A Novel Perspective on PCSK9 in Alzheimer's Disease: A Focus on Amyloid Beta.

The proprotein convertase subtilisin/kexin type 9 (PCSK9) belongs to a member of the proprotein convertase (PC) family, which is mainly secreted by the liver and plays a central role in lipid metabolism. Furthermore, PCSK9 plays a multifunctional role in promoting the inflammatory response, inducing cell apoptosis and pyroptosis and affecting tumor homeostasis. The brain is the organ with the richest lipid content. Incidentally, PCSK9 increased in many brain diseases, including brain injury and Alzheimer's disease (AD). Consequently, the relationship between PCSK9 and brain diseases has attracted increasing research interest. Amyloid beta (Aß) accumulation is the central and initial event in the pathogenesis of AD. This study focuses on the effects of PCSK9 on Aß accumulation in the brain via multiple modalities to explore the potential role of PCSK9 in AD, which is characterized by progressive loss of brain cells by increasing Aß accumulation. The study also explores the new mechanism by which PCSK9 is involved in the pathogenesis of AD, providing interesting and innovative guidance for the future of PCSK9-targeted therapy for AD.

Case report: Successful treatment of advanced colon cancer in an eighty-year-old man with long-term and multi-stage endoscopic minimally invasive therapy.

Background: No previous studies have reported on the use of minimally invasive endoscopic therapy for colon cancer in older patients. Case presentation: An 80-year-old man was admitted to our hospital with haematochezia and diagnosed with advanced colon cancer in 2018. Traditional surgical care was rejected by his family. We successfully treated the patient with multiple minimally invasive endoscopic therapies, such as argon plasma coagulation, from 2018 to 2021. Conclusion: Invasive endoscopic therapy is a feasible way to treat colon cancer in older patients.

Torso hemorrhage: noncompressible? never say never.

Since limb bleeding has been well managed by extremity tourniquets, the management of exsanguinating torso hemorrhage (TH) has become a hot issue both in military and civilian medicine. Conventional hemostatic techniques are ineffective for managing traumatic bleeding of organs and vessels within the torso due to the anatomical features. The designation of noncompressible torso hemorrhage (NCTH) marks a significant step in investigating the injury mechanisms and developing effective methods for bleeding control. Special tourniquets such as abdominal aortic and junctional tourniquet and SAM junctional tourniquet designed for NCTH have been approved by FDA for clinical use. Combat ready clamp and junctional emergency treatment tool also exhibit potential for external NCTH control. In addition, resuscitative endovascular balloon occlusion of the aorta (REBOA) further provides an endovascular solution to alleviate the challenges of NCTH treatment. Notably, NCTH cognitive surveys have revealed that medical staff have deficiencies in understanding relevant concepts and treatment abilities. The stereotypical interpretation of NCTH naming, particularly the term noncompressible, is the root cause of this issue. This review discusses the dynamic relationship between TH and NCTH by tracing the development of external NCTH control techniques. The authors propose to further subdivide the existing NCTH into compressible torso hemorrhage and NCTH' (noncompressible but REBOA controllable) based on whether hemostasis is available via external compression. Finally, due to the irreplaceability of special tourniquets during the prehospital stage, the authors emphasize the importance of a package program to improve the efficacy and safety of external NCTH control. This program includes the promotion of tourniquet redesign and hemostatic strategies, personnel reeducation, and complications prevention.

Feasibility of NDEA formation control from DEDTC in chlorination/chloramination by pre-ozonation: Mechanisms and influencing factors.

