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1.
Glob Health Epidemiol Genom ; 2022: 2270965, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35950011

RESUMO

Rapid identification and tracking of emerging SARS-CoV-2 variants are critical for understanding the transmission dynamics and developing strategies for interrupting the transmission chain. Next-Generation Sequencing (NGS) is an exceptional tool for whole-genome analysis and deciphering new mutations. The technique has been instrumental in identifying the variants of concern (VOC) and tracking this pandemic. However, NGS is complex and expensive for large-scale adoption, and epidemiological monitoring with NGS alone could be unattainable in limited-resource settings. In this study, we explored the application of RT-qPCR-based detection of the variant identified by NGS. We analyzed a total of 78 deidentified samples that screened positive for SARS-CoV-2 from two timeframes, August 2020 and July 2021. All 78 samples were classified into WHO lineages by whole-genome sequencing and then compared with two commercially available RT-qPCR assays for spike protein mutation(s). The data showed good concordance between RT-qPCR and NGS analysis for specific SARS-CoV-2 lineages and characteristic mutations. RT-qPCR assays are quick and cost-effective and thus can be implemented in synergy with NGS for screening NGS-identified mutations of SARS-CoV-2 for clinical and epidemiological interest. Strategic use of NGS and RT-qPCR can offer several COVID-19 epidemiological advantages.


Assuntos
COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , COVID-19/epidemiologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pandemias , SARS-CoV-2/genética
2.
Otol Neurotol ; 2022 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-35941710

RESUMO

OBJECTIVE: To investigate music appreciation in hearing aid (HA) users with varying levels of hearing loss (HL). STUDY DESIGN: Cross-sectional, within-subjects design. SETTING: Tertiary medical center, community. PATIENTS: Adults (≥18 yr) bilateral HA users. INTERVENTIONS: HA usage. MAIN OUTCOME MEASURES: Outcome variables included self-reported music enjoyment measures (pleasantness, musicality, naturalness) with and without HAs assessed with visual analogue scales (10 indicates highest level of enjoyment, 0 the least). Exposure variables include HL (better ear pure-tone average) and speech discrimination (word recognition scores [WRS]). Demographic information was collected. RESULTS: One hundred nine bilateral HA users completed the study. Mean (standard deviation) age was 66.6 years (16.8 yr); 52.3% were female patients. Mean (standard deviation) better ear pure-tone average was 51.1 dB (16.3 dB) HL. Increased severity of HL and worse WRS were associated with decreased music enjoyment (p < 0.05) across all measures without HAs, adjusting for sex, age, education, race, HA type, age of HL diagnosis, duration of HL, duration of HA use, musical preference, and musical experience. However, these associations were attenuated or no longer significant with HA usage. Moreover, among all subjects, HAs (vs. no HAs) provided increased music enjoyment in pleasantness (HA, 6.94, no HA, 5.74; p < 0.01), musicality (HA, 7.35; no HA, 6.13, p < 0.01), and naturalness (HA, 6.75; no HA, 6.02; p = 0.02). CONCLUSION: HA users report increased music enjoyment with HAs compared with without HAs. Increased severity of HL and worse WRS were independently associated with decreased unaided music enjoyment. HA usage seems to mitigate this effect, particularly for those with worse HL.

3.
J Am Geriatr Soc ; 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35860986

RESUMO

BACKGROUND: An emergency department (ED) visit provides a unique opportunity to identify elder abuse and initiate intervention, but emergency providers rarely do. To address this, we developed the Vulnerable Elder Protection Team (VEPT), an ED-based interdisciplinary consultation service. We describe our initial experience in the first two years after the program launch. METHODS: We launched VEPT in a large, urban, academic ED/hospital. From 4/3/17 to 4/2/19, we tracked VEPT activations, including patient characteristics, assessment, and interventions. We compared VEPT activations to frequency of elder abuse identification in the ED before VEPT launch. We examined outcomes for patients evaluated by VEPT, including change in living situation at discharge. We assessed ED providers' experiences with VEPT via written surveys and focus groups. RESULTS: During the program's initial two years, VEPT was activated and provided consultation/care to 200 ED patients. Cases included physical abuse (59%), neglect (56%), financial exploitation (32%), verbal/emotional/psychological abuse (25%), and sexual abuse (2%). Sixty-two percent of patients assessed were determined by VEPT to have high or moderate suspicion for elder abuse. Seventy-five percent of these patients had a change in living/housing situation or were discharged with new or additional home services, with 14% discharged to an elder abuse shelter, 39% to a different living/housing situation, and 22% with new or additional home services. ED providers reported that VEPT made them more likely to consider/assess for elder abuse and recognized the value of the expertise and guidance VEPT provided. Ninety-four percent reported believing that there is merit in establishing a VEPT Program in other EDs. CONCLUSION: VEPT was frequently activated and many patients were discharged with changes in living situation and/or additional home services, which may improve safety. Future research is needed to examine longer-term outcomes.

