Structural biology of shelterin and telomeric chromatin: the pieces and an unfinished puzzle.

The six-subunit shelterin complex binds to mammalian telomeres and protects them from triggering multiple DNA damage response pathways. The loss of this protective function by shelterin can have detrimental effects on cells. In this review, we first discuss structural studies of shelterin, detailing the contributions of each subunit and inter-subunit interactions in protecting chromosome ends. We then examine the influence of telomeric chromatin dynamics on the function of shelterin at telomeres. These studies provide valuable insights and underscore the challenges that future research must tackle to attain high-resolution structures of shelterin.

2.7 Å cryo-EM structure of human telomerase H/ACA ribonucleoprotein.

Telomerase is a ribonucleoprotein (RNP) enzyme that extends telomeric repeats at eukaryotic chromosome ends to counterbalance telomere loss caused by incomplete genome replication. Human telomerase is comprised of two distinct functional lobes tethered by telomerase RNA (hTR): a catalytic core, responsible for DNA extension; and a Hinge and ACA (H/ACA) box RNP, responsible for telomerase biogenesis. H/ACA RNPs also have a general role in pseudouridylation of spliceosomal and ribosomal RNAs, which is critical for the biogenesis of the spliceosome and ribosome. Much of our structural understanding of eukaryotic H/ACA RNPs comes from structures of the human telomerase H/ACA RNP. Here we report a 2.7 Å cryo-electron microscopy structure of the telomerase H/ACA RNP. The significant improvement in resolution over previous 3.3 Å to 8.2 Å structures allows us to uncover new molecular interactions within the H/ACA RNP. Many disease mutations are mapped to these interaction sites. The structure also reveals unprecedented insights into a region critical for pseudouridylation in canonical H/ACA RNPs. Together, our work advances understanding of telomerase-related disease mutations and the mechanism of pseudouridylation by eukaryotic H/ACA RNPs.

Suitability of bamboo to the ecological conditions in Ba Be district, Bac Kan province, Vietnam.

In Vietnamese culture, bamboo holds deep symbolic significance. However, in recent years, as a result of evolving usage patterns and the introduction of alternative materials in the face of a rapidly developing modern market economy, industrialisation, and urbanisation, bamboo's economic and social value has dwindled. Nevertheless, with the pressing challenges of climate change, environmental pollution, and the depletion of natural resources, bamboo is experiencing a resurgence in importance within the lives of Vietnamese people. Ba Be district, situated in Bac Kan province, stands as one of the country's most impoverished regions. Natural bamboo thrives in 14 out of 15 communes, with Dong Phuc commune being the exception. Planted bamboo is found in 14 out of 15 communes, excluding Cho Ra town, covering approximately 7.9 % of the entire district's natural area (NA). The district's vast terrain, featuring slopes exceeding 15°, presents formidable obstacles to socio-economic development. This study aims to shed light on the distribution of bamboo forests in Ba Be district and presents an assessment of bamboo's suitability within its natural surroundings. The study employs the analytical hierarchy process (AHP) method and spatial statistics, using remote sensing data supplied by the Department of Natural Resources and Environment, Ba Be district. The results demonstrate that 60 % of Ba Be district's NA is conducive to bamboo cultivation and growth. The findings of this research provide local authorities with a scientifically grounded basis for strategic planning, enabling bamboo to emerge as a pivotal resource within production forests. This approach outlines the ideal spatial distribution for bamboo cultivation and development, ultimately fostering the sustainable utilisation of local natural resources to support both immediate and long-term local socio-economic development.

Structural basis of telomeric nucleosome recognition by shelterin factor TRF1.

