Variants of NAV3, a neuronal morphogenesis protein, cause intellectual disability, developmental delay, and microcephaly.

Microtubule associated proteins (MAPs) are widely expressed in the central nervous system, and have established roles in cell proliferation, myelination, neurite formation, axon specification, outgrowth, dendrite, and synapse formation. We report eleven individuals from seven families harboring predicted pathogenic biallelic, de novo, and heterozygous variants in the NAV3 gene, which encodes the microtubule positive tip protein neuron navigator 3 (NAV3). All affected individuals have intellectual disability (ID), microcephaly, skeletal deformities, ocular anomalies, and behavioral issues. In mouse brain, Nav3 is expressed throughout the nervous system, with more prominent signatures in postmitotic, excitatory, inhibiting, and sensory neurons. When overexpressed in HEK293T and COS7 cells, pathogenic variants impaired NAV3 ability to stabilize microtubules. Further, knocking-down nav3 in zebrafish led to severe morphological defects, microcephaly, impaired neuronal growth, and behavioral impairment, which were rescued with co-injection of WT NAV3 mRNA and not by transcripts encoding the pathogenic variants. Our findings establish the role of NAV3 in neurodevelopmental disorders, and reveal its involvement in neuronal morphogenesis, and neuromuscular responses.

A Missense Variant in HACE1 Is Associated with Intellectual Disability, Epilepsy, Spasticity, and Psychomotor Impairment in a Pakistani Kindred.

Intellectual disability (ID), which affects around 2% to 3% of the population, accounts for 0.63% of the overall prevalence of neurodevelopmental disorders (NDD). ID is characterized by limitations in a person's intellectual and adaptive functioning, and is caused by pathogenic variants in more than 1000 genes. Here, we report a rare missense variant (c.350T>C; p.(Leu117Ser)) in HACE1 segregating with NDD syndrome with clinical features including ID, epilepsy, spasticity, global developmental delay, and psychomotor impairment in two siblings of a consanguineous Pakistani kindred. HACE1 encodes a HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 (HACE1), which is involved in protein ubiquitination, localization, and cell division. HACE1 is also predicted to interact with several proteins that have been previously implicated in the ID phenotype in humans. The p.(Leu117Ser) variant replaces an evolutionarily conserved residue of HACE1 and is predicted to be deleterious by various in silico algorithms. Previously, eleven protein truncating variants of HACE1 have been reported in individuals with NDD. However, to our knowledge, p.(Leu117Ser) is the second missense variant in HACE1 found in an individual with NDD.

Identifying the Incidence, Predictors, Outcomes, and Prevention of Stent Thrombosis (ST) in Post-percutaneous Coronary Revascularization Patients With Drug-Eluting Stents (DES): A Systematic Review.

Stent thrombosis (ST) is a rare but catastrophic event to happen to a stented coronary artery. The incidence of ST has greatly been reduced after the advent of modern drug-eluting stent (DES) implants, which have become the most preferred treatment option in the stenting category for coronary artery disease (CAD). Although the risk reduction by newer category implant provides substantial benefits, the possibility of thrombosis still exists mostly during the early stage of DES implantation. The development of ST after percutaneous coronary intervention (PCI) can be predicted by multiple factors, but advancements in early diagnostic techniques and modified stent types have greatly reduced the occurrence of this complication. Mortality, which is one of the complications of ST, is primarily influenced by patient-related factors such as incomplete treatment duration of dual antiplatelet therapy (DAPT). The duration of DAPT after DES implantation in patients with acute coronary syndrome (ACS) is determined based on individual characteristics, mainly considered in view of bleeding or ischemia risk. Risk evaluation systems like DAPT/precise-DAPT scores help tailor and personalize the duration of DAPT for each individual patient. This systematic review contains pertinent articles extracted from the PubMed database. We retrieved articles from various study categories, encompassing publications from the period spanning 2014 to 2022. Our analysis highlighted results from studies investigating different aspects contributing to ST development. The most favorable prevention option was the use of customized DAPT intervention based on patient-specific predictable factors. Several complications associated with ST were identified, including recurrent ST, major adverse cardiovascular events (MACE) encompassing all-cause mortality (including cardiac and non-cardiac mortality), cerebrovascular accidents (CVA) or transient ischemic attacks (TIA), hospitalization due to heart failure, and myocardial infarction requiring revascularization. Mortality was also observed as a significant outcome. The umbrella term of ST includes multiple causative factors. Although DES has improved patient survival rates vastly with its usage, careful risk factor assessment and required follow-up, in each individual being stented, further guarantee a more promising reduction in late adverse outcomes.

