bluuebunny/crossref_metadata_2025 huggingface dataset:
A novel nuclear receptor subfamily enlightens the origin of heterodimerization
Authors: Beinsteiner Brice , Markov Gabriel V. , Bourguet Maxime , McEwen Alastair G. , Erb Stéphane , Patel Abdul Kareem Mohideen , El Khaloufi El Khaddar Fatima Z. , Lecroisey Claire , Holzer Guillaume , Essabri Karim , Hazemann Isabelle , Hamiche Ali , Cianférani Sarah , Moras Dino , Laudet Vincent , Billas Isabelle M. L.
Published: October 2022

Background

Nuclear receptors are transcription factors of central importance in human biology and associated diseases. Much of the knowledge related to their major functions, such as ligand and DNA binding or dimerization, derives from functional studies undertaken in classical model animals. It has become evident, however, that a deeper understanding of these molecular functions requires uncovering how these characteristics originated and diversified during evolution, by looking at more species. In particular, the comprehension of how dimerization evolved from ancestral homodimers to a more sophisticated state of heterodimers has been missing, due to a too narrow phylogenetic sampling. Here, we experimentally and phylogenetically define the evolutionary trajectory of nuclear receptor dimerization by analyzing a novel NR7 subgroup, present in various metazoan groups, including cnidarians, annelids, mollusks, sea urchins, and amphioxus, but lost in vertebrates, arthropods, and nematodes.

Results

We focused on NR7 of the cephalochordate amphioxus B. lanceolatum. We present a complementary set of functional, structural, and evolutionary analyses that establish that NR7 lies at a pivotal point in the evolutionary trajectory from homodimerizing to heterodimerizing nuclear receptors. The crystal structure of the NR7 ligand-binding domain suggests that the isolated domain is not capable of dimerizing with the ubiquitous dimerization partner RXR. In contrast, the full-length NR7 dimerizes with RXR in a DNA-dependent manner and acts as a constitutively active receptor. The phylogenetic and sequence analyses position NR7 at a pivotal point, just between the basal class I nuclear receptors that form monomers or homodimers on DNA and the derived class II nuclear receptors that exhibit the classical DNA-independent RXR heterodimers.

Conclusions

Our data suggest that NR7 represents the “missing link” in the transition between class I and class II nuclear receptors and that the DNA independency of heterodimer formation is a feature that was acquired during evolution. Our studies define a novel paradigm of nuclear receptor dimerization that evolved from DNA-dependent to DNA-independent requirements. This new concept emphasizes the importance of DNA in the dimerization of nuclear receptors, such as the glucocorticoid receptor and other members of this pharmacologically important oxosteroid receptor subfamily. Our studies further underline the importance of studying emerging model organisms for supporting cutting-edge research.
Prophylactic cranial irradiation (PCI) versus active surveillance in patients with limited-stage small cell lung cancer: a retrospective, multicentre study
Authors: Chen Yu , Wang Yao , Ren Fei , Huang Zhaoqin , Tan Bingxu , Zhao Zhonghua , Yu Xinshuang , Dong Peng , Yu Jinming , Meng Xiangjiao
Published: October 2022

Background

The recommendation of PCI for limited-stage small cell lung cancer (LS-SCLC) is primarily based on evidence from the pre-magnetic resonance imaging (MRI) era. However, as MRI accuracy improves and stereotactic radiosurgery advances, the role of PCI for LS-SCLC has become uncertain. This study aims to compare the contemporary survival outcomes of patients with LS-SCLC treated with PCI versus active surveillance.

Methods

We conducted a retrospective cohort study in which 1068 patients with LS-SCLC who achieved a good response to first-line chemoradiotherapy were consecutively enrolled from 5 tertiary medical centres between June 2009 and June 2019. Of these patients, 440 received PCI, while 628 received surveillance without PCI. Propensity score matching with a 1:1 ratio was performed to balance the baseline characteristics of the two cohorts. The endpoints were overall survival (OS) and the incidence of brain metastasis (BM).

Results

In total, 648 patients were matched. The baseline characteristics were generally well balanced. At a median follow-up of 64.5 months (range 2–190), patients who underwent PCI had a significantly lower risk for BM than those who underwent surveillance. The 3-year cumulative incidence rate of BM was 28.2% (95% CI 22.5–33.8%) in the PCI cohort and 38.5% (32.6–44.5%) in the surveillance cohort (Gray’s p = 0.002). However, the lower incidence of BM in the PCI cohort did not translate into a significant extension of OS. The median OS was 35.8 months (95% CI 27.6–44.0 months) in the PCI cohort versus 32 months (26.4–37.6 months) in the surveillance cohort (HR 0.90, 95% CI 0.74–1.10, p = 0.29). Multivariable analysis showed that disease stage, chemoradiotherapy sequence, and response to chemoradiotherapy were independent prognostic factors for BM or OS.

Conclusions

Overall, PCI reduces the risk for BM but does not substantially prolong OS compared with active surveillance. A phase 3, prospective clinical trial (NCT04829708) we initiated is currently underway, which is expected to corroborate our results.
Six decades of malaria vector control in southern Africa: a review of the entomological evidence-base
Authors: Nkya Theresia Estomih , Fillinger Ulrike , Sangoro Onyango P. , Marubu Rose , Chanda Emmanuel , Mutero Clifford Maina
Published: October 2022

Background

Countries in the southern Africa region have set targets for malaria elimination between 2020 and 2030. Malaria vector control is among the key strategies being implemented to achieve this goal. This paper critically reviews published entomological research over the past six decades in three frontline malaria elimination countries namely, Botswana Eswatini and Namibia, and three second-line malaria elimination countries including Mozambique, Zambia, and Zimbabwe. The objective of the review is to assess the current knowledge and highlight gaps that need further research attention to strengthen evidence-based decision-making toward malaria elimination.

