Patent analysis of digital sensors for continuous glucose monitoring.

The high need for optimal diabetes management among an ever-increasing number of patients dictates the development and implementation of new digital sensors for continuous glucose monitoring. The purpose of this work is to systematize the global patenting trends of digital sensors for continuous glucose monitoring and analyze their effectiveness in controlling the treatment of diabetes patients of different ages and risk groups. The Lens database was used to build the patent landscape of sensors for continuous glucose monitoring. Retrospective analysis showed that the patenting of sensors for continuous glucose monitoring had positive trend over the analyzed period (2000-2022). Leading development companies are Dexcom Inc., Abbott Diabetes Care Inc., Medtronic Minimed Inc., Roche Diabetes Care Inc., Roche Diagnostics Operations Inc., Roche Diabetes Care Gmbh, and Ascensia Diabetes Care Holdings Ag, among others. Since 2006, a new approach has emerged where digital sensors are used for continuous glucose monitoring, and smartphones act as receivers for the data. Additionally, telemedicine communication is employed to facilitate this process. This opens up new opportunities for assessing the glycemic profile (glycemic curve information, quantitative assessment of the duration and amplitude of glucose fluctuations, and so on), which may contribute to improved diabetes management. A number of digital sensors for minimally invasive glucose monitoring are patented, have received FDA approval, and have been on the market for over 10 years. Their effectiveness in the clinic has been proven, and advantages and disadvantages have been clarified. Digital sensors offer a non-invasive option for monitoring blood glucose levels, providing an alternative to traditional invasive methods. This is particularly useful for patients with diabetes who require frequent monitoring, including before and after meals, during and after exercise, and in other scenarios where glucose levels can fluctuate. However, non-invasive glucose measurements can also benefit patients without diabetes, such as those following a dietary treatment plan, pregnant women, and individuals during fasting periods like Ramadan. The availability of non-invasive monitoring is especially valuable for patients in high-risk groups and across different age ranges. New world trends have been identified in the patenting of digital sensors for non-invasive glucose monitoring in interstitial skin fluid, saliva, sweat, tear fluid, and exhaled air. A number of non-invasive devices have received the CE mark approval, which confirms that the items meet European health, safety, and environmental protection standards (TensorTip Combo-Glucometer, Cnoga Medical Ltd.; SugarBEAT, Nemaura Medical; GlucoTrack, GlucoTrack Inc.), but are not FDA-approved yet. The above-mentioned sensors have characteristics that make them popular in the treatment of diabetes: they do not require implantation, do not cause an organism reaction to a foreign body, and are convenient to use. In the EU, in order to increase clinical safety and the level of transparency about medical devices, manufacturers must obtain certificates in accordance with Regulation (EU) 2017/745, taking into account the transition period. The development of systems, which include digital sensors for continuous glucose monitoring, mobile applications, and web platforms for professional analysis of glycemic control and implementation of unified glycemic assessment principles in mobile healthcare, represent promising approaches for controlling glycaemia in patients.

Patent landscape review of non-invasive medical sensors for continuous monitoring of blood pressure and their validation in critical care practice.

Objectives: Continuous non-invasive monitoring of blood pressure is one of the main factors in ensuring the safety of the patient's condition in anesthesiology, intensive care, surgery, and other areas of medicine. The purpose of this work was to analyze the current patent situation and identify directions and trends in the application of non-invasive medical sensors for continuous blood pressure monitoring, with a focus on clinical experience in critical care and validation thereof. Materials and methods: The research results reflect data collected up to September 30, 2022. Patent databases, Google Scholar, the Lens database, Pubmed, Scopus databases were used to search for patent and clinical information. Results: An analysis of the patent landscape indicates a significant increase in interest in the development of non-invasive devices for continuous blood pressure monitoring and their implementation in medical practice, especially in the last 10 years. The key players in the intellectual property market are the following companies: Cnsystems Medizintechnik; Sotera Wireless INC; Tensys Medical INC; Healthstats Int Pte LTD; Edwards Lifesciences Corp, among others. Systematization of data from validation and clinical studies in critical care practice on patients with various pathological conditions and ages, including children and newborns, revealed that a number of non-invasive medical sensor technologies are quite accurate and comparable to the "gold standard" continuous invasive blood pressure monitoring. They are approved by the FDA for medical applications and certified according to ISO 81060-2, ISO 81060-3, and ISO/TS 81060-5. Unregistered and uncertified medical sensors require further clinical trials. Conclusion: Non-invasive medical sensors for continuous blood pressure monitoring do not replace, but complement, existing methods of regular blood pressure measurement, and it is expected to see more of these technologies broadly implemented in the practice in the near future.