Fingolimod-Associated Macular Edema in the Treatment of Multiple Sclerosis.

Multiple sclerosis is a neurological disorder categorized by inflammatory processes with a high prevalence worldwide. It affects both motor and sensory pathways and is also associated with the visual pathway. Fingolimod is a commonly used drug for relapsing-remitting multiple sclerosis. It is a sphingosine 1-phosphate modulator acting on its receptors for immune cell accumulation, neuronal function, embryological development, vascular permeability, smooth muscle cell function, and endothelial barrier maintenance. This review aims to understand the processes, mechanisms, risks, and management of fingolimod-associated macular edema. Due to the anti-inflammatory properties of fingolimod, it decreases various cytokines, including interleukin (IL)-1B and IL-6, spike wave, and spike amplitude, in electrophysiological activities and decreases insoluble receptors for advanced glycation end product ligand. A daily dosage of 0.5 mg of fingolimod has an increased association with macular edema. The serious adverse events of fingolimod are lymphopenia, cardiovascular events, ocular events, and carcinoma. Fingolimod decreases brain volume and increases vascular permeability, resulting in increased macular volume and damage to the blood-retinal barrier, which causes an increased risk for macular edema. Cystoid macular edema is more common in older individuals suffering from comorbidities affecting the retina, such as diabetes, or those undergoing ophthalmological surgeries. This review also highlights the importance of regular ophthalmology examinations on patients consuming fingolimod both in the initial stages and chronic use. The treatment options for macular edema include nonsteroidal anti-inflammatory drugs, acetazolamide, triamcinolone, ketorolac, corticosteroids, and intravitreal procedures.

Evaluation of Efficacy of Cannabis Use in Patients With Attention Deficit Hyperactivity Disorder: A Systematic Review.

Cannabis is frequently used by people who self-medicate for the signs of mental health conditions. Attention-deficit/hyperactivity disorder (ADHD), a neurodevelopmental illness, has been linked to increased cannabis use. However, compared to other mental disorders, cannabis use by people with ADHD has received much less research. The main goal of this systematic review was to understand the nature of the relationships between cannabis use and ADHD symptoms. We used Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to conduct the systematic review. We included papers published within the previous ten years from online searches on PubMed, PubMed Central (PMC), Google Scholar, and ScienceDirect until January 1st, 2023. The inclusion-exclusion criteria led to the initial selection of 136 studies. We selected twenty research articles after screening and assessing them using quality assessment techniques. These articles included two non-randomized control trials, one cross-sectional study, one meta-analysis, and sixteen observational cohorts. It can be advantageous for people with ADHD and their medical professionals to understand better how ADHD patients use cannabis and its potential risks and advantages on cannabis use disorder, ADHD symptoms, and executive dysfunction. This article further emphasizes the necessity of thorough research to comprehend cannabis use in ADHD patients.

The Effects of Probiotics on Cholesterol Levels in Patients With Metabolic Syndrome: A Systematic Review.

