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1.
J Clin Rheumatol ; 2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38976618

ABSTRACT

BACKGROUND/OBJECTIVE: Rheumatologic diseases encompass a group of disabling conditions that often require expensive clinical treatments and limit an individual's ability to work and maintain a steady income. The purpose of this study was to evaluate contemporary patterns of financial toxicity among patients with rheumatologic disease and assess for any associated demographic factors. METHODS: The cross-sectional National Health Interview Survey was queried from 2013 to 2018 for patients with rheumatologic disease. Patient demographics and self-reported financial metrics were collected or calculated including financial hardship from medical bills, financial distress, food insecurity, and cost-related medication (CRM) nonadherence. Multivariable logistic regressions were used to assess for factors associated with increased financial hardship. RESULTS: During the study period, 20.2% of 41,502 patients with rheumatologic disease faced some degree of financial hardship due to medical bills, 55.0% of whom could not pay those bills. Rheumatologic disease was associated with higher odds of financial hardship from medical bills (adjusted odds ratio, 1.29; 95% confidence interval, 1.22-1.36; p < 0.001) with similar trends for patients suffering from financial distress, food insecurity, and CRM nonadherence (p < 0.001 for all). Financial hardship among patients with rheumatologic disease was associated with being younger, male, Black, and uninsured (p < 0.001 for all). CONCLUSION: In this nationally representative study, we found that a substantial proportion of adults with rheumatologic disease in the United States struggled with paying their medical bills and suffered from food insecurity and CRM nonadherence. National health care efforts and guided public policy should be pursued to help ease the burden of financial hardship for these patients.

2.
J Phys Chem A ; 128(27): 5362-5373, 2024 Jul 11.
Article in English | MEDLINE | ID: mdl-38935631

ABSTRACT

The thermal decomposition of perfluorooctanoic acid (PFOA) under oxidative conditions was investigated using air (O2) and N2O as oxidants over temperatures ranging from 400 to 1000 °C in an α-alumina reactor. In the presence of air, PFOA was found to decompose into perfluorohept-1-ene (C7F14) and perfluoroheptanoyl fluoride (C7F14O) in addition to HF, CO, and CO2. At temperatures above 800 °C, both C7F14 and C7F14O were no longer detected. A comprehensive analysis of the reaction mechanisms through quantum chemical analysis and kinetic modeling in combination with experimental observations was utilized to identify key reaction pathways. Quantum chemical analysis led to the conclusion that oxygen atoms are crucial in decomposing perfluoroalk-1-enes, especially the stable perfluorohept-1-ene (C7F14). Under oxidative conditions, it was found that significant quantities of C2F6 and CF4 were formed. Further quantum chemical analysis suggests that the O atoms facilitate the formation of volatile fluorinated compounds (VFCs) such as tetrafluoromethane (CF4) and hexafluoroethane (C2F6), particularly at higher temperatures. By elucidating these key reactions, an improved understanding of the potential formation products of incomplete combustion (PICs) or products of incomplete destruction (PIDs) is made.

3.
Arthroscopy ; 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38925234

ABSTRACT

PURPOSE: To provide a proof-of-concept analysis of the appropriateness and performance of ChatGPT-4 to triage, synthesize differential diagnoses, and generate treatment plans concerning common presentations of knee pain. METHODS: Twenty knee complaints warranting triage and expanded scenarios were input into ChatGPT-4, with memory cleared prior to each new input to mitigate bias. For the 10 triage complaints, ChatGPT-4 was asked to generate a differential diagnosis which was graded for accuracy and suitability in comparison to a differential created by two orthopaedic sports medicine physicians. For the 10 clinical scenarios, ChatGPT-4 was prompted to provide treatment guidance for the patient, which was again graded. To test the higher-order capabilities of ChatGPT-4, further inquiry into these specific management recommendations was performed and graded. RESULTS: All ChatGPT-4 diagnoses were deemed appropriate within the spectrum of potential pathologies on a differential. The top diagnosis on the differential was identical between surgeons and ChatGPT-4 for 70% of scenarios, and the top diagnosis provided by the surgeon appeared as either the first or second diagnosis in 90% of scenarios. Overall, 16/30 (53.3%) of diagnoses in the differential were identical. When provided with 10 expanded vignettes with a single diagnosis, the accuracy of ChatGPT-4 increased to 100%, with the suitability of management graded as appropriate in 90% of cases. Specific information pertaining to conservative management, surgical approaches, and related treatments was appropriate and accurate in 100% of cases. CONCLUSION: ChatGPT-4 provided clinically reasonable diagnoses to triage patient complaints of knee pain due to various underlying conditions that was generally consistent with differentials provided by sports medicine physicians. Diagnostic performance was enhanced when providing additional information, allowing ChatGPT-4 to reach high predictive accuracy for recommendations concerning management and treatment options. However, ChatGPT-4 may demonstrate clinically important error rates for diagnosis depending on prompting strategy and information provided; therefore, further are necessary to prior to implementation into clinical workflows.

