bluuebunny/crossref_metadata_2025 huggingface dataset:
Peran Kepala Sekolah Dalam Pengembangan Kurikulum Pendidikan Islam Di Madrasah Tsanawiyah Swasta At-Taubah Karawang
Authors: Oktapiani Aryati , Ma’shum Sya’roni , BK M Taufik
Published: May 2023

Pendidikan sangatlah penting dalam kehidupan. Salah satu upaya untuk mencapai keberhasilan pendidikan adalah pengembangan kurikulum. Kurikulum merupakan alat yang sangat penting dalam menentukan arah pendidikan dan apa yang dibutuhkan untuk pengembangan pendidikan, sehingga berhasil tidaknya pendidikan sangat tergantung pada kurikulum yang ada. Peran yang sangat dominan adalah peran manajer, yang merupakan kunci untuk mencapai tujuan pendidikan. Peneliti ini menggunakan data primer dan sekunder. Penelitian ini menggunakan metode penelitian kualitatif yang menghasilkan berbagai data deskriptif namun deskriptif. Teknik pengumpulan data yang digunakan dalam penelitian ini adalah wawancara mendalam, observasi partisipatif, dan studi dokumenter. Data yang terkumpul dianalisis secara induktif dalam tiga tahap yaitu organisasi data, penyajian data, dan penarikan kesimpulan. Berikut adalah temuan penelitian ini: (1) Peran Kepala Sekolah sebagai Leader dalam Pengembangan Kurikulum (2) Peran Kepala Sekolah sebagai Leader dalam Pengembangan Kurikulum (3) Peran Kepala Sekolah sebagai Leader dalam Pengembangan Kurikulum Kepemimpinan Supervisi Kurikulum dalam pengembangan kurikulum dengan membimbing dan memberdayakan guru utama untuk memberikan instruksi individual dan mendukung kegiatan pengawasan.
Manajemen Pembelajaran Matematika dalam Meningkatkan Minat Belajar Siswa SMAN 1 Kualah Selatan
Authors: Amelia Yuli , Fahmi Ansari , Pasaribu Khadijah , Putri Nindi Aulia , Khairuni Tengku Lailan
Published: May 2023

Penelitian ini bertujuan memberikan gambaran tentang minat belajar siswa dan manajemen pembelajaran matematika di SMAN 1 Kualuh Selatan. Hasil penelitian menunjukkan: 1) Siswa-siswi di SMAN 1 Kuauh Selatan memiliki minat belajar pada mata pelajaran matematika yang beragam, diperlukan peran guru dalam membangkitkan sikap positif dan merancang pembelajaran matematika dibutuhkan agar perlahan-lahan dapat menumbuhkan minat belajar siswa terhadap matematika; 2) Untuk meningkatkan minat belajar siswa guru lebih mengoptimalkan       dalam              merencanakan komponen komponen yang ada dalam RPP yaitu tujuan pembelajaran, materi pembelajaran, metode pembelajaran, media pembelajaran, sumber belajar, dan penilaian pembelajaran; 3) Pengorganisasian yang dilakukan dalam menunjang kegiatan belajar matematika diantaranya yaitu pengorganisasian kurikulum, sarana dan prasarana, guru, serta pengorganisasian siswa; 4) Pelaksanaan pembelajaran matematika dilakukan dalam tiga kegiatan yaitu kegiatan pendahuluan, inti, dan penutup dengan tetap menjaga perhatian siswa agar fokus dalam pembelajaran; 5) Evaluasi pembelajaran dilaksanakan dengan jenis evaluasi formatif dan sumatif.
Teachers’ Beliefs and Practice of Interaction Strategies on Students’ Willingness to Communicate
Authors: Abidin Jaenal , Srisudarso Mansyur , Hakim Putri Kamalia
Published: May 2023

Willingness to Communicate (WTC) has become an important concept in second language (L2) classroom context.  WTC is proven as a predictor of classroom participation since students who tend to have high WTC participated more in classroom interaction and they are likely to be ready to get involved in any interactions using their L2 both inside and outside classroom. Given the central role teachers play in pedagogy, who shape the curriculum within the context and content, and shape the decisions of teaching methods and strategy play dynamic role in maintaining students’ willingness to communicate. This study aims: (1) to portray teachers’ beliefs about their role and practice of interaction strategies in maintaining students’ WTC; (2) to find out interaction strategies employed by the teacher in maintaining students’ WTC. Employing narrative inquiry, the two experience English teacher was gathered by means of personal narrative and interview. The findings revealed that teacher plays a very crucial role in students’ WTC. This study also highlight that the use of three interaction strategies such as teacher-front, facilitator-oriented, and learner-oriented strategy can contribute in maintaining students’ WTC, by applying appropriate techniques. This study suggest that teacher should perform various roles to become an ideal guide in shaping students’ WTC. The use of various effective strategies with involving familiar term of topic, and the use of encouragement can be applied in encouraging English interaction. This present study is expected to create awareness on the significance of EFL teachers to share their interaction skills and vary effective interaction strategies improve the quality of English teaching and learning.
Peripаrtal Cardiomyopathy
Authors: Murkamilov I. , Aitbaev K. , Raimzhanov Z. , Yusupova T. , Yusupov F.
Published: May 2023

