bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pathogen-specific structural features of
Candida albicans
Ras1 activation complex: uncovering new antifungal drug targets
Authors: Manso José A. , Carabias Arturo , Sárkány Zsuzsa , de Pereda José M. , Pereira Pedro José Barbosa , Macedo-Ribeiro Sandra 
Published: August 2023

ABSTRACT

An important feature associated with
Candida albicans
pathogenicity is its ability to switch between yeast and hyphal forms, a process in which CaRas1 plays a key role. CaRas1 is activated by the guanine nucleotide exchange factor (GEF) CaCdc25, triggering hyphal growth-related signaling pathways through its conserved GTP-binding (G)-domain. An important function in hyphal growth has also been proposed for the long hypervariable region downstream the G-domain, whose unusual content of polyglutamine stretches and Q/N repeats make CaRas1 unique within Ras proteins. Despite its biological importance, both the structure of CaRas1 and the molecular basis of its activation by CaCdc25 remain unexplored. Here, we show that CaRas1 has an elongated shape and limited conformational flexibility and that its hypervariable region contains helical structural elements, likely forming an intramolecular coiled-coil. Functional assays disclosed that CaRas1-activation by CaCdc25 is highly efficient, with activities up to 2,000-fold higher than reported for human GEFs. The crystal structure of the CaCdc25 catalytic region revealed an active conformation for the α-helical hairpin, critical for CaRas1-activation, unveiling a specific region exclusive to CTG-clade species. Structural studies on CaRas1/CaCdc25 complexes also revealed an interaction surface clearly distinct from that of homologous human complexes. Furthermore, we identified an inhibitory synthetic peptide, prompting the proposal of a key regulatory mechanism for CaCdc25. To our knowledge, this is the first report of specific inhibition of the CaRas1-activation via targeting its GEF. This, together with their unique pathogen-structural features, disclose a set of novel strategies to specifically block this important virulence-related mechanism.

IMPORTANCE

Candida albicans
is the main causative agent of candidiasis, the commonest fungal infection in humans. The eukaryotic nature of
C. albicans
and the rapid emergence of antifungal resistance raise the challenge of identifying novel drug targets to battle this prevalent and life-threatening disease. CaRas1 and CaCdc25 are key players in the activation of signaling pathways triggering multiple virulence traits, including the yeast-to-hypha interconversion. The structural similarity of the conserved G-domain of CaRas1 to those of human homologs and the lack of structural information on CaCdc25 has impeded progress in targeting these proteins. The unique structural and functional features for CaRas1 and CaCdc25 presented here, together with the identification of a synthetic peptide capable of specifically inhibiting the GEF activity of CaCdc25, open new possibilities to uncover new antifungal drug targets against
C. albicans
virulence.
Isolation and genome sequencing of five lytic bacteriophages from hospital wastewater in the Philippines
Authors: Nada Michael Angelou L. , Ancla Joseph B. , Yadao Nikka Mae R. , de Paz Virgilio P. , Manalaysay Jessica G. , Samante Fred Lawrence D. , Bigol Ursela G. 
Published: August 2023

ABSTRACT

Here, we report the genome sequences of five bacteriophages isolated from hospital wastewater, including two new species and two candidates for therapeutic application. No virulence, temperate marker and antibiotic resistance genes were found in the genomes of
Escherichia
phage vB_VIPECOOM03 and
Klebsiella
phage vB_VIPKPNUMC01, making them suitable candidate for therapy.
Restoration of right ventricular function in the treatment of pulmonary arterial hypertension
Authors: Celant Lucas R , Wessels Jeroen N , Kianzad Azar , Marcus J Tim , Meijboom Lilian J , Bogaard Harm Jan , de Man Frances S , Vonk Noordegraaf Anton 
Published: August 2023

