Targeting the chromatin binding of exportin-1 disrupts NFAT and T cell activation.

Exportin-1 (XPO1/CRM1) plays a central role in the nuclear-to-cytoplasmic transport of hundreds of proteins and contributes to other cellular processes, such as centrosome duplication. Small molecules targeting XPO1 induce cytotoxicity, and selinexor was approved by the Food and Drug Administration in 2019 as a cancer chemotherapy for relapsed multiple myeloma. Here, we describe a cell-type-dependent chromatin-binding function for XPO1 that is essential for the chromatin occupancy of NFAT transcription factors and thus the appropriate activation of T cells. Additionally, we establish a class of XPO1-targeting small molecules capable of disrupting the chromatin binding of XPO1 without perturbing nuclear export or inducing cytotoxicity. This work defines a broad transcription regulatory role for XPO1 that is essential for T cell activation as well as a new class of XPO1 modulators to enable therapeutic targeting of XPO1 beyond oncology including in T cell-driven autoimmune disorders.

Complete genome sequences and characteristics of mycobacteriophages Diminimus, Dulcita, Glaske16, and Koreni.

Complete genome sequences of four novel mycobacteriophages, Diminimus, Dulcita, Glaske16, and Koreni, isolated from soil are presented. All these bacteriophages belong to subcluster M1, except Koreni that belongs to subcluster A4. Moreover, all have siphovirus morphologies, with genome sizes ranging from 51,055 to 81,156 bp.

Cardiometabolic outcomes in Kronos Early Estrogen Prevention Study continuation: 14-year follow-up of a hormone therapy trial.

OBJECTIVE: This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS). METHODS: KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17ß-estradiol (Climara, 50 µg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits. RESULTS: Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17ß-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance. CONCLUSIONS: There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years.

Hypomagnesemia Caused by Chronic Use of Over-the-Counter Proton Pump Inhibitor as a Possible Cause of Supraventricular Tachycardia.

Magnesium is an important co-factor that helps regulates the movement of ions through voltage-mediated channels within myocardial tissues by the membrane sodium-potassium pump, and its deficiency can reduce the pump's activity, leading to partial depolarization and changes in the activity of many potential-dependent membrane channels leading to arrhythmias. In this case report, we are looking to establish the direct relationship between hypomagnesemia caused by proton pump inhibitors (PPIs), which could lead to cardiac arrhythmias. Here, we present a 45-year-old Hispanic female, with a known past medical history of supraventricular tachycardia (SVT), hiatal hernia on proton pump inhibitor (PPI), and chronic smoking, who presented to the emergency department complaining of dizziness and palpitations that started two hours prior arrival to the hospital. At triage, the patient was found to have a heart rate of 190 beats per minute (bpm), and an electrocardiogram (EKG) revealed supraventricular tachycardia with a heart rate of 185 bpm. During the review of this case, no other confounding factors besides hypomagnesemia were noted, leaving this one to be the most likely cause of the arrhythmia. Patients on long-term PPI therapy are at higher risk of developing hypomagnesemia, which could lead to cardiac arrhythmia.

The Liver-Heart Connection: A Literature Review of Liver Disease as a Risk Factor for Atrial Fibrillation.

Atrial fibrillation (AFib) is a common type of cardiac arrhythmia, characterized by disorganized atrial electrical activity with features of irregularly irregular heart rhythm and often with rapid ventricular response increasing the risk of stroke and heart failure due to tachyarrhythmia. The pathophysiology mechanism of AFib is either triggered by atrial distension, abnormality in conducting system, catecholamine excess, or increased atrial irritation or automaticity. Risk factors include uncontrolled diabetes, obesity, obstructive sleep apnea, hypothyroidism, and certain stimulants. Based on recent research, liver disease has recently been identified as a risk factor for AFib. Considering the progression of chronic liver disease, this literature review aims to investigate and summarize the relationship between liver disease and AFib and explore clinical interventions that can be utilized to prevent AFib aggravation.

Complete Genome Sequences and Characteristics of Seven Novel Mycobacteriophages Isolated in East Texas.

Full-genome sequences of seven mycobacteriophages isolated from environmental soil samples are presented. These bacteriophages, with their respective clusters or subclusters are Duplo (A2), Dynamo (P1), Gilberta (A11), MaCh (A11), Nikao (K1), Phloss (N), and Skinny (M1). All had siphovirus-like morphologies, with genome sizes ranging from 43,107 to 82,071 bp.

