Structural insights into the human P2X1 receptor and ligand interactions.

The P2X1 receptor is a trimeric ligand-gated ion channel that plays an important role in urogenital and immune functions, offering the potential for new drug treatments. However, progress in this area has been hindered by limited structural information and a lack of well-characterised tool compounds. In this study, we employ cryogenic electron microscopy (cryo-EM) to elucidate the structures of the P2X1 receptor in an ATP-bound desensitised state and an NF449-bound closed state. NF449, a potent P2X1 receptor antagonist, engages the receptor distinctively, while ATP, the endogenous ligand, binds in a manner consistent with other P2X receptors. To explore the molecular basis of receptor inhibition, activation, and ligand interactions, key residues involved in ligand and metal ion binding were mutated. Radioligand binding assays with [3H]-α,ß-methylene ATP and intracellular calcium ion influx assays were used to evaluate the effects of these mutations. These experiments validate key ligand-receptor interactions and identify conserved and non-conserved residues critical for ligand binding or receptor modulation. This research expands our understanding of the P2X1 receptor structure at a molecular level and opens new avenues for in silico drug design targeting the P2X1 receptor.

Maintaining the Balance: Regulation of NK Cell Activity.

Natural Killer (NK) cells, integral components of the innate immune system, play a crucial role in the protection against intracellular threats. Their cytotoxic power requires that activation is tightly controlled, and in this, they take a unique position within the immune system. Rather than depending on the engagement of a single activating receptor, their activation involves a delicate balance between inhibitory and activating signals mediated through an array of surface molecules. Only when this cumulative balance surpasses a specific threshold do NK cells initiate their activity. Remarkably, the activation threshold of NK cells remains robust even when cells express vastly different repertoires of inhibitory and activating receptors. These threshold values seem to be influenced by NK cell interactions with their environment during development and after release from the bone marrow. Understanding how NK cells integrate this intricate pattern of stimuli is an ongoing area of research, particularly relevant for cellular therapies seeking to harness the anti-cancer potential of these cells by modifying surface receptor expression. In this review, we will explore some of the current dogmas regarding NK cell activation and discuss recent literature addressing advances in our understanding of this field.

Intraoperative pneumatic tourniquet application reduces soft-tissue microcirculation, but without affecting wound healing in calcaneal fractures.

BACKGROUND: Wound healing complications are a major challenge following the extended lateral approach in calcaneal fractures. Soft-tissue microcirculation plays an important role via the delivery of oxygen, nutrients, and the regulation of a local milieu. The aim of this clinical study was to examine the effect of intraoperative pneumatic tourniquet application on skin and subcutaneous microcirculation, and its impact on wound healing progression. METHODS: Patients with calcaneal fractures were randomly assigned to two groups defined by a surgery conducted either with use or without use of a tourniquet. Blood flow (BF [AU]), tissue oxygen saturation (SO2[%]) and the relative amount of haemoglobin (rHb[AU]) were intraoperatively measured at two depths (2 and 8 mm) non-invasively by spectrophotometry (Micro-Lightguide O2C®, LEA Medizintechnik, Giessen, Germany). Time points were before and after inflation of the pneumatic tourniquet and also at the end of surgery before deflation. A linear mixed model (LMM) was fitted for statistical analysis. RESULTS: Thirty-four patients (3 women and 31 men) with 37 calcaneal fractures were included. In 22 of them, the surgery was conducted with a tourniquet and in the other 15 without its use. A significant decrease of microcirculation, characterized by decreases in blood flow (p = 0.011) and tissue oxygenation (p = 0.023) was measured in 8 mm depth after inflating the tourniquet. However, these changes did not influence the time of postoperative wound healing. CONCLUSION: The use of a pneumatic tourniquet reduces deep microcirculation without affecting postoperative wound healing. Trial registration The study was registered in www. CLINICALTRIALS: gov (NCT01264146).

Cancer Care Terminology in African Languages.