The purpose of the study is to describe a clinical case of peripartal cardiomyopathy (CM) and conduct literature analysis. Peripartal CM is defined as reduced ejection fraction of the left ventricle <45%, reduced fractional shortening <30%, as well as increased end-diastolic size of the left ventricle > 2.7 cm/m2. At the same time, there should be no detectable causes of heart failure, as well as development of heart failure in the last month of pregnancy or within 5 months after childbirth. The review presents data on possible causes of peripartal CM. Risk factors for peripartal CM are: age younger than 20 years and older than 30 years, preeclampsia, hypertension, multiple pregnancy, prolonged duration of viral infection, macro- and micronutrient insufficiency, etc. Prolactin and its 16 kDa fragment, as well as excessive activity of cathepsin D, play a leading role in pathogenesis of peripartal CM. A step-by-step algorithm for diagnosis of peripartal CM in real clinical conditions is described. Material and methods. The patient is K., 18 years old, in anamnesis: no prior history of cardiovascular diseases, according to the patient, she had pneumonia a year ago. The patient has not registered increased blood pressure. Physiological pregnancy proceeded satisfactorily; natural delivery was on time. On the 56th day after childbirth, the patient was admitted to the intensive care unit with complaints: shortness of breath, muscle weakness, palpitations, lower leg edema. From anamnesis: 1 month after childbirth, the next day after psychoemotional overstrain, the patient began to notice shortness of breath, lack of sleep, muscle weakness, decreased lactation. The examination revealed an increase in the sedimentation rate of erythrocytes, C-reactive blood protein, proteinuria, hematuria, as well as a decrease in the ejection fraction of the left ventricle. Results. Together with standard therapy, addition of prolactin secretion inhibitors and dopamine receptor stimulators led to significant improvement of the patient’s condition: proteinuria significantly decreased, edematous syndrome was gone, and LV contractile function significantly recovered. Conclusion. The clinical case demonstrates the development of a rare variant of peripartal CM, debuting with proteinuria and preserved kidney function, as well as normal serum prolactin levels. Apparently, there are different phenotypes of peripartal CM.
The Truth, the Partial Truth, and Anything but the Truth: Textual Constructions of Veracity in Siobhan Dowd's Bog Child
Authors: Veldhuizen Vera N.
Published: May 2023

This article analyses the narrative techniques employed by children's literature to construct the sense of ‘what really happened’, even in the face of conflicting narratives, from a cognitive narratological perspective. Focusing on metarepresentation and attachment theory, the paper proposes the concept of ‘truth narrative’ to refer to narratives which make a claim about story-world reality. The function and construction of truth narratives is explored through a close reading of Siobhan Dowd's Bog Child.
The predictive effect of immune therapy and chemotherapy under T cell-related gene prognostic index for Gastric cancer
Authors: Chen Jingyao , Li Xing , Mak Tsz Kin , Wang Xiaoqun , Ren Hui , Wang Kang , Kuo Zi Chong , Wu Wenhui , Li Mingzhe , Hao Tengfei , Zhang Changhua , He Yulong
Published: May 2023

Background: Gastric cancer (GC) is one of the most common malignancies in the human digestive tract. CD4+T cells can eliminate tumor cells directly through the mechanism of cytolysis, they can also indirectly attack tumor cells by regulating the tumor TME. A prognostic model of CD4+T cells is urgently needed to improve treatment strategies and explore the specifics of this interaction between CD4+T cells and gastric cancer cells. Methods: The detailed data of GC samples were downloaded from the Cancer Genome Atlas (TCGA), GSE66229, and GSE84437 datasets. CD4+ T cell-related genes were identified to construct a risk-score model by using the Cox regression method and validated with the Gene Expression Omnibus (GEO) dataset. In addition, postoperative pathological tissues of 139 gastric cancer patients were randomly selected for immunohistochemical staining, and their prognostic information were collected for external verification. Immune and molecular characteristics of these samples and their predictive efficacy in immunotherapy and chemotherapy were analysed.

Results: The training set and validation set had consistent results, with GC patients of high PROC and SERPINE1 expression having poorer prognosis. In order to improve their clinical application value, we constructed a risk scoring model and established a high-precision nomogram. Low-risk patients had a better overall survival (OS) than high-risk patients, consistent with the results from the GEO cohort. Furthermore, the risk-score model can predict infiltration of immune cells in the tumor microenvironment of GC, as well as the response of immunotherapy. Correlations between the abundance of immune cells with PROC and SERPINE1 genes were shown in the prognostic model according to the training cohort. Finally, sensitive drugs were identified for patients in different risk subgroup.

Conclusion: The risk model not only provides a basis for better prognosis in GC patients, but also is a potential prognostic indicator to distinguish the molecular and immune characteristics of the tumor, and its response to immune checkpoint inhibitor (ICI) therapy and chemotherapy.
Gaps in the governance of floods, droughts, and heatwaves in the United Kingdom
Authors: Carvalho Priscila , Spataru Catalina
Published: May 2023