Autoimmune alleles at the major histocompatibility locus modify melanoma susceptibility.

Autoimmunity and cancer represent two different aspects of immune dysfunction. Autoimmunity is characterized by breakdowns in immune self-tolerance, while impaired immune surveillance can allow for tumorigenesis. The class I major histocompatibility complex (MHC-I), which displays derivatives of the cellular peptidome for immune surveillance by CD8+ T cells, serves as a common genetic link between these conditions. As melanoma-specific CD8+ T cells have been shown to target melanocyte-specific peptide antigens more often than melanoma-specific antigens, we investigated whether vitiligo- and psoriasis-predisposing MHC-I alleles conferred a melanoma-protective effect. In individuals with cutaneous melanoma from both The Cancer Genome Atlas (n = 451) and an independent validation set (n = 586), MHC-I autoimmune-allele carrier status was significantly associated with a later age of melanoma diagnosis. Furthermore, MHC-I autoimmune-allele carriers were significantly associated with decreased risk of developing melanoma in the Million Veteran Program (OR = 0.962, p = 0.024). Existing melanoma polygenic risk scores (PRSs) did not predict autoimmune-allele carrier status, suggesting these alleles provide orthogonal risk-relevant information. Mechanisms of autoimmune protection were neither associated with improved melanoma-driver mutation association nor improved gene-level conserved antigen presentation relative to common alleles. However, autoimmune alleles showed higher affinity relative to common alleles for particular windows of melanocyte-conserved antigens and loss of heterozygosity of autoimmune alleles caused the greatest reduction in presentation for several conserved antigens across individuals with loss of HLA alleles. Overall, this study presents evidence that MHC-I autoimmune-risk alleles modulate melanoma risk unaccounted for by current PRSs.

Complete Genome Sequence and Characteristics of Mycobacteriophage IkeLoa.

Mycobacteriophage IkeLoa is a lytic myovirus. It has a circularly permuted 155,280-bp genome containing 233 putative protein-coding genes, 32 tRNA genes, one tmRNA gene, and 64.7% G+C content. The RNA genes are distributed in five clusters across the genome. Only 28% of IkeLoa's protein-coding genes can be assigned functions.

Maintaining Momentum for Rotavirus Immunization in Africa during the COVID-19 Era: Report of the 13th African Rotavirus Symposium.

The 13th African Rotavirus Symposium was held as a virtual event hosted by the University of Nairobi, Kenya and The Kenya Paediatric Association on 3rd and 4th November 2021. This biennial event organized under the auspices of the African Rotavirus Network shapes the agenda for rotavirus research and prevention on the continent, attracting key international and regional opinion leaders, researchers, and public health scientists. The African Rotavirus Network is a regional network of institutions initially established in 1999, and now encompassing much of the diarrheal disease and rotavirus related research in Africa, in collaboration with the World Health Organization African Regional Office (WHO-AFRO), Ministries of Health, and other partners. Surges in SARS-CoV2 variants and concomitant travel restrictions limited the meeting to a webinar platform with invited scientific presentations and scientific presentations from selected abstracts. The scientific program covered updates on burden of diarrheal diseases including rotavirus, the genomic characterization of rotavirus strains pre- and post-rotavirus vaccine introduction, and data from clinical evaluation of new rotavirus vaccines in Africa. Finally, 42 of the 54 African countries have fully introduced rotavirus vaccination at the time of the meeting, including the two recently WHO pre-qualified vaccines from India. Nonetheless, the full benefit of rotavirus vaccination is yet to be realized in Africa where approximately 80% of the global burden of rotavirus mortality exists.

The Role and Efficacy of Coenzyme Q10 in the Management of Erectile Dysfunction in a Hypertensive Male: An Interventional Study.