Importance: Effective communication between patients and health care teams is essential in the health care setting for delivering optimal cancer care and increasing cancer awareness. While the significance of communication in health care is widely acknowledged, the topic is largely understudied within African settings. Objective: To assess how the medical language of cancer and oncology translates into African languages and what these translations mean within their cultural context. Design, Setting, and Participants: In this multinational survey study in Africa, health professionals, community health workers, researchers, and scientists involved in cancer care and research and traditional healers were invited to participate in an online survey on a voluntary basis through online platforms. The survey provided 16 cancer and oncologic terms used in cancer diagnosis and treatment (eg, cancer, radiotherapy) to participants, mostly health care workers, who were asked to provide these terms in their local languages (if the terms existed) followed by a direct or close translation of the meaning in English. The survey was open from February to April 2023. Main Outcomes and Measures: Patterns of meaning that recurred across languages were identified using thematic analysis of 16 English-translated terms categorized into 5 themes (neutral, negative, positive, phonetic or borrowed, and unknown). Results: A total of 107 responses (response rate was unavailable given the open and widespread distribution strategy) were collected from 32 countries spanning 44 African languages, with most participants (63 [59%]) aged 18 to 40 years; 54 (50%) were female. Translations for cancer were classified as phonetic or borrowed (34 [32%]), unknown (30 [28%]), neutral (24 [22%]), and negative (19 [18%]), with the latter category including universal connotations of fear, tragedy, incurability, and fatality. Similar elements connoting fear or tragedy were found in translations of terms such as malignant, chronic, and radiotherapy. The term radiotherapy yielded a high percentage of negative connotations (24 [22%]), with a prevailing theme of describing the treatment as being burned or burning with fire, heat, or electricity, which may potentially hinder treatment. Conclusions and Relevance: In this survey study of cancer communication and the translation of oncology terminology in African languages, the findings suggest that the terminology may contribute to fear, health disparities, and barriers to care and pose communication difficulties for health professionals. The results reinforce the need for culturally sensitive cancer terminology for improving cancer awareness and communication.

Structure-Based Design of Bicyclic Helical Peptides That Target the Oncogene ß-Catenin.

The inhibition of intracellular protein-protein interactions is challenging, in particular, when involved interfaces lack pronounced cavities. The transcriptional co-activator protein and oncogene ß­catenin is a prime example of such a challenging target. Despite extensive targeting efforts, available high-affinity binders comprise only large molecular weight Inhibitors. This hampers the further development of therapeutically useful compounds. Herein, we report the design of a considerably smaller peptidomimetic scaffold derived from the α-helical ß­catenin-binding motif of Axin. Sequence maturation and bicyclization provided a stitched peptide with an unprecedented crosslink architecture. The binding mode and site were confirmed by a crystal structure. Further derivatization yielded a ß-catenin inhibitor with single-digit micromolar activity in a cell-based assay. This study sheds a light on how to design helix mimetics with reduced molecular weight thereby improving their biological activity.

Characterization of Mild Traumatic Brain Injury Cohort With Photophobia From the Defense and Veterans Eye Injury and Vision Registry.

INTRODUCTION: Photophobia is a common visual symptom following mild traumatic brain injury (mTBI), which can adversely affect the military readiness and performance of service members (SMs). We employed the Defense and Veterans Eye Injury and Vision Registry (DVEIVR) to identify and describe a cohort of SMs diagnosed with photophobia post-mTBI. The objective of this study was to characterize comorbid conditions and symptoms in an mTBI cohort with photophobia, to assess their co-occurrence, to describe the persistence of photophobia, and to assess the effectiveness of utilization of currently available International Statistical Classification of Diseases and Related Health Problems (ICD) codes in reporting photophobia in this cohort. MATERIALS AND METHODS: The DVEIVR database was searched to identify a cohort of SMs experiencing photophobia after mTBI. Photophobia and other potentially related conditions and symptoms, both coded and descriptive, which were abstracted directly from the medical records of SMs, were found within DVEIVR. The presence of the conditions and symptoms comorbid with photophobia was characterized on both patient and encounter levels. Analysis of co-occurrence of photophobia with these conditions or symptoms was performed on the encounter level using co-occur package in the statistical program R. Persistence of photophobia up to 1 year since the injury was assessed. The utilization of currently available ICD codes for photophobia was analyzed. RESULTS: A total of 639 SMs exhibiting photophobia after mTBI were identified in DVEIVR. Headaches, including migraines, were the most frequently experienced comorbidity affecting 92% of the SMs in the cohort. The second most frequent complaint was dizziness and/or vertigo (53%) followed by nausea (42%), blurry vision (31%), and irritation and discomfort in the eye (17%). In all, 20% of encounters with photophobia had a complaint of headaches, followed by 8.3% of photophobia encounters co-occurring with dizziness and vertigo, 5.7%-with nausea, 4.5%-with blurred vision, and 2.1%-with subjective sensations in the eye. All comorbidities co-occurred with photophobia at probabilities higher than by chance alone. The percentage of mTBI SMs experiencing photophobia declined to 20% at 30 days after the injury, 17% at 3 months, 12% at 6 months, and 7% at 12 months post-injury, respectively. The use of currently available ICD codes for photophobia was very low-only 27.1% of the cohort had at least 1 ICD code recorded in their medical records. CONCLUSIONS: The results of this study support the idea that there is a strong relationship between photophobia and headache after an mTBI. Additional research is warranted to better understand this relationship and its causes so that clinical management improves. The results of this study show a precipitous decline in the numbers of cases of photophobia after mTBI over the first 30 days and a longer-term persistence up to a year in a minority of cases, which is consistent with other research in this field. Various ICD codes, which are currently used to code for photophobia, along with other vision conditions, were not widely used to document photophobia symptoms. It is important to adopt a dedicated ICD code for photophobia to improve the surveillance, data collection, and analysis of this condition.