N-nitrosodiethylamine (NDEA), which is the most toxic nitrosamine among the 9 detected species, has been widely detected in drinking water. Amines containing diethylamine (DEA) groups in the structure would generate NDEA during the disinfection processes. The aim of this study was to evaluate the feasibility of reducing NDEA formation from a commonly used dithiocarbamate pesticide sodium diethyldithiocarbamate (DEDTC) in subsequent chlorination and chloramination by pre-ozonation. The results demonstrated that NDEA could be generated directly during ozonation, its amounts increased from 0 to 14.34 µg/L with increasing ozone dosages (0-4 mg/L), which was higher than that chlorination (2.68 µg/L) and chloramination (4.91 µg/L) when the initial concentration of DEDTC was 20 µM. Pre-ozonation significantly raised NDEA formation from 2.68 to15.32 µg/L in subsequent chlorination; and that from 4.91 to 9.54 µg/L during subsequent chloramination processes. The addition of •OH scavenger tert-butanol (tBA) increased the production of NDEA from 8.14 to 20.80 µg/L during ozonation, and that from 6.76 to17.98 µg/L in O3/HClO process, 8.74 to 17.33 µg/L in O3/NH2Cl process. Except for NO3- and CO32-, most of the co-existing substances promoted NDEA generation from DEDTC under disinfection conditions. Based on the results of Gaussian theory calculations, GC/MS and UPLC-Q-TOFMS analysis, the influencing mechanisms of pre-ozonation on NDEA generation in the subsequent disinfection process were proposed. In addition, not only acute/chronic toxicity calculation but also luminescent bacteria test was performed to assess the possibility of pre-ozonation on the risk control of DEDTC. The research results fill a gap in the control of NDEA pollution and help to develop a safer ozone oxidation technology.

FLAP: a framework for linking free-text addresses to the Ordnance Survey Unique Property Reference Number database.

Introduction: Linking free-text addresses to unique identifiers in a structural address database [the Ordnance Survey unique property reference number (UPRN) in the United Kingdom (UK)] is a necessary step for downstream geospatial analysis in many digital health systems, e.g., for identification of care home residents, understanding housing transitions in later life, and informing decision making on geographical health and social care resource distribution. However, there is a lack of open-source tools for this task with performance validated in a test data set. Methods: In this article, we propose a generalisable solution (A Framework for Linking free-text Addresses to Ordnance Survey UPRN database, FLAP) based on a machine learning-based matching classifier coupled with a fuzzy aligning algorithm for feature generation with better performance than existing tools. The framework is implemented in Python as an Open Source tool (available at Link). We tested the framework in a real-world scenario of linking individual's (n=771,588) addresses recorded as free text in the Community Health Index (CHI) of National Health Service (NHS) Tayside and NHS Fife to the Unique Property Reference Number database (UPRN DB). Results: We achieved an adjusted matching accuracy of 0.992 in a test data set randomly sampled (n=3,876) from NHS Tayside and NHS Fife CHI addresses. FLAP showed robustness against input variations including typographical errors, alternative formats, and partially incorrect information. It has also improved usability compared to existing solutions allowing the use of a customised threshold of matching confidence and selection of top n candidate records. The use of machine learning also provides better adaptability of the tool to new data and enables continuous improvement. Discussion: In conclusion, we have developed a framework, FLAP, for linking free-text UK addresses to the UPRN DB with good performance and usability in a real-world task.

Dual Photo-Responsive Diphenylacetylene Enables PET In-Situ Upcycling with Reverse Enhanced UV-Resistance and Strength.

A novel in situ chemical upcycling strategy for plastic waste is proposed by the customized diphenylacetylene monomer with dual photo-response. That is, diphenylacetylene reactive monomers are in situ inserted into the macromolecular chain of polyethylene terephthalate (PET) plastics/fibers through one-pot transesterification of slight-depolymerization and re-polymerization. On the one hand, the diphenylacetylene group absorbs short-wave high-energy UV rays and then releases long-wave low-energy harmless fluorescence. On the other hand, the UV-induced photo-crosslinking reaction among diphenylacetylene groups produces extended π-conjugated structure, resulting in a red-shift (due to decreased HOMO-LUMO separation) in the UV absorption band and locked crosslink points between PET chains. Therefore, with increasing UV exposure time, the upcycled PET plastics exhibit reverse enhanced UV resistance and mechanical strength (superior to original performance), instead of serious UV-photodegradation and damaged performance. This upcycling strategy at oligomer-scale not only provides a new idea for traditional plastic recycling, but also solves the common problem of gradual degradation of polymer performance during use.

Understanding the performance and reliability of NLP tools: a comparison of four NLP tools predicting stroke phenotypes in radiology reports.