Public interest in different types of masks and its relationship with pandemic and policy measures during the COVID-19 pandemic: a study using Google Trends data.

Google Trends data have been used to investigate various themes on online information seeking. It was unclear if the population from different parts of the world shared the same amount of attention to different mask types during the COVID-19 pandemic. This study aimed to reveal which types of masks were frequently searched by the public in different countries, and evaluated if public attention to masks could be related to mandatory policy, stringency of the policy, and transmission rate of COVID-19. By referring to an open dataset hosted at the online database Our World in Data, the 10 countries with the highest total number of COVID-19 cases as of 9th of February 2022 were identified. For each of these countries, the weekly new cases per million population, reproduction rate (of COVID-19), stringency index, and face covering policy score were computed from the raw daily data. Google Trends were queried to extract the relative search volume (RSV) for different types of masks from each of these countries. Results found that Google searches for N95 masks were predominant in India, whereas surgical masks were predominant in Russia, FFP2 masks were predominant in Spain, and cloth masks were predominant in both France and United Kingdom. The United States, Brazil, Germany, and Turkey had two predominant types of mask. The online searching behavior for masks markedly varied across countries. For most of the surveyed countries, the online searching for masks peaked during the first wave of COVID-19 pandemic before the government implemented mandatory mask wearing. The search for masks positively correlated with the government response stringency index but not with the COVID-19 reproduction rate or the new cases per million.

Are dental x-rays safe? Content analysis of English and Chinese YouTube videos.

Objective: This study provided a content analysis of English and Chinese YouTube videos related to dental radiation safety. Method: The search string, entered in English and Chinese respectively, was: (dental x-ray safe). The searches were performed and exported with Apify YouTube scraper. By screening the resultant videos and their related videos (as recommended by YouTube), a total of 89 videos were screened. Finally, 45 videos (36 English and nine Chinese) were included and analyzed. The specific information regarding dental radiation was evaluated. The Patient Education Material Assessment Tool for Audiovisual Materials was used to assess understandability and actionability. Results: There was no significant difference between the English and Chinese videos in terms of view count, like count, comment count, and video duration. Half of the videos explicitly reassured the audience that dental x-rays are safe. Two of the English videos specifically stated that dental x-rays do not cause cancers. Numerous analogies were made in regard to radiation dose, such as equivalence to taking a flight or eating some bananas. About 41.7% of the English videos and 33.3% of the Chinese videos mentioned that patients could be further protected from scatter radiation by wearing a lead apron and thyroid collar. Videos had a good understandability score (91.3) but a poor actionability score (0). Conclusions: Some of the analogies and the claimed radiation dose were questionable. One Chinese video even wrongly stated that dental x-rays are nonionizing radiation. The videos generally did not mention their information sources or the underlying radiation protection principles.

"Loved ones are not 'visitors' in a patient's life"-The importance of including loved ones in the patient's hospital stay: An international Twitter study of #HospitalsTalkToLovedOnes in times of COVID-19.

