bluuebunny/crossref_metadata_2025 huggingface dataset:
RIF, THE MEXICAN STRATEGY TO COMBAT INFORMALITY
Authors: Hernández Silva Virginia , Tavera Ramírez Flor de María
Published: April 2023

His paper evaluates the effectiveness of the strategies established by the Mexican government since 2014 to decrease the activity carried out by companies in the informal economy. That goal should be reached through the diminishing of informality with incentives to those in the informal economy. These incentives to formality include reduction of income tax, simplification of procedures, access to social security with special fees and credit at preferential rates as well as training to improve business processes. We found that far from increasing the base of taxpayers’ natural persons with Business and Professional Activities the same base has decreased by 9.39% since the Fiscal Reform in 2014.
Ảnh hưởng của khác biệt vùng miền tới phong cách lãnh đạo trong các doanh nghiệp nhỏ và vừa Việt Nam
Authors: Lê Tiến Đạt
Published: April 2023

Khác biệt vùng miền được cho là ảnh hưởng mạnh mẽ tới phong cách của nhà lãnh đạo, đặc biệt trong bối cảnh Việt Nam khi khác biệt văn hóa miền Bắc và miền Nam là rõ nét. Bằng tiếp cận định tính, sử dụng kỹ thuật phỏng vấn bán cấu trúc, nghiên cứu điều tra chuyên sâu nhận thức, phản ánh sự lý giải cụ thể của 54 nhà quản trị doanh nghiệp nhỏ và vừa Việt Nam về ảnh hưởng của khác biệt vùng miền tới tính cách và phong cách lãnh đạo. Với tính cách quyết liệt, ưa thích quyền lực, lãnh đạo miền Bắc thường sử dụng phong cách chuyên quyền còn phong cách dân chủ tự do thường thấy ở lãnh đạo miền Nam. Bài viết đưa ra một số hàm ý cho các lãnh đạo để tận dụng thế mạnh, khắc phục điểm yếu trong phong cách đặc trưng của vùng miền mình. Nghiên cứu đóng góp về mặt lý thuyết khi làm rõ ảnh hưởng của các yếu tố khác biệt vùng miền tới phong cách lãnh đạo trong bối cảnh văn hóa của một quốc gia Đông Nam Á như Việt Nam.
Hiệu ứng của tự do hóa tài chính đối với tăng trưởng kinh tế tại Việt Nam
Authors: Nguyễn Quốc Anh , Nguyễn Thị Thanh Nhàn
Published: April 2023

Bài nghiên cứu được thực hiện nhằm nghiên cứu tác động của tự do hoá tài chính đến tăng trưởng kinh tế tại Việt Nam. Dữ liệu nghiên cứu được lấy tổ chức IMF trong giai đoạn từ năm 2001 đến 2021. Biến phụ thuộc của mô hình là GDP, biến độc lập bao gồm bao gồm BM, IRO và EX. Bài nghiên cứu sử dụng mô hình mô hình VECM và mô hình NARDL để xử lý. Kết quả cho thấy trong ngắn hạn có thể chứng minh được tác động của tự do hoá tài chính đối với tốc độ tăng trưởng GDP. Nghiên cứu cũng cho thấy tài chính đóng một vai trò quan trọng trong việc kích thích tăng trưởng và phát triển kinh tế. Nghiên cứu kết luận rằng sự thiếu hụt nguồn vốn sẽ có những tác động tiêu cực đến tăng trưởng kinh tế ngay lập tức. Từ kết quả nghiên cứu, bài viết đã đề xuất một số giải pháp cho chính sách của FTA, tự do hoá tài chính đối với tăng trưởng kinh tế Việt Nam.
Intravascular Ultrasound-Guided Percutaneous Coronary Intervention Using Gadolinium Contrast Medium
Authors: Guerrero-Marquez Francisco J , Cubero Gomez Jose Maria
Published: April 2023

Introduction: The iodinated contrast media used in coronary angiography have a very low incidence of adverse effects. In cases in which adverse effects occur, other contrast media are necessary as an alternative. Gadolinium is one of these alternatives, as its safety has been demonstrated in patients with renal failure. However, gadolinium has important limitations, such as low radiopacity for the characterization of the coronary arteries and the need to administer low doses (<0.4 mg/kg) to reduce serious complications, such as nephrogenic systemic fibrosis. Materials and Methods: We present the first case series of patients undergoing percutaneous coronary intervention in which gadolinium was used as contrast medium and the procedure was guided by IVUS Results: We report the experience of our center, based on three patients with contraindication to iodinated contrasts who underwent IVUS-guided percutaneous transluminal coronary angioplasty using gadolinium and did not present with significant complications. Discussion and Conclusions: In cases where percutaneous coronary angioplasty is performed, high contrast doses are usually required. Intracoronary diagnostic techniques such as intravascular ultrasound (IVUS) can help reduce the contrast dose and provide great advantages during the intervention, improving the results.
CPT1 and PyK Gene Expression Changes with Different Physiological Conditions between 2 Resistant to Starvation Fly Lines: A Basic Science Experiment
Authors: Borokhovsky Benjamin , Nagengast Alexis
Published: April 2023