Methods

Publications were searched on the PubMed engine using search terms: “(malaria vector control OR vector control OR malaria vector*) AND (Botswana OR Swaziland OR Eswatini OR Zambia OR Zimbabwe OR Mozambique)”. Opinions, perspectives, reports, commentaries, retrospective analysis on secondary data protocols, policy briefs, and reviews were excluded.

Results

The search resulted in 718 publications with 145 eligible and included in this review for the six countries generated over six decades. The majority (139) were from three countries, namely Zambia (59) and Mozambique (48), and Zimbabwe (32) whilst scientific publications were relatively scanty from front-line malaria elimination countries, such as Namibia (2), Botswana (10) and Eswatini (4). Most of the research reported in the publications focused on vector bionomics generated mostly from Mozambique and Zambia, while information on insecticide resistance was mostly available from Mozambique. Extreme gaps were identified in reporting the impact of vector control interventions, both on vectors and disease outcomes. The literature is particularly scanty on important issues such as change of vector ecology over time and space, intervention costs, and uptake of control interventions as well as insecticide resistance.

Conclusions

The review reveals a dearth of information about malaria vectors and their control, most noticeable among the frontline elimination countries: Namibia, Eswatini and Botswana. It is of paramount importance that malaria vector research capacity and routine entomological monitoring and evaluation are strengthened to enhance decision-making, considering changing vector bionomics and insecticide resistance, among other determinants of malaria vector control.
CDK1 serves as a therapeutic target of adrenocortical carcinoma via regulating epithelial–mesenchymal transition, G2/M phase transition, and PANoptosis
Authors: Ren Liwen , Yang Yihui , Li Wan , Zheng Xiangjin , Liu Jinyi , Li Sha , Yang Hong , Zhang Yizhi , Ge Binbin , Zhang Sen , Fu Weiqi , Dong Dexin , Du Guanhua , Wang Jinhua
Published: October 2022

Background

Adrenocortical carcinoma (ACC) is an extremely rare, aggressive tumor with few effective therapeutic options or drugs. Mitotane (Mtn), which is the only authorized therapeutic drug, came out in 1970 and is still the only first-line treatment for ACC in spite of serious adverse reaction and a high recurrence rate.

Methods

By in silico analysis of the ACC dataset in the cancer genome atlas (TCGA), we determined that high expression levels of cyclin-dependent kinase-1 (CDK1) were significantly related to the adverse clinical outcomes of ACC. In vitro and in vivo experiments were performed to evaluate the role of CDK1 in ACC progression through gain and loss of function assays in ACC cells. CDK1 inhibitors were screened to identify potential candidates for the treatment of ACC. RNA sequencing, co-immunoprecipitation, and immunofluorescence assays were used to elucidate the mechanism.

Results

Overexpression of CDK1 in ACC cell lines promoted proliferation and induced the epithelial-to-mesenchymal transition (EMT), whereas knockdown of CDK1 expression inhibited growth of ACC cell lines. The CDK1 inhibitor, cucurbitacin E (CurE), had the best inhibitory effect with good time-and dose-dependent activity both in vitro and in vivo. CurE had a greater inhibitory effect on ACC xenografts in nude mice than mitotane, without obvious adverse effects. Most importantly, combined treatment with CurE and mitotane almost totally eliminated ACC tumors. With respect to mechanism, CDK1 facilitated the EMT of ACC cells via Slug and Twist and locked ACC cells into the G2/M checkpoint through interaction with UBE2C and AURKA/B. CDK1 also regulated pyroptosis, apoptosis, and necroptosis (PANoptosis) of ACC cells through binding with the PANoptosome in a ZBP1-dependent way.

Conclusions

CDK1 could be exploited as an essential therapeutic target of ACC via regulating the EMT, the G2/M checkpoint, and PANoptosis. Thus, CurE may be a potential candidate drug for ACC therapy with good safety and efficacy, which will meet the great need of patients with ACC.
Comprehensive characterization of ubiquitinome of human colorectal cancer and identification of potential survival-related ubiquitination
Authors: Zhang Wei , Yang Yan , Lin Liewen , He Jingquan , Dong Jingjing , Yan Bin , Cai Wanxia , Chen Yumei , Yin Lianghong , Tang Donge , Liu Fanna , Dai Yong
Published: October 2022

Background

According to the Global Cancer Statistics in 2020, the incidence and mortality of colorectal cancer (CRC) rank third and second among all tumors. The disturbance of ubiquitination plays an important role in the initiation and development of CRC, but the ubiquitinome of CRC cells and the survival-relevant ubiquitination are poorly understood.

Methods

The ubiquitinome of CRC patients (n = 6) was characterized using our own data sets of proteomic and ubiquitin-proteomic examinations. Then, the probable survival-relevant ubiquitination was searched based on the analyses of data sets from public databases.