4.
Article in English | MEDLINE | ID: mdl-38918331

ABSTRACT

PURPOSE OF REVIEW: The management of shoulder instability in throwing athletes remains a challenge given the delicate balance between physiologic shoulder laxity facilitating performance and the inherent need for shoulder stability. This review will discuss the evaluation and management of a throwing athlete with suspected instability with a focus on recent findings and developments. RECENT FINDINGS: The vast majority of throwing athletes with shoulder instability experience subtle microinstability as a result of repetitive microtrauma rather than episodes of gross instability. These athletes may present with arm pain, dead arms or reduced throwing velocity. Recent literature reinforces the fact that there is no "silver bullet" for the management of these athletes and an individualized, tailored approach to treatment is required. While initial nonoperative management remains the hallmark for treatment, the results of rehabilitation protocols are mixed, and some patients will ultimately undergo surgical stabilization. In these cases, it is imperative that the surgeon be judicious with the extent of surgical stabilization as overtightening of the glenohumeral joint is possible, which can adversely affect athlete performance. Managing shoulder instability in throwing athletes requires a thorough understanding of its physiologic and biomechanical underpinnings. Inconsistent results seen with surgical stabilization has led to a focus on nonoperative management for these athletes with surgery reserved for cases that fail to improve non-surgically. Overall, more high quality studies into the management of this challenging condition are warranted.

6.
J Cell Biol ; 223(9)2024 Sep 02.
Article in English | MEDLINE | ID: mdl-38869473

ABSTRACT

At each cell division, nanometer-scale motors and microtubules give rise to the micron-scale spindle. Many mitotic motors step helically around microtubules in vitro, and most are predicted to twist the spindle in a left-handed direction. However, the human spindle exhibits only slight global twist, raising the question of how these molecular torques are balanced. Here, we find that anaphase spindles in the epithelial cell line MCF10A have a high baseline twist, and we identify factors that both increase and decrease this twist. The midzone motors KIF4A and MKLP1 are together required for left-handed twist at anaphase, and we show that KIF4A generates left-handed torque in vitro. The actin cytoskeleton also contributes to left-handed twist, but dynein and its cortical recruitment factor LGN counteract it. Together, our work demonstrates that force generators regulate twist in opposite directions from both within and outside the spindle, preventing strong spindle twist during chromosome segregation.


Subject(s)
Anaphase , Kinesins , Microtubules , Spindle Apparatus , Humans , Spindle Apparatus/metabolism , Kinesins/metabolism , Kinesins/genetics , Microtubules/metabolism , Dyneins/metabolism , Dyneins/genetics , Torque , Chromosome Segregation , Actin Cytoskeleton/metabolism , Microtubule-Associated Proteins/metabolism , Microtubule-Associated Proteins/genetics
7.
Resuscitation ; : 110263, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38848964