Background: Natural language processing (NLP) has the potential to automate the reading of radiology reports, but there is a need to demonstrate that NLP methods are adaptable and reliable for use in real-world clinical applications. Methods: We tested the F1 score, precision, and recall to compare NLP tools on a cohort from a study on delirium using images and radiology reports from NHS Fife and a population-based cohort (Generation Scotland) that spans multiple National Health Service health boards. We compared four off-the-shelf rule-based and neural NLP tools (namely, EdIE-R, ALARM+, ESPRESSO, and Sem-EHR) and reported on their performance for three cerebrovascular phenotypes, namely, ischaemic stroke, small vessel disease (SVD), and atrophy. Clinical experts from the EdIE-R team defined phenotypes using labelling techniques developed in the development of EdIE-R, in conjunction with an expert researcher who read underlying images. Results: EdIE-R obtained the highest F1 score in both cohorts for ischaemic stroke, ≥93%, followed by ALARM+, ≥87%. The F1 score of ESPRESSO was ≥74%, whilst that of Sem-EHR is ≥66%, although ESPRESSO had the highest precision in both cohorts, 90% and 98%. For F1 scores for SVD, EdIE-R scored ≥98% and ALARM+ ≥90%. ESPRESSO scored lowest with ≥77% and Sem-EHR ≥81%. In NHS Fife, F1 scores for atrophy by EdIE-R and ALARM+ were 99%, dropping in Generation Scotland to 96% for EdIE-R and 91% for ALARM+. Sem-EHR performed lowest for atrophy at 89% in NHS Fife and 73% in Generation Scotland. When comparing NLP tool output with brain image reads using F1 scores, ALARM+ scored 80%, outperforming EdIE-R at 66% in ischaemic stroke. For SVD, EdIE-R performed best, scoring 84%, with Sem-EHR 82%. For atrophy, EdIE-R and both ALARM+ versions were comparable at 80%. Conclusions: The four NLP tools show varying F1 (and precision/recall) scores across all three phenotypes, although more apparent for ischaemic stroke. If NLP tools are to be used in clinical settings, this cannot be performed "out of the box." It is essential to understand the context of their development to assess whether they are suitable for the task at hand or whether further training, re-training, or modification is required to adapt tools to the target task.

Betula mcallisteri sp. nov. (sect. Acuminatae, Betulaceae), a new diploid species overlooked in the wild and in cultivation, and its relation to the widespread B. luminifera.

Taxa are traditionally identified using morphological proxies for groups of evolutionarily isolated populations. These proxies are common characters deemed by taxonomists as significant. However, there is no general rule on which character or sets of characters are appropriate to circumscribe taxa, leading to discussions and uncertainty. Birch species are notoriously hard to identify due to strong morphological variability and factors such as hybridization and the existence of several ploidy levels. Here, we present evidence for an evolutionarily isolated line of birches from China that are not distinguishable by traditionally assumed taxon recognition proxies, such as fruit or leaf characters. We have discovered that some wild material in China and some cultivated in the Royal Botanic Gardens Edinburgh, formerly recognized as Betula luminifera, differ from other individuals by having a peeling bark and a lack of cambial fragrance. We use restriction site-associated DNA sequencing and flow cytometry to study the evolutionary status of the unidentified Betula samples to assess the extent of hybridization between the unidentified Betula samples and typical B. luminifera in natural populations. Molecular analyses show the unidentified Betula samples as a distinct lineage and reveal very little genetic admixture between the unidentified samples and B. luminifera. This may also be facilitated by the finding that B. luminifera is tetraploid, while the unidentified samples turned out to be diploid. We therefore conclude that the samples represent a yet unrecognized species, which is here described as Betula mcallisteri.

Ontology-driven and weakly supervised rare disease identification from clinical notes.