Results

For the ubiquitinomic examination, we identified 1690 quantifiable sites and 870 quantifiable proteins. We found that the highly-ubiquitinated proteins (n ≥ 10) were specifically involved in the biological processes such as G-protein coupling, glycoprotein coupling, and antigen presentation. Also, we depicted five motif sequences frequently recognized by ubiquitin. Subsequently, we revealed that the ubiquitination content of 1172 proteins were up-regulated and 1700 proteins were down-regulated in CRC cells versus normal adjacent cells. We demonstrated that the differentially ubiquitinated proteins were relevant to the pathways including metabolism, immune regulation, and telomere maintenance. Then, integrated with the proteomic datasets from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) (n = 98), we revealed that the increased ubiquitination of FOCAD at Lys583 and Lys587 was potentially associated with patient survival. Finally, we depicted the mutation map of FOCAD and elucidated its potential functions on RNA localization and translation in CRC.

Conclusions

The findings of this study described the ubiquitinome of CRC cells and identified abnormal ubiquitination(s) potentially affecting the patient survival, thereby offering new probable opportunities for clinical treatment.
Loss of endothelial EMCN drives tumor lung metastasis through the premetastatic niche
Authors: Zhang Guoxin , Li Mengyuan , Zhou Dandan , Yang Xingjiu , Zhang Wenlong , Gao Ran
Published: October 2022

Background

Metastasis is the primary cause of cancer-related mortality. Metastasis involves a complex multistep process during which individual tumor cells spread primarily through destruction of the endothelial barrier, entering the circulatory system to colonize distant organs. However, the role of the endothelial barrier as the rate-limiting process in tumor metastasis and how these processes affect the regulation of the host microenvironment at the molecular level are poorly understood.

Methods

Here, we analyzed differentially expressed genes in breast cancer and lung adenocarcinoma, including metastatic and recurrent specimens, using TCGA dataset. The effects of EMCN on endothelial cells in vitro and in vivo were analyzed by assessing angiogenesis and vascular permeability, respectively. We established a syngeneic mouse model of endothelial cell-specific knockout of EMCN (EMCNecko) to study the role of EMCN in tumor growth and metastasis. Transcriptome sequencing, Western blotting, qPCR and immunofluorescence confirmed important factors in the premetastatic niche. A mouse model of allograft tumor resection with lung metastasis was established to confirm the therapeutic effect of a notch inhibitor combined with an anti-TGF-β antibody.

Results

We found a strong correlation of EMCN deficiency with tumor recurrence and metastasis. Comparative experiments in WT and EMCNecko mice revealed that endothelial EMCN deficiency did not affect primary tumor growth significantly but strongly promoted spontaneous metastasis. EMCN deficiency was associated with gene profiles that regulate cell junctions in vitro and enhance vascular permeability in vivo. Mechanistically, EMCN deficiency mainly affected the host microenvironment and led to the formation of a lung premetastatic niche by recruiting Ly6G+ neutrophils and upregulating MMP9, S100A8/A9 and TGF-β expression. Anti-TGF-β antibody effectively eliminated TGF-β-induced neutrophil polarization, thereby reducing lung metastasis. Notably, the combination of a Notch inhibitor and an anti-TGF-β antibody effectively inhibited tumor growth and lung metastasis and prolonged the survival time of mice.

Conclusions

We present a new translational strategy of EMCN as a new key player in tumor lung metastasis by affecting the host microenvironment. These findings could provide a sound theoretical basis for clinical treatment.
SLAMF7 modulates B cells and adaptive immunity to regulate susceptibility to CNS autoimmunity
Authors: O’Connell Patrick , Blake Maja K. , Godbehere Sarah , Amalfitano Andrea , Aldhamen Yasser A.
Published: October 2022

Background

Multiple sclerosis (MS) is a chronic, debilitating condition characterized by CNS autoimmunity stemming from a complex etiology involving both environmental and genetic factors. Our current understanding of MS points to dysregulation of the immune system as the pathogenic culprit, however, it remains unknown as to how the many genes associated with increased susceptibility to MS are involved. One such gene linked to MS susceptibility and known to regulate immune function is the self-ligand immune cell receptor SLAMF7.

Methods

We subjected WT and SLAMF7−/− mice to multiple EAE models, compared disease severity, and comprehensively profiled the CNS immune landscape of these mice. We identified all SLAMF7-expressing CNS immune cells and compared the entire CNS immune niche between genotypes. We performed deep phenotyping and in vitro functional studies of B and T cells via spectral cytometry and BioPlex assays. Adoptive transfer studies involving the transfer of WT and SLAMF7−/− B cells into B cell-deficient mice (μMT) were also performed. Finally, B–T cell co-culture studies were performed, and a comparative cell–cell interaction network derived from scRNA-seq data of SLAMF7+ vs. SLAMF7− human CSF immune cells was constructed.

Results

We found SLAMF7−/− mice to be more susceptible to EAE compared to WT mice and found SLAMF7 to be expressed on numerous CNS immune cell subsets. Absence of SLAMF7 did not grossly alter the CNS immune landscape, but allowed for altered immune cell subset infiltration during EAE in a model-dependent manner. Global lack of SLAMF7 expression increased myeloid cell activation states along with augmented T cell anti-MOG immunity. B cell profiling studies revealed increased activation states of specific plasma and B cell subsets in SLAMF7−/− mice during EAE, and functional co-culture studies determined that SLAMF7−/− B cells induce exaggerated T cell activation. Adoptive transfer studies revealed that the increased susceptibility of SLAMF7−/− mice to EAE is partly B cell dependent and reconstruction of the human CSF SLAMF7-interactome found B cells to be critical to cell–cell communication between SLAMF7-expressing cells.