ABSTRACT

STUDY OBJECTIVE: Evaluate the association between early naloxone use and outcomes after out-of-hospital cardiac arrest (OHCA) with initial non-shockable rhythms. METHODS: This study was a secondary analysis of data collected in the Portland Cardiac Arrest Epidemiologic Registry, a database containing details of emergency medical services (EMS)-treated OHCA cases in the Portland, Oregon metropolitan region. Eligible patients had non-traumatic OHCA with an initial non-shockable rhythm and received naloxone by EMS or law enforcement prior to IV/IO access (exposure group). The primary outcome was ROSC at emergency department (ED) arrival. Secondary outcomes included survival to admission, survival to hospital discharge, and cerebral performance category score ≤2 at discharge (good neurologic outcome). We performed multivariable logistic regressions adjusting for age, sex, arrest location, witness status, bystander interventions, dispatch to EMS arrival time, initial rhythm, and county of arrest. RESULTS: There were 1807 OHCA cases from 2018 to 2021 meeting eligibility criteria, with 57 receiving naloxone before vascular access. Patients receiving naloxone prior to vascular access attempts had higher adjusted odds (aOR [95% CI]) of ROSC at any time (2.14 [1.20-3.81]), ROSC at ED arrival (2.14 [1.18-3.88]), survival to admission (2.86 [1.60-5.09]), survival to discharge (4.41 [1.78-10.97]), and good neurologic outcome (4.61 [1.74-12.19]). CONCLUSIONS: Patients with initial non-shockable OHCA who received law enforcement or EMS naloxone prior to IV/IO access attempts had higher adjusted odds of ROSC at any time, ROSC at ED arrival, survival to admission, survival to discharge, and good neurologic outcome.

8.
Ann Otol Rhinol Laryngol ; : 34894241256697, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38840493

ABSTRACT

BACKGROUND: The incidence of thyroid cancer in the United States has risen dramatically since the 1970s, driven by an increase in the diagnosis of small tumors. There is a paucity of published New Mexico (NM) specific data regarding thyroid cancer. We hypothesized that due to New Mexico's unique geographic and cultural makeup, the incidence of thyroid cancer and tumor size at diagnosis in this state would differ from that demonstrated on a national level. METHODS: The New Mexico Tumor Registry (NMTR) was queried to include all NM residents diagnosed with thyroid cancer between 1992 and 2019. For 2010 to 2019, age-adjusted incidence rates were calculated via direct method using the 2000 United States population as the adjustment standard. Differences in incidence rate and tumor size by race/ethnicity and residence (metropolitan vs non-metropolitan) were assessed with rate ratios between groups. For 1992 to 2019, temporal trends in age-adjusted incidence rates for major race/ethnic groups in NM [Non-Hispanic White (NHW), Hispanic, and American Indian (AI)] were assessed by joinpoint regression using National Cancer Institute software. RESULTS: Our study included 3,161 patients for the time period 2010 to 2019, including NHW (1518), Hispanic (1425), and AI (218) cases. The overall incidence rates for NM AIs were lower than those for Hispanics and NHWs because of a decreased incidence of very small tumors (<1.1 cm). The incidence rates for large tumors (>5.1 cm) was equivalent among groups. In the early 2000s, Hispanics also had lower rates of small tumors when compared to NHWs but this trend disappeared over time. CONCLUSION: AIs in New Mexico have been left out of the nationwide increase in incidental diagnosis of small thyroid tumors. This same pattern was noted for Hispanics in the early 2000s but changed over time to mirror incidence rates for NHWs. These data are illustrative of the health care disparities that exist among New Mexico's population and how these disparities have changed over time.

9.
bioRxiv ; 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38853979

ABSTRACT

We and others discovered a highly-conserved mitochondrial transmembrane microprotein, named Mitoregulin (Mtln), that supports lipid metabolism. We reported that Mtln strongly binds cardiolipin (CL), increases mitochondrial respiration and Ca 2+ retention capacities, and reduces reactive oxygen species (ROS). Here we extend our observation of Mtln-CL binding and examine Mtln influence on cristae structure and mitochondrial membrane integrity during stress. We demonstrate that mitochondria from constitutive- and inducible Mtln-knockout (KO) mice are susceptible to membrane freeze-damage and that this can be rescued by acute Mtln re-expression. In mitochondrial-simulated lipid monolayers, we show that synthetic Mtln decreases lipid packing and monolayer elasticity. Lipidomics revealed that Mtln-KO heart tissues show broad decreases in 22:6-containing lipids and increased cardiolipin damage/remodeling. Lastly, we demonstrate that Mtln-KO mice suffer worse myocardial ischemia-reperfusion injury, hinting at a translationally-relevant role for Mtln in cardioprotection. Our work supports a model in which Mtln binds cardiolipin and stabilizes mitochondrial membranes to broadly influence diverse mitochondrial functions, including lipid metabolism, while also protecting against stress.

