Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 18.078
Filter
1.
Int J Mol Sci ; 25(14)2024 Jul 16.
Article in English | MEDLINE | ID: mdl-39063037

ABSTRACT

The opening of the Torpedo CLC-0 chloride (Cl-) channel is known to be regulated by two gating mechanisms: fast gating and slow (common) gating. The structural basis underlying the fast-gating mechanism is better understood than that of the slow-gating mechanism, which is still largely a mystery. Our previous study on the intracellular proton (H+i)-induced inhibition of the CLC-0 anionic current led to the conclusion that the inhibition results from the slow-gate closure (also called inactivation). The conclusion was made based on substantial evidence such as a large temperature dependence of the H+i inhibition similar to that of the channel inactivation, a resistance to the H+i inhibition in the inactivation-suppressed C212S mutant, and a similar voltage dependence between the current recovery from the H+i inhibition and the recovery from the channel inactivation. In this work, we further examine the mechanism of the H+i inhibition of wild-type CLC-0 and several mutants. We observe that an anion efflux through the pore of CLC-0 accelerates the recovery from the H+i-induced inhibition, a process corresponding to the slow-gate opening. Furthermore, various inactivation-suppressed mutants exhibit different current recovery kinetics, suggesting the existence of multiple inactivated states (namely, slow-gate closed states). We speculate that protonation of the pore of CLC-0 increases the binding affinity of permeant anions in the pore, thereby generating a pore blockage of ion flow as the first step of inactivation. Subsequent complex protein conformational changes further transition the CLC-0 channel to deeper inactivated states.


Subject(s)
Chloride Channels , Ion Channel Gating , Protons , Chloride Channels/metabolism , Chloride Channels/antagonists & inhibitors , Chloride Channels/chemistry , Chloride Channels/genetics , Ion Channel Gating/drug effects , Animals , Mutation , Kinetics
2.
Open Res Eur ; 4: 60, 2024.
Article in English | MEDLINE | ID: mdl-38946739

ABSTRACT

Hard candies are sugar confections comprising mainly water and sucrose. Corn syrup, colorants and flavors are also usually added to hard candy formulations. The production of hard candy requires heating of the ingredients to very high temperatures to reduce moisture content and subsequent cooling to obtain a solid matrix. Cooling of the mixtures achieves the final, well known glassy state of the products. In this glassy state, the system is kinetically stable and molecular mobility is restricted, providing longer shelf life to hard candies. There are, however, several factors affecting the final quality and consumer acceptance of hard candies. Production methods and parameters, initial formulations as well as storage conditions all play a crucial role in the physicochemical, textural and sensory properties of hard candies. Addition of colorants and flavors also plays a vital role in the final quality. Although hard candy production is a simple process with few production stages, even small changes in the method of production and process parameters may induce substantial changes in the final product characteristics. Additionally, storage conditions such as temperature and humidity can change the product properties leading to graining and stickiness which are the two major problems for hard candies during storage. Both production and storage conditions should therefore be carefully chosen and controlled for desirable hard candy properties. This review addresses the general production methods and considers process parameters and quality parameters of hard candy products. Moreover, a comprehensive review of the related hard candy literature is also presented. The majority of hard candy reviews focus on specific methods and processes, but this review will present a more general frame on the subject.

3.
ACS Nano ; 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38951541

ABSTRACT

Terbium-doped gadolinium oxysulfide (Gd2O2S:Tb3+), commonly referred to as Gadox, is a widely used scintillator material due to its exceptional X-ray attenuation efficiency and high light yield. However, Gadox-based scintillators suffer from low X-ray spatial resolution due to their large particle size, which causes significant light scattering. To address this limitation, we report the synthesis of terbium-doped colloidal Gadox nanoplatelets (NPLs) with near-unity photoluminescence quantum yield (PLQY) and high radioluminescence light yield (LY). In particular, our investigation reveals a strong correlation between PLQY, LY, particle size, and Tb3+concentration. Our synthetic approach allows precise control over the lateral size and thickness of the Gadox NPLs, resulting in a LY of 50,000 photons/MeV. Flexible scintillating screens fabricated with the solution-processable Gadox NPLs exhibited a 20 lp/mm X-ray spatial resolution, surpassing commercial Gadox scintillators. These high-performance and flexible Gadox NPL-based scintillators enable enhanced X-ray imaging capabilities in medicine and security. Our work provides a framework for designing nanomaterial scintillators with superior spatial resolution and efficiency through precise control of dimensions and dopant concentration.