Background: Hospitals are institutions whose primary task is to treat patients. Family-centered care, which considers loved ones as equal partners in patient care, has been gaining recognition in the adult care setting. Our aim was to record experiences of and opinions on communication between hospital-based healthcare providers and patients' loved ones, related but not limited to the rigorous mitigation measures implemented during the COVID-19 pandemic. Methods: The Twitter profile @HospitalsTalkTo and hashtag #HospitalsTalkToLovedOnes were created to interact with the Twitter public between 7 June 2021 and 7 February 2022. Conversations surrounding #HospitalsTalkToLovedOnes were extracted and subjected to natural language processing analysis using term frequency and Markov chain analysis. Qualitative thematic analysis was performed on the 10% most interacted tweets and of tweets mentioning "COVID" from a personal experience-based subset. Results: We collected 4412 unique tweets made or interacted by 7040 Twitter users from 142 different countries. The most frequent words were patient, hospital, care, family, loved and communication. Thematic analysis revealed the importance of communication between patients, patients' loved ones and hospitals; showed that patients and their loved ones need support during a patient's hospital journey; and that pediatric care should be the gold standard for adult care. Visitation restrictions due to COVID-19 are just one barrier to communication, others are a lack of phone signal, no space or time for asking questions, and a complex medical system. We formulate 3 recommendations to improve the inclusion of loved ones into the patient's hospital stay. Conclusions: "Loved ones are not 'visitors' in a patient's life". Irrespective of COVID-19, patient's loved ones need to be included during the patient's hospital journey. Transparent communication and patient empowerment increase patient safety and improve the hospital experience for both the patients and their loved ones. Our findings underline the need for the concept of family-centered care to finally be implemented in adult nursing clinical practice.

COVID-19 Rapid Antigen Tests: Bibliometric Analysis of the Scientific Literature.

As the COVID-19 pandemic continues to disrupt health systems worldwide, conducting Rapid Antigen Testing (RAT) at specified intervals has become an essential part of many people's lives around the world. We identified and analyzed the academic literature on COVID-19 RAT. The Web of Science electronic database was queried on 6 July 2022 to find relevant publications. Publication and citation data were retrieved directly from the database. VOSviewer, a bibliometric software, was then used to relate these data to the semantic content from the titles, abstracts, and keywords. The analysis was based on data from 1000 publications. The most productive authors were from Japan and the United States, led by Dr. Koji Nakamura from Japan (n = 10, 1.0%). The most academically productive countries were in the North America, Europe and Asia, led by the United States of America (n = 266, 26.6%). Sensitivity (n = 32, 3.2%) and specificity (n = 23, 2.3%) were among the most frequently recurring author keywords. Regarding sampling methods, "saliva" (n = 54, 5.4%) was mentioned more frequently than "nasal swab" (n = 32, 3.2%) and "nasopharyngeal swab" (n = 22, 2.2%). Recurring scenarios that required RAT were identified: emergency department, healthcare worker, mass screening, airport, traveler, and workplace. Our bibliometric analysis revealed that COVID-19 RAT has been utilized in a range of studies. RAT results were cross-checked with RT-PCR tests for sensitivity and specificity. These results are consistent with comparable exchanges of methods, results or discussions among laboratorians, authors, institutions and publishers in the involved countries of the world.

Twitter-based crowdsourcing: What kind of measures can help to end the COVID-19 pandemic faster?

Background: Crowdsourcing is a low-cost, adaptable, and innovative method to collect ideas from numerous contributors with diverse backgrounds. Crowdsourcing from social media like Twitter can be used for generating ideas in a noticeably brief time based on contributions from globally distributed users. The world has been challenged by the COVID-19 pandemic in the last several years. Measures to combat the pandemic continue to evolve worldwide, and ideas and opinions on optimal counteraction strategies are of high interest. Objective: This study aimed to validate the use of Twitter as a crowdsourcing platform in order to gain an understanding of public opinion on what measures can help to end the COVID-19 pandemic faster. Methods: This cross-sectional study was conducted during the period from December 22, 2021, to February 4, 2022. Tweets were posted by accounts operated by the authors, asking "How to faster end the COVID-19 pandemic?" and encouraging the viewers to comment on measures that they perceive would be effective to achieve this goal. The ideas from the users' comments were collected and categorized into two major themes - personal and institutional measures. In the final stage of the campaign, a Twitter poll was conducted to get additional comments and to estimate which of the two groups of measures were perceived to be important amongst Twitter users. Results: The crowdsourcing campaign generated seventeen suggested measures categorized into two major themes (personal and institutional) that received a total of 1,727 endorsements (supporting comments, retweets, and likes). The poll received a total of 325 votes with 58% of votes underscoring the importance of both personal and institutional measures, 20% favoring personal measures, 11% favoring institutional measures, and 11% of the votes given just out of curiosity to see the vote results. Conclusions: Twitter was utilized successfully for crowdsourcing ideas on strategies how to end the COVID-19 pandemic faster. The results indicate that the Twitter community highly values the significance of both personal responsibility and institutional measures to counteract the pandemic. This study validates the use of Twitter as a primary tool that could be used for crowdsourcing ideas with healthcare significance.