BACKGROUND: Computational text phenotyping is the practice of identifying patients with certain disorders and traits from clinical notes. Rare diseases are challenging to be identified due to few cases available for machine learning and the need for data annotation from domain experts. METHODS: We propose a method using ontologies and weak supervision, with recent pre-trained contextual representations from Bi-directional Transformers (e.g. BERT). The ontology-driven framework includes two steps: (i) Text-to-UMLS, extracting phenotypes by contextually linking mentions to concepts in Unified Medical Language System (UMLS), with a Named Entity Recognition and Linking (NER+L) tool, SemEHR, and weak supervision with customised rules and contextual mention representation; (ii) UMLS-to-ORDO, matching UMLS concepts to rare diseases in Orphanet Rare Disease Ontology (ORDO). The weakly supervised approach is proposed to learn a phenotype confirmation model to improve Text-to-UMLS linking, without annotated data from domain experts. We evaluated the approach on three clinical datasets, MIMIC-III discharge summaries, MIMIC-III radiology reports, and NHS Tayside brain imaging reports from two institutions in the US and the UK, with annotations. RESULTS: The improvements in the precision were pronounced (by over 30% to 50% absolute score for Text-to-UMLS linking), with almost no loss of recall compared to the existing NER+L tool, SemEHR. Results on radiology reports from MIMIC-III and NHS Tayside were consistent with the discharge summaries. The overall pipeline processing clinical notes can extract rare disease cases, mostly uncaptured in structured data (manually assigned ICD codes). CONCLUSION: The study provides empirical evidence for the task by applying a weakly supervised NLP pipeline on clinical notes. The proposed weak supervised deep learning approach requires no human annotation except for validation and testing, by leveraging ontologies, NER+L tools, and contextual representations. The study also demonstrates that Natural Language Processing (NLP) can complement traditional ICD-based approaches to better estimate rare diseases in clinical notes. We discuss the usefulness and limitations of the weak supervision approach and propose directions for future studies.

Enhanced performance of hybrid supercapacitors by the synergistic effect of Co(OH)2 nanosheets and NiMn layered hydroxides.

A self-supporting composite electrode material with a unique three-dimensional structure was synthesized by in-situ growth of nanoscale NiMnLDH-Co(OH)2 on a nickel foam substrate via hydrothermal electrodeposition. The 3D layer of NiMnLDH-Co(OH)2 provided abundant reactive sites for electrochemical reactions, ensuring a solid and conductive skeleton for charge transfer and resulting in significant enhancement of electrochemical performance. The composite material showed a strong synergistic effect between the small nano-sheet Co(OH)2 and NiMnLDH, which promoted reaction kinetics, while the nickel foam substrate acted as a structural conductivity agent, stabilizer, and good conductive medium. The composite electrode showed impressive electrochemical performance, achieving a specific capacitance of 1870F g-1 at 1 A g-1 and retaining 87% capacitance after 3000 charge-discharge cycles, even at a high current density of 10 A g-1. Moreover, the resulting NiMnLDH-Co(OH)2//AC asymmetric supercapacitor (ASC) demonstrated remarkable specific energy of 58.2 Wh kg-1 at a specific power of 1200 W kg-1, along with outstanding cycle stability (89% capacitance retention after 5000 cycles at 10 A g-1). More importantly, DFT calculations reveal that NiMnLDH-Co(OH)2 facilitates charge transfer, accelerating surface redox reactions and increasing specific capacitance. This study presents a promising approach towards designing and developing advanced electrode materials for high-performance supercapacitors.

Fabrication of b-Oriented MFI Zeolite Membranes by a Printing-Transfer Seed Layer Procedure.

Highly b-oriented MFI zeolite (abbreviated as BOMZ) membranes are attractive due to less grain boundary defects and straight channels normal to the substrate, enhancing selectivity and flux in membrane separation. Herein, we demonstrate a novel, effective and easily-amplified printing-transfer oriented-seed-layer technique to manufacture uniform BOMZ seed monolayer on porous supports. Furthermore, a facile and effective approach for the synthesis of highly BOMZ membranes by introducing poly(hexamethylene biguanide) hydrochloride as a twin crystal inhibitor during seeded growth is demonstrated. Well-intergrown BOMZ membranes (∼650 nm thick) obtained on porous Al2 O3 supports show a flux of 2.8 kg m-2 h-1 with a separation factor as high as 71 for pervaporation in the 60 °C feed of EtOH/H2 O (5 wt%), which is much higher than those of random membranes. The developed seed assembly technique on porous supports underlines great potential for facile preparation of oriented seed layers on porous supports.