4.
Indian Pediatr ; 59(7): 521-523, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35869877
6.
Artigo em Inglês | MEDLINE | ID: mdl-35733311

RESUMO

BACKGROUND: Herpes zoster is a viral infection triggered due to the reactivation of the varicella-zoster virus in the posterior dorsal root ganglion. Herpes zoster infections occur mostly in the facial, cervical and thoracic region of the body beginning with pain and resulted in the vesicular eruption. Recently, this infection is observed during the Covid-19 pandemic and also after the induction of mRNA-based vaccine for coronavirus at an extended level. Nanocochleates are cylindrical (cigar-shape) microstructure lipid-based versatile carriers for the drug delivery systems. Famciclovir is an antiviral agent employed for the treatment of Herpes zoster infections. OBJECTIVE: The current research aimed at the development of a novel nanocochleate gel of Famciclovir for the treatment of herpes zoster infections with higher efficacy. METHODS: The interaction studies using FTIR were carried out and indicated no such interactions among the drug and lipids. The nanocochleates were developed using hydrogel, trapping, liposome before cochleate dialysis, direct calcium dialysis and binary aqueous-aqueous emulsion methods respectively. The 32 Box-Behnken design was applied by considering the concentration of lipids (phosphatidylcholine and cholesterol) and speed of rotation as independent factors, whereas a particle size and entrapment efficiency as dependable factors. RESULTS: The developed nanocochleates were estimated for the particle size (276.3 nm), zeta potential (-16.7 mV), polydispersity index (0.241), entrapment efficiency (73.87±0.19 %) and in-vitro diffusion release (>98.8 % in 10 h). The optimized batch was further converted into the topical gel using carbopol 940 as a gelling agent. The prepared gel was smooth, rapidly spreadable with a viscosity (5998.72 cp), drug content (95.3 %) and remain stable during stability studies. CONCLUSION: A novel nanocochleate gel of Famciclovir was successfully developed for the treatment of infections associated with Herpes Zoster with sustained release action.

7.
Can J Diabetes ; 2022 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-35718690

RESUMO

OBJECTIVES: The impact of type 2 diabetes (T2DM) on biomarkers denoting lipoprotein compositional status was studied in mild and moderate hypertriglyceridemia (HTG). Diabetic dyslipidemia pathophysiology could contribute to differences in lipoprotein compositional status, which could be reflected in the preferred cardiovascular disease risk prediction markers in HTG: non-high-density lipoprotein cholesterol (non-HDLC) and apolipoprotein B (apoB). METHODS: 2,775 fasting lipid profiles from a tertiary-care lipid clinic were analyzed as 2 subgroups (with and without T2DM), stratified by triglyceride (TG) levels: normotriglyceridemia (TG 0.01 to 1.7 mmol/L), mild HTG (TG 1.71 to 5 mmol/L) and moderate HTG (TG 5.01 to 10 mmol/L). The mean non-HDLC:apoB ratio in each TG stratum and subgroup was analyzed. We also used linear regression to assess the correlation between non-HDLC and apoB. RESULTS: The mean non-HDLC:apoB ratio was increased in both subgroups in patients with mild and moderate HTG, compared to those with normotriglyceridemia. In moderate HTG, the mean non-HDLC:apoB ratio in the subgroup with T2DM was significantly lower than the subgroup without T2DM. In mild and moderate HTG, the subgroup with T2DM had a stronger correlation between non-HDLC and apoB than did the subgroup without T2DM. DISCUSSION AND CONCLUSIONS: In mild and moderate HTG, adults with T2DM exhibit lipid profiles that represent a different and more atherogenic lipoprotein compositional status, when compared with adults without T2DM. For the same severity of HTG, the lipoprotein compositional status in diabetic dyslipidemia suggests that there is increased abundance of smaller non-HDL particles and their remnants, which are highly atherogenic.