Promoting Research, Awareness, and Discussion on AI in Medicine Using #MedTwitterAI: A Longitudinal Twitter Hashtag Analysis.

Background: Artificial intelligence (AI) has the potential to reshape medical practice and the delivery of healthcare. Online discussions surrounding AI's utility in these domains are increasingly emerging, likely due to considerable interest from healthcare practitioners, medical technology developers, and other relevant stakeholders. However, many practitioners and medical students report limited understanding and familiarity with AI. Objective: To promote research, events, and resources at the intersection of AI and medicine for the online medical community, we created a Twitter-based campaign using the hashtag #MedTwitterAI. Methods: In the present study, we analyze the use of #MedTwitterAI by tracking tweets containing this hashtag posted from 26th March, 2019 to 26th March, 2021, using the Symplur Signals hashtag analytics tool. The full text of all #MedTwitterAI tweets was also extracted and subjected to a natural language processing analysis. Results: Over this time period, we identified 7,441 tweets containing #MedTwitterAI, posted by 1,519 unique Twitter users which generated 59,455,569 impressions. The most common identifiable locations for users including this hashtag in tweets were the United States (378/1,519), the United Kingdom (80/1,519), Canada (65/1,519), India (46/1,519), Spain (29/1,519), France (24/1,519), Italy (16/1,519), Australia (16/1,519), Germany (16/1,519), and Brazil (15/1,519). Tweets were frequently enhanced with links (80.2%), mentions of other accounts (93.9%), and photos (56.6%). The five most abundant single words were AI (artificial intelligence), patients, medicine, data, and learning. Sentiment analysis revealed an overall majority of positive single word sentiments (e.g., intelligence, improve) with 230 positive and 172 negative sentiments with a total of 658 and 342 mentions of all positive and negative sentiments, respectively. Most frequently mentioned negative sentiments were cancer, risk, and bias. Most common bigrams identified by Markov chain depiction were related to analytical methods (e.g., label-free detection) and medical conditions/biological processes (e.g., rare circulating tumor cells). Conclusion: These results demonstrate the generated considerable interest of using #MedTwitterAI for promoting relevant content and engaging a broad and geographically diverse audience. The use of hashtags in Twitter-based campaigns can be an effective tool to raise awareness of interdisciplinary fields and enable knowledge-sharing on a global scale.

Research on Digital Technology Use in Cardiology: Bibliometric Analysis.

BACKGROUND: Digital technology uses in cardiology have become a popular research focus in recent years. However, there has been no published bibliometric report that analyzed the corresponding academic literature in order to derive key publishing trends and characteristics of this scientific area. OBJECTIVE: We used a bibliometric approach to identify and analyze the academic literature on digital technology uses in cardiology, and to unveil popular research topics, key authors, institutions, countries, and journals. We further captured the cardiovascular conditions and diagnostic tools most commonly investigated within this field. METHODS: The Web of Science electronic database was queried to identify relevant papers on digital technology uses in cardiology. Publication and citation data were acquired directly from the database. Complete bibliographic data were exported to VOSviewer, a dedicated bibliometric software package, and related to the semantic content of titles, abstracts, and keywords. A term map was constructed for findings visualization. RESULTS: The analysis was based on data from 12,529 papers. Of the top 5 most productive institutions, 4 were based in the United States. The United States was the most productive country (4224/12,529, 33.7%), followed by United Kingdom (1136/12,529, 9.1%), Germany (1067/12,529, 8.5%), China (682/12,529, 5.4%), and Italy (622/12,529, 5.0%). Cardiovascular diseases that had been frequently investigated included hypertension (152/12,529, 1.2%), atrial fibrillation (122/12,529, 1.0%), atherosclerosis (116/12,529, 0.9%), heart failure (106/12,529, 0.8%), and arterial stiffness (80/12,529, 0.6%). Recurring modalities were electrocardiography (170/12,529, 1.4%), angiography (127/12,529, 1.0%), echocardiography (127/12,529, 1.0%), digital subtraction angiography (111/12,529, 0.9%), and photoplethysmography (80/12,529, 0.6%). For a literature subset on smartphone apps and wearable devices, the Journal of Medical Internet Research (20/632, 3.2%) and other JMIR portfolio journals (51/632, 8.0%) were the major publishing venues. CONCLUSIONS: Digital technology uses in cardiology target physicians, patients, and the general public. Their functions range from assisting diagnosis, recording cardiovascular parameters, and patient education, to teaching laypersons about cardiopulmonary resuscitation. This field already has had a great impact in health care, and we anticipate continued growth.