ObjectiveA 45% threshold of right ventricular ejection fraction (RVEF) is proposed clinically relevant in patients with pulmonary arterial hypertension (PAH). We aim to determine treatment response, long-term right ventricular (RV) functional stability and prognosis of patients with PAH reaching or maintaining the RVEF 45% threshold.MethodsIncident, treatment-naive, adult PAH patients with cardiac magnetic resonance imaging at baseline and first follow-up were included (total N=127) and followed until date of censoring or death/lung transplantation. Patients were categorised into two groups based on 45% RVEF. Baseline predictors, treatment response and prognosis were assessed with logistic regression analyses, two-way analysis of variance and log-rank tests.ResultsPatients were 50±17 years old, 73% female, of which N=75 reached or maintained the 45% RVEF threshold at follow-up (RVEF≥45%@FU), while N=52 patients did not (RVEF<45%@FU). RV end-diastolic volume and N-terminal pro-B-type natriuretic peptide at baseline were multivariable predictors of an RVEF ≥45% at follow-up. A 40% pulmonary vascular resistance (PVR) reduction resulted in greater improvement in RV function (ΔRVEF 17±11 vs. 5±8; pinteraction<0.001) compared to a PVR reduction <40%, but did not guarantee an RVEF ≥45%. Finally, the 45% RVEF threshold was associated with stable RV function during long-term follow-up and better survival (HR: 1.91 (95% CI: 1.11 to 3.27)). Patients failing to reach or maintain the 45% RVEF threshold at first follow-up mostly stayed below this threshold over the next consecutive visits.ConclusionAfter treatment initiation, 60% of patients with PAH reach or maintain the 45% RVEF threshold, which is associated with a long-term stable RV function and favourable prognosis.
Ethnic inequalities in positive SARS-CoV-2 tests, infection prognosis, COVID-19 hospitalisations and deaths: analysis of 2 years of a record linked national cohort study in Scotland
Authors: Amele Sarah , Kibuchi Eliud , McCabe Ronan , Pearce Anna , Henery Paul , Hainey Kirsten , Fagbamigbe Adeniyi Francis , Kurdi Amanj , McCowan Colin , Simpson Colin R , Dibben Chris , Buchanan Duncan , Demou Evangelia , Almaghrabi Fatima , Anghelescu Gina , Taylor Harry , Tibble Holly , Rudan Igor , Nazroo James , Bécares Laia , Daines Luke , Irizar Patricia , Jayacodi Sandra , Pattaro Serena , Sheikh Aziz , Katikireddi Srinivasa Vittal 
Published: August 2023

BackgroundThis study aims to estimate ethnic inequalities in risk for positive SARS-CoV-2 tests, COVID-19 hospitalisations and deaths over time in Scotland.MethodsWe conducted a population-based cohort study where the 2011 Scottish Census was linked to health records. We included all individuals ≥ 16 years living in Scotland on 1 March 2020. The study period was from 1 March 2020 to 17 April 2022. Self-reported ethnic group was taken from the census and Cox proportional hazard models estimated HRs for positive SARS-CoV-2 tests, hospitalisations and deaths, adjusted for age, sex and health board. We also conducted separate analyses for each of the four waves of COVID-19 to assess changes in risk over time.FindingsOf the 4 358 339 individuals analysed, 1 093 234 positive SARS-CoV-2 tests, 37 437 hospitalisations and 14 158 deaths occurred. The risk of COVID-19 hospitalisation or death among ethnic minority groups was often higher for White Gypsy/Traveller (HR 2.21, 95% CI (1.61 to 3.06)) and Pakistani 2.09 (1.90 to 2.29) groups compared with the white Scottish group. The risk of COVID-19 hospitalisation or death following confirmed positive SARS-CoV-2 test was particularly higher for White Gypsy/Traveller 2.55 (1.81–3.58), Pakistani 1.75 (1.59–1.73) and African 1.61 (1.28–2.03) individuals relative to white Scottish individuals. However, the risk of COVID-19-related death following hospitalisation did not differ. The risk of COVID-19 outcomes for ethnic minority groups was higher in the first three waves compared with the fourth wave.InterpretationMost ethnic minority groups were at increased risk of adverse COVID-19 outcomes in Scotland, especially White Gypsy/Traveller and Pakistani groups. Ethnic inequalities persisted following community infection but not following hospitalisation, suggesting differences in hospital treatment did not substantially contribute to ethnic inequalities.
Treatment with intravenous alteplase in ischaemic stroke patients with onset time between 4.5 and 24 hours (HOPE): protocol for a randomised, controlled, multicentre study
Authors: Luo Zhongyu , Zhou Ying , He Yaode , Yan Shenqiang , Chen Zhicai , Zhang Xuting , Chen Yi , Tong Lu-Sha , Zhong Wansi , Hu Haitao , Zhang Kemeng , Yang Jiansheng , Campbell Bruce C V , Lou Min 
Published: August 2023

Background
While intravenous thrombolysis is recommended for patients who had an acute ischaemic stroke (AIS) within 4.5 hours of symptom onset, there are few randomised trials investigating the benefits of thrombolysis beyond this therapeutic window.

Aim
To determine whether patients who had an AIS selected with the presence of potentially salvageable tissue on CT perfusion at 4.5–24 hours after stroke onset (for stroke with unknown onset time, the midpoint of the time last known to be well and symptom recognition time; for wake-up stroke, the midpoint of the time last known to be well or sleep onset and wake up time) will benefit from intravenous thrombolysis.