10.
Arthroscopy ; 2024 May 21.
Article in English | MEDLINE | ID: mdl-38777001

ABSTRACT

PURPOSE: To (1) analyze trends in the publishing of statistical fragility index (FI)-based systematic reviews in the orthopaedic literature, including the prevalence of misleading or inaccurate statements related to the statistical fragility of randomized controlled trials (RCTs) and patients lost to follow-up (LTF), and (2) determine whether RCTs with relatively "low" FIs are truly as sensitive to patients LTF as previously portrayed in the literature. METHODS: All FI-based studies published in the orthopaedic literature were identified using the Cochrane Database of Systematic Reviews, Web of Science Core Collection, PubMed, and MEDLINE databases. All articles involving application of the FI or reverse FI to study the statistical fragility of studies in orthopaedics were eligible for inclusion in the study. Study characteristics, median FIs and sample sizes, and misleading or inaccurate statements related to the FI and patients LTF were recorded. Misleading or inaccurate statements-defined as those basing conclusions of trial fragility on the false assumption that adding patients LTF back to a trial has the same statistical effect as existing patients in a trial experiencing the opposite outcome-were determined by 2 authors. A theoretical RCT with a sample size of 100, P = .006, and FI of 4 was used to evaluate the difference in effect on statistical significance between flipping outcome events of patients already included in the trial (FI) and adding patients LTF back to the trial to show the true sensitivity of RCTs to patients LTF. RESULTS: Of the 39 FI-based studies, 37 (95%) directly compared the FI with the number of patients LTF. Of these 37 studies, 22 (59%) included a statement regarding the FI and patients LTF that was determined to be inaccurate or misleading. In the theoretical RCT, a reversal of significance was not observed until 7 patients LTF (nearly twice the FI) were added to the trial in the distribution of maximal significance reversal. CONCLUSIONS: The claim that any RCT in which the number of patients LTF exceeds the FI could potentially have its significance reversed simply by maintaining study follow-ups is commonly inaccurate and prevalent in orthopaedic studies applying the FI. Patients LTF and the FI are not equivalent. The minimum number of patients LTF required to flip the significance of a typical RCT was shown to be greater than the FI, suggesting that RCTs with relatively low FIs may not be as sensitive to patients LTF as previously portrayed in the literature; however, only a holistic approach that considers the context in which the trial was conducted, potential biases, and study results can determine the merits of any particular RCT. CLINICAL RELEVANCE: Surgeons may benefit from re-examining their interpretation of prior FI reviews that have made claims of substantial RCT fragility based on comparisons between the FI and patients LTF; it is possible the results are more robust than previously believed.

11.
Kidney Int Rep ; 9(5): 1163-1166, 2024 May.
Article in English | MEDLINE | ID: mdl-38707828
12.
Pest Manag Sci ; 2024 May 08.
Article in English | MEDLINE | ID: mdl-38717312

ABSTRACT

BACKGROUND: Goss's bacterial wilt and leaf blight (Goss's wilt), caused by the bacterium Clavibacter nebraskensis, is a corn disease that has been a top ten yield-reducing disease in North America in the past 15 years. Isoxadifen-ethyl is an herbicide safener that effectively increases cytochrome P450 activity in corn which enhances a plant's metabolism of herbicide molecules. Recent research found a potential link between isoxadifen-ethyl and increased Goss's wilt severity. RESULTS: The application of isoxadifen-ethyl increased (P = 0.014-0.046) area under disease progress curve (AUDPC) by 19%, 7%, and 9% at three environments, independent of accompanying herbicide or herbicide application timing. However, no significant differences in incidence of systemic wilt or corn grain yield occurred among treatments at any environment. CONCLUSION: These data provide evidence for an association between isoxadifen-ethyl safener and Goss's wilt in corn. The reason for this association is unknown, but the safener may affect plant or pathogen physiological mechanisms. While the increased disease severity did not result in decreased grain yield in these experiments, an increase in pathogen inoculum due to higher disease severity could influence Goss' wilt epidemics in future years. © 2024 Society of Chemical Industry.