Effect of SAM junctional tourniquet on respiration when applied in the axilla: A swine model.

PURPOSE: SAM junctional tourniquet (SJT) has been applied to control junctional hemorrhage. However, there is limited information about its safety and efficacy when applied in the axilla. This study aims to investigate the effect of SJT on respiration when used in the axilla in a swine model. METHODS: Eighteen male Yorkshire swines, aged 6-month-old and weighing 55 - 72 kg, were randomized into 3 groups, with 6 in each. An axillary hemorrhage model was established by cutting a 2 mm transverse incision in the axillary artery. Hemorrhagic shock was induced by exsanguinating through the left carotid artery to achieve a controlled volume reduction of 30% of total blood volume. Vascular blocking bands were used to temporarily control axillary hemorrhage before SJT was applied. In Group I, the swine spontaneously breathed, while SJT was applied for 2 h with a pressure of 210 mmHg. In Group II, the swine were mechanically ventilated, and SJT was applied for the same duration and pressure as Group I. In Group III, the swine spontaneously breathed, but the axillary hemorrhage was controlled using vascular blocking bands without SJT compression. The amount of free blood loss was calculated in the axillary wound during the 2 h of hemostasis by SJT application or vascular blocking bands. After then, a temporary vascular shunt was performed in the 3 groups to achieve resuscitation. Pathophysiologic state of each swine was monitored for 1 h with an infusion of 400 mL of autologous whole blood and 500 mL of lactated ringer solution. Tb and T0 represent the time points before and immediate after the 30% volume-controlled hemorrhagic shock, respectively. T30, T60, T90 and T120, denote 30, 60, 90, and 120 min after T0 (hemostasis period), while T150, and T180 denote 150 and 180 min after T0 (resuscitation period). The mean arterial pressure and heart rate were monitored through the right carotid artery catheter. Blood samples were collected at each time point for the analysis of blood gas, complete cell count, serum chemistry, standard coagulation tests, etc., and thromboelastography was conducted subsequently. Movement of the left hemidiaphragm was measured by ultrasonography at Tb and T0 to assess respiration. Data were presented as mean ± standard deviation and analyzed using repeated measures of two-way analysis of variance with pairwise comparisons adjusted using the Bonferroni method. All statistical analyses were processed using GraphPad Prism software. RESULTS: Compared to Tb, a statistically significant increase in the left hemidiaphragm movement at T0 was observed in Groups I and II (both p < 0.001). In Group III, the left hemidiaphragm movement remained unchanged (p = 0.660). Compared to Group I, mechanical ventilation in Group II significantly alleviated the effect of SJT application on the left hemidiaphragm movement (p < 0.001). Blood pressure and heart rate rapidly increased at T0 in all three groups. Respiratory arrest suddenly occurred in Group I after T120, which required immediate manual respiratory assistance. PaO2 in Group I decreased significantly at T120, accompanied by an increase in PaCO2 (both p < 0.001 vs. Groups II and III). Other biochemical metabolic changes were similar among groups. However, in all 3 groups, lactate and potassium increased immediately after 1 min of resuscitation concurrent with a drop in pH. The swine in Group I exhibited the most severe hyperkalemia and metabolic acidosis. The coagulation function test did not show statistically significant differences among three groups at any time point. However, D-dimer levels showed a more than 16-fold increase from T120 to T180 in all groups. CONCLUSION: In the swine model, SJT is effective in controlling axillary hemorrhage during both spontaneous breathing and mechanical ventilation. Mechanical ventilation is found to alleviate the restrictive effect of SJT on thoracic movement without affecting hemostatic efficiency. Therefore, mechanical ventilation could be necessary before SJT removal.

Synthesis of Visible Light Excitable Carbon Dot Phosphor-Al2 O3 Hybrids for Anti-Counterfeiting and Information Encryption.

