injection lung metastatic model, an in-situ bladder cancer model, and a subcutaneous model) with no obvious toxicities. Mechanistically, we showed that FeSiNTs/siSPAG5 repressed PI3K/AKT/mTOR signaling, which suppressed the growth and progression of tumor cells.

Conclusions
The results highlight that FeSiNTs/siSPAG5 caused no activation of the innate immune response nor any systemic toxicity, indicating the possible therapeutic utility of FeSiNTs/siSPAG5 to deliver siSPAG5 to treat bladder cancer.

Graphic abstract
“If I knew I could get that every hour instead of alcohol, I would take the cannabis”: need and feasibility of cannabis substitution implementation in Canadian managed alcohol programs
Authors: Pauly Bernie , Brown Meaghan , Chow Clifton , Wettlaufer Ashley ,   East Side Illicit Drinkers Group for Education (EIDGE), Graham Brittany , Urbanoski Karen , Callaghan Russell , Rose Cindy , Jordan Michelle , Stockwell Tim , Thomas Gerald , Sutherland Christy 
Published: June 2021

Abstract
Background
While there is robust evidence for strategies to reduce harms of illicit drug use, less attention has been paid to alcohol harm reduction for people experiencing severe alcohol use disorder (AUD), homelessness, and street-based illicit drinking. Managed Alcohol Programs (MAPs) provide safer and regulated sources of alcohol and other supports within a harm reduction framework. To reduce the impacts of heavy long-term alcohol use among MAP participants, cannabis substitution has been identified as a potential therapeutic tool.

Methods
To determine the feasibility of cannabis substitution, we conducted a pre-implementation mixed-methods study utilizing structured surveys and open-ended interviews. Data were collected from MAP organizational leaders (n = 7), program participants (n = 19), staff and managers (n = 17) across 6 MAPs in Canada. We used the Consolidated Framework for Implementation Research (CFIR) to inform and organize our analysis.

Results
Five themes describing feasibility of CSP implementation in MAPs were identified. The first theme describes the characteristics of potential CSP participants. Among MAP participants, 63% (n = 12) were already substituting cannabis for alcohol, most often on a weekly basis (n = 8, 42.1%), for alcohol cravings (n = 15, 78.9%,) and withdrawal (n = 10, 52.6%). Most MAP participants expressed willingness to participate in a CSP (n = 16, 84.2%). The second theme describes the characteristics of a feasible and preferred CSP model according to participants and staff. Participants preferred staff administration of dry, smoked cannabis, followed by edibles and capsules with replacement of some doses of alcohol through a partial substitution model. Themes three and four highlight organizational and contextual factors related to feasibility of implementing CSPs. MAP participants requested peer, social, and counselling supports. Staff requested education resources and enhanced clinical staffing. Critically, program staff and leaders identified that sustainable funding and inexpensive, legal, and reliable sourcing of cannabis are needed to support CSP implementation.

Conclusion
Cannabis substitution was considered feasible by all three groups and in some MAPs residents are already using cannabis. Partial substitution of cannabis for doses of alcohol was preferred. All three groups identified a need for additional supports for implementation including peer support, staff education, and counselling. Sourcing and funding cannabis were identified as primary challenges to successful CSP implementation in MAPs.
Community-based HIV testing in The Netherlands: experiences of lay providers and end users at a rapid HIV test checkpoint
Authors: Krabbenborg Nori , Spijker Ralph , Żakowicz Anna Maria , de Moraes Milo , Heijman Titia , de Coul Eline Op 
Published: June 2021

Abstract
Background
The AIDS Healthcare Foundation (AHF-Checkpoint) in The Netherlands offers rapid HIV testing for key populations by lay providers. We explored the experiences and needs of lay providers and end users of HIV testing at AHF-Checkpoint, taking into account the WHO 5C-(consent, confidentiality, counselling, correct-results, connection-to-care) criteria for HIV test services.

Methods
Qualitative evaluation with 15 semi-structured interviews conducted during 2020 with ten lay providers and five gay or bisexual end users. Recorded interviews were thematically analysed, taking data triangulation into account.

Results
Four domains were identified: (1) accessibility of HIV testing, (2) quality of test procedures, (3) bridging (transitional care), and (4) future strategies for service delivery. AHF-Checkpoint fills a gap for key populations including LGBTQ and refugees, who experience HIV testing barriers at sexual health centres or general practices. The level of trust between lay providers and end users was highly valued by end users. They appreciated the low threshold to test at no costs, and the absence of waiting lists or triaging. Needs expressed by lay providers included more preparedness for emotionally charged situations, and extra training to improve STI knowledge. End users expressed a need for a full STI test package. Of the 5Cs, consent, counselling, and correct results were realised but confidentiality was sometimes difficult to achieve at pop-up locations, and referral barriers for confirmation testing (connection-to-care) were occasionally experienced by lay providers during weekends.