Disaster risk reduction (DRR) and equitable resilience have cross-cutting challenges relevant to the Sustainable Development Goals (SDGs), Sendai Framework (SF) and Climate Change Adaptation (CCA). The capacity of governments to assess, prevent, prepare, respond, and recover from disasters depends on effective laws, planning, policies, governance instruments, equity indicators, harmonized standards, and a holistic approach to cross-sectoral issues and multi-scalar challenges. The principle of subsidiarity guides the United Kingdom (UK) approach to disaster governance, with decisions taken at lowest level and coordinated at different scales (national, sub-national, local). Cross-scale work needed to address large-scale issues and enable the pooling of resources, happens at a sub-national tier created especially for this purpose. At national level, there is a government lead department for each risk identified in the National Risk Assessment, with Department for Environment, Food and Rural Affairs (DEFRA) serving as the lead for floods and droughts, while the Department of Health and Social Care is the lead for heatwaves. In this paper we present the current state of the art of the governance of floods, droughts, and heatwaves in the UK, with a focus on pre-emergency phases and the shortage of indicators for assessment of the effectiveness of adaptation for all three disasters, which also compromise the realization and monitoring of targets across all three agendas. The governance of floods counts with the most developed legal framework of the three. Droughts are mainly dealt by the water sector, while heatwaves are treated exclusively as a health issue, leaving gaps with regards to the multiple risks these disasters pose to livelihoods and other sectors. Gaps and challenges that remain are related to siloed institutional approaches, lack of adaptation indicators, lack of cross-sectoral resilience standards, and lack of policy instruments and metrics to promote equitable resilience. Commonly, actions have mainly focused on the response and recovery strategies instead of risk reduction and adaptation to address rising vulnerabilities and exposure.
The need for inclusion of integrated teaching on refugee and asylum seeker health in undergraduate medical curriculum
Authors: Pittala Rajeshwari , Jacob Wright
Published: May 2023

Introduction

Providing care for refugees and asylum seekers requires special knowledge and training. Refugees and asylum seekers often have unique health needs that require specialized care.

Purpose

This research focused on the need and relevance of incorporation of refugee and asylum seekers’ health in undergraduate medical curriculum teaching at King’s College London GKT Medical School.

Methods

A mixed method approach was adopted involving review of available literature on refugee health in the medical curriculum, followed by interview and e-survey on the perspectives of tutors and students, respectively.

Discussion

The research points to an overwhelming agreement on the need, learning outcomes and challenges of integrating refugee and asylum seeker health into undergraduate medical and dental education both from the perspectives of clinical teachers and medical students.

Conclusion

A collaborative approach involving students, teachers and refugee stakeholders will help in developing an effective refugee curriculum to provide equitable healthcare in the UK.
The efficacy of the type of instruction on second language pronunciation acquisition
Authors: Alghazo Sharif , Jarrah Marwan , Al Salem Mohd Nour
Published: May 2023

This study investigates the efficacy of the type of instruction (i.e., perception-based vs. production-based) on second language (L2) pronunciation acquisition in an English as a foreign language (EFL) context. To achieve this objective, 60 tertiary-level Jordanian learners of English were recruited and put into two groups (30 learners in each group). Group A received 6 weeks of perception-based instruction on both segmental and suprasegmental aspects of English pronunciation, and Group B received production-based instruction over the same period and on the same aspects of pronunciation. Progress in L2 pronunciation was assessed at three time points (i.e., week 1, week 6, and week 14). Pre-, post- and delayed post-tests were run to achieve the study’s objective. A statistical analysis was conducted to analyse the data. The results show that both groups demonstrated a significant improvement in L2 pronunciation accuracy; in particular, Group A which received perception-based instruction demonstrated higher gains in segmental, syllabic, and prosodic aspects while Group B which received production-based instruction demonstrated more improvement in both global (i.e., comprehensibility) and temporal (i.e., fluency) aspects of pronunciation. However, both groups demonstrated similar gains on the delayed post-test. The findings provide implications for L2 pronunciation learners and teachers on the impact of the type of instruction on the addressed aspects of pronunciation.
Glycemic variability and the risk of atrial fibrillation: a meta-analysis
Authors: Li Wei , Wang Yang , Zhong Guoqiang
Published: May 2023

Background

Glycemic variability (GV) has been associated with vascular complications in patients with diabetes. However, the relationship between GV and risk of atrial fibrillation (AF) remains not fully determined. We therefore conducted a systematic review and meta-analysis to evaluate the above association.

Methods

Medline, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure were searched for longitudinal follow-up studies comparing the incidence of AF between patients with higher versus lower GV. A random-effects model incorporating the potential heterogeneity was used to pool the results.

Results

Nine cohort studies with 6,877,661 participants were included, and 36,784 (0.53%) participants developed AF during follow-up. Pooled results showed that a high GV was associated with an increased risk of AF (risk ratio [RR]: 1.20, 95% confidence interval [CI]: 1.11 to 1.30, p < 0.001, I2 = 20%). Subgroup analyses suggested consistent association between GV and AF in prospective (RR: 1.29, 95% CI: 1.05 to 1.59, p = 0.01) and retrospective studies (RR: 1.18, 95% CI: 1.08 to 1.29, p = 0.002), in diabetic (RR: 1.24, 95% CI: 1.03 to 1.50, p = 0.03) and non-diabetic subjects (RR: 1.13, 95% CI: 1.00 to 1.28, p = 0.05), in studies with short-term (RR: 1.25, 95% CI: 1.11 to 1.40, p < 0.001) and long-term GV (RR: 1.18, 95% CI: 1.05 to 1.34, p = 0.006), and in studies with different quality scores (p for subgroup difference all > 0.05).