8.
J Neurol Surg B Skull Base ; 83(3): 270-280, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35769793

RESUMO

Objective The center of excellence model of health care hypothesizes that increased volume in a specialized center will lead to better and more affordable care. We sought to characterize the volume-outcome data for surgically treated sinonasal and skull base tumors and (chemo) radiation-treated nasopharyngeal malignancy. Design Systematic review of the literature. Setting This review included national database and multi-institutional studies published between 1990 and 2019. Participants PubMed was interrogated for keywords "hospital volume," "facility volume," and outcomes for "Nasopharyngeal carcinoma," "Sinonasal carcinomas," "Pituitary Tumors," "Acoustic Neuromas," "Chordomas," and "Skull Base Tumors" to identify studies. Single-institution studies and self-reported surveys were excluded. Main outcome measures The main outcome of interest in malignant pathologies was survival; and in benign pathologies it was treatment-related complications. Results A total of 20 studies met inclusion criteria. The average number of patients per study was 4,052, and ranged from 394 to 9,950 patients. Six of seven studies on malignant pathology demonstrated improved survival with treatment in high volume centers and one showed no association with survival. Ten of thirteen studies on benign disease showed reduced risk of complications, while one study demonstrated both an increased and decreased association of complications. Two studies showed no volume-outcome associations. Conclusion This systematic review demonstrates that a positive volume-outcome relationship exists for most pathologies of the skull base, with some exceptions. The relative dearth of literature supports further research to understand the effect of centralization of care on treatment outcomes.

9.
OTO Open ; 6(2): 2473974X221101025, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35663351

RESUMO

Objective: Tracheostomies have been performed in patients with prolonged intubation due to COVID-19. Understanding outcomes in different populations is crucial to tackle future epidemics. Study Design: Prospective cohort study. Setting: Tertiary academic medical center in New York City. Methods: A prospectively collected database of patients with COVID-19 undergoing open tracheostomy between March 2020 and April 2020 was reviewed. Primary endpoints were weaning from the ventilator and from sedation and time to decannulation. Results: Sixty-six patients underwent tracheostomy. There were 42 males (64%) with an average age of 62 years (range, 23-91). Patients were intubated for a median time of 26 days prior to tracheostomy (interquartile range [IQR], 23-30). The median time to weaning from ventilatory support after tracheostomy was 18 days (IQR, 10-29). Of those sedated at the time of tracheostomy, the median time to discontinuation of sedation was 5 days (IQR, 3-9). Of patients who survived, 39 (69%) were decannulated. Of those decannulated before discharge (n = 39), the median time to decannulation was 36 days (IQR, 27-49) following tracheostomy. The median time from ventilator liberation to decannulation was 14 days (IQR, 8-22). Thirteen patients (20.0%) had minor bleeding requiring packing. Two patients (3%) had bleeding requiring neck exploration. The all-cause mortality rate was 10.6%. No patients died of procedural causes, and no surgeons acquired COVID-19. Conclusion: Open tracheostomies were successfully and safely performed at our institution in the peak of the COVID-19 pandemic. The majority of patients were successfully weaned from the ventilator and sedation. Approximately 60% of patients were decannulated prior to hospital discharge.

10.
ACS Omega ; 7(20): 16906-16916, 2022 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-35647428

RESUMO

Graphene oxide-based nanocomposites (NCMs) exhibit diverse photonic and biophotonic applications. Innovative nanoengineering using a task-specific ionic liquid (IL), namely, 1-butyl-3-methyl tetrafluoroborate [C4mim][BF4], allows one to access a unique class of luminescent nanocomposites formed between lanthanide-doped binary fluorides and graphene oxide (GO). Here the IL is used as a solvent, templating agent, and as a reaction partner for the nanocomposite synthesis, that is, "all three in one". Our study shows that GO controls the size of the NCMs; however, it can tune the luminescence properties too. For example, the excitation spectrum of Ce3+ is higher-energy shifted when GO is attached. In addition, magnetic properties of GdF3:Tb3+ nanoparticles (NPs) and GdF3:Tb3+-GO NCMs are also studied at room temperature (300 K) and very low temperature (2 K). High magnetization results for the NPs (e.g., 6.676 emu g-1 at 300 K and 184.449 emu g-1 at 2 K in the applied magnetic field from +50 to -50 kOe) and NCMs promises their uses in many photonic and biphotonic applications including magnetic resonance imaging, etc.