Shelterin and nucleosomes are the key players that organize mammalian chromosome ends into the protective telomere caps. However, how they interact with each other at telomeres remains unknown. We report cryo-electron microscopy structures of a human telomeric nucleosome both unbound and bound to the shelterin factor TRF1. Our structures reveal that TRF1 binds unwrapped nucleosomal DNA ends by engaging both the nucleosomal DNA and the histone octamer. Unexpectedly, TRF1 binding shifts the register of the nucleosomal DNA by 1 bp. We discovered that phosphorylation of the TRF1 C terminus and a noncanomical DNA binding surface on TRF1 are critical for its association with telomeric nucleosomes. These insights into shelterin-chromatin interactions have crucial implications for understanding telomeric chromatin organization and other roles of shelterin at telomeres including replication and transcription.

Progressive Tree-Based Compression of Large-Scale Particle Data.

Scientific simulations and observations using particles have been creating large datasets that require effective and efficient data reduction to store, transfer, and analyze. However, current approaches either compress only small data well while being inefficient for large data, or handle large data but with insufficient compression. Toward effective and scalable compression/decompression of particle positions, we introduce new kinds of particle hierarchies and corresponding traversal orders that quickly reduce reconstruction error while being fast and low in memory footprint. Our solution to compression of large-scale particle data is a flexible block-based hierarchy that supports progressive, random-access, and error-driven decoding, where error estimation heuristics can be supplied by the user. For low-level node encoding, we introduce new schemes that effectively compress both uniform and densely structured particle distributions.

Emergency Medicine with Advanced Surgery Protocols: A Review.

One of the most burning issues in health system is the concern of handling patients that requires emergency surgery. Emergency general surgery is done on both traumatic and nontraumatic acute disorders. Severe traumatic injury and bleeding is one of the causing agents for high mortality rate globally. Another group of patients that are in need of emergency surgery are those with heart failure, and in this particular paper, we analyzed emergency medicine with advanced surgery protocols focusing on gastric cancer, cardiac surgery, and bleeding as well as coagulopathy following traumatic injury.

Type 2 Diabetes Mellitus (T2DM) and Carbohydrate Metabolism in Relation to T2DM from Endocrinology, Neurophysiology, Molecular Biology, and Biochemistry Perspectives.

Type 2 diabetes mellitus (T2DM) is a severe disease caused by metabolic disorders, particularly carbohydrate metabolism disorders. The disease is a fatal global trouble characterised by high prevalence rates, causing death, blindness, kidney failure, myocardial infarction, amputation of lower limps, and stroke. Biochemical metabolic pathways like glycolysis, gluconeogenesis, glycogenesis, and glycogenolysis are critical pathways that regulate blood glucose levels with the glucokinase (GK) enzyme playing a central role in glucose homeostasis. Any factor that perturbs the aforementioned biochemical pathways is detrimental. Endocrinological, neurophysiological, and molecular biological pathways that are linked to carbohydrate metabolism should be studied, grasped, and manipulated in order to alleviate T2DM global chaos. The challenge, howbeit, is that, since the body is an integration of systems that complement one another, studying one "isolated" system is not very useful. This paper serves to discuss endocrinology, neurophysiology, and molecular biology pathways that are involved in carbohydrate metabolism in relation to T2DM.

A Critical Scrutiny on Liposomal Nanoparticles Drug Carriers as Modelled by Topotecan Encapsulation and Release in Treating Cancer.

The medical field is looking for drugs and/or ways of delivering drugs without harming patients. A number of severe drug side effects are reported, such as acute kidney injury (AKI), hepatotoxicity, skin rash, and so on. Nanomedicine has come to the rescue. Liposomal nanoparticles have shown great potential in loading drugs, and delivering drugs to specific targeted sites, hence achieving a needed bioavailability and steady state concentration, which is achieved by a controlled drug release ability by the nanoparticles. The liposomal nanoparticles can be conjugated to cancer receptor tags that give the anticancer-loaded nanoparticles specificity to deliver anticancer agents only at cancerous sites, hence circumventing destruction of normal cells. Also, the particles are biocompatible. The drugs are shielded by attack from the liver and other cytochrome P450 enzymes before reaching the desired sites. The challenge, however, is that the drug release is slow by these nanoparticles on their own. Scientists then came up with several ways to enhance drug release. Magnetic fields, UV light, infrared light, and so on are amongst the enhancers used by scientists to potentiate drug release from nanoparticles. In this paper, synthesis of liposomal nanoparticle formulations (liposomal-quantum dots (L-QDs), liposomal-quantum dots loaded with topotecan (L-QD-TPT)) and their analysis (cytotoxicity, drug internalization, loading efficiency, drug release rate, and the uptake of the drug and nanoparticles by the HeLa cells) are discussed.