Conclusion
AHF-Checkpoint was described as a convenient and easily accessible service by end users and lay providers. Of the WHO 5Cs, connection-to-care could be optimised to ensure HIV confirmation and STI testing through a liaison approach with professionals from the regular healthcare sector.
A precision medicine classification for treatment of acute myeloid leukemia in older patients
Authors: Mims Alice S. , Kohlschmidt Jessica , Borate Uma , Blachly James S. , Orwick Shelley , Eisfeld Ann-Kathrin , Papaioannou Dimitrios , Nicolet Deedra , Mrόzek Krzysztof , Stein Eytan , Bhatnagar Bhavana , Stone Richard M. , Kolitz Jonathan E. , Wang Eunice S. , Powell Bayard L. , Burd Amy , Levine Ross L. , Druker Brian J. , Bloomfield Clara D. , Byrd John C. 
Published: June 2021

Abstract
Background
Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study.

Methods
We classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes.

Results
Our classification identified core-binding factor and NPM1-mutated/FLT3-ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17–42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%.

Conclusions
By classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies.
Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).
TCP1 regulates PI3K/AKT/mTOR signaling pathway to promote proliferation of ovarian cancer cells
Authors: Weng Huixi , Feng Xiushan , Lan Yu , Zheng Zhiqun 
Published: June 2021

Abstract
Objective
TCP1 is one of the eight subunits of the TCP1 ring complex (TRiC) or the multi-protein mammalian cytosolic chaperone complex. TRiC participates in protein folding and regulates the expression of multiple signaling proteins and cytoskeletal components in cells. Although the clinical importance of its subunits has been clarified in various carcinomas, the function of TCP1 in ovarian cancer (OC) remains unclear. We aimed to identify the association between the expression of TCP1 and the development of epithelial OC (EOC) and patient prognosis, and explore the underlying mechanisms of TCP1 on the tumor progression of OC cells.

Methods
TCP1 protein expression was tested in various ovarian tissues by immunohistochemistry, and the correlation between TCP1 expression and clinical physiologic or pathologic parameters of patients with EOC was analyzed. The relationship between TCP1 expression and the prognosis of patients with OC was investigated and analyzed using the Kaplan–Meier (KM) plotter online database. The expression level of TCP1 was then tested in different OC cell lines by Western blotting. Further, a model using OC cell line A2780 was constructed to study the functions of TCP1 in growth, migration, and invasion of human EOC cells. Finally, the possible regulating signaling pathways were discussed.

Results
TCP1 protein expression in OC or borderline tissues was significantly higher than that in benign ovarian tumors and normal ovarian tissue. The upregulated expression of TCP1 in OC was positively associated with the differentiation grade and FIGO stage of tumors and predicted poor clinical outcomes. Compared with IOSE-80 cells, TCP1 protein was overexpressed in A2780 cells. TCP1 knockdown using shRNA lentivirus inhibited the viability of A2780 cells. Western blotting showed that the phosphatidylinositol-3 kinase (PI3K) signaling pathway was activated in the tumor invasion in EOC driven by TCP1.

Conclusion
Upregulated TCP1 is correlated with the poor prognosis of patients with OC. The mechanism of cancer progression promoted by TCP1 upregulation may be linked to the activation of the PI3K signaling pathway, and TCP1 may serve as a novel target for the treatment of OC.
Development of a method to rapidly assess resistance/susceptibility of Micro-Tom tomatoes to Tomato yellow leaf curl virus via agroinoculation of cotyledons
Authors: Mori Tomoaki , Takenaka Kosuke , Domoto Fumiya , Aoyama Yasuhiro , Sera Takashi 
Published: June 2021

Abstract
Objective
Tomato yellow leaf curl virus (TYLCV) is one of the pathogens severely damaging tomato crops. Therefore, methods to treat or prevent TYLCV infection need to be developed. For this purpose, a method to conveniently and quickly assess infection of tomatoes by TYLCV is desired. In the present study, we established a quick method to evaluate TYLCV infection using cotyledons of Micro-Tom, a miniature tomato cultivar.