11.
J Exp Med ; 219(7)2022 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-35670812

RESUMO

Regulatory T (Treg) cells represent a specialized lineage of suppressive CD4+ T cells whose functionality is critically dependent on their ability to migrate to and dwell in the proximity of cells they control. Here we show that continuous expression of the chemokine receptor CXCR4 in Treg cells is required for their ability to accumulate in the bone marrow (BM). Induced CXCR4 ablation in Treg cells led to their rapid depletion and consequent increase in mature B cells, foremost the B-1 subset, observed exclusively in the BM without detectable changes in plasma cells or hematopoietic stem cells or any signs of systemic or local immune activation elsewhere. Dysregulation of BM B-1 B cells was associated with a highly specific increase in IgM autoantibodies and total serum IgM levels. Thus, Treg cells control autoreactive B-1 B cells in a CXCR4-dependent manner. These findings have significant implications for understanding the regulation of B cell autoreactivity and malignancies.


Assuntos
Subpopulações de Linfócitos B , Linfócitos T Reguladores , Subpopulações de Linfócitos B/metabolismo , Medula Óssea/metabolismo , Células da Medula Óssea/metabolismo , Imunoglobulina M/metabolismo , Receptores CXCR4/metabolismo
12.
Chem Sci ; 13(18): 5230-5242, 2022 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-35655577

RESUMO

The photochemistry of DNA systems is characterized by the ultraviolet (UV) absorption of π-stacked nucleobases, resulting in exciton states delocalized over several bases. As their relaxation sensitively depends on local stacking conformations, disentangling the ensuing electronic and structural dynamics has remained an experimental challenge, despite their fundamental role in protecting the genome from potentially harmful UV radiation. Here we use transient absorption and transient absorption anisotropy spectroscopy with broadband femtosecond deep-UV pulses (250-360 nm) to resolve the exciton dynamics of UV-excited adenosine single strands under physiological conditions. Due to the exceptional deep-UV bandwidth and polarization sensitivity of our experimental approach, we simultaneously resolve the population dynamics, charge-transfer (CT) character and conformational changes encoded in the UV transition dipoles of the π-stacked nucleotides. Whilst UV excitation forms fully charge-separated CT excitons in less than 0.3 ps, we find that most decay back to the ground state via a back-electron transfer. Based on the anisotropy measurements, we propose that this mechanism is accompanied by a structural relaxation of the photoexcited base-stack, involving an inter-base rotation of the nucleotides. Our results finally complete the exciton relaxation mechanism for adenosine single strands and offer a direct view into the coupling of electronic and structural dynamics in aggregated photochemical systems.

13.
Toxics ; 10(6)2022 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-35736936

RESUMO

Exposure to environmental pollutants, including dioxin-like polychlorinated biphenyls (PCBs), play an important role in vascular inflammation and cardiometabolic diseases (CMDs) by inducing oxidative stress. Earlier, we demonstrated that oxidative stress-mediated lipid peroxidation derived 4-hydroxy-2-nonenal (4HNE) contributes to CMDs by decreasing the angiogenesis of coronary endothelial cells (CECs). By detoxifying 4HNE, aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme, enhances CEC angiogenesis. Therefore, we hypothesize that ALDH2 activation attenuates a PCB 126-mediated 4HNE-induced decrease in CEC angiogenesis. To test our hypothesis, we treated cultured mouse CECs with 4.4 µM PCB 126 and performed spheroid and aortic ring sprouting assays, the ALDH2 activity assay, and Western blotting for the 4HNE adduct levels and real-time qPCR to determine the expression levels of Cyp1b1 and oxidative stress-related genes. PCB 126 increased the gene expression and 4HNE adduct levels, whereas it decreased the ALDH2 activity and angiogenesis significantly in MCECs. However, pretreatment with 2.5 µM disulfiram (DSF), an ALDH2 inhibitor, or 10 µM Alda 1, an ALDH2 activator, before the PCB 126 challenge exacerbated and rescued the PCB 126-mediated decrease in coronary angiogenesis by modulating the 4HNE adduct levels respectively. Finally, we conclude that ALDH2 can be a therapeutic target to alleviate environmental pollutant-induced CMDs.

