Strategies to Optimize Global Cleft Care

Orofacial clefts represent the most common congenital craniofacial anomaly worldwide. This condition is best managed by an interdisciplinary team of specialists, often with gratifying results for both the patient and the care providers. Despite recent advances in the management, it remains a challenge today to provide cleft care in low- and middle-income countries (LMIC) due to the lack of basic health care infrastructure and long-term follow-up. International cleft mission trips have traditionally been successful in providing reconstructive plastic surgery to communities with limited resources. More recently, there has been a global effort in the cleft care community to facilitate development of sustainable local cleft care centers that are capable of providing longitudinal, comprehensive care to the indigenous population. This chapter focuses on the elements that are necessary for running a successful international cleft mission and a local cleft care facility, which include the essential personnel, operational protocols, equipment, logistics, patient selection, and follow-up. The challenges and future directions of providing cleft care in LMIC are also discussed

BRCA1-regulated nuclear innate sensing of Herpesviral genome by IFI16 and IFI16’s acetylation is critical for its cytoplasmic trafficking and induction of innate responses: DOI: 10.14800/ics.1076

Sensing of invading DNA virus genomes appear to be triggered by a number of host cell DNA sensors depending on their subcellular localization which stimulate innate anti-viral responses such as the activation of type-I interferons (IFNs) and/or inflammasomes resulting in the  production of inflammatory IL-1? and IL-18 cytokines. With growing understanding of diverse identities whether these proteins function alone or  with other host cell molecules and the post-translational modifications affecting their functions are under intense investigations. Nuclear resident IFI16 have been shown to sense the episomal DNA genomes of herpes viruses resulting in the induction of IFI16-inflammasome and/or interferon responses. Here, we highlight our recent finding regarding the role of cellular  BRCA1, a transcription factor and DNA damage response protein, forming a distinct complex with IFI16 to regulate the nuclear innate sensing of herpes viral DNA and subsequent IFI16-ASC-procaspase-1 inflammasome complex formation and distribution to the cytoplasm leading into caspase-1 and IL-1? production. BRCA1 is also responsible for the cytoplasmic IFI16-STING signalosome activation and induction of IFN-? during de novo KSHV and HSV-1 infection. Our concurrent studies have also revealed that the histone acetyl transferase p300 mediated acetylation of nuclear IFI16 is a dynamic post-genome recognition event responsible for Ran dependent nuclear to cytoplasmic trafficking of IFI16 during herpesvirus infection. This post-translational modification is essential for IFI16-ASC interaction and inflammasome activation as well as for the association with STING in the cytoplasm resulting in IRF-3 phosphorylation, nuclear pIRF-3 localization and interferon-? production. Collectively, these comprehensive studies highlight that BRCA1 plays a hitherto unidentified immunomodulatory role to facilitate the anti-viral functions of IFI16 and acetylation of nuclear IFI16 is a necessary post-translational modification for innate responses during herpesvirus infection. These studies open up a new understanding of virus-host interplay, viral genome sensing and host innate anti-viral defense mechanisms

BRCA1-regulated nuclear innate sensing of Herpesviral genome by IFI16 and IFI16’s acetylation is critical for its cytoplasmic trafficking and induction of innate responses

Sensing of invading DNA virus genomes appear to be triggered by a number of host cell DNA sensors depending on their subcellular localization which stimulate innate anti-viral responses such as the activation of type-I interferons (IFNs) and/or inflammasomes resulting in the  production of inflammatory IL-1β and IL-18 cytokines. With growing understanding of diverse identities whether these proteins function alone or  with other host cell molecules and the post-translational modifications affecting their functions are under intense investigations. Nuclear resident IFI16 have been shown to sense the episomal DNA genomes of herpes viruses resulting in the induction of IFI16-inflammasome and/or interferon responses. Here, we highlight our recent finding regarding the role of cellular  BRCA1, a transcription factor and DNA damage response protein, forming a distinct complex with IFI16 to regulate the nuclear innate sensing of herpes viral DNA and subsequent IFI16-ASC-procaspase-1 inflammasome complex formation and distribution to the cytoplasm leading into caspase-1 and IL-1β production. BRCA1 is also responsible for the cytoplasmic IFI16-STING signalosome activation and induction of IFN-β during de novo KSHV and HSV-1 infection. Our concurrent studies have also revealed that the histone acetyl transferase p300 mediated acetylation of nuclear IFI16 is a dynamic post-genome recognition event responsible for Ran dependent nuclear to cytoplasmic trafficking of IFI16 during herpesvirus infection. This post-translational modification is essential for IFI16-ASC interaction and inflammasome activation as well as for the association with STING in the cytoplasm resulting in IRF-3 phosphorylation, nuclear pIRF-3 localization and interferon-β production. Collectively, these comprehensive studies highlight that BRCA1 plays a hitherto unidentified immunomodulatory role to facilitate the anti-viral functions of IFI16 and acetylation of nuclear IFI16 is a necessary post-translational modification for innate responses during herpesvirus infection. These studies open up a new understanding of virus-host interplay, viral genome sensing and host innate anti-viral defense mechanisms