The Use of Bacteria in Cancer Treatment: A Review from the Perspective of Cellular Microbiology.

Cellular microbiology, which is the interaction between harmful microbes and infected cells, is important in the determination of the bacterial infection processes and in the progression of data of different cellular mechanisms. The therapeutic role of bacteria has gained attention since the known methods such as radiation, chemotherapy, and immunotherapy have got drawbacks. Bacteria have demonstrated a favorable impact in treating cancer through eradication of tumors. Bacteria, in cancer treatment, have proven to be promising and have been shown in some of the previous work that it can successfully suppress the growth of tumors. In this paper, we analyzed the difficulties and settlement for using bacteria in cancer therapy as well the mechanisms in which bacteria works in order to achieve tumor eradication. Future works may focus on the use of bacteria along with other treatments in order to achieve effective tumor therapy.

Preparation of PCL Electrospun Fibers Loaded with Cisplatin and Their Potential Application for the Treatment of Prostate Cancer.

Prostate cancer is a global fatal type of cancer. It is a type of cancer that affect men. Signs and symptoms of the disease include blood in the urine, pain when one micturates, and difficulties in penis erection. Cisplatin chemotherapy is a principal treatment normally given to the prostate cancer patients. Nonetheless, on its own, cisplatin loses efficacy once administered due to liver pass effects and other biochemical attacks. In this paper, we looked at preparation of PCL nanoparticles loaded with cisplatin and their potential for the treatment of prostate cancer. PCL nanoparticles protect cisplatin from biochemical attack, thus increasing drug efficacy. Incorporation of P-glycoprotein inhibitors in PCL nanoparticles (NPs) loaded with cisplatin could improve prostate cancer treatment even more.

Biochemical Behaviours of Salmeterol/Fluticasone Propionate in Treating Asthma and Chronic Obstructive Pulmonary Diseases (COPD).

Chronic obstructive pulmonary diseases (COPD) and asthma are fatal. The respiratory tract may be blocked, robbed of the adequate amounts of oxygen; hence, death ensues if a quick medical attention is not provided. The treatment available for the duo are inhaled corticosteroids (ICS). The ICS can work synergically with LABAS (long-acting ß 2-antagonists) and so many other medicines like bronchodilators. The drugs used for the treatment of asthma and COPD are metabolised once in the body system and at the same time exerting the therapeutic effect provided the concentration of the drug is within the therapeutic window. The CYP3A isoforms metabolise the ICS, in this case, salmeterol and fluticasone propionate (FP). Methods of administration are not limited to inhalation. Specific doses are prescribed accurately paying attention to factors like age, gender, race, and genetic makeup since these affect drug metabolisms. Generally, the ICS work by translocating glucocorticoid receptors to the nucleus from the cytosol. The mechanism is potentiated by the ß-antagonists and this brings about an anti-inflammatory effect which is greater than either of the two drugs alone. Once this happens, it is not necessary to increase ICS dose. The ICS, in addition, cause more production of ß-receptors by activating the ß-receptor genes. This mode of action begets the LABAs' bronchodilator-effects. The challenge is that ICS are not limited only to "double" therapy. Analysing such therapies is daunting since coadministration interferes with pharmacology and pharmacokinetics of drugs. This work focuses on salmeterol/fluticasone propionate combination and aspects which has to do with administration, monitoring, metabolism, toxicity, and adverse effects.

AMM: Adaptive Multilinear Meshes.