Conclusions

Our studies have identified novel roles for SLAMF7 in CNS immune regulation and B cell function, and illuminate underpinnings of the genetic association between SLAMF7 and MS.
Microglial–oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain injury
Authors: Song Shanshan , Hasan Md Nabiul , Yu Lauren , Paruchuri Satya S. , Bielanin John P. , Metwally Shamseldin , Oft Helena C. M. , Fischer Sydney G. , Fiesler Victoria M. , Sen Tanusree , Gupta Rajaneesh K. , Foley Lesley M. , Hitchens T. Kevin , Dixon C. Edward , Cambi Franca , Sen Nilkantha , Sun Dandan
Published: October 2022

Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia–OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+/H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-CreERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-CreERT2;Nhe1flox/flox, Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage and accelerated chronic phase of OL regeneration at 30 days post-TBI. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes in cKO mice were recapitulated in C57BL6J wild-type TBI mice receiving treatment of a potent NHE1 inhibitor HOE642 for 1–7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation in oligodendrogenesis and neuroprotection, which contributes to accelerated brain repair and neurological function recovery after TBI.
Parental genomes segregate into distinct blastomeres during multipolar zygotic divisions leading to mixoploid and chimeric blastocysts
Authors: De Coster Tine , Masset Heleen , Tšuiko Olga , Catteeuw Maaike , Zhao Yan , Dierckxsens Nicolas , Aparicio Ainhoa Larreategui , Dimitriadou Eftychia , Debrock Sophie , Peeraer Karen , de Ruijter-Villani Marta , Smits Katrien , Van Soom Ann , Vermeesch Joris Robert
Published: October 2022

Background

During normal zygotic division, two haploid parental genomes replicate, unite and segregate into two biparental diploid blastomeres.

Results

Contrary to this fundamental biological tenet, we demonstrate here that parental genomes can segregate to distinct blastomeres during the zygotic division resulting in haploid or uniparental diploid and polyploid cells, a phenomenon coined heterogoneic division. By mapping the genomic landscape of 82 blastomeres from 25 bovine zygotes, we show that multipolar zygotic division is a tell-tale of whole-genome segregation errors. Based on the haplotypes and live-imaging of zygotic divisions, we demonstrate that various combinations of androgenetic, gynogenetic, diploid, and polyploid blastomeres arise via distinct parental genome segregation errors including the formation of additional paternal, private parental, or tripolar spindles, or by extrusion of paternal genomes. Hence, we provide evidence that private parental spindles, if failing to congress before anaphase, can lead to whole-genome segregation errors. In addition, anuclear blastomeres are common, indicating that cytokinesis can be uncoupled from karyokinesis. Dissociation of blastocyst-stage embryos further demonstrates that whole-genome segregation errors might lead to mixoploid or chimeric development in both human and cow. Yet, following multipolar zygotic division, fewer embryos reach the blastocyst stage and diploidization occurs frequently indicating that alternatively, blastomeres with genome-wide errors resulting from whole-genome segregation errors can be selected against or contribute to embryonic arrest.

Conclusions

Heterogoneic zygotic division provides an overarching paradigm for the development of mixoploid and chimeric individuals and moles and can be an important cause of embryonic and fetal arrest following natural conception or IVF.
Excretory-secretory products from the brown stomach worm, Teladorsagia circumcincta, exert antimicrobial activity in in vitro growth assays
Authors: Rooney James , Williams Timothy L. , Northcote Holly M. , Frankl Fiona E. Karet , Price Daniel R. G. , Nisbet Alasdair J. , Morphew Russell M. , Cantacessi Cinzia
Published: October 2022

Background

Over the past decade, evidence has emerged of the ability of gastrointestinal (GI) helminth parasites to alter the composition of the host gut microbiome; however, the mechanism(s) underpinning such interactions remain unclear. In the current study, we (i) undertake proteomic analyses of the excretory-secretory products (ESPs), including secreted extracellular vesicles (EVs), of the ‘brown stomach worm’ Teladorsagia circumcincta, one of the major agents causing parasite gastroenteritis in temperate areas worldwide; (ii) conduct bioinformatic analyses to identify and characterise antimicrobial peptides (AMPs) with putative antimicrobial activity; and (iii) assess the bactericidal and/or bacteriostatic properties of T. circumcincta EVs, and whole and EV-depleted ESPs, using bacterial growth inhibition assays.

Methods

Size-exclusion chromatography was applied to the isolation of EVs from whole T. circumcincta ESPs, followed by EV characterisation via nanoparticle tracking analysis and transmission electron microscopy. Proteomic analysis of EVs and EV-depleted ESPs was conducted using liquid chromatography-tandem mass spectrometry, and prediction of putative AMPs was performed using available online tools. The antimicrobial activities of T. circumcincta EVs and of whole and EV-depleted ESPs against Escherichia coli were evaluated using bacterial growth inhibition assays.

Results

Several molecules with putative antimicrobial activity were identified in both EVs and EV-depleted ESPs from adult T. circumcincta. Whilst exposure of E. coli to whole ESPs resulted in a significant reduction of colony-forming units over 3 h, bacterial growth was not reduced following exposure to worm EVs or EV-depleted ESPs.

Conclusions

Our data points towards a bactericidal and/or bacteriostatic function of T. circumcincta ESPs, likely mediated by molecules with antimicrobial activity.