Conclusion

A high GV may predict an increased risk of AF in adult population.
Assessing the environmental impact of industrial pollution using the complex intuitionistic fuzzy ELECTREE method: a case study of pollution control measures
Authors: Ashraf Shahzaib , Ali Mubashar , Sohail Muhammad , Eldin Sayed M.
Published: May 2023

Environmental pollution has become a major issue in today’s world, and controlling it is crucial for the sustainable development of our planet. Industries play a significant role in environmental pollution, and their impact must be controlled and minimized. In this paper, we present a novel approach, the complex intuitionistic fuzzy ELECTREE method (CIF–ELECTREE), for environmental impact assessment of industries. The method combines the principles of CIF sets and the ELECTREE method to provide a comprehensive and reliable assessment of the environmental impact of industries. The proposed method has been applied to real-world data, and the results obtained demonstrate the effectiveness of the CIF–ELECTREE method in controlling and reducing the environmental impact of industries. The results show that the CIF–ELECTREE method can provide a more accurate assessment of the environmental impact of industries compared to traditional methods. This study contributes to the existing literature by introducing a novel approach for environmental impact assessment and highlights the importance of considering both the uncertainty and vagueness in real-world data for reliable decision making.
River mouth morphodynamics and deflection over the short term: effects on spit growth and mangrove dynamics
Authors: Oyedotun Temitope D. Timothy , Nedd Gordon Ansel
Published: May 2023

The river mouth shows the influence of the dynamics of sediment deposition and the processes organising the deposits. The river mouths of the Guyana coast, as with other coastal systems in the Guianas, are influenced by the deposition of mud banks from the Amazon River and other rivers. This study analysed and probed the influence of the riverine and marine influences on small river mouth morphological developments. In this study, the morphological dynamics of the system were carried out from satellite images through the comparison of the inter-annual morphodynamics of the river mouths, complemented by data from hydrodynamic processes among others. This study demonstrates that the recent advancement and availability of Synthetic Aperture Radar (SAR), remotely sensed data, allow for the classification of migrating river mouth action and processes; effective monitoring of mudflats development and spit formation; and, the exhibition of river mouth transitioning and infilling. Sentinel-1 images of the Mahaica-Mahaicony river mouth in Guyana were processed and analysed using Google Earth Engine (GEE) and ArcGIS to observe the mud dynamics and its effects on deflecting the river mouth, influencing the development of spit and mangrove dynamics. The results of the analyses show that the dynamics of the mud shoal and river mouth are governed by feedback from various estuarine and hydrodynamic processes resulting from the interactions between the river and ocean. The results have not only highlighted the importance of mud infilling and sediment build-up for spit development and river-mouth deflection but the impact of the sediment morphological dynamics on the ecosystem (mangrove) associated with the river mouth.
Case report: A rare variant m.4135T>C in the MT-ND1 gene leads to Leber hereditary optic neuropathy and altered respiratory chain supercomplexes
Authors: Rákosníková Tereza , Kelifová Silvie , Štufková Hana , Lokvencová Kateřina , Lišková Petra , Kousal Bohdan , Honzík Tomáš , Hansíková Hana , Martínek Václav , Tesařová Markéta
Published: May 2023

Leber hereditary optic neuropathy is a primary mitochondrial disease characterized by acute visual loss due to the degeneration of retinal ganglion cells. In this study, we describe a patient carrying a rare missense heteroplasmic variant in MT-ND1, NC_012920.1:m.4135T>C (p.Tyr277His) manifesting with a typical bilateral painless decrease of the visual function, triggered by physical exercise or higher ambient temperature. Functional studies in muscle and fibroblasts show that amino acid substitution Tyr277 with His leads to only a negligibly decreased level of respiratory chain complex I (CI), but the formation of supercomplexes and the activity of the enzyme are disturbed noticeably. Our data indicate that although CI is successfully assembled in the patient’s mitochondria, its function is hampered by the m.4135T>C variant, probably by stabilizing CI in its inactive form. We conclude that the m.4135T>C variant together with a combination of external factors is necessary to manifest the phenotype.
Coping with rapid and cascading changes in Svalbard: the case of nature-based tourism in Svalbard
Authors: Dannevig Halvor , Søreide Janne E. , Sveinsdóttir Anna G. , Olsen Julia , Hovelsrud Grete K. , Rusdal Tone , Dale Ragnhild F.
Published: May 2023

Tourism has been booming in Svalbard and has almost returned to pre-pandemic levels. At the same time, the island is a hotspot of rapid and cascading climate and environmental changes, which are already placing natural and social systems under stress. There is more precipitation, less sea ice, and glaciers are shrinking at an increasing rate. Presently, sweeping legislative changes are underway in Svalbard that hold the potential to change the scope and conditions of tourism in multiple ways. Drawing on a review of literature presenting recent projections for climate and environmental change and interviews with tourism actors (n=25), this article outlines how climate and environmental changes are currently impacting nature-based tourism actors in the archipelago and discusses opportunities and barriers for their adaptation to current and projected changes. We define impacts in three broad categories: increased vulnerability of ecosystems; climate risks to tourism; and climate change benefits to tourism. We find that tourism actors have a high adaptive capacity to said changes, taking advantage of increased access due to shrinking ice in the fjords and extending the summer season into the autumn months due to higher temperatures. Avalanches and other natural hazard risks are increasing, causing a higher frequency of disruptions to organized tours and excursions. This article contributes to ongoing discussions about how the tourism industry and residents will be impacted by the cascading and cumulative effects of climatic and environmental changes on Svalbard.
Prognostic value of human leukocyte antigen G expression in solid tumors: a systematic review and meta-analysis
Authors: Bartolome Jorge , Molto Consolacion , Benitez-Fuentes Javier David , Fernandez-Hinojal Gonzalo , Manzano Aranzazu , Perez-Segura Pedro , Mittal Abhenil , Tamimi Faris , Amir Eitan , Ocana Alberto
Published: May 2023

Introduction

Identification of modulators of the immune response with inhibitory properties that could be susceptible for therapeutic intervention is a key goal in cancer research. An example is the human leukocyte antigen G (HLA-G), a nonclassical major histocompatibility complex (MHC) class I molecule, involved in cancer progression.