5.
Mem Cognit ; 2024 Jul 03.
Article in English | MEDLINE | ID: mdl-38961049

ABSTRACT

The levels-of-processing (LOP) framework, proposing that deep processing yields superior retention, has provided an important paradigm for memory research and a practical means of improving learning. However, the available levels-of-processing literature focuses on immediate memory performance. It is assumed within the LOP framework that deep processing will lead to slower forgetting than will shallow processing. However, it is unclear whether, or how, the initial level of processing affects the forgetting slopes over longer retention intervals. The present three experiments were designed to explore whether items encoded at qualitatively different LOP are forgotten at different rates. In the first two experiments, depth of processing was manipulated within-participants at encoding under deep and shallow conditions (semantic vs. rhyme judgement in Experiment 1; semantic vs. consonant-vowel pattern decision in Experiment 2). Recognition accuracy (d prime) was measured between-participants immediately after learning and at 30-min, 2-h, and 24-h delays. The third experiment employed a between-participants design, contrasting the rates of forgetting following semantic and phonological (rhyme) processing at immediate, 30-min, 2-h, and 6-h delays. Results from the three experiments consistently demonstrated a large effect size of levels of processing on immediate performance and a medium-to-large level effect size on delayed recognition, but crucially no LOP × delay group interaction. Analysis of the retention curves revealed no significant differences between the slopes of forgetting for deep and shallow processing. These results suggest that the rates of forgetting are independent of the qualitatively distinct encoding operations manipulated by levels of processing.

6.
Am J Surg Pathol ; 2024 Jul 04.
Article in English | MEDLINE | ID: mdl-38963187

ABSTRACT

We investigated the frequency and associated pathology of embryoid bodies in ovarian tumors by evaluating neoplasms in which they are known to occur: 100 immature teratomas, 125 malignant mixed germ cell tumors, and 6 polyembryomas. Three immature teratomas contained a single relatively well-formed embryoid body, whereas these and 11 others showed foci we categorized as embryoid body remnants consisting of microscopic aggregates of embryonal or yolk sac-type epithelium associated with spaces consistent with yolk sac or amniotic cavity but lacking a classic embryoid body structure. Teratomas with these foci were all high grade. A well-formed embryoid body was found in only 1 malignant mixed tumor, but embryoid body remnants were present in 25%, invariably associated with foci of immature teratoma (100%) and often with yolk sac tumor (97%), embryonal carcinoma (35%), or both (32%). These foci usually took the form of round to oval aggregates, often well-circumscribed, for which the term "polyembryoma background" has been proposed. The polyembryomas were typically grossly hemorrhagic and occurred in patients from 9 to 43 years of age. The embryoid bodies in them generally grew in lobules within an edematous to occasionally myxoid stroma. Four tumors contained liver-like cells, 4 numerous glands likely recapitulating the allantois, 3 syncytiotrophoblast cells, 2 prominent cysts, and 2 striking vascular proliferations. This study indicates that (1) typical embryoid bodies are rare in immature teratomas but about 14% of them have embryoid body remnants. (2) Embryoid body remnants are seen in 25% of malignant mixed germ cell tumors with a teratomatous component and often proliferate to form yolk sac tumor and embryonal carcinoma. (3) Well-formed embryoid bodies growing in a confluent manner (polyembryoma) are rare, and minor foci of teratoma, yolk sac tumor, or embryonal carcinoma are almost always present, indicating that these are fundamentally malignant mixed germ cell tumors but the polyembryoma component is dominant and distinctive which, in our opinion, justifies its own nomenclature. (4) Embryoid bodies are not a feature of other germ cell tumors.