14.
Lancet Reg Health Southeast Asia ; 3: 100023, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35769163

RESUMO

Background: Surge of SARS CoV-2 infections ascribed to omicron variant began in December 2021 in New Delhi. We determined the infection and reinfection density in a cohort of health care workers (HCWs) along with vaccine effectiveness (VE) against symptomatic infection within omicron transmission period (considered from December 01, 2021 to February 25, 2022. Methods: This is an observational study from the All India Institute of Medical Sciences, New Delhi. Data were collected telephonically. Person-time at risk was counted from November 30, 2021 till date of infection/ reinfection, or date of interview. Comparison of clinical features and severity was done with previous pandemic periods. VE was estimated using test-negative case-control design [matched pairs (for age and sex)]. Vaccination status was compared and adjusted odds ratios (OR) were computed by conditional logistic regression. VE was estimated as (1-adjusted OR)X100-. Findings: 11474 HCWs participated in this study. The mean age was 36⋅2 (±10⋅7) years. Complete vaccination with two doses were reported by 9522 (83%) HCWs [8394 (88%) Covaxin and 1072 Covishield (11%)]. The incidence density of all infections and reinfection during the omicron transmission period was 34⋅8 [95% Confidence Interval (CI): 33⋅5-36⋅2] and 45⋅6 [95% CI: 42⋅9-48⋅5] per 10000 person days respectively. The infection was milder as compared to previous periods. VE was 52⋅5% (95% CI: 3⋅9-76⋅5, p = 0⋅036) for those who were tested within 14-60 days of receiving second dose and beyond this period (61-180 days), modest effect was observed. Interpretation: Almost one-fifth of HCWs were infected with SARS CoV-2 during omicron transmission period, with predominant mild spectrum of COVID-19 disease. Waning effects of vaccine protection were noted with increase in time intervals since vaccination. Funding: None.

15.
J Emerg Med ; 2022 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-35637048

RESUMO

BACKGROUND: Burn injuries in geriatric patients are common and may have significant associated morbidity and mortality. Most research has focused on the care of hospitalized patients after admission to burn units. Little is known about the clinical characteristics of geriatric burn victims who present to the emergency department (ED) and their ED assessment and management. OBJECTIVE: Our aim was to describe the clinical characteristics and outcomes of geriatric patients presenting to the ED with burn injuries. METHODS: We performed a comprehensive retrospective chart review on all patients 60 years and older with a burn injury presenting from January 2011 through September 2015 to a large, urban, academic ED in a hospital with a 20-bed burn center. RESULTS: A total of 459 patients 60 years and older were treated for burn injuries during the study period. Median age of burn patients was 71 years, 23.7% were 80 years and older, and 56.6% were female. The most common burn types were hot water scalds (43.6%) and flame burns (23.1%). Median burn size was 3% total body surface area (TBSA), 17.1% had burns > 10% TBSA, and 7.8% of patients had inhalation injuries. After initial evaluation, 46.4% of patients were discharged from the ED. Among patients discharged from the ED, only 1.9% were re-admitted for any reason within 30 days. Of the patients intubated in the ED, 7.1% were extubated during the first 2 days of admission, and 64.3% contracted ventilator-associated pneumonia. CONCLUSIONS: Better understanding of ED care for geriatric burn injuries may identify areas in which to improve emergency care for these vulnerable patients.