Adaptive representations are increasingly indispensable for reducing the in-memory and on-disk footprints of large-scale data. Usual solutions are designed broadly along two themes: reducing data precision, e.g., through compression, or adapting data resolution, e.g., using spatial hierarchies. Recent research suggests that combining the two approaches, i.e., adapting both resolution and precision simultaneously, can offer significant gains over using them individually. However, there currently exist no practical solutions to creating and evaluating such representations at scale. In this work, we present a new resolution-precision-adaptive representation to support hybrid data reduction schemes and offer an interface to existing tools and algorithms. Through novelties in spatial hierarchy, our representation, Adaptive Multilinear Meshes (AMM), provides considerable reduction in the mesh size. AMM creates a piecewise multilinear representation of uniformly sampled scalar data and can selectively relax or enforce constraints on conformity, continuity, and coverage, delivering a flexible adaptive representation. AMM also supports representing the function using mixed-precision values to further the achievable gains in data reduction. We describe a practical approach to creating AMM incrementally using arbitrary orderings of data and demonstrate AMM on six types of resolution and precision datastreams. By interfacing with state-of-the-art rendering tools through VTK, we demonstrate the practical and computational advantages of our representation for visualization techniques. With an open-source release of our tool to create AMM, we make such evaluation of data reduction accessible to the community, which we hope will foster new opportunities and future data reduction schemes.

Structural basis of human telomerase recruitment by TPP1-POT1.

Telomerase maintains genome stability by extending the 3' telomeric repeats at eukaryotic chromosome ends, thereby counterbalancing progressive loss caused by incomplete genome replication. In mammals, telomerase recruitment to telomeres is mediated by TPP1, which assembles as a heterodimer with POT1. We report structures of DNA-bound telomerase in complex with TPP1 and with TPP1-POT1 at 3.2- and 3.9-angstrom resolution, respectively. Our structures define interactions between telomerase and TPP1-POT1 that are crucial for telomerase recruitment to telomeres. The presence of TPP1-POT1 stabilizes the DNA, revealing an unexpected path by which DNA exits the telomerase active site and a DNA anchor site on telomerase that is important for telomerase processivity. Our findings rationalize extensive prior genetic and biochemical findings and provide a framework for future mechanistic work on telomerase regulation.

Structural biology of human telomerase: progress and prospects.

Telomerase ribonucleoprotein was discovered over three decades ago as a specialized reverse transcriptase that adds telomeric repeats to the ends of linear eukaryotic chromosomes. Telomerase plays key roles in maintaining genome stability; and its dysfunction and misregulation have been linked to different types of cancers and a spectrum of human genetic disorders. Over the years, a wealth of genetic and biochemical studies of human telomerase have illuminated its numerous fascinating features. Yet, structural studies of human telomerase have lagged behind due to various challenges. Recent technical developments in cryo-electron microscopy have allowed for the first detailed visualization of the human telomerase holoenzyme, revealing unprecedented insights into its active site and assembly. This review summarizes the cumulative work leading to the recent structural advances, as well as highlights how the future structural work will further advance our understanding of this enzyme.

Structure of human telomerase holoenzyme with bound telomeric DNA.

Telomerase adds telomeric repeats at chromosome ends to compensate for the telomere loss that is caused by incomplete genome end replication1. In humans, telomerase is upregulated during embryogenesis and in cancers, and mutations that compromise the function of telomerase result in disease2. A previous structure of human telomerase at a resolution of 8 Å revealed a vertebrate-specific composition and architecture3, comprising a catalytic core that is flexibly tethered to an H and ACA (hereafter, H/ACA) box ribonucleoprotein (RNP) lobe by telomerase RNA. High-resolution structural information is necessary to develop treatments that can effectively modulate telomerase activity as a therapeutic approach against cancers and disease. Here we used cryo-electron microscopy to determine the structure of human telomerase holoenzyme bound to telomeric DNA at sub-4 Å resolution, which reveals crucial DNA- and RNA-binding interfaces in the active site of telomerase as well as the locations of mutations that alter telomerase activity. We identified a histone H2A-H2B dimer within the holoenzyme that was bound to an essential telomerase RNA motif, which suggests a role for histones in the folding and function of telomerase RNA. Furthermore, this structure of a eukaryotic H/ACA RNP reveals the molecular recognition of conserved RNA and protein motifs, as well as interactions that are crucial for understanding the molecular pathology of many mutations that cause disease. Our findings provide the structural details of the assembly and active site of human telomerase, which paves the way for the development of therapeutic agents that target this enzyme.