Background: Many organisms adapt to different physiological conditions by changing their gene expression to increase their chances of survival. Drosophila melanogaster fly line 765 show low resistance to starvation and line 362 show high resistance to starvation and were selected to examine how their gene expression would change based on a starved and refed environment. The genes selected were both metabolic genes CPT1 and PyK. CPT1 is responsible for fat breaking and PyK is responsible for the catalysis of the final stage in glycolysis. Methods: Specific Drosophila melanogaster fly lines were selected that showed either a high or low resistance to starvation. These lines were selected to examine how their gene expression would change based on a starved and re-fed environment. RNA was isolated from both sets of flies so that reverse transcriptase reactions could be performed using RT-PCR to generate complementary DNA using reverse transcriptase. The complementary DNA served as a template for amplification using endpoint and quantitative PCR to determine if gene expression would change between the two fly lines. A survival curve was also generated to illustrate the graphical differences among the various fly lines. Results: Quantitative PCR and gene expression data concluded that there was a difference between gene expression of CPT1 and PyK between the two lines. CPT1 quantitative PCR data did not match gene expression predictions, whereas, PyK did in both line 765 and 362. Conclusions: The finding that CPT1 was able to generate Ct values but was unable to adhere to the expected predictions of gene expression is indicative of line 765 having a problem sensing the nutrients and unlikely to be a problem in transcription. Future directions include to characterize both glycogen and triglyceride levels at time t=0 hrs, starved, and re-fed conditions and to investigate if there is a connection between enzyme efficiency and condition type between the two lines.
Using Social Media Engagement to Raise Pre-Diabetes Awareness for Rural Idaho Hispanics or Latinos
Authors: Woods Tanna M , Lewis Heidi K , Nies Mary A
Published: April 2023

Background: Pre-diabetes is a condition that usually has no symptoms, which can lead to decreased awareness of its presence. Like other chronic diseases, pre-diabetes disproportionately affects Hispanic/Latinos populations and places them at greater risk for severe consequences. Latinos are not fully aware of what pre-diabetes is or how it differs from diabetes. This represents a healthcare disparity that requires engagement with the Latino population to address it. Complications of diabetes could be dramatically reduced by increasing awareness of pre-diabetes through engagement with Latinos, health care providers, and pre-diabetes awareness for Latinos. Objective: The purpose of this study was to understand how effective the use of a targeted social media campaign could increase awareness of prediabetes. Design and sample: A two-week long Facebook campaign was conducted with four ads targeted to Idahoans aged 18 plus. These messages involved awareness of prediabetes. The amount of engagement was tracked including shares, reactions, and views. Paid boosts were used to evaluate the natural reach of the messages versus reach with a paid boost. Results: Combined reach of all four posts was 36,578. Organic reach was 7,416 or 20.2% of views while paid reach comprised 29,162 or 79.7% of views. Total reactions totaled 627 with 538 or 85.8% being “like.” The second highest reaction was sad with 37 or 6.7%; all the sad reactions were limited to post one and post three. Conclusion: Use of Facebook appears appropriate to reach individuals with health-related messages, though it is clear that the use of paid boosts improves reach.
Changing AAPI Knowledge, Attitude, and Practice (KAP) Toward COVID-19 Pandemic in Pima County
Authors: Eng Howard J
Published: April 2023

Background: COVID-19 had significantly impacted on the Asian American and Pacific Islander (AAPI) populations in Pima County. The Arizona and COVID-19 Update Articles (ACUA) were established to provide the latest COVID-19 information, to encourage preventive health behaviors, and to reduce the anxiety levels associated with the virus. The ACUA used the Health Belief Model as its framework. The articles addressed two of three World Health Organization dimensions of health (physical and mental). There had been 24 issues published. After two-year, an assessment was conducted to determine whether there was still a need for the articles and their impacts. Methods: This was a cross-sectional study. A KAP survey was used to collect information on knowledge gain, information usefulness, attitude/belief changes, behavior changes, and anxiety reduction. A convenience sample of AAPI leaders, community members, and health professionals was used. Results: The ACUA increased knowledge in all five areas examined. Of the five areas, more than 75 percent of the respondents indicated the knowledge gained were useful in four areas. Of the respondents, 96 percent practice preventive COVID health behaviors regularly and 80 percent were fully vaccinated for COVID and gotten their boosters. Conclusion: Three-quarter of the respondents indicated that the articles are still useful and needed. The Health Belief Model was an effective framework used in the ACUA to accomplish its health promotional goals. This health educational approach could be used in minority and underserved communities during the COVID-19 pandemic.
FORMULASI DAN EVALUASI SEDIAAN KRIM PELEMBAP DAN ANTIOKSIDAN KOMBINASI EKSTRAK KULIT BUAH MANGGIS Garcinia mangostana L DAN LIDAH BUAYA Aloe vera L
Authors: Rahayu Putri , Monica Eva , Yulinda Cesa Fibe
Published: April 2023