The preparation of room temperature phosphorescent carbon dots still faces great challenges, especially in the case of carbon dots endowed of visible-light excitable room temperature phosphorescence (RTP). To date, a limited number of substrates have been exploited to synthesize room temperature phosphorescent carbon dots, and most of them can emit RTP only in solid state. Here, the synthesis of a composite obtained from the calcination of green carbon dots (g-CDs) blended with aluminum hydroxide (Al(OH)3 ) is reported. The resultant hybrid material g-CDs@Al2 O3 exhibits blue fluorescence and green RTP emissions in an on/off switch process at 365 nm. Notably, this composite manifests strong resistance to extreme acid and basic conditions up to 30 days of treatment. The dense structure of Al2 O3 formed by calcination contributes to the phosphorescent emission of g-CDs. Surprisingly, g-CDs@Al2 O3 can also emit yellow RTP under irradiation with white light. The multicolor emissions can be employed for anti-counterfeiting and information encryption. This work provides a straightforward approach to produce room temperature phosphorescent carbon dots for a wide range of applications.

Single-cell RNA-Seq analysis of diabetic wound macrophages in STZ-induced mice.

The crucial role of macrophages in the healing of chronic diabetic wounds is widely known, but previous in vitro classification and marker genes of macrophages may not be fully applicable to cells in the microenvironment of chronic wounds. The heterogeneity of macrophages was studied and classified at the single-cell level in a chronic wound model. We performed single-cell sequencing of CD45 + immune cells within the wound edge and obtained 17 clusters of cells, including 4 clusters of macrophages. One of these clusters is a previously undescribed population of macrophages possessing osteoclast gene expression, for which analysis of differential genes revealed possible functions. We also analysed the differences in gene expression between groups of macrophages in the control and diabetic wound groups at different sampling times. We described the differentiation profile of mononuclear macrophages, which has provided an important reference for the study of immune-related mechanisms in diabetic chronic wounds.

Receptor activity-modifying protein 1 regulates mouse skin fibroblast proliferation via the Gαi3-PKA-CREB-YAP axis.

BACKGROUND: Skin innervation is crucial for normal wound healing. However, the relationship between nerve receptors and wound healing and the intrinsic mechanism remains to be further identified. In this study, we investigated the role of a calcitonin gene-related peptide (CGRP) receptor component, receptor activity-modifying protein 1 (RAMP1), in mouse skin fibroblast (MSF) proliferation. METHODS: In vivo, Western blotting and immunohistochemical (IHC) staining of mouse skin wounds tissue was used to detect changes in RAMP1 expression. In vitro, RAMP1 was overexpressed in MSF cell lines by infection with Tet-On-Flag-RAMP1 lentivirus and doxycycline (DOX) induction. An IncuCyte S3 Live-Cell Analysis System was used to assess and compare the proliferation rate differences between different treatment groups. Total protein and subcellular extraction Western blot analysis, quantitative real-time-polymerase chain reaction (qPCR) analysis, and immunofluorescence (IF) staining analysis were conducted to detect signalling molecule expression and/or distribution. The CUT & RUN assay and dual-luciferase reporter assay were applied to measure protein-DNA interactions. RESULTS: RAMP1 expression levels were altered during skin wound healing in mice. RAMP1 overexpression promoted MSF proliferation. Mechanistically, total Yes-associated protein (YAP) and nuclear YAP protein expression was increased in RAMP1-overexpressing MSFs. RAMP1 overexpression increased inhibitory guanine nucleotide-binding protein (G protein) α subunit 3 (Gαi3) expression and activated downstream protein kinase A (PKA), and both elevated the expression of cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB) and activated it, promoting the transcription of YAP, elevating the total YAP level and promoting MSF proliferation. CONCLUSIONS: Based on these data, we report, for the first time, that changes in the total RAMP1 levels during wound healing and RAMP1 overexpression alone can promote MSF proliferation via the Gαi3-PKA-CREB-YAP axis, a finding critical for understanding RAMP1 function, suggesting that this pathway is an attractive and accurate nerve target for skin wound treatment. Video Abstract.

Increased COVID-19 mortality rate in rare disease patients: a retrospective cohort study in participants of the Genomics England 100,000 Genomes project.