Real-Time EEG Signal Classification for Monitoring and Predicting the Transition Between Different Anaesthetic States.

Quantitative identification of the transitions between anaesthetic states is very essential for optimizing patient safety and quality care during surgery but poses a very challenging task. The state-of-the-art monitors are still not capable of providing their manifest variables, so the practitioners must diagnose them based on their own experience. The present paper proposes a novel real-time method to identify these transitions. Firstly, the Hurst method is used to pre-process the de-noised electro-encephalograph (EEG) signals. The maximum of Hurst's ranges is then accepted as the EEG real-time response, which induces a new real-time feature under moving average framework. Its maximum power spectral density is found to be very differentiated into the distinct transitions of anaesthetic states and thus can be used as the quantitative index for their identification.

Efficient and Flexible Hierarchical Data Layouts for a Unified Encoding of Scalar Field Precision and Resolution.

To address the problem of ever-growing scientific data sizes making data movement a major hindrance to analysis, we introduce a novel encoding for scalar fields: a unified tree of resolution and precision, specifically constructed so that valid cuts correspond to sensible approximations of the original field in the precision-resolution space. Furthermore, we introduce a highly flexible encoding of such trees that forms a parameterized family of data hierarchies. We discuss how different parameter choices lead to different trade-offs in practice, and show how specific choices result in known data representation schemes such as zfp [52], idx [58], and jpeg2000 [76]. Finally, we provide system-level details and empirical evidence on how such hierarchies facilitate common approximate queries with minimal data movement and time, using real-world data sets ranging from a few gigabytes to nearly a terabyte in size. Experiments suggest that our new strategy of combining reductions in resolution and precision is competitive with state-of-the-art compression techniques with respect to data quality, while being significantly more flexible and orders of magnitude faster, and requiring significantly reduced resources.

Misalignment of global COVID-19 breastfeeding and newborn care guidelines with World Health Organization recommendations.

INTRODUCTION: Recommendations for the clinical management of new mothers with suspected or confirmed COVID-19 and their infants are required. Guidance must weigh the risk posed by transmission of SARS-CoV-2 against the protection that maternal proximity and breastfeeding provide infants. Our aim was to review international COVID-19 guidance for maternal and newborn care, assessing alignment with WHO recommendations and the extent to which policy supported or undermined breastfeeding. METHODS: Guidance documents from 33 countries on the care of infants whose mothers were suspected or confirmed as having COVID-19 were assessed for alignment with WHO recommendations regarding: (1) skin-to-skin contact; (2) early initiation of breastfeeding; (3); rooming-in; (4) direct breastfeeding; (5) provision of expressed breastmilk; (6) provision of donor human milk; (7) wet nursing; (8) provision of breastmilk substitutes; (9) psychological support for separated mothers; and (10) psychological support for separated infants. RESULTS: Considerable inconsistency in recommendations were found. Recommendations against practices supportive of breastfeeding were common, even in countries with high infant mortality rates. None of the guidance documents reviewed recommended all aspects of WHO guidance. The presence of influential guidance conflicting with WHO recommendations and an undervaluing of the importance of maternal proximity and breastfeeding to infant health appeared to contribute to this poor alignment. CONCLUSION: Those developing guidance in the COVID-19 pandemic and other infectious disease outbreaks need to appropriately consider the importance of skin-to-skin contact, early initiation of breastfeeding, rooming-in and breastfeeding to maternal and infant physical and psychological health. In weighing the value of recommendations of others in future guidance development, countries should consider past reliability and value placed on breastfeeding. Recommendations against maternal proximity and breastfeeding should not be made without compelling evidence that they are necessary, and less harmful than maintaining dyad integrity.