Relevant Type Research Articles

Identification of susceptibility loci and relevant cell type for IgA nephropathy in Han Chinese by integrative genome-wide analysis.

Although many susceptibility loci for IgA nephropathy (IgAN) have been identified, they only account for 11.0% of the overall IgAN variance. We performed a large genome-wide meta-analysis of IgAN in Han Chinese with 3616 cases and 10 417 controls to identify additional genetic loci of IgAN. Considering that inflammatory bowel disease (IBD) and asthma might share an etiology of dysregulated mucosal immunity with IgAN, we performed cross-trait integrative analysis by leveraging functional annotations of relevant cell type and the pleiotropic information from IBD and asthma. Among 8 669 456 imputed variants, we identified a novel locus at 4p14 containing the long noncoding RNA LOC101060498. Cell type enrichment analysis based on annotations suggested that PMA-I-stimulated CD4+CD25-IL17+ Th17 cell was the most relevant cell type for IgAN, which highlights the essential role of Th17 pathway in the pathogenesis of IgAN. Furthermore, we identified six more novel loci associated with IgAN, which included three loci showing pleiotropic effects with IBD or asthma (2q35/PNKD, 6q25.2/SCAF8, and 22q11.21/UBE2L3) and three loci specific to IgAN (14q32.32/TRAF3, 16q22.2/TXNL4B, and 21q21.3/LINC00113) in the pleiotropic analysis. Our findings support the involvement of mucosal immunity, especially T cell immune response and IL-17 signal pathway, in the development of IgAN and shed light on further investigation of IgAN.

Comparison of the quality of life in peritoneal dialysis and hemodialysis patients

Chronic kidney disease (CKD) has a profound impact on patients' health-related quality of life (QoL). Particular problems are caused by the end-stage disease, which leads to the need for renal replacement therapy (RRT). Physicians and patients face the challenge of choosing a type of RRT. In this case, it is necessary to take into account not only survival rates but also the quality of life of patients who undergo the therapy, because the ability to function and maintain well-being is one of the treatment goals recommended by the World Health Organization. Therefore, assessing QoL and identifying factors influencing it becomes increasingly important in terms of therapy effectiveness and measures aimed at improving outcomes. The purpose of this work was to review recent scientific studies assessing the quality of life among peritoneal dialysis (PD) and hemodialysis (HD) patients, as well as identifying the better RRT type and risk factors that affect the quality of life. In order to identify the most relevant RRT type, the general questionnaires SF-36 and EQ-5D were used. A search for scientific studies was carried out in the international PubMed/MEDLINE database in April 2024 using the keywords: chronic kidney disease, quality of life, SF-36, EQ-5D, hemodialysis, and peritoneal dialysis. We selected papers published from 2018 to 2024 where the quality of life of patients with CKD receiving such RRT types as hemodialysis and peritoneal dialysis was studied. The results showed that PD is more preferable than HD. To achieve a high quality of life, it is also necessary to carefully treat disorders of calcium and phosphate metabolism and anemia, adequately manage concomitant diseases, assist patients with medical care provided at home, organize educational programs to increase patients’ self-efficacy and self-management, and provide psychological assistance if necessary.

When is a brain organoid a sentience candidate?

It would be unwise to dismiss the possibility of human brain organoids developing sentience. However, scepticism about this idea is appropriate when considering current organoids. It is a point of consensus that a brain-dead human is not sentient, and current organoids lack a functioning brainstem. There are nonetheless troubling early warning signs, suggesting organoid research may create forms of sentience in the near future. To err on the side of caution, researchers with very different views about the neural basis of sentience should unite behind the “brainstem rule”: if a neural organoid develops or innervates a functioning brainstem that regulates arousal, and leads to sleep-wake cycles, then it is a sentience candidate. If organoid research leads to the creation of sentience candidates, a moratorium or indefinite ban on the creation of the relevant type of organoid may be appropriate. A different way forward, more consistent with existing approaches to animal research, would be to require ethical review and harm-benefit analysis for all research on sentience candidates.

A Potential Link between Myeloperoxidase Modified LDL, Atherosclerosis and Depression.