Design
HOPE is a prospective, multicentre, randomised, open-label blinded endpoint trial with the stage of phase III. The treatment allocation employs 1:1 randomisation. The treatment arm under investigation is alteplase with standard therapy, the control arm is standard therapy. Eligibility imaging criteria include ischaemic core volume ≤70 mL, penumbra ≥10 mL and mismatch ≥20%.

Study outcomes
The primary outcome is non-disabled functional outcome (assessed as modified Rankin Scale score of 0–1 at 90 days).

Discussion
HOPE is the first trial to investigate whether intravenous thrombolysis with alteplase offers benefits in patients who had an AIS presenting within 4.5–24 hours, which has the potential to extend time window and expand eligible population for thrombolysis therapy.
Not All Populations of Hispanic Children Have an Increased Frequency of Acute Lymphoblastic Leukemia
Authors: Mejía-Aranguré Juan Manuel , Núñez-Enríquez Juan Carlos 
Published: August 2023

Abstract
The frequency of acute lymphoblastic leukemia (ALL) has been reported with a higher incidence among the populations of Hispanic children. However, in the article by Montes-Rodríguez and colleagues, they found that in the Puerto Rican population, the frequency was below the incidence reported for the U.S. Hispanic pediatric population, but they found that the incidence of ALL had an annual increase of 5%. In other Hispanic pediatric populations during the 1980s, the incidence of ALL was found to be even lower than the general rate in the United States. However, in less than 20 years that incidence had already been exceeded. It is evident that the Hispanic pediatric population is more susceptible to develop ALL than other populations, so it is important to consider that what is happening to the pediatric population of Puerto Rico gives us a great opportunity to identify risk factors that could potentially explain this increase. It is more likely that the risk factors that are capable of causing ALL could be identified in their role in the origin of the disease in populations with high susceptibility, given the greater number of cases of ALL that said factor is causing in that population.
See related article by Montes-Rodríguez et al., p. 1030
Specific Targeting of Multiple Myeloma by Dual Split-signaling Chimeric Antigen Receptor T cells Directed against CD38 and CD138
Authors: van der Schans Jort J. , Wang Ziyu , van Arkel Jennemiek , van Schaik Thijs , Katsarou Afroditi , Ruiter Ruud , Baardemans Thomas , Yuan Huipin , de Bruijn Joost , Zweegman Sonja , van de Donk Niels W.C.J. , Groen Richard W.J. , Themeli Maria , Mutis Tuna 
Published: August 2023

Abstract

Purpose:
The success of B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells illustrates the potential of this novel therapy for multiple myeloma. Nonetheless, broadening CAR T-cell therapy beyond BCMA requires inventive strategies as there are only a few multiple myeloma– or plasma cell–specific target antigens. We investigated the feasibility of achieving multiple myeloma specificity by dual-split CD38/CD138 CAR targeting, whereby the stimulatory and costimulatory signals for T-cell activation are split into two separate stimulatory (sCAR) and costimulatory CARs (cCAR).

Experimental Design:
Using various combinations of CD38 and CD138 sCARs and cCARs with different affinities, we generated several dual-split CAR T cells and analyzed them for multiple myeloma–specific effector functions in vitro. The best-functioning CAR T cells were tested in vivo in a murine xenograft model.

Results:
We found optimal designs of both CD38sCAR/CD138cCAR and CD138sCAR/CD38cCAR combinations, that effectively lysed multiple myeloma cells but spared single CD38- or CD138-positive healthy hematopoietic cells. While the CD38sCAR/CD138cCAR T cells achieved multiple myeloma–specific activity solely due to the low affinity of the CD38sCARs, the multiple myeloma–specific cytotoxicity, cytokine release, and proliferation of CD138sCAR/CD38cCAR T cells were established through a true combinatorial stimulatory and costimulatory effect. The most optimal combination comprised a low-affinity CD138sCAR combined with a high-affinity CD38cCAR. These CD138sCAR/CD38cCAR T cells also showed dual-antigen specific anti–multiple myeloma effects in vivo. Importantly, they were also effective against multiple myeloma cells from daratumumab pretreated patients with decreased CD38 expression levels.