The prevalence of metabolic syndrome has been increasing over the past few years, especially in the United States. As a result, it increases the risk of heart disease, stroke, and diabetes mellitus, thus causing significant health issues. Probiotics have been studied to have effects on maintaining blood cholesterol levels by altering the gut microbiota. This systematic review aims to find the effects that probiotics would have on lipid levels when given to patients with metabolic syndrome. In total, articles collected from PubMed, Google Scholar, and ScienceDirect were analysed. The results of the majority of the studies revealed that probiotics have some significant effects on cholesterol levels. It has shown a reduction in triglycerides and lower-density lipoprotein (LDL), thereby decreasing cholesterol levels in the blood. However, further investigations must be carried out so in order to create a more detailed and specific explanation of the effects and mechanisms of probiotics on maintaining cholesterol levels in the blood.

Assessing the Efficacy of Planmeca ProMax® 3D Cone-Beam CT Machine in the Detection of Root Fractures With Varied Metal Artifact Reduction Settings and Three Kilovoltage Peak Levels.

BACKGROUND: This study aims to examine the accuracy of cone-beam computed tomography (CBCT) machines in detecting root fracture when using different metal artifact reduction (MAR) settings at different kilovoltage peak (kVp) levels. METHODOLOGY: Sixty-six tooth roots were treated endodontically using a standardized technique. Of these, 33 roots were randomly selected to be fractured; the other 33 roots were intact and used as controls. The roots were placed randomly in prepared beef ribs to mimic the alveolar bone. Imaging was performed by Planmeca ProMax® 3D (Planmeca, Helsinki, Finland) using different MAR settings (no, low, mid, and high) at three different levels of kVp: 70, 80, and 90. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated. RESULTS: There was a significant difference in accuracy when using different MAR settings within the group of 70 kVp. Likewise, within the group of 90 kVp. There was no significant difference between different MAR settings at 80 kVp. Using low MAR/90 kVp had significantly higher accuracy relative to other MAR settings at 90 kVp; it also had the highest values of sensitivity, specificity, and AUC in the study. Using mid and high MAR at 70 kVp or 90 kVp decreased accuracy significantly. Mid MAR/90 kVp was the least effective setting in this study. CONCLUSIONS:  Using low MAR at 90 kVp significantly increased the accuracy within the group of 90 kVp. In contrast, mid MAR and high MAR in 70 and 90 kVp, respectively, decreased accuracy significantly.

Next-generation whole exome sequencing to delineate the genetic basis of primary congenital glaucoma.

To delineate the genetic bases of primary congenital glaucoma (PCG), we ascertained a large cohort consisting of 48 consanguineous families. Of these, we previously reported 26 families with mutations in CYP1B1 and six families with LTBP2, whereas the genetic bases responsible for PCG in 16 families remained elusive. We employed next-generation whole exome sequencing to delineate the genetic basis of PCG in four of these 16 familial cases. Exclusion of linkage to reported PCG loci was established followed by next-generation whole exome sequencing, which was performed on 10 affected individuals manifesting cardinal systems of PCG belonging to four unresolved families along with four control samples consisting of genomic DNAs of individuals harboring mutations in CYP1B1 and LTBP2. The analyses of sequencing datasets failed to identify potential causal alleles in the 10 exomes whereas c.1169G > A (p. Arg390His) in CYP1B1 and c.3427delC (p.Gln1143Argfs*35) in LTBP2 were identified in the control samples. Taken together, next-generation whole exome sequencing failed to delineate the genetic basis of PCG in familial cases excluded from mutations in CYP1B1 and LTBP2. These data strengthen the notion that compound heterozygous coding variants or non-coding variants might contribute to PCG.

The Role of Glucosamine and Chondroitin Sulfate in the Prevention of Colorectal Cancer: A Systematic Review.