Atherosclerosis is a chronic inflammatory disease that involves modified low-density lipoproteins (LDL) which play a pivotal role in the initiation and progression of the disease. Myeloperoxidase oxidized LDL (Mox-LDL) is considered to be the most patho-physiologically relevant type of modified LDL and has been reported to be ubiquitously present in atheroma plaques of patients with atherosclerosis. Besides its involvement in the latter disease state, Mox-LDL has also been shown to be implicated in the pathogenesis of various illnesses including sleep disorders, which are in turn associated with heart disease and depression in many intricate ways. Meanwhile, we have recently shown that lox-1-mediated Mox-LDL signaling modulates neuroserpin activity in endothelial cells, which could have major implications that go beyond the pathophysiology of stroke and cerebrovascular disease (CD). Of note is that tissue plasminogen activator (tPA), which is the main target of neuroserpin in the brain, has a crucial function in the processing of brain-derived neurotrophic factor (BDNF) into its mature form. This factor is known to be involved in major depressive disorder (MDD) development and pathogenesis. Since tPA is more conventionally recognized as being involved in fibrinolytic mechanisms, and its effect on the BDNF system in the context of MDD is still not extensively studied, we speculate that any Mox-LDL-driven change in the activity of tPA in patients with atherosclerosis may lead to a decrease in the production of mature BDNF, resulting in impaired neural plasticity and depression. Deciphering the mechanisms of interaction between those factors could help in better understanding the potentially overlapping pathological mechanisms that regulate disease processes in CD and MDD, supporting the possibility of novel and common therapeutic opportunities for millions of patients worldwide.

Exome-wide association study identifies KDELR3 mutations in extreme myopia

Extreme myopia (EM), defined as a spherical equivalent (SE) ≤ −10.00 diopters (D), is one of the leading causes of sight impairment. Known EM-associated variants only explain limited risk and are inadequate for clinical decision-making. To discover risk genes, we performed a whole-exome sequencing (WES) on 449 EM individuals and 9606 controls. We find a significant excess of rare protein-truncating variants (PTVs) in EM cases, enriched in the retrograde vesicle-mediated transport pathway. Employing single-cell RNA-sequencing (scRNA-seq) and a single-cell polygenic burden score (scPBS), we pinpointed PI16 + /SFRP4+ fibroblasts as the most relevant cell type. We observed that KDELR3 is highly expressed in scleral fibroblast and involved in scleral extracellular matrix (ECM) organization. The zebrafish model revealed that kdelr3 downregulation leads to elongated ocular axial length and increased lens diameter. Together, our study provides insight into the genetics of EM in humans and highlights KDELR3’s role in EM pathogenesis.

Variation in levels of professionalism in healthcare policymaking during the Obama, Trump, and Biden administrations.

During the Trump administration it was widely asserted in the news media that the administration's agency appointees were less professional than appointees from previous administrations. Using qualitative data from 35 interviews with lobbyists, congressional staffers, and executive branch officials, and quantitative and qualitative data on years of relevant experience and job type at the date of nomination, it is demonstrated that indeed the Trump administration attracted less talent than the Obama and Biden administrations, which resulted in less supply and demand for expertise and thus a diminished role of expertise in the policymaking process.

Antigen-driven Convergent Evolution of Polysaccharide-specific "DH-less" B Cells in Glycoconjugate Immunized Mice.

Glycoconjugate vaccines elicit robust anti-polysaccharide Ab response by recruiting T-cell help. Multiple doses of glycoconjugate vaccine are required to induce long-lasting immunity. The characteristics of anti-polysaccharide Ab response have been reported previously. However, the effect of glycoconjugate booster immunization on anti-polysaccharide and anti-carrier protein Ab repertoire remains poorly understood. In this study, we used clinically relevant pneumococcal capsular polysaccharide type 14 (PCP14) conjugated with cross-reactive material 197 (CRM197) as a model glycoconjugate Ag (PCP14-CRM197). We performed a comprehensive sequence analysis of mouse mAbs generated against PCP14 and CRM197 following immunization with one or three doses of PCP14-CRM197. Analysis of the paired Ig H and L chain transcripts revealed that anti-PCP14 Ab repertoire is extremely restricted. The reoccurrence of five replacement mutations at identical positions in anti-polysaccharide mAbs generated from different mice provided evidence for Ag-driven selection in PCP14-specific B cells. Convergent evolution was observed wherein distinct V(D)J rearrangements resulted in identical or nearly identical CDR3 in anti-PCP14 mAbs. Abs that lacked DH encoded amino acids dominated the anti-PCP14 Ab response. In contrast, anti-CRM197 Ab response was quite diverse, with fewer mutations compared with the anti-PCP14 mAbs, suggesting that conjugation of the polysaccharide to a carrier protein interferes with the development of carrier protein-specific Ab responses. Our findings provide molecular insights into the maturation of Ab responses driven by booster doses of glycoconjugate. This has fundamental implications for the design of glycoconjugate vaccines, especially where the development of Ab response against the carrier protein is also crucial.