7.
Mov Disord ; 2024 Jun 30.
Article in English | MEDLINE | ID: mdl-38946200

ABSTRACT

Various forms of Parkinson's disease, including its common sporadic form, are characterized by prominent α-synuclein (αSyn) aggregation in affected brain regions. However, the role of αSyn in the pathogenesis and evolution of the disease remains unclear, despite vast research efforts of more than a quarter century. A better understanding of the role of αSyn, either primary or secondary, is critical for developing disease-modifying therapies. Previous attempts to hone this research have been challenged by experimental limitations, but recent technological advances may facilitate progress. The Scientific Issues Committee of the International Parkinson and Movement Disorder Society (MDS) charged a panel of experts in the field to discuss current scientific priorities and identify research strategies with potential for a breakthrough. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

8.
World Neurosurg ; 2024 Jul 14.
Article in English | MEDLINE | ID: mdl-39013500

ABSTRACT

BACKGROUND AND OBJECTIVES: Despite their asymptomatic occurrence, unruptured intracranial aneurysms (UIAs) account for a significant proportion of hospital charges and healthcare resource utilization in the United States. Hospital length of stay (LOS) is a reimbursement metric utilized to incentivize value-based care. Our study identifies predictors of extended LOS (eLOS) after elective treatment of UIAs. METHODS: This was a retrospective study of 525 patients who underwent elective treatment of an unruptured intracranial aneurysm (UIA) at a single institution. Data was collected with regard to demographics, clinical presentation, treatment characteristics and post-operative outcomes. The primary outcome, eLOS, was defined as hospital stay in the upper quartile of the median (≥75th percentile). Univariate and multivariate analyses was performed to identify factors predictive of eLOS in this cohort. RESULTS: The average age of the cohort was 61.40, standard deviation (SD)= 11.41. 77.3% of the cohort was female. The median duration of LOS was 2 days (interquartile range (IQR): 1-5). 11.6% experienced eLOS (≥5 days). Multivariate logistic regression identified age (OR: 1.04, 95% confidence interval (CI): 1.01- 1.07), co-existent vascular pathology (OR: 21.33, 95% CI: 8.06- 56.39), open surgery (OR: 3.93, 95% CI: 1.85- 8.34) and post-operative stroke (OR: 11.72, 95% CI: 3.18- 43.18) as independent predictors of eLOS. CONCLUSION: Our study identified predictors of eLOS that could help promote risk stratification prior to treatment of UIAs. Future research that identifies predictors of long term outcomes based on treatment modality could help identify ways to improve healthcare resource utilization in this cohort.

9.
Front Cardiovasc Med ; 11: 1423680, 2024.
Article in English | MEDLINE | ID: mdl-39027004

ABSTRACT

Medical practitioners are entrusted with the pivotal task of making optimal decisions in healthcare delivery. Despite rigorous training, our confidence in reasoning can fail when faced with pressures, uncertainties, urgencies, difficulties, and occasional errors. Day-to-day decisions rely on swift, intuitive cognitive processes known as heuristic or type 1 decision-making, which, while efficient in most scenarios, harbor inherent vulnerabilities leading to systematic errors. Cognitive biases receive limited explicit discussion during our training as junior doctors in the domain of paediatric cardiology. As pediatric cardiologists, we frequently confront emergencies necessitating rapid decision-making, while contending with the pressures of stress, fatigue, an earnest interest in "doing the right thing" and the impact of parental involvement. This article aims to describe cognitive biases in pediatric cardiology, highlighting their influence on therapeutic interventions for congenital heart disease. Whether future pediatric cardiologists or experienced professionals, understanding and actively combating cognitive biases are essential components of our ongoing medical education. Furthermore, it is our responsibility to thoroughly examine our own practices in our unwavering commitment to providing high-quality care.

10.
Cell Rep ; 43(8): 114493, 2024 Jul 18.
Article in English | MEDLINE | ID: mdl-39028622

ABSTRACT

Severe malnutrition is associated with infections, namely lower respiratory tract infections (LRTIs), diarrhea, and sepsis, and underlies the high risk of morbidity and mortality in children under 5 years of age. Dysregulations in neutrophil responses in the acute phase of infection are speculated to underlie these severe adverse outcomes; however, very little is known about their biology in this context. Here, in a lipopolysaccharide-challenged low-protein diet (LPD) mouse model, as a model of malnutrition, we show that protein deficiency disrupts neutrophil mitochondrial dynamics and ATP generation to obstruct the neutrophil differentiation cascade. This promotes the accumulation of atypical immature neutrophils that are incapable of optimal antimicrobial response and, in turn, exacerbate systemic pathogen spread and the permeability of the alveolocapillary membrane with the resultant lung damage. Thus, this perturbed response may contribute to higher mortality risk in malnutrition. We also offer a nutritional therapeutic strategy, nicotinamide, to boost neutrophil-mediated immunity in LPD-fed mice.

