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Mtorc1 in Distal Convoluted Tubule (DCT) and Renal Potassium (K+) Handling
No full textBackground: Mechanistic-target-of-rapamycin-complex-1 (mTORc1) plays a role in maintaining K+ homeostasis. We now examine whether mTORc1 of distal-convoluted-tubule (DCT) regulates Kir4.1/Kir5.1 channels and thiazide-sensitive-Na-Cl cotransporter, which plays a role in regulating renal K+ excretion. Methods: We used patch-clamp-technique to examine basolateral Kir4.1/Kir5.1 in early-DCT, immunoblotting to examine NCC expression and in vivo measurement of urinary K+-excretion to determine baseline renal K+-excretion (EK) in the mice treated with rapamycin and in DCT-specific regulatory-associated-protein-of-mechanisticc-target-of-rapamycin knockout mice (DCT-RAPTOR-KO). Results: Application of rapamycin decreased Kir4.1/Kir5.1-mediated K+-currents and depolarized DCT-membrane-potential in Fkbp1aflox/flox mice. However, the effect of rapamycin on Kir4.1/Kir5.1 was absent in kidney-specific-FKBP12-knockout mice (Ks-FKBP12-KO). Rapamycin decreased basolateral 40-pS K+-channel activity (Kir4.1/Kir5.1 heterotetramer) of the DCT. This effect was absent in the DCT treated with H2O2 which stimulated the 40-pS K+-channel activity, suggesting the role of reactive-oxygen-species (ROS) in mediating the effect of mTORc1 on Kir4.1/Kir5.1. Rapamycin treatment significantly decreased the abundance of both phosphorylated-NCC and total-NCC in Fkbp1aflox/flox mice but not in Ks-FKBP12-KO mice. Moreover, in vivo measurement of urinary Na+-excretion and urinary K+-excretion demonstrated that rapamycin treatment decreased hydrochlorothiazide-induced natriuresis but increased renal K+-excretion in Fkbp1aflox/flox mice. Moreover, Kir4.1/Kir5.1 mediated K+-currents of the DCT were lower and DCT membrane potential was less negative in DCT-RAPTOR-KO than those of Ncc-Cre-Raptorflox/flox mice. Also, the abundance of phosphorylated-NCC was lower in DCT-RAPTOR-KO mice than Ncc-Cre-Raptorflox/flox mice. In contrast, the abundance of phosphorylated-NKCC2 was the same between two genotypes while cleaved αENaC abundance was higher in DCT-RAPTOR-KO mice than Ncc-Cre-Raptorflox/flox mice. Consequently, DCT-RAPTOR-KO mice had a higher urinary K+-excretion and lower plasma K+ concentrations than Ncc-Cre-Raptorflox/flox.Conclusions: mTORc1 in the DCT plays a significant role in maintaining K+ homeostasis by controlling the basolateral Kir4.1/Kir5.1 of the DCT and NCC
Opposing Human Genetic Engineering
No full textThe past five decades have been a time of substantial change in the technological capacity to modify genetic material. During this period, I have maintained an unwavering stance against human germline modification. As a biologist who has researched the complexities of genotype-phenotype relationships, I remain convinced embryo-stage human genetic modification will always remain in the realm of uncontrolled experimentation. Based on my observations and participation in the twists and turns of genetics and society, I point to the limits of calls for “broad societal consensus
Evaluation of the Impact of Race/Ethnicity on Medical Student\u27s Away Rotations and Residency Match
No full textPurpose: Many studies have examined the impact away rotations have on the residency match outcomes of medical students, the common impression being that they are beneficial for match success. Little is known about whether race/ethnicity affects the relationship between away rotations and match success. This study explored the impact that race/ethnicity has on the likelihood of a medical student matching at a program where they did an away rotation to help inform student\u27s decision making. Methods: Alumni and post-match medical students at a US medical school, residents and attendings at the hospital associated with the medical school, and Black medical organization members completed a survey about their away rotation and match experience. Responses were collected from August 2023 to March 2024. The statistical analysis was done with Graphpad Prism. Results: We analyzed 298 survey responses and found that while the respondents of all races did not feel that attending away rotations affected their match outcomes, Black respondents were significantly less likely to match at a program where they did an away rotation (p=0.02). There was a difference in the rates of students going into competitive specialties who matched at a place where they rotated between those who are underrepresented in medicine (23.1 %) and those who are not (44.1 %), but this difference was not statistically significant (p=0.16). Conclusion: A one-size-fits-all recommendation for away rotations does not take into account the different realities faced by medical students. The impact that race/ethnicity can have on a student\u27s match success should be acknowledged by students and advisors when making decisions about away rotations
Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease With Aseptic Meningitis-Like Presentation in a Paediatric Patient