Methods

In this article we performed a systematic review and meta-analysis on the association between HLA-G expression and outcome in solid tumors. This study was performed in accordance with PRISMA guidelines and registered in PROSPERO.

Results

A total of 25 studies met the inclusion criteria. These studies comprised data from 4871 patients reporting overall survival (OS), and 961 patients, reporting disease free survival (DFS). HLA-G expression was associated with worse OS (HR 2.09, 95% CI = 1.67 to 2.63; P < .001), that was higher in gastric (HR = 3.40; 95% CI = 1.64 to 7.03), pancreatic (HR = 1.72; 95% CI = 0.79 to 3.74) and colorectal (HR = 1.55; 95% CI = 1.16 to 2.07) cancer. No significant differences were observed between the most commonly utilized antibody (4H84) and other methods of detection. HLA-G expression was associated with DFS which approached but did not meet statistical significance.

Discussion

In summary, we describe the first meta-analysis associating HLA-G expression and worse survival in a variety of solid tumors.

Systematic Review Registration

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022311973.
New progresses on cell surface protein HSPA5/BiP/GRP78 in cancers and COVID-19
Authors: Li Ting , Fu Jiewen , Cheng Jingliang , Elfiky Abdo A. , Wei Chunli , Fu Junjiang
Published: May 2023

Heat-shock-protein family A (Hsp70) member 5 (HSPA5), aliases GRP78 or BiP, is a protein encoded with 654 amino acids by the HSPA5 gene located on human chromosome 9q33.3. When the endoplasmic reticulum (ER) was stressed, HSPA5 translocated to the cell surface, the mitochondria, and the nucleus complexed with other proteins to execute its functions. On the cell surface, HSPA5/BiP/GRP78 can play diverse functional roles in cell viability, proliferation, apoptosis, attachments, and innate and adaptive immunity regulations, which lead to various diseases, including cancers and coronavirus disease 2019 (COVID-19). COVID-19 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which caused the pandemic since the first outbreak in late December 2019. HSPA5, highly expressed in the malignant tumors, likely plays a critical role in SARS-CoV-2 invasion/attack in cancer patients via tumor tissues. In the current study, we review the newest research progresses on cell surface protein HSPA5 expressions, functions, and mechanisms for cancers and SARS-CoV-2 invasion. The therapeutic and prognostic significances and prospects in cancers and COVID-19 disease by targeting HSPA5 are also discussed. Targeting HSPA5 expression by natural products may imply the significance in clinical for both anti-COVID-19 and anti-cancers in the future.
Mycobacterial-specific secretion of cytokines and chemokines in healthcare workers with apparent resistance to infection with Mycobacterium tuberculosis
Authors: Shey Muki Shehu , Balfour Avuyonke , Masina Nomawethu , Bekiswa Abulele , Schutz Charlotte , Goliath Rene , Dielle Rachel , Katoto Patrick DMC. , Wilkinson Katalin Andrea , Lewinsohn David , Lewinsohn Deborah Anne , Meintjes Graeme
Published: May 2023

Background

Currently, diagnosis of latent TB infection (LTBI) is based on the secretion of IFN-γ in response to Mycobacterium tuberculosis (Mtb) antigens, the absence of which is regarded as no infection. Some individuals appear to resist Mtb infection despite sustained exposure (resisters). In this study, we aimed to assess cytokines, chemokines and antibodies that may be associated with resistance to Mtb infection. We hypothesized that there may be an alternative immune response to Mtb exposure in the absence of IFN-γ in resisters.

Methods

We enrolled HIV-uninfected healthcare workers who had worked in high TB-exposure environments for 5 years or longer. We screened them for LTBI using the tuberculin skin test and the QuantiFERON-TB Gold Plus assay. We performed multiplex Luminex to measure concentrations of T cell-associated cytokines and chemokines as well as total antibodies in plasma collected from unstimulated fresh whole blood and supernatants from QuantiFERON-TB Gold Plus tubes following incubation of whole blood for 16-24 hours with ESAT6/CFP10 peptides.

Results

Samples from 78 individuals were analyzed: 33 resisters (TST<10mm; IGRA<0.35 IU/mL), 33 with LTBI (TST≥10mm and IGRA≥0.35 IU/mL) and 12 discordant (TST=0mm; IGRA≥1.0 IU/mL). There were no differences in concentrations of cytokines and chemokines in plasma between the different groups. Resisters had significantly lower concentrations of IFN-γ, IL-2, TNF-α, MIP-1α, MIP-1β, ITAC, IL-13 and GM-CSF in supernatants compared with LTBI group. There were no significant differences in the concentrations in supernatants of IL-10, IL-1β, IL-17A, IL-21, IL-23, MIP-3α, IL-4, IL-5, IL-6, IL-7, IL-8, Fractalkine and IL-12p70 between the groups. We observed that resisters had similar concentrations of total antibodies (IgG1, IgG2, IgG3, IgG4, IgA, and IgM) in plasma and supernatants compared to the LTBI and discordant groups.