Digital Teaching in Medical Education: Scientific Literature Landscape Review.

BACKGROUND: Digital teaching in medical education has grown in popularity in the recent years. However, to the best of our knowledge, no bibliometric report to date has been published that analyzes this important literature set to reveal prevailing topics and trends and their impacts reflected in citation counts. OBJECTIVE: We used a bibliometric approach to unveil and evaluate the scientific literature on digital teaching research in medical education, demonstrating recurring research topics, productive authors, research organizations, countries, and journals. We further aimed to discuss some of the topics and findings reported by specific highly cited works. METHODS: The Web of Science electronic database was searched to identify relevant papers on digital teaching research in medical education. Basic bibliographic data were obtained by the "Analyze" and "Create Citation Report" functions of the database. Complete bibliographic data were exported to VOSviewer for further analyses. Visualization maps were generated to display the recurring author keywords and terms mentioned in the titles and abstracts of the publications. RESULTS: The analysis was based on data from 3978 papers that were identified. The literature received worldwide contributions with the most productive countries being the United States and United Kingdom. Reviews were significantly more cited, but the citations between open access vs non-open access papers did not significantly differ. Some themes were cited more often, reflected by terms such as virtual reality, innovation, trial, effectiveness, and anatomy. Different aspects in medical education were experimented for digital teaching, such as gross anatomy education, histology, complementary medicine, medicinal chemistry, and basic life support. Some studies have shown that digital teaching could increase learning satisfaction, knowledge gain, and even cost-effectiveness. More studies were conducted on trainees than on undergraduate students. CONCLUSIONS: Digital teaching in medical education is expected to flourish in the future, especially during this era of COVID-19 pandemic.

Official Websites Providing Information on COVID-19 Vaccination: Readability and Content Analysis.

BACKGROUND: Online information on COVID-19 vaccination may influence people's perception and willingness to be vaccinated. Official websites of vaccination programs have not been systematically assessed before. OBJECTIVE: This study aims to assess and compare the readability and content quality of web-based information on COVID-19 vaccination posted on official/governmental websites. Furthermore, the relationship between evaluated website parameters and country vaccination rates were calculated. METHODS: By referring to an open data set hosted at Our World in Data, the 58 countries/regions with the highest total vaccination count as of July 8, 2021, were identified. Together with the websites from the World Health Organization and European Union, a total of 60 vaccination campaign websites were targeted. The "frequently asked questions" or "questions and answers" section of the websites were evaluated in terms of readability (Flesch Reading Ease score and Flesch-Kincaid Grade Level), quality (Health On the Net Foundation code [HONcode] certification and Quality Evaluation Scoring Tool), and content stating vaccination duration of protection and potential side effects. RESULTS: In terms of readability, the Flesch Reading Ease score of the vaccination frequently asked questions websites ranged between 11.2 and 69.5, with a mean of 40.9 (SD 13.2). Meanwhile, the Flesch-Kincaid Grade Level ranged between 6.5 and 17.6, with a mean of 12.1 (SD 2.8). In terms of quality, only 2 websites were HONcode certified, and the Quality Evaluation Scoring Tool score of the websites ranged between 7 and 20, with a mean of 15.3 (SD 3.1). Half of the websites (25/50) did not present a publication date or date of the last update. Regarding the duration of protection offered by the vaccines, 46% (23/50) of the websites stated that they do not know, and another 40% (20/50) did not address it. Five side effects of the vaccinations were most frequently mentioned, namely, fever/chill (41/50, 82%), various injection site discomfort events (eg, swelling, redness, or pain; 39/50, 78%), headache (36/50, 72%), fatigue (33/50, 66%), and muscle/joint pain (31/50, 62%). CONCLUSIONS: In general, the content quality of most of the evaluated websites was good, but HONcode certification should be considered, content should be written in a more readable manner, and a publication date or date of the last update should be presented.