Penuaan kulit merupakan proses fisiologis yang tidak dapat dihindari. Pemakaian senyawa antioksi dan dengan cara sistemik ataupun lokal banyak disukai sebab dipercaya bisa menangkal beragam jenis gangguan kulit serta dapat melindungi kulit dari kerusakan akibat radikal. Antioksidan adalah suatu molekul yang dapat menghambat oksidasi dari molekul lainnya. Tanaman yang memiliki khasiat sebagai antioksidan yaitu kulit buah manggis (Garcinia mangostana L.) dan lidah buaya (Aloe vera L.). Lidah buaya (Aloe vera L.) mengandung metabolit sekunder flavonoid yang merupakan antioksidan sekaligus dapat digunakan sebagai pelembap kulit. Pada penelitian ini bertujuan untuk mendapatkan formulasi sediaan krim yang baik dan stabil dari hasil evaluasi sediaan yang meliputi uji organoleptis, uji homogenitas, uji daya sebar, uji daya lekat, uji distribusi ukuran partikel, uji pH dan uji tipe krim, serta untuk mengetahui aktivitas antioksidan sediaan krim menggunakan metode DPPH. Hasil dan kesimpulan penelitian menunjukkan bahwa perbandingan konsentrasi ekstrak kulit buah manggis dan lidah buaya 3%:5%, 4%:6%, dan 6%:7% menunjukkan hasil yang berbeda pada setiap uji, namun hasil tersebut memenuhi persyaratan yang tertera. Selain itu, diperoleh hasil nilai antioksidan sebesar 85,85 ppm pada perbandingan konsentrasi ekstrak 4%:6%. Saran untuk penelitian ini yaitu perlunya uji antioksidan secara in vivo untuk mengetahui efektivitas krim serta uji stabilitas untuk mengetahui ketahanan dan kualitas sediaan pada waktu tertentu.
Red-cockaded woodpecker habitat characteristics associated with partial brood loss in the Upper East Gulf Coastal Plain, USA
Authors: Martin EJ , Gigliotti F , Ferguson PFB
Published: April 2023

Some red-cockaded woodpecker (RCW)Dryobates borealispopulations remain understudied. This is notable because management that incorporates population demographics and site characteristics may benefit RCW recovery. The Oakmulgee Ranger District of the Talladega National Forest (Alabama, USA) has no wiregrassAristida stricta, small forest stand sizes, rolling topography, and contains an understudied RCW population. Our goal in the Oakmulgee was to characterize RCW habitat, possibly identify ways in which habitat differed from other regions, and estimate associations between habitat and reproductive output. We found that 70.2 and 92.5% of sampled stands met recovery standard thresholds for small and large pine basal area (BA) as defined in the United States Fish and Wildlife Service (USFWS) RCW Recovery Plan. While 74.6% of longleaf pinePinus palustris-dominated stands met the threshold for overstory hardwood canopy composition, 60.0% of loblolly pineP. taeda-dominated stands did not. Few stands met the recommended percentage of herbaceous understory (19.8%) or recommended absence of hardwood midstory. A lower rate of partial brood loss was associated with a greater area of large pines (≥25.4 cm diameter at breast height; DBH), a smaller area of small pines (≥10 and <25.4 cm DBH), a larger area burned in the dormant season, and higher RCW density. In our models, hardwood overstory and midstory did not influence egg or hatchling production. Hardwoods in the Oakmulgee could contribute to unfavorable habitat, as indicated in the USFWS RCW Recovery Plan, as well as relate to variation in habitat across the RCW’s range. Regions of the RCW’s range are understudied, and limited staffing and funding impede advances in understanding and conservation.
Population genetics of freshwater stingray require investigation to confirm DNA contamination: Reply to Alshari et al. (2023)
Authors: Lim KC , Then AY
Published: April 2023

Alshari et al. (2023; Endang Species Res 50:311-313) were able to collect 3 Fluvitrygon kittipongi specimens from the Pahang River, which were not available to us at the time of our study (Lim & Then 2022; Endang Species Res 48:43-50). The cytochrome c oxidase I (COI) sequences (or haplotypes) of these 3 stingrays were identical to each other but differed from the haplotypes of our Perak River specimens. The result of 100% similarity between COI sequences of our Perak River rays and the eDNA water samples isolated from Pahang River in our study was suggested by Alshari et al. (2023) as DNA contamination in our study, which is plausible. However, further population genetics studies would be necessary to ascertain that the Perak River haplotype does not occur in stingrays of the Pahang River.
Step by Step
Authors:   , Suir Imke Elize Frederike
Published: April 2023

Summary
Infants born very preterm - before 32 weeks gestation and ≤1500 grams birthweight - are at risk of developmental problems. Gross motor development is an early marker in the first year of life to identify developmental delay. As in other developmental domains, gross motor development is characterized by variability between infants known to be related to both infant and environmental factors. This variability makes predicting infant motor development difficult and with that clinical decision-making on initiating early intervention. Repeatedly, within the same child, measuring gross motor development over time makes discrimination of typical or atypical development and developmental progress possible.
The Alberta Infant Motor Scale (AIMS) is an observational instrument frequently used by paediatric physiotherapists worldwide to measure infant gross motor development. Among other things, this dissertation describes cross-cultural research to examine the validity of the Canadian norm values of the AIMS for the Dutch population of infants from birth to independent walking. Next, a longitudinal study was conducted to explore the variation in course and speed of gross motor development of Dutch very preterm infants until independent walking and influencing factors. Parents made multiple home video recordings of their infant (corrected age 3.5 to 17.5 months), from which gross motor development was assessed with AIMS. Lastly, parental beliefs about their child's motor development and experiences with the home-video method were examined.
Main outcomes of the studies are 1) Dutch infants develop at a slower pace than Canadian infants from birth until independent walking, 2) there is strong evidence for the association of birthweight and moderate evidence for gestational age and sleeping position with infant gross motor development, 3) gross motor growth curves showed that three profiles, comparable to profiles observed among term born infants, can be distinguished: early developers, gradual developers and late bloomers and, 4) parents of very preterm infants believed stimulating motor development to be more important than parents of term born infants.
Activation and modulation of ligand-gated ion channels
Authors: Krůšek J , Dittert I , Hendrych T , Hník P , Horák H , Petrovic M , Sedláček M , Sušánková K , Svobodová L , Toušová K , Ujec E , Vlachová V , Vyklický L , Vyskočil F , Vyklický L
Published: April 2023