Introduction Erectile dysfunction (ED) is a prevalent medical condition that affects millions of men globally. A number of pharmacological and complementary options are used in the management of ED, including Coenzyme Q10 (CoQ10). Oxidative stress has been linked to the progression of ED, and Co Q10 protects against oxidative damages and improves erectile function as well as the activity of antioxidant enzymes. This study aimed to determine the efficacy of CoQ10 in the treatment of erectile dysfunction in hypertensive males. Method An open-labeled parallel arm interventional study was conducted in the cardiology unit of Hayatabad Medical Complex Hospital, Peshawar, Pakistan, from March 2020 to March 2021. Hypertensive male patients (n = 230) were randomly allocated to either receiving 200-gram CoQ10 daily along with their current antihypertensive therapy (n=104) or anti-hypertensive treatment only (n=105). The patient's erectile function was assessed at baseline and three months using the International Index of Erectile Function Test (IIEF-5) during the study period. Result Of the total 230, 209 (90.87%) patients were included in the final analysis. There were no significant differences in demographics, history of illness, co-morbid conditions, and current medication of both groups. After three months, 21 (20.1%) participants scored more than 17 in the IIEF-5 and no longer had ED. Overall, no significant difference was found in the mean IIEF-5 score between the study group and control group (14.41 ± 4.49 Vs. 15.61 ± 4.82; p=0.06). However, in subgroup analysis, significant improvement in the study group was seen in participants with mild ED (p=0.03). Conclusion With the demonstration of its efficacy in hypertensive patients with mild ED, co-enzyme Q10 supplementation can be proposed as a potential candidate in patients with long-term hypertension and can play a role in erectile dysfunction.

Ifetroban reduces coronary artery dysfunction in a mouse model of Duchenne muscular dystrophy.

Dilated cardiomyopathy contributes to morbidity and mortality in Duchenne muscular dystrophy (DMD), an inheritable muscle-wasting disease caused by a mutation in the dystrophin gene. Preclinical studies in mouse models of muscular dystrophy have demonstrated reduced cardiomyopathy and improved cardiac function following oral treatment with the potent and selective thromboxane A2/prostanoid receptor (TPr) antagonist ifetroban. Furthermore, a phase 2 clinical trial (NCT03340675, Cumberland Pharmaceuticals) is currently recruiting subjects to determine whether ifetroban can improve cardiac function in patients with DMD. Although TPr is a promising therapeutic target for the treatment of dilated cardiomyopathy in DMD, little is known about TPr function in coronary arteries that perfuse blood through the cardiac tissue. In the current study, isolated coronary arteries from young (∼3-5 mo) and aged (∼9-12 mo) mdx mice, a widely used mouse model of DMD, and age-matched controls were examined using wire myography. Vasoconstriction to increasing concentrations of TPr agonist U-46619 (U4) was enhanced in young mdx mice versus controls. In addition, young mdx mice displayed a significant attenuation in endothelial cell-mediated vasodilation to increasing concentrations of the muscarinic agonist acetylcholine (ACh). Since TPr activation was enhanced in young mdx mice, U4-mediated vasoconstriction was measured in the absence and the presence of ifetroban. Ifetroban reduced U4-mediated vasoconstriction in young mdx mice and both aged mdx and control mice. Overall, our data demonstrate enhanced coronary arterial vasoconstriction to TPr activation in young mdx mice, a phenotype that could be reversed with ifetroban. These data could have important therapeutic implications for improving cardiovascular function in DMD.NEW & NOTEWORTHY This investigation revealed 1) impaired acetylcholine-mediated vasodilation, 2) increased U-46619-mediated vasoconstriction, and 3) reversal of the increase in U-46619-mediated vasoconstriction by the thromboxane A2/prostanoid receptor (TPr) antagonist ifetroban in left anterior descending coronary arteries isolated from young mdx mice, a model of Duchenne muscular dystrophy (DMD). Ifetroban has been used in preclinical studies to demonstrate improved cardiac function in mouse models of muscular dystrophy and is currently being investigated in a phase 2 clinical trial in patients with DMD. The current study supports the role of ifetroban in improving coronary artery function in preclinical DMD models, which may contribute to improved cardiovascular health.

Double emulsions with ultrathin shell by microfluidic step-emulsification.