Conclusions:
We demonstrate the possibility to specifically target multiple myeloma cells, even after CD38 targeted therapy, with carefully-designed dual-split CARs directed against CD38 and CD138.
Cotargeting Phosphoinositide 3-Kinase and Focal Adhesion Kinase Pathways Inhibits Proliferation of NF2 Schwannoma Cells
Authors: Hardin Haley M. , Dinh Christine T. , Huegel Julianne , Petrilli Alejandra M. , Bracho Olena , Allaf Abdulrahman M. , Karajannis Matthias A. , Griswold Anthony J. , Ivan Michael E. , Morcos Jacques , Gultekin Sakir H. , Telischi Fred F. , Liu Xue Zhong , Fernandez-Valle Cristina 
Published: August 2023

Abstract
Neurofibromatosis Type 2 (NF2) is a tumor predisposition syndrome caused by germline inactivating mutations in the NF2 gene encoding the merlin tumor suppressor. Patients develop multiple benign tumor types in the nervous system including bilateral vestibular schwannomas (VS). Standard treatments include surgery and radiation therapy, which may lead to loss of hearing, impaired facial nerve function, and other complications. Kinase inhibitor monotherapies have been evaluated clinically for NF2 patients with limited success, and more effective nonsurgical therapies are urgently needed. Schwannoma model cells treated with PI3K inhibitors upregulate activity of the focal adhesion kinase (FAK) family as a compensatory survival pathway. We screened combinations of 13 clinically relevant PI3K and FAK inhibitors using human isogenic normal and merlin-deficient Schwann cell lines. The most efficacious combination was PI3K/mTOR inhibitor omipalisib with SRC/FAK inhibitor dasatinib. Sub-GI50 doses of the single drugs blocked phosphorylation of their major target proteins. The combination was superior to either single agent in promoting a G1 cell-cycle arrest and produced a 44% decrease in tumor growth over a 2-week period in a pilot orthotopic allograft model. Evaluation of single and combination drugs in six human primary VS cell models revealed the combination was superior to the monotherapies in 3 of 6 VS samples, highlighting inter-tumor variability between patients consistent with observations from clinical trials with other molecular targeted agents. Dasatinib alone performed as well as the combination in the remaining three samples. Preclinically validated combination therapies hold promise for NF2 patients and warrants further study in clinical trials.
Exon Junction Complex Mediates the Cap-Independent Translation of Circular RNA
Authors: Lin Hui-Hsuan , Chang Chiu-Yuan , Huang Yi-Ren , Shen Che-Hung , Wu Yu-Chen , Chang Kai-Li , Lee Yueh-Chun , Lin Ya-Chi , Ting Wen-Chien , Chien Han-Ju , Zheng Yi-Feng , Lai Chien-Chen , Hsiao Kuei-Yang 
Published: August 2023

Abstract

Evidence that circular RNAs (circRNA) serve as protein template is accumulating. However, how the cap-independent translation is controlled remains largely uncharacterized. Here, we show that the presence of intron and thus splicing promote cap-independent translation. By acquiring the exon junction complex (EJC) after splicing, the interaction between circRNA and ribosomes was promoted, thereby facilitating translation. Prevention of splicing by treatment with spliceosome inhibitor or mutating splicing signal hindered cap-independent translation of circRNA. Moreover, EJC-tethering using Cas13 technology reconstituted EJC-dependent circRNA translation. Finally, the level of a coding circRNA from succinate dehydrogenase assembly factor 2 (circSDHAF2) was found to be elevated in the tumorous tissues from patients with colorectal cancer, and shown to be critical in tumorigenesis of colorectal cancer in both cell and murine models. These findings reveal that EJC-dependent control of circSDHAF2 translation is involved in the regulation of oncogenic pathways.

Implications:
EJC-mediated cap-independent translation of circRNA is implicated in the tumorigenesis of colorectal cancer.
Reaction of soybean cultivars to two races of Meloidogyne enterolobii and their aggressiveness under plastic house conditions
Authors: Verssiani Jorge B.S. , Souza Caio F.B. , Santos Paulo S. , Arias Carlos A.A. , Cares Juvenil E. , Carneiro Regina M.D.G. 
Published: August 2023