Ligand-gated ionic channels are integral membrane proteins that enable rapid and selective ion fluxes across biological membranes. In excitable cells, their role is crucial for generation and propagation of electrical signals. This survey describes recent results from studies performed in the Department of Cellular Neurophysiology, Institute of Physiology ASCR, aimed at exploring the conformational dynamics of the acetylcholine, glutamate and vanilloid receptors during their activation, inactivation and desensitization. Distinct families of ion channels were selected to illustrate a rich complexity of the functional states and conformational transitions these proteins undergo. Particular attention is focused on structure-function studies and allosteric modulation of their activity. Comprehension of the fundamental principles of mechanisms involved in the operation of ligand-gated ion channels at the cellular and molecular level is an essential prerequisite for gaining an insight into the pathogenesis of many psychiatric and neurological disorders and for efficient development of novel specifically targeted drugs.
Seasonal molecular timekeeping within the rat circadian clock
Authors: Sumová A , Bendová Z , Sládek M , Kováčiková Z , Illnerová H
Published: April 2023

In temperate zones duration of daylight, i.e. photoperiod, changes with the seasons. The changing photoperiod affects animal as well as human physiology. All mammals exhibit circadian rhythms and a circadian clock controlling the rhythms is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN consists of two parts differing morphologically and functionally, namely of the ventrolateral (VL) and the dorsomedial (DM). Many aspects of SCN-driven rhythmicity are affected by the photoperiod. The aim of the present overview is to summarize data about the effect of the photoperiod on the molecular timekeeping mechanism in the rat SCN, especially the effect on core clock genes, clock-controlled genes and clock-related genes expression. The summarized data indicate that the photoperiod affects i) clock-driven rhythm in photoinduction of c-fos gene and its protein product within the VL SCN, ii) clock-driven spontaneous rhythms in clock-controlled, i.e. arginine-vasopressin, and in clock-related, i.e. c-fos, gene expression within the DM SCN, and iii) the core clockwork mechanism within the rat SCN. Hence, the whole central timekeeping mechanism within the rat circadian clock measures not only the daytime but also the time of the year, i.e. the actual season.
From spreading depression to spatial cognition
Authors: Bureš J , Lánský P
Published: April 2023

The Laboratory of Neurophysiology of Memory started its existence in 1954 by systematic research into spreading depression of EEG activity of laboratory rodents and by the use of this remarkable phenomenon as a functional ablation method in behavioral research. Its main contributions were in the study of memory formation and consolidation, interhemispheric transfer, motor learning, conditioned taste aversion and spatial orientation and navigation. In the last five years it concentrated on navigation of rats in multiple reference frames, on electrophysiological evidence for the role of hippocampal place cells support of behavior in such dissociated frames, on the analysis of idiothetic and allothetic forms of navigation and on the mathematical methods allowing assessment of the contribution of goal directed locomotion to place cell activity. The methods used in spatial memory research in rats were used for examination of human subjects in a laboratory equipped with a tracking system for humans in the hospital Homolka. Animal models of Alzheimer disease were studied in transgenic mice with the human gene for the beta amyloid precursor protein.
Corticosteroid regulation of colonic ion transport during postnatal development and methods for corticosteroid analysis
Authors: Pácha J , Mikšík I , Mrnka L , Zemanová Z , Bryndová J , Mazancová K , Kučka M
Published: April 2023

Many mammalian species including human are immature at birth and undergo major developmental changes during suckling and weaning period. This problem is also conspicuous for the gastrointestinal tract that undergoes abrupt transitions coinciding with birth and weaning. This review deals with the maturation of ion transport functions in colon, the intestinal segment that plays an important role in sodium and potassium absorption and secretion. The purpose of the present review is to summarize the mechanism of sodium and potassium transport pathways and show how these transport processes change postnatally and how hormones, particularly corticosteroids, modify the pattern of development. Finally we describe some of the ways, how to analyze corticosteroid metabolism in target tissue.
Yeast as a model organism to study transport and homeostasis of alkali metal cations
Authors: Sychrová H
Published: April 2023

To maintain an optimum cytoplasmic K(+)/Na+ ratio, cells employ three distinct strategies: 1) strict discrimination among alkali metal cations at the level of influx, 2) efficient efflux of toxic cations from cells, and 3) selective sequestration of cations in organelles. Cation efflux and influx are mediated in cells by systems with different substrate specificities and diverse mechanisms, e.g. ATPases, symporters, antiporters, and channels. Simple eukaryotic yeast Saccharomyces cerevisiae cells proved to be an excellent model for studying the transport properties and physiological function of alkali-metal-cation transporters, and the existence of mutant strains lacking their own transport systems provided an efficient tool for a molecular study of alkali-metal-cation transporters from higher eukaryotes upon their expression in yeast cells.
Down-regulation of model yeast proteins by ubiquitin-dependent proteolysis
Authors: Horák J
Published: April 2023

Ubiquitination is a versatile tool used by all eukaryotic organisms for controlling the stability, function, and intracellular localization of a multitude of proteins. I will attempt to bring together our recent data on the down-regulation of two yeast model proteins, the galactose transporter Gal2 and fructose-1,6-bisphosphatase, by ubiquitin-dependent proteolysis triggered by the addition of easily fermentable carbon sources.
Marriage, Political Alliance, and Imperial Polities in Early Ghaznavid History
Authors: Auer Blain
Published: April 2023