Double emulsions with ultrathin shells are important in some biomedical applications, such as controlled drug release. However, the existing production techniques require two or more manipulation steps, or more complicated channel geometry, to form thin-shell double emulsions. This work presents a novel microfluidic tri-phasic step-emulsification device, with an easily fabricated double-layer PDMS channel, for production of oil-in-oil-in-water and water-in-water-in-oil double emulsions in a single step. The shell thickness is controlled by the flow rates and can reach 1.4% of the µm-size droplet diameter. Four distinct emulsification regimes are observed depending on the experimental conditions. A theoretical model for the tri-phasic step-emulsification is proposed to predict the boundaries separating the four regimes of emulsification in plane of two dimensionless capillary numbers, Ca. The theory yields two coupled nonlinear differential equations that can be solved numerically to find the approximate shape of the free interfaces in the shallow (Hele-Shaw) microfluidic channel. This approximation is then used as the initial guess for the more accurate finite element method solution, showing very good agreement with the experimental findings. This study demonstrates the feasibility of co-flow step-emulsification as a promising method to production of double (and multiple) emulsions and micro-capsules with ultrathin shells of controllable thickness.

Autologous Fat Grafting in Young Patients: A Simple and Effective Way to Achieve Facial Balance.

GOALS/PURPOSE: Rhinoplasty is the most common procedure seen in the teenage population. Many of these patients have facial imbalance both recognized and unrecognized by the individual and family. Most often it involves chin or midface deficiency. When the discussion involves the possibility of additional surgery, such as an alloplastic chin implant or a surgical osteotomy, the conversation halts because the patient and family seek a simpler solution.Autologous fat transfer is a useful adjunct to achieve facial balance in chin and cheek in the teen population. More recently, we have been using this technique to correct facial disharmony in rhinoplasty patients. METHODS/TECHNIQUE: Fat grafting was performed at the time of rhinoplasty in 22 patients (age, 15-19 years). Presurgical planning involved cephalometric and computer-enhanced photographic analysis of the face. Midface retrusion and underprojected mentum were treated. Deficient sites were treated with small aliquots of fat, which were injected into the supraperiosteal plane. The average amounts of fat grafting injected per region were 2 to 3 mL for the malar region and 8 to 10 mL for the chin and geniomandibular borders. RESULTS/COMPLICATIONS: Twenty-two patients underwent augmentation of soft tissue and skeletal deficiencies. Analysis of postoperative results showed excellent outcomes with enhancement of facial profile and proportions. The mean follow-up was 3 years. The majority of patients reported high degree of satisfaction. No complications were observed. CONCLUSIONS: The combination of rhinoplasty and autologous fat grafting offers very satisfactory esthetic outcomes and improvement of facial balance with minimal added time, cost, and risk.

Role, Extent, and Impact of Comorbidity on Prognosis and Survival in Advanced Metastatic Melanoma: A Review.

Increased incidence of comorbidity in advanced metastatic melanoma (AMM) is emerging as an important factor in patient prognosis, treatment, and survival. This paper reviews the impact of comorbidities on the prognosis and survival outcomes of patients diagnosed with AMM. Our search initially yielded limited results. We then broadened our search to include breast, colorectal, and prostate cancer and covered malignancies in which screening (like melanoma) is associated with the detection of early-stage disease. Most studies showed that a higher prevalence of comorbidity was associated with more advanced cancer stage. Both treatment and survival of patients were influenced by age and the extent of comorbidity. Racial differences in survival were greatest for patients with no comorbidities and less evident at higher levels of comorbidity. Comorbid conditions showed differential effects for prognosis, treatment, and survival. Limited Information in the literature demonstrates that more research is warranted with respect to comorbidities and AMM.

Correction to: Polymorphisms in chloroquine resistance-associated genes in Plasmodium vivax in Ethiopia.

After publication of the original article [1], it came to the authors' attention that the primers mentioned in Table 1 for the amplification of the pvcrt-o gene of Plasmodium vivax are not the ones actually used for the experiments. The correct primers and PCR product size are as below.

Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse.