Medical and Health-Related Misinformation on Social Media: Bibliometric Study of the Scientific Literature.

BACKGROUND: Social media has been extensively used for the communication of health-related information and consecutively for the potential spread of medical misinformation. Conventional systematic reviews have been published on this topic to identify original articles and to summarize their methodological approaches and themes. A bibliometric study could complement their findings, for instance, by evaluating the geographical distribution of the publications and determining if they were well cited and disseminated in high-impact journals. OBJECTIVE: The aim of this study was to perform a bibliometric analysis of the current literature to discover the prevalent trends and topics related to medical misinformation on social media. METHODS: The Web of Science Core Collection electronic database was accessed to identify relevant papers with the following search string: ALL=(misinformati* OR "wrong informati*" OR disinformati* OR "misleading informati*" OR "fake news*") AND ALL=(medic* OR illness* OR disease* OR health* OR pharma* OR drug* OR therap*) AND ALL=("social media*" OR Facebook* OR Twitter* OR Instagram* OR YouTube* OR Weibo* OR Whatsapp* OR Reddit* OR TikTok* OR WeChat*). Full records were exported to a bibliometric software, VOSviewer, to link bibliographic information with citation data. Term and keyword maps were created to illustrate recurring terms and keywords. RESULTS: Based on an analysis of 529 papers on medical and health-related misinformation on social media, we found that the most popularly investigated social media platforms were Twitter (n=90), YouTube (n=67), and Facebook (n=57). Articles targeting these 3 platforms had higher citations per paper (>13.7) than articles covering other social media platforms (Instagram, Weibo, WhatsApp, Reddit, and WeChat; citations per paper <8.7). Moreover, social media platform-specific papers accounted for 44.1% (233/529) of all identified publications. Investigations on these platforms had different foci. Twitter-based research explored cyberchondria and hypochondriasis, YouTube-based research explored tobacco smoking, and Facebook-based research studied vaccine hesitancy related to autism. COVID-19 was a common topic investigated across all platforms. Overall, the United States contributed to half of all identified papers, and 80% of the top 10 most productive institutions were based in this country. The identified papers were mostly published in journals of the categories public environmental and occupational health, communication, health care sciences services, medical informatics, and medicine general internal, with the top journal being the Journal of Medical Internet Research. CONCLUSIONS: There is a significant platform-specific topic preference for social media investigations on medical misinformation. With a large population of internet users from China, it may be reasonably expected that Weibo, WeChat, and TikTok (and its Chinese version Douyin) would be more investigated in future studies. Currently, these platforms present research gaps that leave their usage and information dissemination warranting further evaluation. Future studies should also include social platforms targeting non-English users to provide a wider global perspective.

Molecular Mechanisms Underlying Hepatocellular Carcinoma Induction by Aberrant NRF2 Activation-Mediated Transcription Networks: Interaction of NRF2-KEAP1 Controls the Fate of Hepatocarcinogenesis.

NF-E2-related factor 2 (NRF2) is a basic leucine zipper transcription factor, a master regulator of redox homeostasis regulating a variety of genes for antioxidant and detoxification enzymes. NRF2 was, therefore, initially thought to protect the liver from oxidative stress. Recent studies, however, have revealed that mutations in NRF2 cause aberrant accumulation of NRF2 in the nucleus and exert the upregulation of NRF2 target genes. Moreover, among all molecular changes in hepatocellular carcinoma (HCC), NRF2 activation has been revealed as a more prominent pathway contributing to the progression of precancerous lesions to malignancy. Nevertheless, how its activation leads to poor prognosis in HCC patients remains unclear. In this review, we provide an overview of how aberrant activation of NRF2 triggers HCC development. We also summarize the emerging roles of other NRF family members in liver cancer development.

Prdm9 Intersubspecific Interactions in Hybrid Male Sterility of House Mouse.