This article considers how marriages were utilized in early Ghaznavid history to forge political alliances, establish relationships of power and to bind together different royal family households. Marriage was employed as a diplomatic tool to ease political tensions and to strengthen coalitions. The Ghaznavid ruler Maḥmūd (r. 388–421/998–1030) utilized marriage alliances with great success to consolidate and expand his territories. In 391/1001, he forged a coalition with the Karakhanids through a marriage to the daughter of Naṣr b. ʿAlī (d. 403/1012–3). In 406/1015–16, Maḥmūd married his own sister Ḥurra Kāljī to the Khwarazmshah al-Maʾmūn II (r. 399–407/1009–17). This paper attempts to answer unstudied questions concerning the role of marriage and the influence of female royal family members in the construction of imperial polities of the medieval period in Central Asia, Iran, and Afghanistan. It shows that the effective creation of strategic marriage alliances was a key factor in the success of the early Ghaznavid empire.
Curcumin-loaded graphene oxide quantum dots enhance otoprotective effects via blocking cuproptosis
Authors: Hu An , Zhang Jian-Wei , Yang Li-Yun , Qiao Pei-Pei , Lu Dan , Yu Ya-Feng
Published: April 2023

Graphical Abstract

Mechanisms by which exposure to cisplatin disrupts the inner ear system are not yet known. Here, we show that cisplatin exposure is associated with dysregulation of oxidative stress in the inner ear of the rodent. Furthermore, we found that, unlike controls, the response parameters of auditory cells of rats exposed to cisplatin were related to an imbalance in copper metabolism. These data suggest that curcumin related changes in the inner ear are depend on their effects on the mechanism of balance of the copper metabolism and that exposure to cisplatin can disrupt the plastic copper metabolism mechanisms needed to restore normal processing in peripheral auditory cells after hearing loss.
Role of the tumor microenvironment in malignant melanoma organoids during the development and metastasis of tumors
Authors: Zhou Siyu , Lu Jinghan , Liu Shiyang , Shao Jiaqi , Liu Zhanwei , Li Jianjun , Xiao Wan’an
Published: April 2023

Malignant melanoma (MM) is the most metastatic and aggressive form of skin cancer, and carries a high risk of death. Immune-checkpoint inhibitor therapy and molecular-targeted therapy can prolong the survival of patients with advanced MM significantly. However, the low response rate and inevitable drug resistance prevent further improvements in efficacy, which is closely related to the tumor microenvironment (TME). The TME refers to the tumor stroma, including fibroblasts, keratinocytes, immune cells, soluble molecules, and extracellular matrix (ECM). The dynamic interaction between the TME and tumor cells is very important for the growth, local invasion, and metastatic spread of tumor cells. A patient-derived organoid (PDO) model involves isolation of tumor tissue from patients with MM and culturing it in vitro in a three-dimensional pattern. Compared with traditional cultivation methods, the PDO model preserves the heterogeneity of the tissue structure of MM and demonstrates the interaction between MM cells and the TME. It can reproduce the characteristics of proliferation, migration, and invasion of MM cells, and better simulate the structural function of MM in vivo. This review explores the role of each TME component in development of the PDO model. This review will provide a reference for research on the drug screening and targeted treatment using PDOs, particularly for the immunotherapy of MM.
A phase I study to assess safety, pharmacokinetics, and pharmacodynamics of a vaginal insert containing tenofovir alafenamide and elvitegravir
Authors: Thurman Andrea R. , Ouattara Louise A. , Yousefieh Nazita , Anderson Peter L. , Bushman Lane R. , Fang Xi , Hanif Homaira , Clark Meredith , Singh Onkar , Doncel Gustavo F.
Published: April 2023

Background

New multi-purpose prevention technology (MPT) products are needed to prevent human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV2). In this study, we evaluated a fast-dissolve insert that may be used vaginally or rectally for prevention of infection.

Objective

To describe the safety, acceptability, multi-compartment pharmacokinetics (PK), and in vitro modeled pharmacodynamics (PD) after a single vaginal dose of an insert containing tenofovir alafenamide (TAF) and elvitegravir (EVG) in healthy women.

Methods

This was a Phase I, open-label, study. Women (n=16) applied one TAF (20mg)/EVG (16mg) vaginal insert and were randomized (1:1) to sample collection time groups for up to 7 days post dosing. Safety was assessed by treatment-emergent adverse events (TEAEs). EVG, TAF and tenofovir (TFV) concentrations were measured in plasma, vaginal fluid and tissue, and TFV-diphosphate (TFV-DP) concentration in vaginal tissue. PD was modeled in vitro by quantifying the change in inhibitory activity of vaginal fluid and vaginal tissue against HIV and HSV2 from baseline to after treatment. Acceptability data was collected by a quantitative survey at baseline and post treatment.

Results

The TAF/EVG insert was safe, with all TEAEs graded as mild, and acceptable to participants. Systemic plasma exposure was low, consistent with topical delivery, while high mucosal levels were detected, with median TFV vaginal fluid concentrations exceeding 200,000 ng/mL and 1,000 ng/mL for up to 24 hours and 7 days post dosing, respectively. All participants had vaginal tissue EVG concentrations of > 1 ng/mg at 4 and 24 hours post dosing. The majority had tissue TFV-DP concentrations exceeding 1000 fmol/mg by 24 – 72 hours post dosing. Vaginal fluid inhibition of HIV-1 and HSV-2 in vitro significantly increased from baseline and was similarly high at 4 and 24 hours post dosing. Consistent with high tissue TFV-DP concentrations, p24 HIV antigen production from ectocervical tissues infected ex vivo with HIV-1 significantly decreased from baseline at 4 hours post dosing. HSV-2 production from tissue also decreased post treatment.