Conclusion

Resistance to Mtb infection despite sustained exposure is associated with lower Mtb-specific secretion of Th1-associated cytokines and chemokines. However, resisters showed secreted concentrations after Mtb stimulation of total antibodies and cytokines/chemokines associated with innate and Th17 immune responses similar to those with Mtb infection. This suggests an ability to mount non-IFN-γ immune responses to Mtb in apparent resisters.
Lytic granule exocytosis at immune synapses: lessons from neuronal synapses
Authors: Chang Hsin-Fang , Schirra Claudia , Pattu Varsha , Krause Elmar , Becherer Ute
Published: May 2023

Regulated exocytosis is a central mechanism of cellular communication. It is not only the basis for neurotransmission and hormone release, but also plays an important role in the immune system for the release of cytokines and cytotoxic molecules. In cytotoxic T lymphocytes (CTLs), the formation of the immunological synapse is required for the delivery of the cytotoxic substances such as granzymes and perforin, which are stored in lytic granules and released via exocytosis. The molecular mechanisms of their fusion with the plasma membrane are only partially understood. In this review, we discuss the molecular players involved in the regulated exocytosis of CTL, highlighting the parallels and differences to neuronal synaptic transmission. Additionally, we examine the strengths and weaknesses of both systems to study exocytosis.
No genetic causal association between systemic lupus erythematosus and COVID-19
Authors: Xu Shu-Zhen , Wang Zhi-Xin , Fang Xi , Chen Cong , Yang Xiao-Ke , Shuai Zong-Wen , Tao Sha-Sha
Published: May 2023

Objective

Emerging evidence suggests an increased prevalence of coronavirus disease 2019 (COVID-19) in patients with systemic lupus erythematosus (SLE), the prototype of autoimmune disease, compared to the general population. However, the conclusions were inconsistent, and the causal relationship between COVID-19 and SLE remains unknown.

Methods

In this study, we aimed to evaluate the bidirectional causal relationship between COVID-19 and SLE using bidirectional Mendelian randomization (MR) analysis, including MR-Egger, weighted median, weighted mode, and the inverse variance weighting (IVW) method.

Results

The results of IVW showed a negative effect of SLE on severe COVID-19 (OR = 0.962, p = 0.040) and COVID-19 infection (OR = 0.988, p = 0.025), which disappeared after Bonferroni correction. No causal effect of SLE on hospitalized COVID-19 was observed (OR = 0.983, p = 0.148). In the reverse analysis, no causal effects of severe COVID-19 infection (OR = 1.045, p = 0.664), hospitalized COVID-19 (OR = 0.872, p = 0.109), and COVID-19 infection (OR = 0.943, p = 0.811) on SLE were found.

Conclusion

The findings of our bidirectional causal inference analysis did not support a genetically predicted causal relationship between SLE and COVID-19; thus, their association observed in previous observational studies may have been caused by confounding factors.
Dysregulation in IFN-γ signaling and response: the barricade to tumor immunotherapy
Authors: Han Jiashu , Wu Mengwei , Liu Ziwen
Published: May 2023

Interferon-gamma (IFN-γ) has been identified as a crucial factor in determining the responsiveness to immunotherapy. Produced primarily by natural killer (NK) and T cells, IFN-γ promotes activation, maturation, proliferation, cytokine expression, and effector function in immune cells, while simultaneously inducing antigen presentation, growth arrest, and apoptosis in tumor cells. However, tumor cells can hijack the IFN-γ signaling pathway to mount IFN-γ resistance: rather than increasing antigenicity and succumbing to death, tumor cells acquire stemness characteristics and express immunosuppressive molecules to defend against antitumor immunity. In this review, we summarize the potential mechanisms of IFN-γ resistance occurring at two critical stages: disrupted signal transduction along the IFNG/IFNGR/JAK/STAT pathway, or preferential expression of specific interferon-stimulated genes (ISGs). Elucidating the molecular mechanisms through which tumor cells develop IFN-γ resistance help identify promising therapeutic targets to improve immunotherapy, with broad application value in conjugation with targeted, antibody or cellular therapies.
Flagellar-based motility accelerates IgA-mediated agglutination of Salmonella Typhimurium at high bacterial cell densities
Authors: Lindberg Samantha K. , Willsey Graham G. , Mantis Nicholas J.
Published: May 2023

Introduction

Secretory IgA (SIgA) protects the intestinal epithelium from enteric pathogens such as Salmonella enterica serovar Typhimurium (STm) through a process known as immune exclusion, where invading bacteria are aggregated via antibody cross-linking, encased in mucus, and then cleared from the intestinal tract via peristalsis. At high cell densities, the STm aggregates form a tightly packed network that is reminiscent of early bacterial biofilms. However, the underlying mechanism of how SIgA mediates this transition from a motile and invasive state to an avirulent sessile state in STm is currently unknown.

Methods

In this report, we developed and validated a methodology known as the “snow globe” assay to enable real-time imaging and quantification of STm agglutination by the mouse monoclonal IgA Sal4.

Results

We observed that agglutination in the snow globe assay was dose-dependent, antigen-specific, and influenced by antibody isotype. We determined that flagellar-based motility was a prerequisite for rapid onset of agglutination, even at high cell densities where cell-cell contacts are expected to be frequent. We also investigated the roles of individual cyclic-di-GMP metabolizing enzymes previously implicated in motility and biofilm formation in Sal4 IgA-mediated agglutination.