Graphical Abstract
Africa-wide meta-analysis on the prevalence and distribution of human cystic echinococcosis and canine Echinococcus granulosus infections
Authors: Karshima Solomon Ngutor , Ahmed Musa Isiyaku , Adamu Nuhu Bala , Magaji Abdullahi Alhaji , Zakariah Musa , Mohammed Konto
Published: October 2022

Background

Echinococcosis is a neglected zoonosis of increasing public health concern worldwide. According to the World Health Organization, 19,300 lives and 871,000 disability-adjusted life-years are lost globally each year because of cystic echinococcosis. Annual costs associated with cystic echinococcosis were estimated at US$ 3 billion because of treatment of cases and losses in the livestock industry.

Methods

We performed the random-effects model of meta-analysis using 51-year (1970–2021) data available from AJOL, Google Scholar, PubMed, Science Direct, Scopus and Web of Science. We also applied the Joanna Briggs Institute critical appraisal instrument for studies reporting prevalence data, the Cochran’s Q-test, Egger’s regression test and the single study deletion technique to respectively examine within-study bias, heterogeneity, across-study bias and sensitivity.

Results

Thirty-nine eligible studies on human cystic echinococcosis (HCE) from 13 countries across the five African sub-regions showed an overall prevalence of 1.7% (95% CI 1.1, 2.6) with a statistically significant (P < 0.001) sub-group range of 0.0% (95% CI 0.0, 14.1) to 11.0% (95% CI 7.6, 15.7). Highest prevalences were observed in Eastern Africa (2.7%; 95% CI 1.4, 5.4) by sub-region and Sudan (49.6%; 95% 41.2, 58.1) by country. Another set of 42 studies on Echinococcus granulosus infections (EGI) in dogs from 14 countries across the five African sub-regions revealed an overall prevalence of 16.9% (95% CI 12.7, 22.3) with a significant (P < 0.001) variation of 0.4 (95% CI 0.0, 5.9) to 35.8% (95% CI 25.4, 47.8) across sub-groups. Highest prevalences of E. granulosus were observed in North Africa (25.6%; 95% CI 20.4, 31.6) by sub-region and Libya (9.2%; 95% CI 5.7, 13.9) by country.

Conclusion

Human cystic echinococcosis and EGI are respectively prevalent among Africans and African dogs. We recommend a holistic control approach that targets humans, livestock, dogs and the environment, which all play roles in disease transmission. This approach should involve strategic use of anthelminthics in animals, standardized veterinary meat inspection in abattoirs, control of stray dogs to reduce environmental contamination and proper environmental sanitation. Mass screening of humans in hyper-endemic regions will also encourage early detection and treatment.

Graphical abstract
Modelling the optimal dosing schedule for artemether-lumefantrine chemoprophylaxis against malaria
Authors: Tarning Joel , von Seidlein Lorenz , Dondorp Arjen M. , White Nicholas J. , Maude Richard J.
Published: October 2022

Objective

Antimalarial chemoprophylaxis for high risk groups in endemic areas of Southeast Asia has the potential to reduce malaria transmission and accelerate elimination. However, the optimal choice of medication and dosing for many potential candidates is not clear. For a planned randomised controlled trial of prophylaxis for forest goers in Cambodia, artemether-lumefantrine (AL) was selected because of its ongoing efficacy and excellent tolerability and safety. As AL had not been used before for this purpose, a previously published pooled pharmacometric meta-model was used to determine the optimal dosing schedule.

Results

A full 3 day AL treatment course given twice a month, and twice daily treatment given once a week, resulted in trough concentrations consistently above the therapeutic threshold of 200 ng/mL. However, the most favourable exposure profile, and arguably most practical dosing scenario, was an initial 3 day full AL treatment course followed by twice daily dosing given once a week for the duration of chemoprevention. The latter was adopted as the dosing schedule for the trial.
Anti-asthmatic miR-224-5p inhibits the FHL1/MAPK pathway to repress airway smooth muscle cell proliferation in a murine model of asthma-like airway inflammation
Authors: Zhuang Zhifang , Zhou Yanjuan , Xu Jiao , Pan Leying
Published: October 2022

Background

The proliferation of airway smooth muscle cells (ASMCs) contributes to the contractility and inflammation in the pathophysiology of asthma. This intrigued us to clarify the effect of microRNA (miR)-224-5p on biological characteristics of ASMCs in mice with asthma-like airway inflammation and responses through the FHL1-dependent MAPK pathway.

Methods

An ovalbumin (OVA)-induced asthma mouse model was established, where ASMCs were isolated. The expression of FHL1 was determined in asthmatic mice. Artificial modulation of FHL1 expression was performed to explore its effect on airway inflammation of asthmatic mice and ASMC proliferation and apoptosis. Afterwards, we analyzed the interaction among miR-224-5p, FHL1 and the MAPK pathway, and explored their combined impacts on airway inflammation of asthmatic mice and ASMC proliferation and apoptosis.

Results

FHL1 was highly expressed and miR-224-5p was poorly expressed in asthmatic mice. FHL1 was verified to be a target of miR-224-5p. Loss of FHL1 function reduced airway inflammation in asthmatic mice and proliferation of ASMCs while inducing their apoptosis. Besides, miR-224-5p inhibited the MAPK pathway by binding to FHL1. Overexpression of miR-224-5p relieved airway inflammation, inhibited ASMC proliferation, and increased apoptosis, which could be reversed by overexpression of FHL1.