Results
First, we constructed a binary plasmid harboring 1.5 copies of the TYLCV genome and transformed Agrobacterium with the plasmid. By injecting agroinoculum from the resulting transformant into the branches of Micro-Tom, we confirmed the susceptibility of Micro-Tom to TYLCV. To shorten the evaluation process of TYLCV infection further, we agroinoculated cotyledons of Micro-Tom 10 days after sowing seeds. We consistently observed typical symptoms of TYLCV infection on true leaves 10 days after agroinoculation. Molecular analysis detected TYLCV progeny DNA in all leaves demonstrating symptoms 6 days after agroinoculation. Therefore, our new protocol enabled assessment of TYLCV infection within 20 days after sowing seeds. Thus, agroinoculation of Micro-Tom cotyledons will accelerate the process of screening TYLCV-resistant Micro-Toms and enable screening of larger numbers of plants more quickly, contributing to the development of TYLCV-resistant tomatoes.
On solutions of nonlinear BVPs with general boundary conditions by using a generalized Riesz–Caputo operator
Authors: Aleem Muhammad , Ur Rehman Mujeeb , Alzabut Jehad , Etemad Sina , Rezapour Shahram 
Published: June 2021

AbstractIn this work, we study the existence, uniqueness, and continuous dependence of solutions for a class of fractional differential equations by using a generalized Riesz fractional operator. One can view the results of this work as a refinement for the existence theory of fractional differential equations with Riemann–Liouville, Caputo, and classical Riesz derivative. Some special cases can be derived to obtain corresponding existence results for fractional differential equations. We provide an illustrated example for the unique solution of our main result.
Analysis of factors contributing to occupational health inequality in Korea: a cross-sectional study using nationally representative survey data
Authors: Noh Eunjeong , Khang Young-Ho 
Published: June 2021

Abstract
Background
Despite the consensus that higher occupational classes tend to have better health and lower mortality rates, one study has reported reversed occupational gradients in mortality rates among Korean men after the economic crisis in the late 2000s. To examine these patterns of health inequality in more detail, we investigated the tendency of occupational gradients in socioeconomic position and multiple pathway indicators known to affect mortality in Korea.

Methods
We used data from 4176 men aged 35–64 in Korea derived from the 2007–2009 and 2013–2015 Korean National Health and Nutrition Examination Surveys. We compared the age-standardized prevalence and age-adjusted mean values of each contributing factor to health inequality among occupational groups, which are divided into upper non-manual workers, lower non-manual workers, manual workers, and others. Contributing factors included childhood and adulthood socioeconomic position indicators, biological risk factors, health behaviors, psychosocial factors, and work environment.

Results
Upper non-manual workers had prominently higher levels of education, income, parental education, and economic activity than lower non-manual and manual workers. The rates of smoking and high-risk alcohol consumption were lower, and the rate of weight control activities was higher, in the non-manual classes. Further, the rates of depression and suicidal ideation were lower, and perceptions of the work environment were more favorable, among non-manual workers than among their manual counterparts.

Conclusions
We detected occupational inequality in a wide range of socioeconomic positions and pathway indicators in Korea with consistently favorable patterns for upper non-manual workers. These occupational gradients do not support the previously reported reversed pattern of higher mortality rates in non-manual groups versus in the manual job class in Korea.
Effects of stand density on soil respiration and labile organic carbon in different aged Larix principis-rupprechtii plantations
Authors: Liu Tairui , Peng Daoli , Tan Zhijie , Guo Jinping , Zhang Yunxiang 
Published: June 2021

AbstractBackgroundThe carbon pools of forest soils play a vital role in global carbon sequestration and emissions. Forest management can regulate the sequestration and output of forest soil carbon pools to a certain extent; however, the kinetics of the effects of forest density on soil carbon pools require further investigation.MethodsWe established sample plots with stand density gradients in three different agedLarix principis-rupprechtiiplantations and quantified the soil respiration, soil organic carbon (SOC), soil dissolved organic carbon (DOC), microbial biomass carbon (MBC), light fraction organic carbon (LFOC), and readily oxidized carbon (ROC).Results and conclusionsDuring the growth and development of plantations, stand density is an essential factor that impacts soil respiration and its associated elements. Moderate density was observed to promote both the soil and heterotrophic respiration rates and the sequestration of MBC and LFOC, whereas it inhibited the sequestration of ROC. The soil, heterotrophic, and autotrophic respiration rates of older forest stands were relatively rapid, whereas the contents of SOC, MBC, LFOC, DOC, and ROC were higher and more sensitive to changes in stand density. The MBC, LFOC, and ROC in soil labile organic carbon were closely related to both the soil and heterotrophic respiration, but not the SOC. Among them, the LFOC and MBC played the roles of “warehouse” and “tool” and were significantly correlated with soil and heterotrophic respiration. The ROC, as a “raw material”, exhibited a significantly negative correlation with the soil and heterotrophic respiration. When the soil and heterotrophic respiration rates were rapid, the ROC content in the soil maintained the low level of a “dynamically stabilized” state. The stand density regulated heterotrophic respiration by affecting the soil labile organic carbon, which provided an essential path for the stand density to regulate soil respiration.