Discussion

Taken together, our results demonstrate that IgA-mediated agglutination is a dynamic process influenced by bacterial motility and cell-cell collisions. We conclude that the snow globe assay is a viable platform to further decipher the molecular and genetic determinants that drive this interaction.
Inflammatory microRNAs in cardiovascular pathology: another brick in the wall
Authors: Zapata-Martínez Laura , Águila Sonia , de los Reyes-García Ascensión M. , Carrillo-Tornel Salvador , Lozano María L. , González-Conejero Rocío , Martínez Constantino
Published: May 2023

The regulatory role of microRNAs (miRNAs) is mainly mediated by their effect on protein expression and is recognized in a multitude of pathophysiological processes. In recent decades, accumulating evidence has interest in these factors as modulatory elements of cardiovascular pathophysiology. Furthermore, additional biological processes have been identified as new components of cardiovascular disease etiology. In particular, inflammation is now considered an important cardiovascular risk factor. Thus, in the present review, we will focus on the role of a subset of miRNAs called inflamma-miRs that may regulate inflammatory status in the development of cardiovascular pathology. According to published data, the most representative candidates that play functional roles in thromboinflammation are miR-21, miR-33, miR-34a, miR-146a, miR-155, and miR-223. We will describe the functions of these miRNAs in several cardiovascular pathologies in depth, with specific emphasis on the molecular mechanisms related to atherogenesis. We will also discuss the latest findings on the role of miRNAs as regulators of neutrophil extracellular traps and their impact on cardiovascular diseases. Overall, the data suggest that the use of miRNAs as therapeutic tools or biomarkers may improve the diagnosis or prognosis of adverse cardiovascular events in inflammatory diseases. Thus, targeting or increasing the levels of adequate inflamma-miRs at different stages of disease could help mitigate or avoid the development of cardiovascular morbidities.
Daily timescale dynamics of planktonic foraminifera shell-size distributions
Authors: Chernihovsky Natalie , Torfstein Adi , Almogi-Labin Ahuva
Published: May 2023

Planktonic foraminifera (PF) shells comprise a significant fraction of the global oceanic carbonate flux and serve as a primary archive of the history of the oceans. Yet, a limited understanding of their life cycles dynamics and biological rhythms, hampers their application as palaeoceanographic proxies. Here, we present the flux of ten PF species and their shell-size distributions at a daily timescale resolution in the Gulf of Aqaba (GOA), northern Red Sea. We report diameter measurements of ~13,500 shells, associated with ten PF species, retrieved using an automated time-series sediment trap deployed at a water depth of ~410 m (seafloor depth 610 m) throughout more than a full annual cycle between 2015 and 2016. Most of the PF species display a wide intraspecific shell-size distribution among adult PF, while six abundant species (G. ruber, G. rubescens + G. tenellus, G. glutinata, G. calida and G. siphonifera) display significantly smaller shell-sizes compared with corresponding specimens from sediment traps and seafloor sediments across other tropical, subtropical and upwelling regions. The results indicate that PF generation cycles can be classified according to three patterns: (1) Quiescent: minimal shell-size and extended life cycles due to unfavorable conditions and food scarcity when the water column is stratified and oligotrophic, (2) Transient: the gradual increase of Chlorophyll-a (Chl-a) concentrations and food availability enhance shorter life-cycles, although PF do not necessarily reach maximal shell-sizes, (3) Successive: PF fluxes and Chl-a concentrations are maximal, the generation time is extended and individuals might display growth to maximal shell-sizes.
Dynamic cyclic fatigue resistance of NiTi instruments in a double-curved stainless steel canal with variable distances of displacement
Authors: Pham Van-Khoa
Published: May 2023

The present study aimed to measure the number of cycles to fracture (NCF) of different instruments using pecking motion at constant and varying distances of movement at body temperature. This study included 20 files from each brand: ProTaper Universal F2, ProTaper Next X2, and WaveOne Gold Primary (Dentsply Sirona, Maillefer, Ballaigues, Switzerland). Instruments from each brand were divided into two groups (ten files for each group) that experienced constant or variable distances in a stainless-steel artificial double-curved canal in a platform that ensured that the instrument rotated at a stable temperature with a minimum fluctuation of the environment. While running, the platform was programmatically controlled to move at any desired distance of instrument displacement to simulate the clinical pecking motion at variable distances. The files were rotated using proprietary programs. The times to fracture were recorded and then transformed into the number of cycles to fracture (NCF). Data were analyzed using Minitab with proper tests. All fragments were observed under a scanning electron microscope to capture and describe the characteristics of the fracture surface. The WaveOne Gold had the highest NCF, while the ProTaper Universal had the lowest NCF. The manufacturer brands and the modes of displacement of the experimental instrument showed interactive effects. The fracture surface revealed no striation. A new design, material, mode of rotation, and different distances of movement have certain effects on the cyclic fatigue resistance of the instrument.
Collaborative training of regulators as an approach for strengthening regulatory systems in LMICs: experiences of the WHO and Swissmedic
Authors: Dehaghi Razieh Ostad Ali , Khadem Broojerdi Alireza , Paganini Lodovico , Sillo Hiiti B.
Published: May 2023

Introduction

Training opportunities for health product regulators are among the critical aspects in the strengthening of regulatory systems across the world. The need for training is reasonably higher among the National Regulatory Agencies (NRAs) in the Low- and Middle-Income countries (LMICs) which are faced with many regulatory challenges mostly rooted in the low availability of resources. The current study aimed at evaluating the suitability, impacts, and challenges related to the training of regulators from LMICs offered by the Swissmedic in collaboration with the World Health Organization (WHO).