Code-Aware Prompting: A Study of Coverage-Guided Test Generation in Regression Setting using LLM

Testing plays a pivotal role in ensuring software quality, yet conventional Search Based Software Testing (SBST) methods often struggle with complex software units, achieving suboptimal test coverage. Recent work using large language models (LLMs) for test generation have focused on improving generation quality through optimizing the test generation context and correcting errors in model outputs, but use fixed prompting strategies that prompt the model to generate tests without additional guidance. As a result LLM-generated testsuites still suffer from low coverage. In this paper, we present SymPrompt, a code-aware prompting strategy for LLMs in test generation. SymPrompt’s approach is based on recent work that demonstrates LLMs can solve more complex logical problems when prompted to reason about the problem in a multi-step fashion. We apply this methodology to test generation by deconstructing the testsuite generation process into a multi-stage sequence, each of which is driven by a specific prompt aligned with the execution paths of the method under test, and exposing relevant type and dependency focal context to the model. Our approach enables pretrained LLMs to generate more complete test cases without any additional training. We implement SymPrompt using the TreeSitter parsing framework and evaluate on a benchmark challenging methods from open source Python projects. SymPrompt enhances correct test generations by a factor of 5 and bolsters relative coverage by 26% for CodeGen2. Notably, when applied to GPT-4, SymPrompt improves coverage by over 2x compared to baseline prompting strategies.

O-260 Identifying seminiferous tubules for sperm retrieval during microdissection testicular sperm extraction (M-TESE) using deep learning

Abstract Study question Is it possible to utilize artificial intelligence (AI) in the selection of seminiferous tubules for sperm retrieval during microdissection testicular sperm extraction (M-TESE)? Summary answer AI algorithm was able to segment seminiferous tubules deemed to be good candidates for sperm retrieval with IoU of 0.746 and F1 score of 72.5%. What is known already M-TESE is an advanced surgical procedure reserved for sperm retrieval in men with non-obstructive azoospermia (NOA). Meta-analysis have shown M-TESE might be superior in relation to sperm retrieval rates and postsurgical complications when compared to conventional techniques. Limitations of the technique are the relatively long learning curve for the surgeons and the longer intraoperative time required to identify the tubules with active spermatogenesis. Convolutional neural networks (CNNs) have been shown to successfully identify areas of interest in medical images such as CT and MRI scans. The possibility of utilizing trained CNNs in M-TESE procedures has so far not been studied. Study design, size, duration This is a cross sectional study analyzing image data gathered during M-TESE procedures including the first five men enrolled in a prospective study designed specifically to test the utilization of AI in the treatment of NOA. All participants signed written informed consent. Images were collected intraoperatively with low and high resolution cameras according to predefined protocol. Participants/materials, setting, methods CNN model with down and upsampling architecture was trained using patch-based technique with corresponding labelled truth image pairs based on combination of semi-automated hue saturation value thresholding and manual segmentation of seminiferous tubules. Tubules were allocated into two different classes by the operating surgeon according to the visual perception of their morphology as type 1 (i.e. larger, opaque, good candidates for micro dissection) and type 2 (i.e. sclerotic or atrophic; unlikely to harbor active spermatogenesis). Main results and the role of chance CNN models were trained on 1809 patches with corresponding ground truth segmented images. Two algorithms were tested: the first was trained solely to detect and semantically distinguish type 1 seminiferous tubules. The second was trained to semantically segment the major anatomical structures: tunica albuginea, testicular parenchyma, blood vessels; lobules and the two types of seminiferous tubules describe above. Validation was performed on 988 image patches not previously shown to the algorithm. After grid search for optimal learning rate and augmentation the first algorithm was able to segment type 1 tubules with F1 score of 72.5% and Jaccard Index (IoU) of 0.746. Training took 856 minutes on 48 core high performance computer (HPC) equipped with single graphics processing unit (GPU). Same computational environment was used in the training of the second algorithm. This model was able to segment anatomical structures such as parenchyma (IoU=0.732) and testicular lobules (IoU=0.683) but performed sub optimally on the clinically relevant type 1 tubules (IoU=0.432). The first trained algorithm was able to segment a single high resolution surgical image in 3.4 seconds on an HPC. However, the same procedure took 5.5 minutes on standard desktop computer with 8 core Intel processor without GPU. Limitations, reasons for caution The number of patients is relatively small and therefore more training data would be needed to achieve robust performance. Training data were labelled by single surgeon limiting the generalizability and possibly biasing the selection process. The need of HPC environment for real time segmentation can limit the clinical use. Wider implications of the findings This pilot study shows the potential of AI to help in choosing suitable tubules for micro dissection, shortening the learning curve for young andrological surgeons. The access to cluster based computation is getting easier by the day and can soon allow instant intraoperative AI segmentation, thus shortening the surgical procedure. Trial registration number NA