The classical definition posits hybrid sterility as a phenomenon when two parental taxa each of which is fertile produce a hybrid that is sterile. The first hybrid sterility gene in vertebrates, Prdm9, coding for a histone methyltransferase, was identified in crosses between two laboratory mouse strains derived from Mus mus musculus and M. m. domesticus subspecies. The unique function of PRDM9 protein in the initiation of meiotic recombination led to the discovery of the basic molecular mechanism of hybrid sterility in laboratory crosses. However, the role of this protein as a component of reproductive barrier outside the laboratory model remained unclear. Here, we show that the Prdm9 allelic incompatibilities represent the primary cause of reduced fertility in intersubspecific hybrids between M. m. musculus and M. m. domesticus including 16 musculus and domesticus wild-derived strains. Disruption of fertility phenotypes correlated with the rate of failure of synapsis between homologous chromosomes in meiosis I and with early meiotic arrest. All phenotypes were restored to normal when the domesticus Prdm9dom2 allele was substituted with the Prdm9dom2H humanized variant. To conclude, our data show for the first time the male infertility of wild-derived musculus and domesticus subspecies F1 hybrids controlled by Prdm9 as the major hybrid sterility gene. The impairment of fertility surrogates, testes weight and sperm count, correlated with increasing difficulties of meiotic synapsis of homologous chromosomes and with meiotic arrest, which we suppose reflect the increasing asymmetry of PRDM9-dependent DNA double-strand breaks.

Corrigendum: Ethnopharmacological Approaches for Therapy of Jaundice: Part II. Highly Used Plant Species from Acanthaceae, Euphorbiaceae, Asteraceae, Combretaceae, and Fabaceae Families.

[This corrects the article on p. 519 in vol. 8, PMID: 28848436.].

Ethnopharmacological Approaches for Therapy of Jaundice: Part I.

Jaundice is a very common symptom especially in the developing countries. It is associated with several hepatic diseases which are still major causes of death. There are many different approaches to jaundice treatment and the growing number of ethnomedicinal studies shows the plant pharmacology as very promising direction. Many medicinal plants are used for the treatment of jaundice, however a comprehensive review on this subject has not been published. The use of medicinal plants in drug discovery is highly emphasized (based on their traditional and safe uses in different folk medicine systems from ancient times). Many sophisticated analytical techniques are emerging in the pharmaceutical field to validate and discover new biologically active chemical entities derived from plants. Here, we aim to classify and categorize medicinal plants relevant for the treatment of jaundice according to their origin, geographical location, and usage. Our search included various databases like Pubmed, ScienceDirect, Google Scholar. Keywords and phrases used for these searches included: "jaundice," "hyperbilirubinemia," "serum glutamate," "bilirubin," "Ayurveda." The first part of the review focuses on the variety of medicinal plant used for the treatment of jaundice (a total of 207 medicinal plants). In the second part, possible mechanisms of action of biologically active secondary metabolites of plants from five families for jaundice treatment are discussed.

Ethnopharmacological Approaches for Therapy of Jaundice: Part II. Highly Used Plant Species from Acanthaceae, Euphorbiaceae, Asteraceae, Combretaceae, and Fabaceae Families.

In many developing countries, jaundice is the common symptom of hepatic diseases which are a major cause of mortality. The use of natural product-based therapies is very popular for such hepatic disorders. A great number of medicinal plants have been utilized for this purpose and some facilitated the discovery of active compounds which helped the development of new synthetic drugs against jaundice. However, more epidemiological studies and clinical trials are required for the practical implementation of the plant pharmacotherapy of jaundice. The focus of this second part of our review is on several of the most prominent plants used against jaundice identified in the analysis performed in the first part of the review viz. Andrographis paniculata (Burm.f.) Nees, Silybum marianum (L.) Gaertn., Terminalia chebula Retz., Glycyrrhiza glabra L. and some species of genus Phyllanthus. Furthermore, we discuss their physiological effects, biologically active ingredients, and the potential mechanisms of action. Some of the most important active ingredients were silybin (also recommended by German commission), phyllanthin and andrographolide, whose action leads to bilirubin reduction and normalization of the levels of relevant serum enzymes indicative for the pathophysiological status of the liver.

PRDM9 interactions with other proteins provide a link between recombination hotspots and the chromosomal axis in meiosis.