13.
Nat Genet ; 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811841

ABSTRACT

Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9 (Cas9) is a powerful tool for introducing targeted mutations in DNA, but recent studies have shown that it can have unintended effects such as structural changes. However, these studies have not yet looked genome wide or across data types. Here we performed a phenotypic CRISPR-Cas9 scan targeting 17,065 genes in primary human cells, revealing a 'proximity bias' in which CRISPR knockouts show unexpected similarities to unrelated genes on the same chromosome arm. This bias was found to be consistent across cell types, laboratories, Cas9 delivery methods and assay modalities, and the data suggest that it is caused by telomeric truncations of chromosome arms, with cell cycle and apoptotic pathways playing a mediating role. Additionally, a simple correction is demonstrated to mitigate this pervasive bias while preserving biological relationships. This previously uncharacterized effect has implications for functional genomic studies using CRISPR-Cas9, with applications in discovery biology, drug-target identification, cell therapies and genetic therapeutics.

14.
J Evid Based Soc Work (2019) ; : 1-21, 2024 May 19.
Article in English | MEDLINE | ID: mdl-38762851

ABSTRACT

PURPOSE: Domestic violence manifests in unique ways in South Asian immigrant communities. Given the need to uphold family honor, formal help-seeking remains minimal within this community. Individuals experiencing victimization rely on friends and family members as informal sources of support. These friends and family members may also be bystanders who witness victimization. Therefore, the goal of this study was to examine differences in participant responses to an online interactive bystander intervention developed for South Asians. METHODS: To get community response to the intervention, B.R.A.K.E. The Cycle, a Qualtrics link with all the intervention scenarios was posted on 21 sub-Reddit pages. Screeners to ensure that participants were of South Asian origin, 18 or older and currently residing in the United States (US) were added. True to the study purpose, to examine differences across gender and generational position, we conducted descriptive analysis and chi-square tests. RESULTS: There were differences in scenarios by gender and immigration position. Some of the main findings point to the need to report domestic violence, seek help (formal or informal) as well as surprisingly some responses justified the use of force by a male partner. We discuss these in-depth by scenarios. DISCUSSION: This is the first study to examine differences in bystander preference and response to using an intervention that was developed specifically for the South Asian community. Social workers can utilize this intervention to create dialogue around domestic violence prevention and the role of bystander within the South Asian and potentially other immigrant communities.

15.
Analyst ; 149(13): 3564-3574, 2024 Jun 24.
Article in English | MEDLINE | ID: mdl-38717518

ABSTRACT

Field-forward analytical technologies, such as portable mass spectrometry (MS), enable essential capabilities for real-time monitoring and point-of-care diagnostic applications. Significant and recent investments improving the features of miniaturized mass spectrometers enable various new applications outside of small molecule detection. Most notably, the addition of tandem mass spectrometry scans (MS/MS) allows the instrument to isolate and fragment ions and increase the analytical specificity by measuring unique chemical signatures for ions of interest. Notwithstanding these technological advancements, low-cost, portable systems still struggle to confidently identify clinically significant organisms of interest, such as bacteria, viruses, and proteinaceous toxins, due to the limitations in resolving power. To overcome these limitations, we developed a novel multidimensional mass fingerprinting technique that uses tandem mass spectrometry to increase the chemical specificity for low-resolution mass spectral profiles. We demonstrated the method's capabilities for differentiating four different bacteria, including attentuated strains of Yersinia pestis. This approach allowed for the accurate (>92%) identification of each organism at the strain level using de-resolved matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) data to mimic the performance characteristics of miniaturized mass spectrometers. This work demonstrates that low-resolution mass spectrometers, equipped with tandem MS acquisition modes, can accurately identify clinically relevant bacteria. These findings support the future application of these technologies for field-forward and point-of-care applications where high-performance mass spectrometers would be cost-prohibitive or otherwise impractical.