YOUTH TOURISM AS AN INNOVATIVE METHOD OF ATTRACTING TOURISTS

In an era, full of challenges for the tourism industry, tourism for young people is a very important market segment, being a resource for change and innovation. Young travelers increased level in decades since they first began to travel and the populations of countries that are developing. These trips are often made of raw relatively wealthy youth. Nowadays the sphere of youth tourism seems to be a very promising and relevant type of tourism, which includes a variety of directions and forms that contribute to the implementation of tourist services.

New evidence on the identity of the European Helorus species (Hymenoptera, Proctotrupoidea, Heloridae).

Species of Helorus Latreille 1802 are rarely collected endoparasitoids of Chrysopidae larvae (Neuroptera). Previous work on the limits between the European species of this species-poor genus, based on morphology only, has left some uncertainties. Here, we approach these cases and revisit previous taxonomic decisions using freshly collected and museum material. We generated the first large-scale Heloridae DNA barcode dataset, combined these with morphological data in an integrative taxonomic approach, and added information from studying all relevant type material. We found five species, Helorusanomalipes (Panzer, 1798), H.coruscus Haliday, 1857 stat. rev., H.nigripes Förster, 1856, H.ruficornis Förster, 1856, and H.striolatus Cameron, 1906, for which we provide an updated identification key. DNA barcode data are added to publicly available DNA barcode reference databases, for all species, except H.nigripes.

Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.

Cutaneous adverse drug reactions in children with a focus on hypersensitivity to systemic drugs: A narrative review

Drug hypersensitivity in children is rare compared to adults. Children more frequently develop an infection-associated exanthema. Nevertheless, about 95% of children with drug hypersensitivity present with mucocutaneous involvement. Early recognition of typical clinical symptoms is important to reduce morbidity and mortality. We review relevant type I and type IV disorders of drug hypersensitivity in children and discuss their differential diagnoses and treatment.

Application of statistics in biomedical research

Abstract Statistical tools for data analysis vary depending on the kind of data and measurement scales used. The objective of this review is to offer a deep insight into these various data types and measuring systems. This overview offers comprehensive details on the various data kinds and measurement scales along with examples. Applying the proper statistical techniques and drawing reliable conclusions require knowledge of the relevant data type or analysis procedure.

Optimizing lentiviral vector formulation conditions for efficient ex vivo transduction of primary human T cells in chimeric antigen receptor T-cell manufacturing

Background aimsChimeric antigen receptor (CAR) T-cell products are commonly generated using lentiviral vector (LV) transduction. Optimal final formulation buffer (FFB) supporting LV stability during cryostorage is crucial for cost-effective manufacturing. MethodsTo identify the ideal LV FFB composition for ex vivo CAR-T production, primary human T cells were transduced with vesicular stomatitis virus G-protein (VSV-G) -pseudotyped LVs (encoding a reporter gene or an anti-CD19-CAR). The formulations included phosphate-buffered saline (PBS), HEPES, or X-VIVOTM 15, and stabilizing excipients. The functional and viral particle titers and vector copy number were measured after LV cryopreservation and up to 24 h post-thaw incubation. CAR-Ts were produced with LVs in selected FFBs, and the resulting cells were characterized. ResultsPost-cryopreservation, HEPES-based FFBs provided higher LV functional titers than PBS and X-VIVOTM 15, and 10% trehalose-20 mM MgCl2 improved LV transduction efficiency in PBS and 50 mM HEPES. Thawed vectors remained stable at +4°C, while a ≤ 25% median decrease in the functional titer occurred during 24 h at room temperature. Tested excipients did not enhance LV post-thaw stability. CAR-Ts produced using LVs cryopreserved in 10% trehalose- or sucrose-20 mM MgCl2 in 50 mM HEPES showed comparable transduction rates, cell yield, viability, phenotype, and in vitro functionality. ConclusionA buffer consisting of 10% trehalose-20 mM MgCl2 in 50 mM HEPES provided a feasible FFB to cryopreserve a VSV-G -pseudotyped LV for CAR-T-cell production. The LVs remained relatively stable for at least 24 h post-thaw, even at ambient temperatures. This study provides insights into process development, showing LV formulation data generated using the relevant target cell type for CAR-T-cell manufacturing.