Summary
Limited information is available regarding the susceptibility or resistance of soybean cultivars to Meloidogyne enterolobii. Recently, a new race of this species was detected in Brazil parasitising cotton and soybean. This nematode has the potential to pose a problem in both of these crops, since it is pathogenic and virulent to several economically important plants that have resistance genes to other Meloidogyne species. The aim of this study was to assess the responses of EMBRAPA’s main soybean cultivars with confirmed resistance to M. incognita and M. javanica to the two races of M. enterolobii detected in Brazil. Additionally, this study aimed to characterise the aggressiveness of these nematode races. The experiments were conducted in a plastic house, in a factorial scheme with 16 soybean cultivars × two M. enterolobii races (guava and cotton), totalling 32 treatments × eight replications, and evaluated with two replications over time. Soybean sowing took place in pots containing 1.7 l of a mixture of soil, sand and Bioplant® substrate (1:1:1), previously autoclaved. Each soybean plant was inoculated with 5000 eggs of M. enterolobii. After 75 days for the first experiment, and 90 days for the second, the following variables were evaluated: gall index (GI), egg mass index (EMI), total number of eggs per g root (NEGR) and the reproduction factor (RF). Both races of M. enterolobii showed reproductive ability in all soybean genotypes (with or without known genetic resistance), albeit with moderate to low values in comparison to their reproduction on tomato plants. The race from cotton was considered statistically more aggressive than the guava population on soybean cultivars. Only ‘BRS 7180 IPRO’ was moderately resistant to both races in both experiments. In view of the importance and prospects for expansion of the soybean crop, the findings of this study contribute to a better understanding of the resistance and aggressiveness exhibited by the two races of M. enterolobii, Moreover, the study highlights the significant challenge that lies ahead in developing breeding programmes to select soybean genotypes with multiple resistance to Meloidogyne spp.
Aphelenchoides tenuis n. sp. (Tylenchina: Aphelenchoididae) found in loblolly pine logs imported from the USA
Authors: Gu Jianfeng , Fang Yiwu , Ma Xinxin , Sánchez-Monge Alcides 
Published: August 2023

Summary
Aphelenchoides tenuis n. sp. found in loblolly pine (Pinus taeda L.) logs imported from the USA, is described. It is characterised by a very slim body (a = 56.8 (45.8-67.2) and 49.1 (42.2-54.2) in males and females, respectively), three incisures in the lateral field, short stylet (9-12 μm), the excretory pore located at the level of nerve ring, the vagina is not sclerotised, the vulva has slightly protruding lips and lacks a flap and the post-uterine sac is well developed, forming ca 36.2 (28.4-48.2)% of the vulva to anus distance. The spicules are smoothly arcuate, the apex and rostrum are rounded and well developed, and the dorsal limb is 23.3 (21.1-25.5) μm long, without a hook-like structure at the distal tip. The male tail bears three pairs (2 + 2 + 2) of caudal papillae. The tail of both sexes is sub-cylindrical, the terminus bearing a bluntly pointed mucron with tiny nodular protuberances. The new species belongs to the Group 2 category of Aphelenchoides species sensu Shahina and is defined as A2-B1/2-C1-D1/2-E2-F2/3 according to the categorisation codes of OEPP/EPPO. Phylogenetic analysis based on 18S and 28S D2-D3 of rDNA, along with ITS and mtCOI, confirmed its status as a new species.
Economic Governance Quality and Effective Taxation System in Africa
Authors: Bekana Dejene M. 
Published: August 2023

Abstract
The study aims at examining the effect of Economic governance institutions on tax revenue mobilization using an empirical panel dataset from 30 African countries for the period 1996–2018. The empirical estimation methods employed in this study is based on Quantile Regression techniques. To this end, one bundled economic governance institution indicator (i.e., general economic governance) is employed. The inspiration for this estimation technique is based on two fundamental reasons. First, the argument that the effect of governance quality on taxation effectiveness is contingent on the existing level of tax revenue mobilization. Second, the economic governance – tax revenue mobilization policies, to be effective, need to be tailored differently across countries with low, intermediate and high levels of tax mobilization effort. The general findings are as follows: First, development in economic governance institutions promotes tax mobilization effort. Second, the effect of economic governance is stronger in terms of significance and magnitude for direct taxes than for indirect taxes. Third, in most of the cases, the impact of economic governance institutions is higher in terms of magnitude in the upper quantiles of the economic governance distributions. The results remain robust over alternative econometric estimation techniques.
Angels of Destruction (Mal’akhei Ḥabalah): Two Millennia of Jewish Horror
Authors: Kabalek Kobi , Zinger Nimrod 
Published: August 2023

Abstract
This article traces the meanings and uses of the Hebrew concept mal’akhei ḥabalah [angels of destruction], a common designation for monsters that has been mentioned in Jewish texts for over two millennia. Thus far, scholars have considered mal’akhei ḥabalah only in isolated contexts. In contrast, we examine these monsters’ long history, which provided Jews with familiar horror images and figures to visualize and embody experienced and anticipated fears and threats. We argue that Jewish references to them were intended to horrify in order to deter people from sin and to express God’s might and authority, thus maintaining religious and communal order in Jewish societies. At the same time, mal’akhei ḥabalah were used to articulate the crises that threatened and challenged the existing social and political order. Although mal’akhei ḥabalah developed within religious interpretations, by the modern era they expanded their applications and relevance for various avenues of Jewish life.