The multiple morphological abnormalities of the flagella (MMAF) phenotype is among the most severe forms of sperm defects responsible for male infertility. The phenotype is characterized by the presence in the ejaculate of immotile spermatozoa with severe flagellar abnormalities including flagella being short, coiled, absent, and of irregular caliber. Recent studies have demonstrated that MMAF is genetically heterogeneous, and genes thus far associated with MMAF account for only one-third of cases. Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF. CFAP69 encodes an evolutionarily conserved protein found at high levels in the testis. Immunostaining experiments in sperm from fertile control individuals showed that CFAP69 localized to the midpiece of the flagellum, and the absence of CFAP69 was confirmed in both individuals carrying CFPA69 mutations. Additionally, we found that sperm from a Cfap69 knockout mouse model recapitulated the MMAF phenotype. Ultrastructural analysis of testicular sperm from the knockout mice showed severe disruption of flagellum structure, but histological analysis of testes from these mice revealed the presence of all stages of the seminiferous epithelium, indicating that the overall progression of spermatogenesis is preserved and that the sperm defects likely arise during spermiogenesis. Together, our data indicate that CFAP69 is necessary for flagellum assembly/stability and that in both humans and mice, biallelic truncating mutations in CFAP69 cause autosomal-recessive MMAF and primary male infertility.

High-density lipoprotein (HDL) functionality and its relevance to atherosclerotic cardiovascular disease.

Several prospective epidemiological studies have shown that there is a clear inverse relationship between serum high-density lipoprotein-cholesterol (HDL-C) concentrations and risk for coronary heart disease (CHD), even at low-density lipoprotein-cholesterol (LDL-C) levels below 70 mg/dL. However, more recent evidence from genetic studies and clinical research has come to challenge the long-standing notion that higher HDL-C levels are always beneficial, while lower HDL-C levels are always detrimental. Thus, it becomes apparent that HDL functionality plays a much more important role in atheroprotection than circulating HDL-C levels. HDL cholesterol efflux capacity (CEC) from macrophages is a key metric of HDL functionality and exhibits a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease (CAD), independent of the HDL-C level. Thus, extensive research is being conducted to identify new agents with a favorable side effect profile, which would be able to enhance CEC, improve HDL functionality and potentially decrease cardiovascular risk. This review aims to present and discuss the current clinical and scientific evidence pertaining to the significance of HDL functionality over the actual HDL-C concentration in mediating the favorable effects on the cardiovascular system. Thus, we conducted a PubMed search until December 2017 through the English literature using the search terms 'HDL function/functionality', 'HDL properties', 'cardiovascular risk' and 'cholesterol efflux capacity'. We also included references from the articles identified and publications available in the authors' libraries.

Dynamic Cleft Maxillary Orthopedics and Periosteoplasty.

In 1985 this cleft team, dissatisfied with the treatment and results from cleft lip and palate repair, began a longitudinal long-term study using dynamic maxillary orthopedics and periosteoplasty as was originally described by Drs Millard and Latham. All cases were carefully documented through adolescence, including clinical assessments, orthodontic, radiographic, and cephalometric analyses. In 1998, in this journal, we published our data on 35 complete unilateral and 10 complete bilateral cleft patients. At that time facial growth was following normal cephalometric patterns. Crossbites were dental and treated with orthodontics. There was radiologic evidence of bone within the alveolus with elimination of the oronasal fistula, and facial aesthetics revealed soft faded scars and balanced noses.That publication was a preliminary study with the intent to provide long-term results when full facial growth was achieved. This article reports on 25 patients from the initial cohort (20 unilateral and 5 bilateral) that we were able to closely follow up for 25 years, with the same clinical team, making it the longest study of its kind.At this stage, data revealed continued growth of the midface both vertically and horizontally. Secondary alveolar cleft bone grafting when required was in small aliquots placed into well-healed tissue, and orthodontic movement of teeth was through a consolidated alveolus. Orthognathic procedures were performed in 2 of 5 bilateral and 0 of 20 unilateral cases.We concluded that in this cohort, dynamic maxillary orthopedics and periosteoplasty, despite controversy in the literature, did not negatively impact facial growth and provided the benefit of early structural normalization and social integration by consolidation of the maxilla, closure of the oronasal fistula, tension free closure of the lip, and by balancing the nose.

Genome Sequences of Mycobacteriophages Amgine, Amohnition, Bella96, Cain, DarthP, Hammy, Krueger, LastHope, Peanam, PhelpsODU, Phrank, SirPhilip, Slimphazie, and Unicorn.

We report the genome sequences of 14 cluster K mycobacteriophages isolated using Mycobacterium smegmatis mc²155 as host. Four are closely related to subcluster K1 phages, and 10 are members of subcluster K6. The phage genomes span considerable sequence diversity, including multiple types of integrases and integration sites.