Conclusions

A single dose of TAF/EVG inserts met PK benchmarks, with PK data supporting an extended window of high mucosal protection. PD modeling supports mucosal protection against both HIV-1 and HSV-2. The inserts were safe and highly acceptable.

Clinical trial registration

ClinicalTrials.gov, identifier NCT03762772.
A pro-oxidant property of vitamin C to overcome the burden of latent Mycobacterium tuberculosis infection: A cross-talk review with Fenton reaction
Authors: Gaglani Pratikkumar , Dwivedi Manish , Upadhyay Tarun Kumar , Kaushal Radhey Shyam , Ahmad Irfan , Saeed Mohd
Published: April 2023

Tuberculosis (TB), caused by the bacillus M. tuberculosis, is one of the deadliest infectious illnesses of our day, along with HIV and malaria.Chemotherapy, the cornerstone of TB control efforts, is jeopardized by the advent of M. tuberculosis strains resistant to many, if not all, of the existing medications.Isoniazid (INH), rifampicin (RIF), pyrazinamide, and ethambutol are used to treat drug-susceptible TB for two months, followed by four months of INH and RIF, but chemotherapy with potentially harmful side effects is sometimes needed to treat multidrug-resistant (MDR) TB for up to two years. Chemotherapy might be greatly shortened by drugs that kill M. tuberculosis more quickly while simultaneously limiting the emergence of drug resistance.Regardless of their intended target, bactericidal medicines commonly kill pathogenic bacteria (gram-negative and gram-positive) by producing hydroxyl radicals via the Fenton reaction.Researchers have concentrated on vitamins with bactericidal properties to address the rising cases globally and have discovered that these vitamins are effective when given along with first-line drugs. The presence of elevated iron content, reactive oxygen species (ROS) generation, and DNA damage all contributed to VC’s sterilizing action on M. tb in vitro. Moreover, it has a pleiotropic effect on a variety of biological processes such as detoxification, protein folding – chaperons, cell wall processes, information pathways, regulatory, virulence, metabolism etc.In this review report, the authors extensively discussed the effects of VC on M. tb., such as the generation of free radicals and bactericidal mechanisms with existing treatments, and their further drug development based on ROS production.
An in vivo humanized model to study homing and sequestration of Plasmodium falciparum transmission stages in the bone marrow
Authors: Donsante Samantha , Siciliano Giulia , Ciardo Mariagrazia , Palmisano Biagio , Messina Valeria , de Turris Valeria , Farinacci Giorgia , Serafini Marta , Silvestrini Francesco , Corsi Alessandro , Riminucci Mara , Alano Pietro
Published: April 2023

Introduction

Recent evidence suggests that the bone marrow (BM) plays a key role in the diffusion of P. falciparum malaria by providing a “niche” for the maturation of the parasite gametocytes, responsible for human-to-mosquito transmission. Suitable humanized in vivo models to study the mechanisms of the interplay between the parasite and the human BM components are still missing.

Methods

We report a novel experimental system based on the infusion of immature P. falciparum gametocytes into immunocompromised mice carrying chimeric ectopic ossicles whose stromal and bone compartments derive from human osteoprogenitor cells.

Results

We demonstrate that immature gametocytes home within minutes to the ossicles and reach the extravascular regions, where they are retained in contact with different human BM stromal cell types.

Discussion

Our model represents a powerful tool to study BM function and the interplay essential for parasite transmission in P. falciparum malaria and can be extended to study other infections in which the human BM plays a role.
Disseminated varicella-zoster virus infection in an aplastic anemia- paroxysmal nocturnal hemoglobinuria syndrome patient: A case report
Authors: Wang Jie , Yang Zheng , Ren Danhong , Shi Zhanli , Fang Kun , Li Zhihui
Published: April 2023

Background

Varicella-zoster virus (VZV) is a common and widespread human-restricted pathogen. It is famous for its dermatological manifestations, such as varicella and herpes zoster. Patients with aplastic anemia-paroxysmal nocturnal hemoglobinuria (AA-PNH) syndrome complicated with fatal disseminated varicella zoster virus infection are very rare and in danger.

Patient concerns

A 26-year-old man with a history of AA-PNH syndrome was receiving cyclosporine and corticosteroid treatment in the hematology department. During his hospitalization in our hospital, he developed fever, abdominal pain, and lower back pain, and his face, penis, trunk, and limbs developed itchy rash. Subsequently, the patient had to undergo cardiopulmonary resuscitation because of sudden cardiac arrest, and be transferred to ICU for treatment. It was presumed that the cause is unknown severe sepsis. The patient’s condition quickly progressed to multiple organ failure, accompanied by liver, respiratory, and circulatory failure, and signs of disseminated intravascular coagulation. Unfortunately, the patient died after 8 h of active treatment. Finally, we collected all the evidence and concluded that the patient died of AA-PNH syndrome combined with poxzoster virus.