Conclusion

Altogether, miR-224-5p inhibited airway inflammation in asthmatic mice and ASMC proliferation through blocking the MAPK pathway by down-regulating FHL1.
Two cases of dupilumab-associated conjunctivitis with high expression of IL-8 mRNA on the ocular surface: a case report
Authors: Adachi Rumi , Shoji Jun , Hirota Akira , Tomioka Akiko , Tonozuka Yukiko , Inada Noriko , Yamagami Satoru
Published: October 2022

Background

Dupilumab-induced ocular surface disease (DIOSD) has been reported in patients with atopic dermatitis treated with dupilumab, and has been recognized as an adverse event of dupilumab. Our objective was to describe two cases of DIOSD with alterations in eotaxin-2 and interleukin (IL)-8 messenger ribonucleic acid (mRNA) expression on the ocular surface.

Case presentation

In the ocular surface test, specimens were collected from the patient's ocular surface, and eotaxin-2 and IL-8 mRNA levels in the specimens were measured using real-time polymerase chain reaction. The clinical score of ocular surface findings was quantified using a 5-5-5 exacerbation grading scale for allergic conjunctivitis. The first case was of a 27-year-old man who developed DIOSD 3 months after starting treatment with dupilumab injection for atopic dermatitis. After 5 weeks of topical instillation of tacrolimus ophthalmic suspension, the clinical score of ocular surface findings improved and IL-8 and eotaxin-2 mRNA expression levels gradually decreased. The second patient was a 55-year-old man who developed DIOSD 11 weeks after the start of treatment with dupilumab injection for atopic dermatitis. Four weeks after starting ophthalmological treatment with tacrolimus ophthalmic suspension, his clinical scores on ocular surface findings improved and IL-8 mRNA expression levels decreased. The ocular surface test in this case revealed increased expression levels of IL-8 mRNA on the ocular surface at the onset of DIOSD, which decreased with the improvement of objective findings.

Conclusions

DIOSD, which has been successfully treated with tacrolimus ophthalmic suspension, may involve IL-8-related inflammation in addition to type 2 inflammation.
Descemet’s membrane folds in ochronosis: a case report
Authors: de Azevedo Magalhaes Otavio , Abdel Rahman Abu Hwas Dunia
Published: October 2022

Background

We present this report of a new ophthalmic finding in a patient with ochronosis.

Case presentation

An 85-year-old Caucasian male patient with bilateral dark temporal and nasal pigmentation of conjunctiva and sclera was referred to our hospital owing to low visual acuity. On biomicroscopic examination, bilateral horizontal Descemet’s membrane folds were observed. Corneal tomography revealed irregular and asymmetric “against-the-rule” astigmatism in both eyes. Anterior segment optical coherence tomography demonstrated numerous central Descemet’s without edema or other corneal structure alterations.

Conclusion

This is the first report of Descemet’s membrane folds in ochronosis. These corneal findings suggest that the accumulation of homogentisic acid in the sclera leads to thickening and stiffness of this region. These alterations could remarkably decrease visual acuity owing to topographic corneal curvature alterations, especially in elderly patients.
A mouse model of vitiligo based on endogenous auto-reactive CD8 + T cell targeting skin melanocyte
Authors: Chen Daoming , Xu Zijian , Cui Jun , Chen Ting
Published: October 2022

Vitiligo is the most common human skin depigmenting disorder. It is mediated by endogenous autoreactive CD8 + T cells that destruct skin melanocytes. This disease has an estimated prevalence of 1% of the global population and currently has no cure. Animal models are indispensable tools for understanding vitiligo pathogenesis and for developing new therapies. Here, we describe a vitiligo mouse model which recapitulates key clinical features of vitiligo, including epidermis depigmentation, CD8 + T cell infiltration in skin, and melanocyte loss. To activate endogenous autoreactive cytotoxic CD8 + T cells targeting melanocytes, this model relies on transient inoculation of B16F10 melanoma cells and depletion of CD4 + regulatory T cells. At cellular level, epidermal CD8 + T cell infiltration and melanocyte loss start as early as Day 19 after treatment. Visually apparent epidermis depigmentation occurs 2 months later. This protocol can efficiently induce vitiligo in any C57BL/6 background mouse strain, using only commercially available reagents. This enables researchers to carry out in-depth in vivo vitiligo studies utilizing mouse genetics tools, and provides a powerful platform for drug discovery.
The impact of spinal anaesthesia on perioperative opioid consumption, postoperative pain and oncological outcome in radical retropubic prostatectomy—a retrospective before-and-after effectiveness study
Authors: Funcke Sandra , Schick-Bengardt Xenia , Pinnschmidt Hans O. , Beyer Burkhard , Fischer Marlene , Kahl Ursula , Nitzschke Rainer
Published: October 2022

Background

Spinal anaesthesia preceding general anaesthesia has been conducted for open radical retropubic prostatectomy (RRP) to decrease immediate postoperative pain for many years. Nevertheless, the effectiveness of spinal anaesthesia to reduce postoperative opioid requirements remains unknown. The aim of the present study was to determine the effect of spinal anaesthesia preceding general anaesthesia on opioid requirements, postoperative pain and biochemical cancer-free survival.

Methods

This before-and-after effectiveness study investigated effects of two different anaesthesia techniques in 636 patients with RRP. Three hundred eighteen consecutive patients in the SPA group (spinal anaesthesia preceding general anaesthesia) were compared with 318 patients in the GA group (general anaesthesia alone). The primary endpoint of the study was opioid consumption in the post-anaesthesia care unit. Secondary endpoints were intraoperative opioid consumption, postoperative pain, postoperative recovery time, the length of hospital-stay, persistence of pain 1 year after surgery and cancer-free survival. Differences between the groups were analysed by a two-sided t-test, χ2-test, Fisher’s exact test and Mann–Whitney U test and the influence of possible confounders on opioid consumption with a general linear model. Cancer-free survival was determined by Kaplan–Meier curves and group differences by log-rank tests and multivariable Cox regression analyses.