No full textIn the paediatric population, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) phenotypes continue to be identified. We present a case of seropositive MOGAD that began as what appeared to be aseptic meningitis with elevated intracranial pressure, followed by inflammatory myelopathy. The paediatric patient presented with a four-day history of persistent frontal headache, vomiting and episodic confusion without a fever. Lumbar puncture showed elevated cerebrospinal fluid opening pressure and lymphocytic pleocytosis. Her headaches worsened despite treatment for increased pressure with acetazolamide. Her symptoms of inflammatory myelopathy emerged four days after admission. MRI brain at presentation demonstrated bilateral narrowing of the transverse sinuses as seen with idiopathic intracranial hypertension (IIH). After development of urinary retention and lower extremity symptoms, MRI spine showed signal abnormalities within the grey and white matter of both the cervical and thoracic spinal cord consistent with an inflammatory myelopathy. Serum MOG antibodies were positive. Here, we present a case of MOGAD that began with an aseptic meningitis-like presentation, but without the more commonly described initial presentations of MOGAD to illustrate an emerging phenotype. Aseptic meningitis with imaging suggestive of IIH, as well as persistent or evolving symptoms in a paediatric patient, should raise suspicions for MOGAD and prompt MOG antibody testing
Identification of Proteins in Semen-Derived Extracellular Vesicles That Bind to Tat and NF-Κb and That May Impair HIV Replication
No full textReplication of HIV-1 requires the coordinated action of host and viral transcription factors, most critically the viral transactivator Tat and the host nuclear factor κB (NF-κB). This activity is disrupted in infected cells that are cultured with extracellular vesicles (EVs) present in human semen, suggesting that they contain factors that could inform the development of new therapeutics. Here, we explored the contents of semen-derived EVs (SEVs) from uninfected donors and individuals with HIV-1 and identified host proteins that interacted with HIV Tat and the NF-κB subunit p65. Integrative network and pathway enrichment analyses of these complexes revealed associations with an array of biological functions regulating gene expression. Several proteins in SEVs bound to both Tat and NF-κB p65: the scaffolding and cell signaling regulatory protein AKAP9, the G protein signaling regulator ARHGEF28, the epigenetic reader BRD2, the small nuclear RNA processor INTS1, and the transcription elongation inhibitor NELFB. When complexed with p65, NELFB also interacted with HEXIM1, another transcription elongation inhibitor, suggesting that SEVs may inhibit HIV-1 propagation through multiple networks of transcriptional activation and repression. Exploring these data and the underlying mechanisms may inform the development of more effective or more durable therapeutics against HIV
Outpatient Orthopedic Conditions in the Pregnant Patient: A Review of the Literature
No full textPregnancy induces a range of physiological and musculoskeletal changes that can lead to orthopedic issues. This article examines etiologies and management strategies for outpatient orthopedic problems encountered during pregnancy. Hormonal changes, weight gain, and altered biomechanics contribute to common musculoskeletal complaints such as low back pain, pelvic girdle pain, and carpal tunnel syndrome. Although less common, osteoporosis can present during pregnancy. Additionally, domestic violence and interpartner violence are disproportionately more frequent in this population. This review highlights evidence-based approaches for diagnosis and treatment and emphasizes the importance of multidisciplinary care, including obstetricians, orthopedic surgeons, endocrinologists, primary care physicians, and physical therapists
Mass Spectrometry Combined With Machine Learning Identifies Novel Protein Signatures as Demonstrated With Multisystem Inflammatory Syndrome in Children
No full textRapid and accurate diagnosis of emerging inflammatory illnesses is challenging due to overlapping clinical features with existing conditions. We demonstrate an approach that integrates proteomic analysis with machine learning to identify diagnostic protein signatures, using the example of SARS-CoV-2-induced multisystem inflammatory syndrome in children (MIS-C). We used plasma samples collected from subjects diagnosed with MIS-C and compared them first to controls with asymptomatic/mild SARS-CoV-2 infection and then to controls with pneumonia or Kawasaki disease. We used mass spectrometry to identify proteins and support vector machine (SVM) algorithm-based classification schemes to identify protein signatures. Diagnostic accuracy was assessed by calculating sensitivity, specificity, and area under the ROC curve (AUC), and corrected for overfitting by cross-validation. Proteomic analysis of a training dataset containing MIS-C (N = 17), and asymptomatic/mild SARS-CoV-2 infected control samples (N = 20) identified 643 proteins, of which 101 were differentially expressed. Plasma proteins associated with inflammation increased, and those associated with metabolism and coagulation decreased in MIS-C relative to controls. The SVM machine learning algorithm identified a three-protein model (ORM1, AZGP1, SERPINA3) that achieved 90.0% specificity, 88.2% sensitivity, and 93.5% AUC, distinguishing MIS-C from controls in the training set. Performance was retained in the validation dataset utilizing MIS-C (N = 19) and asymptomatic/mild SARS-CoV-2 infected control samples (N = 10) (90.0% specificity, 84.2% sensitivity, 87.4% AUC). We next replicated our approach to compare MIS-C with similarly presenting syndromes, such as pneumonia (N = 17) and Kawasaki disease (N = 13), and found a distinct three-protein signature (VWF, FCGBP, and SERPINA3) that accurately distinguished MIS-C from the other conditions (97.5% specificity, 89.5% sensitivity, 95.6% AUC). A software tool was also developed that may be used to evaluate other protein signatures using our data. These results demonstrate that the use of mass spectrometry to identify candidate plasma proteins followed by machine learning, specifically SVM, is an efficient strategy for identifying and evaluating biomarker signatures for disease classification
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