Currently, colorectal cancer is the third most common cancer in the world. Recently, glucosamine and chondroitin have gained popularity for their beneficial effects on cancer. They have already been recognized for their therapeutic role in osteoarthritis. This systematic review aims to analyze the relationship between the combined consumption of glucosamine and chondroitin and the prevention of colorectal cancer. Three databases: PubMed, Google Scholar, and Science Direct, were searched to collect relevant articles. After screening full-text articles, seven studies were included in the systematic review. The review found a supportive association between glucosamine and chondroitin and the decreased incidence of colorectal cancer. Through an anti-inflammatory effect on the cell signaling pathway, the supplementation caused a reduction in colorectal cancer occurrence. The dose, frequency of usage of the supplement, and weight of individuals, along with the use of non-steroidal anti-inflammatory drugs, also affected the efficacy. To further assess this relationship, it is necessary to conduct double-blind, randomized controls trials for the supplements in cancer prevention and further explore their safety and efficacy with different ethnicities, drugs, doses, and weight individuals.

Using Echocardiography and Biomarkers to Determine Prognosis in Peripartum Cardiomyopathy: A Systematic Review.

Peripartum cardiomyopathy (PPCM) is a rare but debilitating form of heart failure that affects pregnant women. Although PPCM has a high rate of complete resolution, some patients often have a progressive disease and develop significant morbidity and mortality. Making an accurate prediction of outcomes and identifying those patients at the highest risk has proven difficult over the years. This study aimed to establish if we can use echocardiographic parameters and biomarkers as reliable indicators of prognosis. A predetermined systematic search strategy was employed in four databases: PubMed, Google Scholar, Science Direct, and Cochrane Library to include articles from the last 15 years (January 2007 to January 2022). Data from 12 studies were synthesized and included in this study. Although no parameter proved consistent in all the studies, echocardiographic parameters, including strain profiles and biomarkers, proved significant in the prognostication of patients with PPCM in the various studies evaluated. Therefore, a holistic approach is still needed in the risk stratification of patients with PPCM. Future studies should evaluate these parameters as well as clinical characteristics in a larger cohort study with a long follow-up period of more than one year in order to potentially develop prognostic score criteria that can be used to accurately identify those patients at the highest risk of developing severe disease or death to allow for timely and targeted therapies to improve outcomes in these patients.

Transcatheter Occluder Devices for the Closure of Atrial Septal Defect in Children: How Safe and Effective Are They? A Systematic Review.

Atrial septal defect (ASD) is a hole in the interatrial septum (IAS) of the heart that is one of the most common congenital heart diseases (CHD). Percutaneous transcatheter device occlusion is one of the techniques that have been developed for the closure of atrial septal defects. The primary objective of this study is to assess the safety and efficacy of septal occluder devices in the management of atrial septal defect in children. We searched PubMed, Science Direct, and Google Scholar databases to collect relevant articles according to a predetermined eligibility criteria and included 21 papers of different study designs in this systematic review. We found that transcatheter closure is safe and effective in most children with ASD. The major complications reported could be avoided by comprehensive clinical assessment and echocardiographic evaluation to determine appropriate device size and implantation strategy per individual child. Further research involving more clinical trials with larger sample size and longer duration of followup is required to improve the safety of existing devices for their use in all children with ASD despite their weight and defect size, and also the efficacy of newer devices such as biodegradable septal occluders.

COVID-19 Vaccination-Associated Myocarditis: A Literature Review.

Myocarditis is defined as a non-ischemic inflammation of the middle layer of the heart. It ensues changes that can lead to acute heart failure, dilated cardiomyopathy, and sudden death. Myocarditis is caused by several infectious and non-infectious agents. Vaccines are also known to cause myocarditis. The use of the coronavirus disease (COVID-19) vaccination was started to combat the severity of the COVID-19 infection and reduce the mortality and morbidity associated with it. The vaccination, however, caused side effects like myocarditis, among others. In order to investigate the association between the COVID-19 vaccination and myocarditis in adults and adolescents, we conducted a literature review by searching three databases: Google Scholar, PubMed, and ScienceDirect. From the published literature, we found that, though it is rare, the various vaccinations available can cause symptoms of myocarditis as a side effect more commonly in patients who have received both doses of a particular vaccine and that there are significant changes in cardiac magnetic resonance imaging (CMRI) and other biochemical markers, with young males being more commonly affected. Further prospective trial-based studies are required to establish a concrete relationship between myocarditis and the COVID-19 vaccine.