Subject(s)
Tandem Mass Spectrometry , Yersinia pestis , Yersinia pestis/isolation & purification , Tandem Mass Spectrometry/methods , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/methods , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization/instrumentation , Bacteria/isolation & purification
16.
J Burn Care Res ; 2024 Apr 11.
Article in English | MEDLINE | ID: mdl-38602148

ABSTRACT

Burn injuries often lead to psychological distress, from depression and anxiety to adjustment concerns and posttraumatic stress. There is some evidence that the anatomical location of burn injuries (e.g., head/neck, feet) has a specific negative impact on psychological functioning. The purpose of this study was to examine the associations between burn injury location and emotional distress. First, we administered self-report questionnaires to burn survivors with ≤ 5% TBSA at a single adult outpatient burn clinic. Second, we used a cross-sectional analysis of the Burn Model System National Database. The mean values of each measure of psychological distress (i.e., quality of life, self-esteem, depression, posttraumatic stress, anxiety, and, for contrast, posttraumatic growth) were examined for each anatomical location for those participants with a burn in those anatomical areas against those with burn in other areas, Using Kruskal-Wallis tests to compare psychological distress, we found no significant differences in outcome measures in either sample analyzed in our study. These findings contrast with prior literature indicating the negative psychological impact of burn injuries to certain locations in the body. Further research should explore whether larger burns (i.e., greater than 5% TBSA) affecting critical areas of the body may be associated with psychological distress.

17.
JACC Clin Electrophysiol ; 10(5): 930-940, 2024 May.
Article in English | MEDLINE | ID: mdl-38661602

ABSTRACT

BACKGROUND: Postoperative atrial fibrillation (POAF) is associated with increased morbidity and mortality. Epicardial injection of botulinum toxin may suppress POAF. OBJECTIVES: This study sought to assess the safety and efficacy of AGN-151607 for the prevention of POAF after cardiac surgery. METHODS: This phase 2, randomized, placebo-controlled trial assessed the safety and efficacy of AGN-151607, 125 U and 250 U vs placebo (1:1:1), for the prevention of POAF after cardiac surgery. Randomization was stratified by age (<65, ≥65 years) and type of surgery (nonvalvular/valve surgery). The primary endpoint was the occurrence of continuous AF ≥30 seconds. RESULTS: Among 312 modified intention-to-treat participants (placebo, n = 102; 125 U, n = 104; and 250 U, n = 106), the mean age was 66.9 ± 6.8 years; 17% were female; and 64% had coronary artery bypass graft (CABG) only, 12% had CABG + valve, and 24% had valve surgery. The primary endpoint occurred in 46.1% of the placebo group, 36.5% of the 125-U group (relative risk [RR] vs placebo: 0.80; 95% CI: 0.58-1.10; P = 0.16), and 47.2% of the 250-U group (RR vs placebo: 1.04; 95% CI: 0.79-1.37; P = 0.78). The primary endpoint was reduced in the 125-U group in those ≥65 years of age (RR: 0.64; 95% CI: 0.43-0.94; P = 0.02) with a greater reduction in CABG-only participants ≥65 years of age (RR: 0.49; 95% CI: 0.27-0.87; P = 0.01). Rehospitalization and rates of adverse events were similar across the 3 groups. CONCLUSIONS: There were no significant differences in the rate of POAF with either dose compared with placebo; however, there was a lower rate of POAF in participants ≥65 years undergoing CABG only and receiving 125 U of AGN-151607. These hypothesis-generating findings require investigation in a larger, adequately powered randomized clinical trial. (Botulinum Toxin Type A [AGN-151607] for the Prevention of Post-operative Atrial Fibrillation in Adult Participants Undergoing Open-chest Cardiac Surgery [NOVA]; NCT03779841); A Phase 2, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Dose Ranging Study to Evaluate the Efficacy and Safety of Botulinum Toxin Type A [AGN 151607] Injections into the Epicardial Fat Pads to Prevent Post-Operative Atrial Fibrillation in Patients Undergoing Open-Chest Cardiac Surgery; 2017-004399-68).