Results

The total amount of morphine equivalent administered postoperatively was 7.5 [6.9; 8.1] mg in the SPA group and 6.0 [5.5; 6.5] mg in the GA group (mean [95% CI], p < 0.001). The amount of intraoperative sufentanil was 56.9 [55.1; 58.7] μg in the SPA group and 84.5 [82.5; 86.5] μg in the GA group (mean [95% CI], p < 0.001). There was no difference found in the postoperative pain level, length of hospital-stay and pain level 1 year after surgery. Biochemical cancer-free survival was highly related to TNM stage (p < 0.001, pT3 vs. pT2 hazard ratio 5.4 [95%CI 3.3; 9.2]) but not to the type of anaesthesia (p = 0.29).

Conclusions

Spinal anaesthesia preceding general anaesthesia for RRP is associated with increased postoperative opioid consumption compared to general anaesthesia alone. Postoperative pain level and the oncological outcome are not affected by the adjunctive use of spinal anaesthesia. Thus, the addition of spinal anaesthesia to general anaesthesia has no advantage in RRP.

Trial registration

ClinicalTrial.gov, NCT03565705.
Effects of omega-3 supplementation on components of the endocannabinoid system and metabolic and inflammatory responses in adipose and liver of peripartum dairy cows
Authors: Kra Gitit , Daddam Jayasimha Rayalu , Moallem Uzi , Kamer Hadar , Kočvarová Radka , Nemirovski Alina , Contreras G. Andres , Tam Joseph , Zachut Maya
Published: October 2022

Background

Dietary supplementation of omega-3 fatty acids can reduce the activation of the endocannabinoid system (ECS) by decreasing the availability of arachidonic acid, thus lowering endocannabinoids (eCBs) levels. The ECS is a modulator of energy metabolism, stress response and inflammation in mammals, yet there is little information on the roles of the ECS in transition dairy cows. During the periparturient period, the adipose tissue and liver are the main metabolic organs that participate in the adaptations of dairy cows to onset of lactation; however, exceeded adipose tissue lipolysis and accumulation of lipids in the liver have adverse effects on cows’ physiology. Here we aimed to examine whether omega-3 supplementation during the transition period will modulate ECS activation and affect metabolic and inflammatory indices in postpartum dairy cows, by supplementing twenty-eight transition Holstein dairy cows with either saturated fat (CTL) or encapsulated flaxseed oil (FLX). Components of the ECS, metabolic and inflammatory markers were measured in blood, liver, and subcutaneous adipose tissue.

Results

FLX supplementation reduced feed intake by 8.1% (P < 0.01) and reduced plasma levels of arachidonic acid (by 44.2%; P = 0.02) and anandamide (by 49.7%; P = 0.03) postpartum compared to CTL. The mRNA transcription levels of the cannabinoid receptor 1 (CNR1/CB1) tended to be lower (2.5 folds) in white blood cells of FLX than in CTL (P = 0.10), and protein abundance of ECS enzyme monoacylglycerol lipase was higher in peripheral blood mononuclear cells of FLX than in CTL (P = 0.04). In adipose tissue, palmitoylethanolamide levels were lower in FLX than in CTL (by 61.5%; P = 0.02), relative mRNA transcription of lipogenic genes were higher, and the protein abundance of cannabinoid receptor 2 (P = 0.08) and monoacylglycerol lipase (P = 0.10) tended to be higher in FLX compared to CTL. Hepatic 2-arachidonoylglycerol tended to be higher (by 73.1%; P = 0.07), and interlukin-6 mRNA transcription level was 1.5 folds lower in liver of FLX than in CTL (P = 0.03).

Conclusions

Nutritional supplementation of omega-3 fatty acids seems to partly modulate ECS activation, which could be related to lower feed intake. The altered ECS components in blood, adipose tissue and liver are associated with moderate modulations in lipid metabolism in the adipose and inflammation in liver of peripartum dairy cows.
Quantitative evaluation of training method in placing miniscrews in orthodontic graduate program
Authors: Mitchell Bobby , Liu Jie , Lee Sanghee , Watanabe Keiichiro , Kim Do-Gyoon , Fields Henry W. , Guo Xiaohan , Wei-En Lu , Deguchi Toru
Published: October 2022

Background

The purpose of this study was to assess the effectiveness of training residents in an orthodontic program in the placement of miniscrews by using cone beam computed tomography (CBCT) images. A total of 90 miniscrews were placed in 15 pig mandibles over a 3-year period by 15 first-year orthodontic residents. Miniscrews were divided into three groups (Control group: no radiographs; 2D group: placement with 2D radiographs; CBCT group: placement with CBCT). Proximity of the miniscrew to the neighboring root was measured. The miniscrew success rate was examined in the graduate clinic from 2015 to 2021.

Results

The percentage of root contact for each group was: 36.7% (11/30), 20.0% (6/30), 0% (0/30), for the Control, 2D, and CBCT groups, respectively. The CBCT group was significantly different from the Control and 2D groups (p < 0.05). For root proximity, the miniscrews were significantly closer to the roots in the Control (p < 0.001) and 2D (p < 0.001) groups compared with the CBCT group. No significant difference was observed between the Control and 2D groups (p = 0.80). There was no significant difference among the years in the miniscrew success rate.