Non-coding RNAs in endodontic disease.

The immunocompetence and regeneration potential of the dental pulp and its surrounding apical tissues have been investigated extensively in the field of endodontics. While research on the role of non-coding RNAs in these tissues is still in its infancy, it is envisioned that improved understanding of the regulatory function of ncRNAs in pulpal and periapical immune response will help prevent or treat endodontic disease. Of particular importance is the role of these RNAs in regenerating the dentin-pulp complex. In this review, we highlight recent progress on the role of non-coding RNAs in the immune response to endodontic infection as well as the repair and regenerative response to injury.

Patient Centered Outcomes among a Cohort Receiving Regenerative Endodontic Procedures or Apexification Treatments.

INTRODUCTION: This multicentered cohort study evaluated factors associated with patient-centered outcomes of immature permanent teeth that received regenerative endodontic procedures (REPs) or apexification treatment (APEX). METHODS: A record review identified teeth treated with REPs or APEX between September 2005 and December 2014. Data regarding treatment and patient-centered outcomes were extracted from records with a 3-month minimum recall. When possible, participants presented for an in-person prospective research visit. Patient-centered success was defined as an asymptomatic, functional tooth not requiring further endodontic or surgical intervention after completion of the original treatment during the study observation. Risk ratios and adjusted and unadjusted Cox proportional hazard ratios were calculated. RESULTS: The analytic cohort of 187 individuals included 211 teeth (93 REPs and 118 APEX) with an average follow-up of 32 months. Most cases were successful (81% REPs and 92% APEX) and survived the observation period (96% REPs and 97% APEX). The success rate of REPs was lower than APEX and decreased more rapidly over time. Cox regression analysis demonstrated that when controlling for other variables, the association between treatment type and outcome is not significant. Preoperative infection, teeth with more immature roots, and REP treatment are potentially important predictors. Among teeth receiving REPs, a lower failure rate was observed for teeth that received multiantibiotic paste (3/43) compared with calcium hydroxide (11/45). CONCLUSIONS: Teeth receiving REPs required clinical intervention earlier than teeth that received APEX treatment, although a preoperative abscess and more immature root also affected this outcome. Using multiantibiotic paste versus calcium hydroxide in REPs may improve success.

Assessment of Informed Consent and the Impact of Simulation on Anesthesia Trainees.

Introduction Over the years, the process of obtaining informed consent has evolved and now places an emphasis on the concept that patients should play a major role in medical decision making. Failure to adequately involve patients in making decisions regarding their health can lead to medicolegal consequences. Therefore, taking informed consent is a fundamental component of anaesthesia training. Simulation, for training, is an excellent tool that is being utilised widely in the training of medical professionals. The use of simulated training for teaching the process of informed consent is an innovative initiative that can provide improved results. Material and methods After approval from the institutional review board, a prospective clinical study was conducted at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, from August 2019 to September 2020. Sixteen anaesthesia trainees were randomly selected for the study. The study was divided into pre-interventional, interventional and post interventional phases. For data collection, a predesigned checklist was used. Data collected was analysed using SPSS version 23 (IBM Inc., Armonk, New York). The McNemar test was deployed to assess the difference between the baseline assessment and post-simulated training assessment; p-value < 0.05 was taken to be significant. Results Of the 16 participants, the majority were males (n= 13). A positive impact was observed in terms of improvement of the outcome of the following study components i.e., description of benefits of the procedure (p=0.01), disclosure of associated minor risks (p=0.005), disclosure of major risks (p=0.01), discussion of alternatives (p=0.001), teach back (p=0.001), documentation of patients' verbal agreement (p=0.01), and communication skills involving utilising the process of connecting, introduction, communication, permission, response, and exit (p = 0.01). Conclusion Simulated training had a positive impact in improving outcomes in the following study components: description of benefits of the procedure, disclosure of associated risks, discussion of alternatives, teach back, documentation of patients' verbal agreement, and utilisation of the process of connecting, introduction, communication, permission, responding, and exiting.