16.
Ann Gastroenterol ; 35(3): 249-259, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35599928

RESUMO

Background: The aim of this study was to investigate obese gastroparesis (GP) hospitalizations in the United States (US). Methods: We analyzed the National Inpatient Sample (NIS) from 2007-2017 to identify all adult obese (body mass index ≥30 kg/m2) GP hospitalizations. These were compared with non-obese GP hospitalizations. The demographic trends, adverse outcomes, and healthcare burden were analyzed. Results: From 2007-2017, obese GP hospitalizations accounted for 13.75% of all GP hospitalizations in the US. There was an increasing trend in obese GP hospitalizations, from 2286 in 2007 to 47,265 in 2017 (P=0.0019), and in the proportion of obese GP hospitalizations, from 6.16% in 2007 to 17.96% in 2017 (P<0.001). Males, Blacks, Hispanics, and Asians showed a rising trend in obese GP hospitalizations. Although rates of upper endoscopy declined from 8.28% in 2007 to 5.36% in 2017 (P<0.001), obese GP hospitalizations had higher rates of upper endoscopy utilization (6.05 vs. 5.42%, P<0.001) compared to the non-obese cohort. Inpatient mortality for obese GP hospitalizations increased from 0.64% in 2007 to 1.10% in 2017 (P<0.001). Furthermore, we noted a rising trend in mean length of stay (LOS), from 4.64 in 2007 to 6.05 days in 2017 (P=0.0029), and mean total hospital charge (THC), from $22,306 in 2007 to $62,220 in 2017 (P<0.001) for obese GP hospitalizations. Conclusions: The prevalence of obese GP hospitalizations along with inpatient mortality, LOS, and THC rose significantly. However, the overall rate of upper endoscopy utilization has decreased for these patients.

17.
Int J Biol Macromol ; 212: 451-464, 2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35618089

RESUMO

Antibiotics have been a source of concern since they are causing resistance in bacteria that live in water and air. As a result, green technology was used to manufacture silver and copper nanoparticles, which were encapsulated with the biopolymer chitosan derived from the root extract of the Potentilla astrosanguinea plant. XRD, FTIR, TEM, EDX, and UV-Visible spectroscopy were methods used for structural and spectroscopic analysis. These nanomaterials have a roughly spherical 2-30 nm average size and a face-centered cubic (FCC) shape, according to the findings. The photocatalytic drug degradation and antibacterial properties of the produced nanocomposites were outstanding, with some resistance lasting longer than 180 days. The current study discovered that under UV light exposure, silver nanocomposites degrade drugs rapidly within 40 min, with an average rate of over 95%, while copper nanocomposites degrade drugs rapidly within 70 min, with an average rate of 84%. These nanocomposites have demonstrated exceptionally compelling antibacterial action against Gram-positive, Gram-negative, and fungal pathogens in addition to photocatalytic activity. The lowest recorded MIC values were 10.30 µg/mL and 10.84 µg/mL, respectively, whereas the lowest MBC values were 91.24 µg/mL and 99.50 µg/mL.


Assuntos
Quitosana , Nanopartículas Metálicas , Nanocompostos , Antibacterianos/química , Antibacterianos/farmacologia , Cefuroxima/análogos & derivados , Quitosana/química , Cobre , Nanopartículas Metálicas/química , Testes de Sensibilidade Microbiana , Nanocompostos/química , Prata/química
18.
Proc Natl Acad Sci U S A ; 119(19): e2203967119, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35503911

RESUMO

Certain DNA sequences, including mirror-symmetric polypyrimidine•polypurine runs, are capable of folding into a triple-helix­containing non­B-form DNA structure called H-DNA. Such H-DNA­forming sequences occur frequently in many eukaryotic genomes, including in mammals, and multiple lines of evidence indicate that these motifs are mutagenic and can impinge on DNA replication, transcription, and other aspects of genome function. In this study, we show that the triplex-forming potential of H-DNA motifs in the mouse genome can be evaluated using S1-sequencing (S1-seq), which uses the single-stranded DNA (ssDNA)­specific nuclease S1 to generate deep-sequencing libraries that report on the position of ssDNA throughout the genome. When S1-seq was applied to genomic DNA isolated from mouse testis cells and splenic B cells, we observed prominent clusters of S1-seq reads that appeared to be independent of endogenous double-strand breaks, that coincided with H-DNA motifs, and that correlated strongly with the triplex-forming potential of the motifs. Fine-scale patterns of S1-seq reads, including a pronounced strand asymmetry in favor of centrally positioned reads on the pyrimidine-containing strand, suggested that this S1-seq signal is specific for one of the four possible isomers of H-DNA (H-y5). By leveraging the abundance and complexity of naturally occurring H-DNA motifs across the mouse genome, we further defined how polypyrimidine repeat length and the presence of repeat-interrupting substitutions modify the structure of H-DNA. This study provides an approach for studying DNA secondary structure genome-wide at high spatial resolution.