Subject(s)
Atrial Fibrillation , Botulinum Toxins, Type A , Postoperative Complications , Humans , Atrial Fibrillation/prevention & control , Female , Male , Aged , Botulinum Toxins, Type A/therapeutic use , Botulinum Toxins, Type A/administration & dosage , Middle Aged , Postoperative Complications/prevention & control , Double-Blind Method , Cardiac Surgical Procedures/adverse effects , Treatment Outcome , Coronary Artery Bypass/adverse effects
18.
Cell Syst ; 15(4): 388-408.e4, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38636458

ABSTRACT

Genome-wide measurement of ribosome occupancy on mRNAs has enabled empirical identification of translated regions, but high-confidence detection of coding regions that overlap annotated coding regions has remained challenging. Here, we report a sensitive and robust algorithm that revealed the translation of 388 N-terminally truncated proteins in budding yeast-more than 30-fold more than previously known. We extensively experimentally validated them and defined two classes. The first class lacks large portions of the annotated protein and tends to be produced from a truncated transcript. We show that two such cases, Yap5truncation and Pus1truncation, have condition-specific regulation and distinct functions from their respective annotated isoforms. The second class of truncated protein isoforms lacks only a small region of the annotated protein and is less likely to be produced from an alternative transcript isoform. Many display different subcellular localizations than their annotated counterpart, representing a common strategy for dual localization of otherwise functionally identical proteins. A record of this paper's transparent peer review process is included in the supplemental information.


Subject(s)
Saccharomyces cerevisiae Proteins , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Protein Isoforms/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism , Ribosomes/genetics , Ribosomes/metabolism , Genome , Saccharomyces cerevisiae Proteins/genetics , Basic-Leucine Zipper Transcription Factors
20.
Am J Cancer Res ; 14(2): 562-584, 2024.
Article in English | MEDLINE | ID: mdl-38455403

ABSTRACT

Previous studies reported that alternating electric fields (EFs) in the intermediate frequency (100-300 kHz) and low intensity (1-3 V/cm) regime - termed "Tumor Treating Fields" (TTFields) - have a specific, anti-proliferative effect on glioblastoma multiforme (GBM) cells. However, the mechanism(s) of action remain(s) incompletely understood, hindering the clinical adoption of treatments based on TTFields. To advance the study of such treatment in vitro, we developed an inductive device to deliver EFs to cell cultures which improves thermal and osmolar regulation compared to prior devices. Using this inductive device, we applied continuous, 200 kHz electromagnetic fields (EMFs) with a radial EF amplitude profile spanning 0-6.5 V/cm to cultures of primary rat astrocytes and several human GBM cell lines - U87, U118, GSC827, and GSC923 - for a duration of 72 hours. Cell density was assessed via segmented pixel densities from GFP expression (U87, U118) or from staining (astrocytes, GSC827, GSC923). Further RNA-Seq analyses were performed on GSC827 and GSC923 cells. Treated cultures of all cell lines exhibited little to no change in proliferation at lower EF amplitudes (0-3 V/cm). At higher amplitudes (> 4 V/cm), different effects were observed. Apparent cell densities increased (U87), decreased (GSC827, GSC923), or showed little change (U118, astrocytes). RNA-Seq analyses on treated and untreated GSC827 and GSC923 cells revealed differentially expressed gene sets of interest, such as those related to cell cycle control. Up- and down-regulation, however, was not consistent across cell lines nor EF amplitudes. Our results indicate no consistent, anti-proliferative effect of 200 kHz EMFs across GBM cell lines and thus contradict previous in vitro findings. Rather, effects varied across different cell lines and EF amplitude regimes, highlighting the need to assess the effect(s) of TTFields and similar treatments on a per cell line basis.

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