BACKGROUND: Several common conditions have been widely recognised as risk factors for COVID-19 related death, but risks borne by people with rare diseases are largely unknown. Therefore, we aim to estimate the difference of risk for people with rare diseases comparing to the unaffected. METHOD: To estimate the correlation between rare diseases and COVID-19 related death, we performed a retrospective cohort study in Genomics England 100k Genomes participants, who tested positive for Sars-Cov-2 during the first wave (16-03-2020 until 31-July-2020) of COVID-19 pandemic in the UK (n = 283). COVID-19 related mortality rates were calculated in two groups: rare disease patients (n = 158) and unaffected relatives (n = 125). Fisher's exact test and logistic regression was used for univariable and multivariable analysis, respectively. RESULTS: People with rare diseases had increased risk of COVID19-related deaths compared to the unaffected relatives (OR [95% CI] = 3.47 [1.21- 12.2]). Although, the effect was insignificant after adjusting for age and number of comorbidities (OR [95% CI] = 1.94 [0.65-5.80]). Neurology and neurodevelopmental diseases was significantly associated with COVID19-related death in both univariable (OR [95% CI] = 4.07 [1.61-10.38]) and multivariable analysis (OR [95% CI] = 4.22 [1.60-11.08]). CONCLUSIONS: Our results showed that rare disease patients, especially ones affected by neurology and neurodevelopmental disorders, in the Genomics England cohort had increased risk of COVID-19 related death during the first wave of the pandemic in UK. The high risk is likely associated with rare diseases themselves, while we cannot rule out possible mediators due to the small sample size. We would like to raise the awareness that rare disease patients may face increased risk for COVID-19 related death. Proper considerations for rare disease patients should be taken when relevant policies (e.g., returning to workplace) are made.

Quantitative proteomics approach reveals novel biomarkers and pathological mechanism of keloid.

BACKGROUND: Keloid is a pathological skin scar formation with complex and unclear molecular pathology mechanism. Novel biomarkers and associated mechanisms are needed to improve current therapies. OBJECTIVES: To identify novel biomarkers and underlying pathological mechanisms of keloids. METHODS: Six pairs of keloid scar tissues and corresponding normal skin tissues were quantitatively analyzed by a high-resolution label-free mass spectrometry-based proteomics approach. Differential protein expression data was further analyzed by a comprehensive bioinformatics approach to identify novel biomarkers and mechanistic pathways for keloid formation. Candidate biomarkers were validated experimentally. RESULTS: In total, 1359 proteins were identified by proteomic analysis. Of these, 206 proteins exhibited a significant difference in expression between keloid scar and normal skin tissues. RCN3 and CALU were significantly upregulated in keloids. RCN1 and PDGFRL were uniquely expressed in keloids. Pathway analysis suggested that the XBP1-mediated unfolded protein response (UPR) pathway was involved in keloid formation. Moreover, a PDGFRL centric gene coexpression network was constructed to illustrate its function in skin. CONCLUSIONS AND CLINICAL RELEVANCE: Our study proposed four novel biomarkers and highlighted the role of XBP1-mediated UPR pathway in the pathology of keloids. It provided novel biological insights that contribute to develop novel therapeutic strategies for keloids.

Towards Double Defense Network Security Based on Multi-Identifier Network Architecture.

Recently, more and more mobile devices have been connected to the Internet. The Internet environment is complicated, and network security incidents emerge endlessly. Traditional blocking and killing passive defense measures cannot fundamentally meet the network security requirements. Inspired by the heuristic establishment of multiple lines of defense in immunology, we designed and prototyped a Double Defense strategy with Endogenous Safety and Security (DDESS) based on multi-identifier network (MIN) architecture. DDESS adopts the idea of a zero-trust network, with identity authentication as the core for access control, which solves security problems of traditional IP networks. In addition, DDESS achieves individual static security defense through encryption and decryption, consortium blockchain, trusted computing whitelist, and remote attestation strategies. At the same time, with the dynamic collection of data traffic and access logs, as well as the understanding and prediction of the situation, DDESS can realize the situation awareness of network security and the cultivation of immune vaccines against unknown network attacks, thus achieving the active herd defense of network security.