Conclusion

AA-PNH syndrome patients treated with steroids and immunosuppressants are prone to various infections, considering that herpes virus infection with chickenpox and rash as the initial manifestations is characterized by rapid progress and often accompanied by serious complications. It is more difficult to distinguish it from AA-PNH syndrome with skin bleeding points. If it is not identified in time, it may delay the treatment opportunity, make the condition worse, and cause serious adverse prognosis. Therefore, clinicians need to pay attention to it.
“Super” SERPINs—A stabilizing force against fibrinolysis in thromboinflammatory conditions
Authors: Humphreys Steven J. , Whyte Claire S. , Mutch Nicola J.
Published: April 2023

The superfamily of serine protease inhibitors (SERPINs) are a class of inhibitors that utilise a dynamic conformational change to trap and inhibit their target enzymes. Their powerful nature lends itself well to regulation of complex physiological enzymatic cascades, such as the haemostatic, inflammatory and complement pathways. The SERPINs α2-antiplasmin, plasminogen-activator inhibitor-1, plasminogen-activator inhibitor-2, protease nexin-1, and C1-inhibitor play crucial inhibitory roles in regulation of the fibrinolytic system and inflammation. Elevated levels of these SERPINs are associated with increased risk of thrombotic complications, obesity, type 2 diabetes, and hypertension. Conversely, deficiencies of these SERPINs have been linked to hyperfibrinolysis with bleeding and angioedema. In recent years SERPINs have been implicated in the modulation of the immune response and various thromboinflammatory conditions, such as sepsis and COVID-19. Here, we highlight the current understanding of the physiological role of SERPINs in haemostasis and inflammatory disease progression, with emphasis on the fibrinolytic pathway, and how this becomes dysregulated during disease. Finally, we consider the role of these SERPINs as potential biomarkers of disease progression and therapeutic targets for thromboinflammatory diseases.
Factors associated with lipid control in outpatients with heart failure
Authors: Jarab Anan S. , Al-Qerem Walid , Hamam Hanan , Abu Heshmeh Shrouq , Mukattash Tareq L. , Alefishat Eman A.
Published: April 2023

Background

Dyslipidemia is common among patients with heart failure, and it negatively impacts clinical outcomes. Limited data regarding the factors associated with poor lipid control in patients with HF patients. Therefore, this study aimed to evaluate lipid control and to explore the factors associated with poor lipid control in patients with HF.

Methods

The current cross-sectional study was conducted at outpatient cardiology clinics at two major hospitals in Jordan. Variables including socio-demographics, biomedical variables, in addition to disease and medication characteristics were collected using medical records and custom-designed questionnaire. Medication adherence was assessed using the validated 4-item Medication Adherence Scale. Binary logistic regression analysis was conducted to explore significant and independent predictors of poor lipid control among the study participants.

Results

A total of 428 HF patients participated in the study. Results showed that 78% of the participants had poor lipid control. The predictors that were associated with poor lipid control included uncontrolled BP (OR = 0.552; 95% CI: 0.330–0.923; P < 0.05), higher Hb levels (OR = 1.178; 95% CI: 1.013–1.369; P < 0.05), and higher WBC (OR = 1.133; 95% CI: 1.031–1.246; P < 0.05).

Conclusions

This study revealed poor lipid control among patients with HF. Future intervention programs should focus on blood pressure control in order to improve health outcomes among HF patients with dyslipidemia.
Metallogeny in the Bangong–Nujiang belt, central Tibet, China: A review
Authors: Song Yang , Tang Juxing , Lin Bin , Yang Chao , Sun Hao
Published: April 2023

The Bangong–Nujiang metallogenic belt consists of scattered Tethyan oceanic blocks, mainly distributed underneath the margins of the Qiangtang and Lhasa terranes in central Tibet. A new world-class metallogenic belt has been reported in this region recently, based on the geological mapping and ore deposit prospecting over the last two decades. It currently comprises inferred resources of 30 Mt Cu and 500 t Au, together with several Cr–Ni, Fe, and W (Mo) resources, forming a significant potential area for future mineral exploration. These metals are mainly hosted in porphyry copper, skarn copper, skarn iron, orogenic gold, quartz-vein tungsten, and ophitic chromite deposits. The mineral deposits in the Bangong–Nujiang metallogenic belt have been widely recognized in different localities, including the southern edge of the southern Qiangtang block, part of the north Lhasa block, and even part of the central Lhasa block, indicating they were formed in variable geological settings, from the initial opening, subduction, and collision to the extension of the Bangong–Nujiang Ocean. Specifically, five major tectonic events contributed to mineralization, including the stage 1 (240–165 Ma) initial opening of the Bangong–Nujiang Ocean, stage 2 (165–145 Ma) oceanic subduction, stage 3 (145–100 Ma) close of the ocean, stage 4 (100–65 Ma) continent–continent collisional orogenesis, and stage 5 (65–0 Ma) post-orogenesis. At stage 1, Cr–Ni deposits were formed during the initial opening of the ocean; porphyry–epithermal Cu (Au), skarn Fe, and minor orogenic Au deposits were formed at stage 2 and stage 3; a younger pulse of a few porphyry–skarn Cu ± Mo and orogenic Au deposits were formed during stage 4; finally, W(Mo) deposits were generated in stage 5. In general, porphyry Cu systems, orogenic Au, and skarn Cu polymetallic deposits that occurred in the subduction and post-collision settings related W(Mo) deposits have the most potential for future exploration. An in-depth investigation of several scientific problems, such as addressing the tectonic setting, magmatism, and metallogeny of this region and genetic linkage of these deposit preservations to plateau uplift, is essential for the future success of exploration in the Bangong–Nujiang metallogenic belt.
Endometrial whole metabolome profile at the receptive phase: influence of Mediterranean Diet and infertility
Authors: Molina Nerea M. , Jurado-Fasoli Lucas , Sola-Leyva Alberto , Sevilla-Lorente Raquel , Canha-Gouveia Analuce , Ruiz-Durán Susana , Fontes Juan , Aguilera Concepción M. , Altmäe Signe
Published: April 2023