Epidemiology of Cleft Lip and Palate

Orofacial cleft (OFC) anomalies are amongst the most common congenital anomalies and the most common craniofacial anomalies. Despite their poorly characterized etiologies, cases of OFC are usually grouped by epidemiological studies as cleft lip, with or without cleft palate (CL/P), and cleft palate alone (CPO). Incidence of CL/P and CPO differs according to gender and ancestry and may vary widely across studies. Cases of OFC are characterized as either “syndromic” or “nonsyndromic,” with further classification of nonsyndromic cases into isolated cases and cases that present with additional malformations. The genetic bases for many syndromic cases of OFC have been previously elucidated. Genetic associations have been described for nonsyndromic OFC as well. Importantly, etiology of OFC is known to involve interaction between genetic and environmental factors, including maternal nutrition and exposure to teratogenic agents. Furthermore, evidence points toward epigenetic as well as genetic factors influencing OFC etiology. Recent studies have begun to explore the association between CL/P and cancer. These studies report higher incidence of cancer among patients with CL/P and their family members as well as identification of common genetic markers mediating this increased risk, although much remains unknown about this link

Poly (ADP-Ribose) Polymerase Mediates Diabetes-Induced Retinal Neuropathy

Retinal neuropathy is an early event in the development of diabetic retinopathy. One of the potential enzymes that are activated by oxidative stress in the diabetic retina is poly (ADP-ribose) polymerase (PARP). We investigated the effect of the PARP inhibitor 1,5-isoquinolinediol on the expression of the neurodegeneration mediators and markers in the retinas of diabetic rats. After two weeks of streptozotocin-induced diabetes, rats were treated with 1,5-isoquinolinediol (3 mg/kg/day). After 4 weeks of diabetes, the retinas were harvested and the levels of reactive oxygen species (ROS) were determined fluorometrically and the expressions of PARP, phosporylated-ERK(1/2), BDNF, synaptophysin, glutamine synthetase (GS), and caspase-3 were determined by Western blot analysis. Retinal levels of ROS, PARP-1/2, phosphorylated ERK(1/2), and cleaved caspase-3 were significantly increased, whereas the expressions of BDNF synaptophysin and GS were significantly decreased in the retinas of diabetic rats, compared to nondiabetic rats. Administration of 1,5-isoquinolinediol did not affect the metabolic status of the diabetic rats, but it significantly attenuated diabetes-induced upregulation of PARP, ROS, ERK(1/2) phosphorylation, and cleaved caspase-3 and downregulation of BDNF, synaptophysin, and GS. These findings suggest a beneficial effect of the PARP inhibitor in increasing neurotrophic support and ameliorating early retinal neuropathy induced by diabetes

Unveiling common markers in COVID-19: ADAMTS2, PCSK9, and OLAH emerged as key differential gene expression profiles in PBMCs across diverse disease conditions

Diverse COVID-19 severity levels and a spectrum of clinical manifestations underscore the need to comprehend the underlying genetic mechanisms. Such knowledge is essential for improving disease management and therapeutic approaches. This study aims to explore and uncover pivotal genes and pathways linked to distinct COVID-19 conditions, providing insights into potential therapeutic avenues. Gene expression data from COVID-19 patients across different conditions were analyzed using differential gene expression analysis. Significant genes were subjected to pathway analysis and protein–protein interaction network analysis. Gene ontology was used to identify the functions of these genes. The genes ADAMTS2, PCSK9, and OLAH were upregulated across all disease conditions including SARS-CoV-2 bacterial coinfection, potentially serving as therapeutic targets. The proteins, including RPL and CEACAM, could serve as a potential therapeutic target. The deregulated genes were majorly involved in inflammation, lipid metabolism, and immune regulation. The study's findings reveal significant gene expression differences among COVID-19 disease conditions. These insights guide future research toward targeted therapies and an improved understanding of disease progression and long-term consequences

Core/clad phosphate glass fibres containing iron and/or titanium

Phosphate glasses are novel amorphous biomaterials due to their fully resorbable characteristics, with controllable degradation profiles. In this study, phosphate glasses containing titanium and/or iron were identified to exhibit sufficiently matched thermal properties (glass transition temperature, thermal expansion coefficient and viscosity) which enabled successful co-extrusion of glass billets to form a core/clad preform. The cladding composition for the core/clad preforms were also reversed. Fe clad and Ti clad fibres were successfully drawn with an average diameter of between 30~50 μm. The average cladding annular thickness was estimated to be less than 2 μm. Annealed core/clad fibres were degraded in PBS for a period of 27 days. The strength of the Fe clad fibres appeared to increase from 303 ± 73 MPa to 386 ± 45 MPa after nearly 2 weeks in the dissolution medium (phosphate buffered solution) before decreasing by day 27. The strength of the Ti clad fibres revealed an increase from 236 ± 53 MPa to 295 ± 61 MPa when compared at week 3. The tensile modulus measured for both core/clad fibres ranged between 51 GPa to 60 GPa. During the dissolution study, Fe clad fibres showed a peeling mechanism compared to the Ti clad fibres

Osteoprotegerin is a new regulator of inflammation and angiogenesis in proliferative diabetic retinopathy

Osteoprotegerin (OPG) is a novel regulator of endothelial cell function, angiogenesis, and vasculogenesis. We correlated expression levels of OPG with those of the angiogenic and inflammatory factors vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1/CCL2) in proliferative diabetic retinopathy (PDR). We also examined expression of OPG in retinas from diabetic rats and diabetic patients and measured production of OPG by human retinal microvascular endothelial cells (HRMEC) and investigated its angiogenic activity.status: publishe