The immunology of sickness metabolism.

Everyone knows that an infection can make you feel sick. Although we perceive infection-induced changes in metabolism as a pathology, they are a part of a carefully regulated process that depends on tissue-specific interactions between the immune system and organs involved in the regulation of systemic homeostasis. Immune-mediated changes in homeostatic parameters lead to altered production and uptake of nutrients in circulation, which modifies the metabolic rate of key organs. This is what we experience as being sick. The purpose of sickness metabolism is to generate a metabolic environment in which the body is optimally able to fight infection while denying vital nutrients for the replication of pathogens. Sickness metabolism depends on tissue-specific immune cells, which mediate responses tailored to the nature and magnitude of the threat. As an infection increases in severity, so do the number and type of immune cells involved and the level to which organs are affected, which dictates the degree to which we feel sick. Interestingly, many alterations associated with metabolic disease appear to overlap with immune-mediated changes observed following infection. Targeting processes involving tissue-specific interactions between activated immune cells and metabolic organs therefore holds great potential for treating both people with severe infection and those with metabolic disease. In this review, we will discuss how the immune system communicates in situ with organs involved in the regulation of homeostasis and how this communication is impacted by infection.

Reconsideration of the alar base cinch suture technique involving the perinasal musculature: an in-depth review.

Orthognathic surgery affects both function and aesthetics. An important aesthetic complication is the nasal alteration that can result from Le Fort I osteotomy. A common method for countering this complication is the alar base cinch suture technique. Although the method for this suture has been standardized, the results vary and are inconsistent; further improvements are therefore required. The objective of this study was to review the literature data on the alar base cinch suture technique and associated results. In this review, the PubMed, Ovid, and Ichushi-Web electronic databases were searched using logical combinations of keywords related to the perinasal musculature and alar base cinch suture technique. Following screening of the results, 42 publications were included. The review findings prompted several conclusions. The anatomy of the myrtiformis muscle and depressor septi nasalis may differ between ethnicities, and it is essential to take certain factors related to ethnicity into account when implementing the alar base cinch suture technique. It is also important to consider factors such as the patient's aesthetic preferences.

How to talk about dying? The development of an evidence-based model for communication with patients in their last days of life and their family caregivers.

Objective: To help healthcare professionals (HCP) act with more confidence when communicating about approaching death, we sought to develop a communication model for HCP to facilitate conversations with dying patients and family caregivers (FC) in nonemergency situations. Methods: We used a four-phase integrative approach: (1) creation of a preliminary model based on a systematic literature review and expert knowledge, (2) review of the model draft by international palliative care experts, (3) review by key stakeholders, and (4) final appraisal by communication experts. Results: After the clinical recognition of dying, the communication model provides a structure and practical communication aids for navigating the conversation based on three phases. It describes the content and relational level as core dimensions of effective conversations about approaching death and highlights the importance of HCP self-awareness and self-care when caring for the dying. Conclusion: Based on systematic involvement of key stakeholders, the model supports clinicians navigating challenging conversations about approaching death with dying patients and their FC successfully and with more confidence. Innovation: This study expands the theoretical basis for communication about approaching death and offers a pragmatic model for educational interventions and clinical use.

Historical control data of rare events: Issues, chronological patterns and their relevance for toxicological evaluations.

Historical control data (HCD) give context for a measurement by providing a biological reference frame. HCD are used in the evaluation of toxicological bioassays for quality and performance control, informal statistical false discovery rate mitigation, and to estimate the biological relevance of observed potentially adverse findings. The current commentary shortly highlights 5 points that should be considered when working with HCD of rare events: 1) HCD database (HCDB) size, 2) the issue of rare events, 3) potential chronological patterns, 4) using point estimates to summarize HCD and 5) independence from treatment bias, i.e., HCD are mostly informative for primary toxicity. It is argued to use exploratory data analysis and to apply ad hoc time windows for assessment based on an HCDB that is as large as possible to monitor for potential structure and systemic bias in the data.