Introduction

Several metabolite classes have been identified in human endometrium, including lipids, nucleotides, amino acids, organic acids, and sugars. The first studies suggest the importance of metabolites in endometrial functions, as imbalance in uterine metabolites has been associated with low implantation rate and endometriosis. Nevertheless, most of studies have put emphasis on specific metabolite classes, and we lack the knowledge of the whole metabolome composition in human uterus. Further, a healthy dietary pattern has been shown to potentially protect against different endometrial dysfunctions and is a potential modulator of metabolomic composition and, consequently, the intrauterine microenvironment. The Mediterranean Diet (MD), characterized by a high intake of fruits, vegetables, cereals, nuts, legumes, fish, and olive oil, and a low consumption of meat, dairy products, and processed foods, has been associated with a wide range of benefits for health. Indeed, the MD pattern has displayed a beneficial role in endometriosis management and fertility; however, the relationship between the MD and the endometrial metabolome is still unknown. In our study, we set out to analyze receptive-phase endometrial metabolome profiles among women with infertility and their associations with MD.

Methods

The study included women with male factor infertility (n=8), unexplained infertility (n=10), recurrent implantation failure (n=14), and endometriosis (n=13). The endometrial metabolome was analyzed with ultrahigh-performance liquid chromatography-tandem mass spectroscopy (UPLC–MS/MS). The MD adherence of the participants was assessed using the 14-point MEDAS questionnaire of adherence to the MD.

Results

We provide the whole metabolome profile of the endometrium, where 925 different metabolites were identified. Among these metabolites, lipids comprised the largest part, where polyunsaturated fatty acids (PUFAs) prevailed. Women with endometriosis and recurrent implantation failure were found to have lower levels of PUFAs compared to women with male factor and unexplained infertility (i.e., no clear endometrial alterations), identifying a metabolome profile associated with infertility diagnoses where altered endometrial functions are suspected. Moreover, MD adherence seemed to be associated with the endometrial metabolomic profile in a manner dependent on the health status of the uterus.

Conclusion

The study findings provide insight into the molecular background of female infertility and lead to identification of potential molecular biomarkers and possibilities for modulating the endometrial microenvironment and, thereby, endometrial functions involved in embryo implantation and infertility.
Effects of a low-sodium diet in patients with idiopathic hyperaldosteronism: a randomized controlled trial
Authors: Zhou Lihua , Jiang Yiran , Zhang Cui , Su Tingwei , Jiang Lei , Zhou Weiwei , Zhong Xu , Wu Luming , Wang Weiqing
Published: April 2023

Background

Idiopathic hyperaldosteronism (IHA) is one of the most common types of primary aldosteronism (PA), an important cause of hypertension. Although high dietary sodium is a major risk factor for hypertension, there is no consensus on the recommended dietary sodium intake for IHA.

Objective

This study investigated the effect of a low-sodium diet on hemodynamic variables and relevant disease biomarkers in IHA patients, with the aim of providing a useful reference for clinical treatment.

Methods

Fifty IHA patients were evenly randomized into two groups and provided, after a 7-day run-in period (100 mmol/d sodium), either a low-sodium diet (50 mmol/d sodium) or a normal sodium diet (100 mmol/d sodium) for an additional 7 days. After the 14-day intervention (conducted without potassium supplementation), changes in blood pressure (BP) and serum potassium were evaluated in both groups.

Results

After the dietary intervention, the low sodium group exhibited, compared to the normal sodium group, decreased BP (SBP: 121.8 ± 12.8 vs. 129.9 ± 12.1 mmHg, p < 0.05; DBP: 82.6 ± 7.6 vs. 86.4 ± 8.2 mmHg, p < 0.05; MAP: 95.7 ± 8.8 vs. 100.9 ± 8.4 mmHg, p < 0.05) and increased serum potassium levels (3.38 ± 0.33 vs. 3.07 ± 0.27 mmol/L, p < 0.001). The low sodium group showed also better control of both BP and serum potassium: BP <140/90 mmHg in 70.0% of total patients (76.0% vs. 64.0%, in the low and normal sodium groups, respectively; p > 0.05), BP <130/85 mmHg in 38.0% of total patients (56.0% vs. 20.0%, p < 0.05), BP <120/80 mmHg in 28.0% of total patients (44.0% vs. 12.0%, p < 0.05); serum potassium ≥3.5 mmol/L in 22.0% of total patients (32.0% vs. 12.0% in the low and normal sodium groups, respectively; p = 0.088). There were differences between the controlled BP group (<120/80 mmHg) and the non-controlled BP group (≥120/80 mmHg) in gender, BP at baseline, and type of diet (low vs. normal sodium). Female gender and low-sodium diet were protective factors for BP control.

Conclusions

A low-sodium diet is effective in lowering BP and elevating serum potassium in IHA patients. Female patients on a low-sodium diet are more likely to achieve BP control (<120/80 mmHg). We advocate a dietary sodium intake of 50 mmol/d for IHA patients.

Clinical trial registration

https://clinicaltrials.gov, Identifier NCT05649631.