11.
Annu Rev Microbiol ; 2024 Jul 17.
Article in English | MEDLINE | ID: mdl-39018471

ABSTRACT

The micronutrient iron is essential for phytoplankton growth due to its central role in a wide variety of key metabolic processes including photosynthesis and nitrate assimilation. As a result of scarce bioavailable iron in seawater, marine primary productivity is often iron-limited with future iron supplies remaining uncertain. Although evolutionary constraints resulted in high cellular iron requirements, phytoplankton evolved diverse mechanisms that enable uptake of multiple forms of iron, storage of iron over short and long timescales, and modulation of their iron requirement under stress. Genomics continues to increase our understanding of iron-related proteins that are homologous to those characterized in other model organisms, while recently, molecular and cell biology is revealing unique genes and processes with connections to iron acquisition or use. Moreover, there are an increasing number of examples showing the interplay between iron uptake and extracellular processes such as boundary layer chemistry and microbial interactions.

12.
J Phys Chem Lett ; : 7788-7792, 2024 Jul 24.
Article in English | MEDLINE | ID: mdl-39048317

ABSTRACT

Synthesis-induced defects in single-walled carbon nanotubes (SWCNTs) enable diverse catalytic reactions, but the nature of catalytic intermediates and how active species regeneration occurs are unclear. Using a quantum mechanics/molecular mechanics (QM/MM) hybrid methodology based on density functional theory (DFT) and a classical force-field, we explore the reactivity and electrochemical regeneration of a vacancy defect in a zigzag SWCNT. Our findings indicate that hydrolysis of the defect forms a ketone group on one carbon atom and C-H bonds on two adjacent carbons. Applying an electrochemical potential of ESHE = -0.740 V triggers a proton-coupled electron transfer (PCET), converting the ketone to a hydroxyl group. Further reduction at ESHE = -1.08 V induces another PCET, expelling the hydroxyl as water and forming an active carbon with carbene character that can react with hydrogen peroxide and perchlorate. The hydrogen atoms on neighboring carbons prevent further water dissociation, maintaining the catalytic vacancy.

13.
Article in English | MEDLINE | ID: mdl-39054009

ABSTRACT

The human in vitro organotypic air-liquid-interface (ALI) airway tissue model is structurally and functionally similar to the human large airway epithelium and, as a result, is being used increasingly for studying the toxicity of inhaled substances. Our previous research demonstrated that DNA damage and mutagenesis can be detected in human airway tissue models under conditions used to assess general and respiratory toxicity endpoints. Expanding upon our previous proof-of-principle study, human airway epithelial tissue models were treated with 6.25-100 µg/mL ethyl methanesulfonate (EMS) for 28 days, followed by a 28-day recovery period. Mutagenesis was evaluated by Duplex Sequencing (DS), and clonal expansion of bronchial-cancer-specific cancer-driver mutations (CDMs) was investigated by CarcSeq to determine if both mutation-based endpoints can be assessed in the same system. Additionally, DNA damage and tissue-specific responses were analyzed during the treatment and following the recovery period. EMS exposure led to time-dependent increases in mutagenesis over the 28-day treatment period, without expansion of clones containing CDMs; the mutation frequencies remained elevated following the recovery. EMS also produced an increase in DNA damage measured by the CometChip and MultiFlow assays and the elevated levels of DNA damage were reduced (but not eliminated) following the recovery period. Cytotoxicity and most tissue-function changes induced by EMS treatment recovered to control levels, the exception being reduced proliferating cell frequency. Our results indicate that general, respiratory-tissue-specific and genotoxicity endpoints increased with repeat EMS dosing; expansion of CDM clones, however, was not detected using this repeat treatment protocol. DISCLAIMER: This article reflects the views of its authors and does not necessarily reflect those of the U.S. Food and Drug Administration. Any mention of commercial products is for clarification only and is not intended as approval, endorsement, or recommendation.