Conclusions

Training the residents in an orthodontic graduate program using CBCT may be helpful to avoid root damage and to decrease the miniscrew failure rate.
Comparison of white-to-white measurements using four devices and their determination of ICL sizing
Authors: Ang Robert Edward T. , Reyes Edward Kenneth F. , Ayuyao Fernando Amado J. , Umali Maria Isabel N. , Cruz Emerson M.
Published: October 2022

Background

To compare the measurements obtained from the Orbscan II, IOLMaster 700, Pentacam AXL, and Castroviejo caliper and their effects on calculating the recommended implantable collamer lens (ICL) size and postoperative vault measurements.

Methods

This is a retrospective cross-sectional study of patients who underwent ICL surgery by a single surgeon from March 1, 2018 to July 31, 2021. Records were reviewed for the anterior chamber depth (ACD) and white-to-white (WTW) measurements obtained from the Orbscan II, IOLMaster 700, Pentacam AXL, and Castroviejo caliper (WTW only). These were used to calculate the recommended ICL size. The actual ICL size implanted, and vault measurements obtained one month postoperatively were also collected.

Results

One hundred seven eyes with a mean age of 27.9 ± 7.7 years were included in the study. Mean WTW measurements were significantly different between devices (P < 0.0001), with the IOLMaster 700 having the highest value (12.14 ± 0.04 mm) and the caliper having the lowest value (11.45 ± 0.04 mm). Mean ACD measurements were the lowest in Orbscan II (3.12 ± 0.25 mm) and the highest in Pentacam AXL (3.16 ± 0.24 mm). The Pentacam AXL produced an ICL size similar to the Orbscan in 69.2% of eyes. The IOLMaster yielded an ICL measurement one size larger than Orbscan-based calculations in 64.5% of eyes. Using the Orbscan WTW and ACD, the desired vault of 0.25 to 0.75 mm and 0.25 to 1.00 mm was achieved in 70% and 91% of eyes, respectively. Substituting caliper WTW to IOLMaster 700 or Pentacam AXL WTW increases the percentage of achieving the desired vault to 80%, similar to the Orbscan.

Conclusions

The Orbscan II, IOLMaster 700, and Pentacam AXL cannot be used interchangeably for calculating ICL sizing. Combining the WTW from caliper measurement with the ACD of the IOLMaster 700 or Pentacam AXL could improve ICL sizing and achieve a higher percentage of eyes with the desired vault.
Time to initiate postpartum modern contraceptive use and predictors among women of reproductive age group in Dilla Town, Southern Ethiopia: a retrospective cohort study
Authors: MaeregayehuTibo  , Adem Atnafu , Dache Azmach
Published: October 2022

Background

Globally 1 in 7 women aren’t using family planning as a result, larger numbers of women get pregnant within 7–9 months of childbirth. The aim of this study was to estimate the time to initiate postpartum modern contraceptive use and predictors among women of reproductive age group within the first 12 months of delivery in Della Town, Southern, Ethiopia.

Methods

A retrospective cohort study from March 25, 2019, to March 25, 2020, was conducted in Dilla town. A Systematic sampling technique was used to select 594 study participants. A Cox proportional hazards model was used to determine factors associated with time to initiate postpartum modern contraceptive use at 95% CI with a P-value of < 0.05.

Results

A total of 576 postpartum women were participated making a response rate of 96.9%. The median time to initiate postpartum modern contraceptive use was 7 months (IQR: 6, 8). Education [AHR = 3.01 (95% CI = 1.32, 6.83)], knowledge on family planning [AHR = 1.56(95% CI = 1.20, 2.02)], and family planning counseling during postnatal care [AHR = 2.22 (95% CI = 1.46, 3.38)] were predictors positively associated with time to initiate postpartum modern contraceptive.

Conclusions

The time to initiate postpartum modern contraceptive use was delayed longer than compared to the World Health Organization recommendation. Education level of women, knowledge of family planning, and family planning counseling during postnatal care were some predictors positively associated with time to initiate postpartum modern contraceptive use.
Translanguaging and multilingual society of Macau: past, present and future
Authors: Lam Johnny F. I. , Ieong Wai In
Published: October 2022

This paper aims to explore the development and evolution of multilingual languages in Macau over the past 400 years, as well as the relationship and interaction of these languages with Macau society. The complex relationship between translation and society in multilingual societies is also discussed. By doing so, this study attempts to fill the current research gap by investigating the formation and evolution of multilingualism in a multicultural context from a historical perspective. To understand the evolving changes in Macau’s languages and the relationship with society at large, this paper provides a review of the evolution of the multilingual society in Macau from a historical perspective while analyzing the features of Macau's multiple languages in different historical periods and revealing the influence of multilingualism on Macau’s development. This review argues that there are three stages in the formation of a multilingual society and culture in Macau: Chinese as the predominant language in Macau (ancient times-1553), the early introduction of foreign languages and the official status of Portuguese languages in Macau (1553–1987), and Chinese, Portuguese, and English as the three mainstream languages in Macau (1987-present). Through a review of the past for insights into the formation of the multilingual society in Macau, the paper sheds light on the long history of Macau’s Chinese and Portuguese cultures and their main linguistic influence on Macau’s society and culture. Findings reveal that Macau could utilize its Portuguese characteristics and play an influential role in world communications, bridging the gap between China and Portuguese-speaking countries.