Pharmacological Management of Acute Endodontic Pain.

Pain associated with infections of the tooth pulp and periapical tissues is intense and often the most common reason for patients seeking emergency dental care. Effective management of acute dental pain requires a deep understanding of pain mechanisms, which enables accurate diagnosis and definitive treatment. While drugs are only used as an adjunct to definitive dental treatment, a thorough understanding of their mechanism of action and effectiveness enables clinicians to effectively control intra-operative and post-operative pain and prevent persistent pain. This review describes how pain is detected, processed, and perceived. It also provides information on evidence-based strategies on the use of different classes of drugs to effectively manage endodontic pain.

Identification and validation of novel biomarkers and therapeutics for pulpitis using connectivity mapping.

AIM: To create an irreversible pulpitis gene signature from microarray data of healthy and inflamed dental pulps, followed by a bioinformatics approach using connectivity mapping to identify therapeutic compounds that could potentially treat pulpitis. METHODOLOGY: The Gene Expression Omnibus (GEO) database, an international public repository of genomics data sets, was searched for human microarray datasets assessing pulpitis. An irreversible pulpitis gene expression signature was generated by differential expression analysis. The statistically significant connectivity map (ssCMap) method was used to identify compounds with a highly correlating gene expression pattern. qPCR was used to validate novel pulpitis genes. An ex vivo pulpitis model was used to test the effects of the compounds identified, and the level of inflammatory cytokines was measured with qPCR, ELISA and multiplex array. Means were compared using the t-test or ANOVA with the level of significance set at p ≤ .05. RESULTS: Pulpitis gene signatures were created using differential gene expression analysis at cutoff points p = .0001 and .000018. Top upregulated genes were selected as potential pulpitis biomarkers. Among these, IL8, IL6 and MMP9 were previously identified as pulpitis biomarkers. Novel upregulated genes, chemokine (C-C motif) ligand 21 (CCL21), metallothionein 1H (MT1H) and aquaporin 9 (AQP9) were validated in the pulp tissue of teeth clinically diagnosed with irreversible pulpitis using qPCR. ssCMap analysis identified fluvastatin (Statin) and dequalinium chloride (Quaternary ammonium) as compounds with the strongest correlation to the gene signatures (p = .0001). Fluvastatin reduced IL8, IL6, CCL21, AQP9 (p < .001) and MMP9 (p < .05) in the ex vivo pulpitis model, while dequalinium chloride reduced AQP9 (p < .001) but had no significant effect on the other biomarkers. CONCLUSIONS: AQP9, MT1H and CCL21 were identified and validated as novel biomarkers for pulpitis. Fluvastatin and dequalinium chloride identified by the ssCMap as potential therapeutics for pulpitis reduced selected pulpitis biomarkers in an ex vivo pulpitis model. In vivo testing of these licenced drugs is warranted.

Clinical and Demographic Characteristics Including Comorbidities and Their Outcomes Among Patients Hospitalized With COVID-19 in Four Tertiary Care Hospitals Across Lahore.