In mammals, meiotic recombination occurs at 1- to 2-kb genomic regions termed hotspots, whose positions and activities are determined by PRDM9, a DNA-binding histone methyltransferase. We show that the KRAB domain of PRDM9 forms complexes with additional proteins to allow hotspots to proceed into the next phase of recombination. By a combination of yeast-two hybrid assay, in vitro binding, and coimmunoprecipitation from mouse spermatocytes, we identified four proteins that directly interact with PRDM9's KRAB domain, namely CXXC1, EWSR1, EHMT2, and CDYL. These proteins are coexpressed in spermatocytes at the early stages of meiotic prophase I, the limited period when PRDM9 is expressed. We also detected association of PRDM9-bound complexes with the meiotic cohesin REC8 and the synaptonemal complex proteins SYCP3 and SYCP1. Our results suggest a model in which PRDM9-bound hotspot DNA is brought to the chromosomal axis by the action of these proteins, ensuring the proper chromatin and spatial environment for subsequent recombination events.

The Meiotic Recombination Activator PRDM9 Trimethylates Both H3K36 and H3K4 at Recombination Hotspots In Vivo.

In many mammals, including humans and mice, the zinc finger histone methyltransferase PRDM9 performs the first step in meiotic recombination by specifying the locations of hotspots, the sites of genetic recombination. PRDM9 binds to DNA at hotspots through its zinc finger domain and activates recombination by trimethylating histone H3K4 on adjacent nucleosomes through its PR/SET domain. Recently, the isolated PR/SET domain of PRDM9 was shown capable of also trimethylating H3K36 in vitro, raising the question of whether this reaction occurs in vivo during meiosis, and if so, what its function might be. Here, we show that full-length PRDM9 does trimethylate H3K36 in vivo in mouse spermatocytes. Levels of H3K4me3 and H3K36me3 are highly correlated at hotspots, but mutually exclusive elsewhere. In vitro, we find that although PRDM9 trimethylates H3K36 much more slowly than it does H3K4, PRDM9 is capable of placing both marks on the same histone molecules. In accord with these results, we also show that PRDM9 can trimethylate both K4 and K36 on the same nucleosomes in vivo, but the ratio of K4me3/K36me3 is much higher for the pair of nucleosomes adjacent to the PRDM9 binding site compared to the next pair further away. Importantly, H3K4me3/H3K36me3-double-positive nucleosomes occur only in regions of recombination: hotspots and the pseudoautosomal (PAR) region of the sex chromosomes. These double-positive nucleosomes are dramatically reduced when PRDM9 is absent, showing that this signature is PRDM9-dependent at hotspots; the residual double-positive nucleosomes most likely come from the PRDM9-independent PAR. These results, together with the fact that PRDM9 is the only known mammalian histone methyltransferase with both H3K4 and H3K36 trimethylation activity, suggest that trimethylation of H3K36 plays an important role in the recombination process. Given the known requirement of H3K36me3 for double strand break repair by homologous recombination in somatic cells, we suggest that it may play the same role in meiosis.

DNA binding specificities of the long zinc-finger recombination protein PRDM9.

BACKGROUND: Meiotic recombination ensures proper segregation of homologous chromosomes and creates genetic variation. In many organisms, recombination occurs at limited sites, termed 'hotspots', whose positions in mammals are determined by PR domain member 9 (PRDM9), a long-array zinc-finger and chromatin-modifier protein. Determining the rules governing the DNA binding of PRDM9 is a major issue in understanding how it functions. RESULTS: Mouse PRDM9 protein variants bind to hotspot DNA sequences in a manner that is specific for both PRDM9 and DNA haplotypes, and that in vitro binding parallels its in vivo biological activity. Examining four hotspots, three activated by Prdm9Cst and one activated by Prdm9Dom2, we found that all binding sites required the full array of 11 or 12 contiguous fingers, depending on the allele, and that there was little sequence similarity between the binding sites of the three Prdm9Cst activated hotspots. The binding specificity of each position in the Hlx1 binding site, activated by Prdm9Cst, was tested by mutating each nucleotide to its three alternatives. The 31 positions along the binding site varied considerably in the ability of alternative bases to support binding, which also implicates a role for additional binding to the DNA phosphate backbone. CONCLUSIONS: These results, which provide the first detailed mapping of PRDM9 binding to DNA and, to our knowledge, the most detailed analysis yet of DNA binding by a long zinc-finger array, make clear that the binding specificities of PRDM9, and possibly other long-array zinc-finger proteins, are unusually complex.