THE EVOLUTION OF THE SYSTEM OF SECONDARY VOCATIONAL EDUCATION IN CHUVASHIA (1920s – 1950s)

In the realities of modern times, a big problem for Russia is the shortage of young professional personnel. Important suppliers of workers are secondary vocational educational institutions. In order to understand how the process of “growing” in-demand specialists occurs, researchers are faced with a number of pressing questions. First of all, it is necessary to find out which educational institutions train personnel in what areas and professions? Therefore, the purpose of this study is to study the development of the secondary vocational education system in the 1920s – 1950s using the example of one of the constituent entities of the Russian Federation – the Chuvash Republic. Materials and methods. The scientific and theoretical basis of the article is headed by the scientific principles of historicism, objectivity, social approach, alternativeness, which fundamentally reflect the study of various processes taking into account the dynamic development and interaction of elements. Research results. An independent stage in the development of the education system and secondary vocational education was associated with the proclamation of Soviet power in the country and the creation of the Chuvash Autonomous Region in 1920. In Chuvashia, there was a need to create independent educational institutions. Technical schools became the most relevant type of educational institutions. In the 1930s. There is an increase in the number of secondary specialized educational institutions, which contributed to the growth in the number of specialized personnel. The training of new specialists was carried out at enterprises in Chuvashia, as well as at special courses. The impetus for increasing the rate of training of workers from among the Chuvash population was the opening of factory apprenticeship schools and workers’ faculties. In the 1940s Schools for working youth were created, and evening schools for rural youth began to function. Conclusions. In modern conditions, secondary vocational education is a sought-after level of education, within which personnel are trained in applied professions, which Chuvashia clearly needs. It is no coincidence that over the more than 100-year period of its development, the republic has created a whole complex of secondary specialized institutions, most of which continue to produce specialists. The first such institutions began to form in the 1920s and 1930s. This period included many difficulties in the education system, which was largely due to the lack of professional teachers and difficulties in the logistics of the social sphere. The period of the end of the Second World War created a new impetus for the opening of vocational education organizations, which was associated with the restoration of the state’s economy. By the early 1950s. There were 22 such educational institutions in the republic, which became an important link in the education system of Chuvashia.

Cornea-Specific Human Adipose Stem Cell-Derived Extracellular Matrix for Corneal Stroma Tissue Engineering.

Utilizing tissue-specific extracellular matrices (ECMs) is vital for replicating the composition of native tissues and developing biologically relevant biomaterials. Human- or animal-derived donor tissues and organs are the current gold standard for the source of these ECMs. To overcome the several limitations related to these ECM sources, including the highly limited availability of donor tissues, cell-derived ECM offers an alternative approach for engineering tissue-specific biomaterials, such as bioinks for three-dimensional (3D) bioprinting. 3D bioprinting is a state-of-the-art biofabrication technology that addresses the global need for donor tissues and organs. In fact, there is a vast global demand for human donor corneas that are used for treating corneal blindness, often resulting from damage in the corneal stromal microstructure. Human adipose tissue is one of the most abundant tissues and easy to access, and adipose tissue-derived stem cells (hASCs) are a highly advantageous cell type for tissue engineering. Furthermore, hASCs have already been studied in clinical trials for treating corneal stromal pathologies. In this study, a corneal stroma-specific ECM was engineered without the need for donor corneas by differentiating hASCs toward corneal stromal keratocytes (hASC-CSKs). Furthermore, this ECM was utilized as a component for corneal stroma-specific bioink where hASC-CSKs were printed to produce corneal stroma structures. This cost-effective approach combined with a clinically relevant cell type provides valuable information on developing more sustainable tissue-specific solutions and advances the field of corneal tissue engineering.