Background The first case of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was diagnosed in Wuhan, China, in 2019. By the first half of 2020, coronavirus disease 2019 (COVID-19) turned into a global pandemic. Objectives The aim of this study is to describe the clinical and demographic characteristics including comorbidities and their outcomes among patients hospitalized with COVID-19 in four tertiary care hospitals across Lahore. This retrospective study was conducted at Fatima Memorial Hospital, Sir Ganga Ram Hospital, Lahore General Hospital, and Jinnah Hospital, all in Lahore, Pakistan, from May 1, 2020, to June 30, 2020. The sample size was 445, which was derived using the convenient sampling method. Clinical outcomes during hospitalization included the requirement of invasive positive pressure ventilation, need for renal replacement therapy (RRT), and death. Data regarding demographics, baseline comorbidities, important vital signs on reporting, and initial workup with results were also collected. Results A total of 445 patients' data were studied, of whom 291 (65.4%) were male patients and 154 (34.6%) female patients. The median age was 54 years (interquartile range [IQR]: 24). The most common comorbidities were hypertension (HTN) (195; 43.8%) followed by diabetes mellitus (DM) (168; 37.8%) and cardiovascular disease (CVD) (61; 13.7%). The median length of hospital stay was eight days (IQR: 3). Of the total patients, 137 (30.7%) were treated in intensive care unit settings, 40 (9%) received invasive mechanical ventilation, 40 (9%) patients had acute kidney injury, 38 (8.5%) received RRT, and 37 (8.3%) died. It was seen that more patients who were either diabetic or hypertensive received invasive mechanical ventilation as compared to those who did not have these comorbidities. The most common radiological finding on chest X-ray was the classical ground-glass appearance of COVID-19, which was found in 318 (71.4%) patients. Conclusions Patients with one or more underlying comorbidities had poor clinical outcomes compared to those with no comorbidities, with the most vulnerable group being patients with chronic kidney disease, DM, HTN, and CVD in descending order.

A missense allele of PEX5 is responsible for the defective import of PTS2 cargo proteins into peroxisomes.

Peroxisomes, single-membrane intracellular organelles, play an important role in various metabolic pathways. The translocation of proteins from the cytosol to peroxisomes depends on peroxisome import receptor proteins and defects in peroxisome transport result in a wide spectrum of peroxisomal disorders. Here, we report a large consanguineous family with autosomal recessive congenital cataracts and developmental defects. Genome-wide linkage analysis localized the critical interval to chromosome 12p with a maximum two-point LOD score of 4.2 (θ = 0). Next-generation exome sequencing identified a novel homozygous missense variant (c.653 T > C; p.F218S) in peroxisomal biogenesis factor 5 (PEX5), a peroxisome import receptor protein. This missense mutation was confirmed by bidirectional Sanger sequencing. It segregated with the disease phenotype in the family and was absent in ethnically matched control chromosomes. The lens-specific knockout mice of Pex5 recapitulated the cataractous phenotype. In vitro import assays revealed a normal capacity of the mutant PEX5 to enter the peroxisomal Docking/Translocation Module (DTM) in the presence of peroxisome targeting signal 1 (PTS1) cargo protein, be monoubiquitinated and exported back into the cytosol. Importantly, the mutant PEX5 protein was unable to form a stable trimeric complex with peroxisomal biogenesis factor 7 (PEX7) and a peroxisome targeting signal 2 (PTS2) cargo protein and, therefore, failed to promote the import of PTS2 cargo proteins into peroxisomes. In conclusion, we report a novel missense mutation in PEX5 responsible for the defective import of PTS2 cargo proteins into peroxisomes resulting in congenital cataracts and developmental defects.

Predicting the response of the dental pulp to SARS-CoV2 infection: a transcriptome-wide effect cross-analysis.

Pulpitis, inflammation of the dental pulp, is a disease that often necessitates emergency dental care. While pulpitis is considered to be a microbial disease primarily caused by bacteria, viruses have also been implicated in its pathogenesis. Here, we determined the expression of the SARS-CoV2 receptor, angiotensin converting enzyme 2 (ACE2) and its associated cellular serine protease TPMRSS2 in the dental pulp under normal and inflamed conditions. Next, we explored the relationship between the SARS-CoV-2/human interactome and genes expressed in pulpitis. Using existing datasets we show that both ACE2 and TPMRSS2 are expressed in the dental pulp and, that their expression does not change under conditions of inflammation. Furthermore, Master Regulator Analysis of the SARS-CoV2/human interactome identified 75 relevant genes whose expression values are either up-regulated or down-regulated in both the human interactome and pulpitis. Our results suggest that the dental pulp is vulnerable to SARS-CoV2 infection and that SARS-CoV-2 infection of the dental pulp may contribute to worse outcomes of pulpitis.