Methodology

An exploratory case study design using a qualitative approach was adopted to collect data from a total of 17 NRAs in different WHO regions using in-depth interviews and qualitative questionnaires.

Results

The participation of the trainees in the training was revealed to be motivated by the need to apply the obtained knowledge in addressing various challenges within their NRAs. Many lessons covering all key areas of health products regulation were reported by the trainees, whereby most of the lessons were already being implemented within their respective NRAs. However, challenges related to human, financial, and infrastructural resources were highlighted to hinder the ongoing efforts in putting the learned aspects into practice. Additionally, areas in which further regulatory assistance and suggestions for improving the training activities were pointed out.

Conclusion

The highlighted gains from the WHO-Swissmedic collaborative training program call for other agencies and organizations to join hands in offering much-needed support towards addressing critical challenges facing the regulatory sector in the LMICs.
Assessing the efficacy of probiotics in augmenting bovine reproductive health: an integrated in vitro, in silico, and in vivo study
Authors: Gohil Purva , Nanavati Bhavya , Patel Kajal , Suthar Vishal , Joshi Madhvi , Patil Deepak B. , Joshi Chaitanya G.
Published: May 2023

The aim of this study was to isolate and characterize bovine-vaginal probiotics genotypically and phenotypically using in silico and evaluate their in vivo performance in buffaloes with endometritis. For the in vitro isolation and characterization, vaginal swabs were collected from 34 cows and 17 buffaloes, and 709 primary bacterial isolates with probiotic activity were obtained using MRS agar media. Two isolates Lactiplantibacillus plantarum KUGBRC (LPKUGBRC) and Pediococcus pentosaceus GBRCKU (PPGBRCKU) demonstrated optimum in vitro probiotic activities as compared to Lacticaseibacillus rhamnosus GG including, acid production, secretion of fatty acids and exopolysaccharide, cell surface hydrophobicity, self-aggregating and co-aggregating capacity with pathogens, anti-microbial activity and bacteriocin-like compounds against pathogens Escherichia coli and Staphylococcus aureus in cell-free supernatant and absence of hemolytic activity. Their phenotypic capacity was confirmed by analyzing the whole genome sequencing data and identifying genes and pathways associated with probiotic properties. These probiotic isolates have shown no virulence genes were discovered in their genomic study. In vivo study of 92 buffaloes suffering from clinical endometritis with purulent cervico-vaginal mucus (CVM) were randomly allocated 40 × 108 CFU/ml LPKUGBRC and PPGBRCKU and 40 ml Normal saline. The LPKUGBRC reduced the duration between administration of probiotic to induction of healthy estrus significantly. However, no effect was observed on pregnancy rate. These results suggest that LPKUGBRC and PPGBRCKU probiotic bacteria demonstrate probiotic efficiency and adaptability. Further sourced from the same niche as the targeted infection, they offer a distinct advantage in targeting the specific microbial population associated with endometritis. The findings of this study highlight the potential of LPKUGBRC and PPGBRCKU probiotics in treating endometritis and suggest further exploration of their clinical applications.
Whole genome sequencing of Mycobacterium bovis directly from clinical tissue samples without culture
Authors: Zeineldin Mohamed , Camp Patrick , Farrell David , Lehman Kimberly , Thacker Tyler
Published: May 2023

Advancement in next generation sequencing offers the possibility of routine use of whole genome sequencing (WGS) for Mycobacterium bovis (M. bovis) genomes in clinical reference laboratories. To date, the M. bovis genome could only be sequenced if the mycobacteria were cultured from tissue. This requirement for culture has been due to the overwhelmingly large amount of host DNA present when DNA is prepared directly from a granuloma. To overcome this formidable hurdle, we evaluated the usefulness of an RNA-based targeted enrichment method to sequence M. bovis DNA directly from tissue samples without culture. Initial spiking experiments for method development were established by spiking DNA extracted from tissue samples with serially diluted M. bovis BCG DNA at the following concentration range: 0.1 ng/μl to 0.1 pg/μl (10–1 to 10–4). Library preparation, hybridization and enrichment was performed using SureSelect custom capture library RNA baits and the SureSelect XT HS2 target enrichment system for Illumina paired-end sequencing. The method validation was then assessed using direct WGS of M. bovis DNA extracted from tissue samples from naturally (n = 6) and experimentally (n = 6) infected animals with variable Ct values. Direct WGS of spiked DNA samples achieved 99.1% mean genome coverage (mean depth of coverage: 108×) and 98.8% mean genome coverage (mean depth of coverage: 26.4×) for tissue samples spiked with BCG DNA at 10–1 (mean Ct value: 20.3) and 10–2 (mean Ct value: 23.4), respectively. The M. bovis genome from the experimentally and naturally infected tissue samples was successfully sequenced with a mean genome coverage of 99.56% and depth of genome coverage ranging from 9.2× to 72.1×. The spoligoyping and M. bovis group assignment derived from sequencing DNA directly from the infected tissue samples matched that of the cultured isolates from the same sample. Our results show that direct sequencing of M. bovis DNA from tissue samples has the potential to provide accurate sequencing of M. bovis genomes significantly faster than WGS from cultures in research and diagnostic settings.