Distinct early role of PTEN regulation during HCMV infection of monocytes

Human cytomegalovirus (HCMV) infection of monocytes is essential for viral dissemination and persistence. We previously identified that HCMV entry/internalization and subsequent productive infection of this clinically relevant cell type is distinct when compared to other infected cells. We showed that internalization and productive infection required activation of epidermal growth factor receptor (EGFR) and integrin/c-Src, via binding of viral glycoprotein B to EGFR, and the pentamer complex to β1/β3 integrins. To understand how virus attachment drives entry, we compared infection of monocytes with viruses containing the pentamer vs. those without the pentamer and then used a phosphoproteomic screen to identify potential phosphorylated proteins that influence HCMV entry and trafficking. The screen revealed that the most prominent pentamer-biased phosphorylated protein was the lipid- and protein-phosphatase phosphatase and tensin homolog (PTEN). PTEN knockdown with siRNA or PTEN inhibition with a PTEN inhibitor decreased pentamer-mediated HCMV entry, without affecting trimer-mediated entry. Inhibition of PTEN activity affected lipid metabolism and interfered with the onset of the endocytic processes required for HCMV entry. PTEN inactivation was sufficient to rescue pentamer-null HCMV from lysosomal degradation. We next examined dephosphorylation of a PTEN substrate Rab7, a regulator of endosomal maturation. Inhibition of PTEN activity prevented dephosphorylation of Rab7. Phosphorylated Rab7, in turn, blocked early endosome to late endosome maturation and promoted nuclear localization of the virus and productive infection.

Downregulation of endogenous nectin1 in human keratinocytes by herpes simplex virus 1 glycoprotein D excludes superinfection but does not affect NK cell function.

Many viruses downregulate their cognate receptors, facilitating virus replication and pathogenesis via processes that are not yet fully understood. In the case of herpes simplex virus 1 (HSV1), the receptor binding protein glycoprotein D (gD) has been implicated in downregulation of its receptor nectin1, but current understanding of the process is limited. Some studies suggest that gD on the incoming virion is sufficient to achieve nectin1 downregulation, but the virus-encoded E3 ubiquitin ligase ICP0 has also been implicated. Here we have used the physiologically relevant nTERT human keratinocyte cell type - which we have previously shown to express readily detectable levels of endogenous nectin1 - to conduct a detailed investigation of nectin1 expression during HSV1 infection. In these cells, nectin1, but not nectin2 or the transferrin receptor, disappeared from the cell surface in a process that required virus protein synthesis rather than incoming virus, but did not involve virus-induced host shutoff. Furthermore, gD was not only required but was sufficient for nectin1 depletion, indicating that no other virus proteins are essential. NK cells were shown to be activated in the presence of keratinocytes, a process that was greatly inhibited in cells infected with wild-type virus. However, degranulation of NK cells was also inhibited in ΔgD-infected cells, indicating that blocking of NK cell activation was independent of gD downregulation of nectin1. By contrast, a superinfection time-course revealed that the ability of HSV1 infection to block subsequent infection of a GFP-expressing HSV1 was dependent on gD and occurred in line with the timing of nectin1 downregulation. Thus, the role of gD-dependent nectin1 impairment during HSV infection is important for virus infection, but not immune evasion, which is achieved by other mechanisms.

Translational application of human keratinocyte-fibroblast cell sheets for accelerated wound healing in a clinically relevant type 2 diabetic rat model

Despite advancements in wound care, wound healing remains a challenge, especially in individuals with type 2 diabetes. Cell sheet technology has emerged as an efficient and promising therapy for tissue regeneration and wound repair. Among these, bilayered human keratinocyte-fibroblast cell sheets constructed using temperature-responsive culture surfaces have been shown to mimic a normal tissue-like structure and secrete essential cytokines and growth factors that regulate the wound healing process. Therefore, this study aimed to evaluate the safety and therapeutic potential of human skin cell sheets to treat full-thickness skin defects in a rat model of type 2 diabetes. Our findings demonstrate that diabetic wounds transplanted with bilayered cell sheets resulted in accelerated re-epithelialization, increased angiogenesis, enhanced macrophage polarization and regeneration of tissue that closely resembled healthy skin. In contrast, the control group that did not receive cell sheet transplantation presented characteristic symptoms of impaired and delayed wound healing associated with type 2 diabetes. The secretory cytokines and the upregulation of Nrf2 expression in response to cell sheet transplantation are believed to have played a key role in the improved wound healing observed in diabetic rats. Our study suggests that human keratinocyte-fibroblast cell sheets hold great potential as a therapeutic alternative for diabetic ulcers.