Assuntos
Genoma , Motivos de Nucleotídeos , Animais , Sequência de Bases , Genoma/genética , Camundongos , Conformação de Ácido Nucleico
19.
Artigo em Inglês | MEDLINE | ID: mdl-35619937

RESUMO

Objective: Endoscopic approaches for sinus and skull base surgery are increasing in popularity. The objective of this narrative review is to characterize risk factors for internal carotid artery injury in endoscopic endonasal surgery (EES), highlight preventative measures, and illustrate key management principles. Data Sources: Comprehensive literature review. Methods: Relevant literature was reviewed using PubMed/MEDLINE. Results: Carotid artery injury in EES is rare, with most studies reporting an incidence below 0.1%. Anatomic aberrancies, wide dissection margins, as well as specific provider and hospital factors, may increase the risk of injury. Multidisciplinary teams, comprehensive preoperative imaging, patient risk assessment, and formal training in vascular emergencies may reduce the risk. Management protocols should emphasize proper visualization of the injury site, fluid replacement, rapid packing, angiography, and endovascular techniques to achieve hemostasis. Conclusions: While EES is a relatively safe procedure, carotid artery injury is a devastating complication that warrants full consideration in surgical planning. Important preventative measures include identifying patients with notable risk factors and obtaining preoperative imaging. Multidisciplinary teams and management protocols are ultimately necessary to reduce morbidity and mortality.

20.
FASEB J ; 36 Suppl 12022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35553123

RESUMO

Pannexin channel isoforms (Panx1-3) are thought to release nucleotides into the extracellular milieu and have been shown to effect vascular hemodynamics. For this reason, we examined their mRNA and protein expression in hypertensive humans and genetically-inbred hypertensive mice. In both mouse and humans, we found a significant reduction in Panx3 expression in resistance artery endothelium. Thus, we hypothesized Panx3 may be a regulator of vascular function. In en face endothelial preparations from 3rd order mesenteric arteries, we localized Panx3 to the Golgi Apparatus as opposed to Panx1 which localized to the plasma membrane. Next, we generated an inducible, endothelial cell Panx3 knockout mouse (Panx3ECKO ). Radiotelemetry revealed a renin-independent spontaneous hypertension, with unremarkable immune infiltration in the kidney. There was no change in cytoplasmic or released ATP. To understand how Panx3 may regulate blood pressure, we examined whether Panx3 interacted with B Cell Lymphoma 6 (BCL6), a potential binding partner. En face proximity ligation assays demonstrated an interaction between Panx3 and BCL6 in the Golgi. Panx3ECKO mice exhibited significantly decreased BCL6 protein, hinting that Panx3 may stabilize BCL6 by binding at the BCL6 ubiquitin sites. In silico "threading" of the Panx3 sequence onto the cryo-EM structure of Panx1 confirmed this site of interaction. BCL6 is a NFκB repressor, thus its degradation in Panx3ECKO mice caused an increase in NFκB activity with IκBα and p100 significantly upregulated. A novel mimetic peptide designed to block Panx3-BCL6 interactions was administered into C57Bl/6J mice, which recapitulated these results. In addition, Panx3ECKO mice had increased endothelial NOX4 (but not NOX1 or NOX2), likely due to increased NFκB activity-this correlated with a significant increase in plasma H2 O2 , nitrotyrosine (NT3), and 4-hydroxynonenal (4-HNE). In line with this observation, 3rd order mesenteric arteries from Panx3ECKO mice constricted (not dilated) to acetylcholine, which was rescued with the H2 O2 -scavenger catalase (1000U/mL), suggesting that vascular oxidative stress drives hypertension in Panx3ECKO mice. Interestingly, Panx3ECKO mice also exhibit a significant increase in IL-4 receptors on endothelium, and increased IL-4 cytokines in bone marrow lysates. Because IL-4 can drive BCL6 expression in other cell types, we suggest a possible homeostatic immune-endothelial signaling axis. These data elucidate a novel Golgi-localized oxidative signaling pathway in endothelium with a potential immune-derived negative feedback loop.

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