Subject(s)
DNA Damage , Ethyl Methanesulfonate , Mutation , Humans , Ethyl Methanesulfonate/pharmacology , Ethyl Methanesulfonate/toxicity , Mutation/drug effects , DNA Damage/drug effects , Mutagenesis/drug effects , Mutagens/toxicity , Bronchi/drug effects , Bronchi/cytology
14.
Front Oncol ; 14: 1375096, 2024.
Article in English | MEDLINE | ID: mdl-39055552

ABSTRACT

Purpose: To evaluate organ at risk (OAR) auto-segmentation in the head and neck region of computed tomography images using two different commercially available deep-learning-based auto-segmentation (DLAS) tools in a single institutional clinical applications. Methods: Twenty-two OARs were manually contoured by clinicians according to published guidelines on planning computed tomography (pCT) images for 40 clinical head and neck cancer (HNC) cases. Automatic contours were generated for each patient using two deep-learning-based auto-segmentation models-Manteia AccuContour and MIM ProtégéAI. The accuracy and integrity of autocontours (ACs) were then compared to expert contours (ECs) using the Sørensen-Dice similarity coefficient (DSC) and Mean Distance (MD) metrics. Results: ACs were generated for 22 OARs using AccuContour and 17 OARs using ProtégéAI with average contour generation time of 1 min/patient and 5 min/patient respectively. EC and AC agreement was highest for the mandible (DSC 0.90 ± 0.16) and (DSC 0.91 ± 0.03), and lowest for the chiasm (DSC 0.28 ± 0.14) and (DSC 0.30 ± 0.14) for AccuContour and ProtégéAI respectively. Using AccuContour, the average MD was<1mm for 10 of the 22 OARs contoured, 1-2mm for 6 OARs, and 2-3mm for 6 OARs. For ProtégéAI, the average mean distance was<1mm for 8 out of 17 OARs, 1-2mm for 6 OARs, and 2-3mm for 3 OARs. Conclusions: Both DLAS programs were proven to be valuable tools to significantly reduce the time required to generate large amounts of OAR contours in the head and neck region, even though manual editing of ACs is likely needed prior to implementation into treatment planning. The DSCs and MDs achieved were similar to those reported in other studies that evaluated various other DLAS solutions. Still, small volume structures with nonideal contrast in CT images, such as nerves, are very challenging and will require additional solutions to achieve sufficient results.

15.
Curr Biol ; 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-39059394

ABSTRACT

Hermansky-Pudlak syndrome (HPS) is an inherited disorder of intracellular vesicle trafficking affecting the function of lysosome-related organelles (LROs). At least 11 genes underlie the disease, encoding four protein complexes, of which biogenesis of lysosome-related organelles complex-2 (BLOC-2) is the last whose molecular action is unknown. We find that the unicellular eukaryote Dictyostelium unexpectedly contains a complete BLOC-2, comprising orthologs of the mammalian subunits HPS3, -5, and -6, and a fourth subunit, an ortholog of the Drosophila LRO-biogenesis gene, Claret. Lysosomes from Dictyostelium BLOC-2 mutants fail to mature, similar to LROs from HPS patients, but for all endolysosomes rather than a specialized subset. They also strongly resemble lysosomes from WASH mutants. Dictyostelium BLOC-2 localizes to the same compartments as WASH, and in BLOC-2 mutants, WASH is inefficiently recruited, accounting for their impaired lysosomal maturation. BLOC-2 is recruited to endolysosomes via its HPS3 subunit. Structural modeling suggests that all four subunits are proto-coatomer proteins, with important implications for BLOC-2's molecular function. The discovery of Dictyostelium BLOC-2 permits identification of orthologs throughout eukaryotes. BLOC-2 and lysosome-related organelles, therefore, pre-date the evolution of Metazoa and have broader and more conserved functions than previously thought.

16.
Pathogens ; 13(7)2024 Jun 27.
Article in English | MEDLINE | ID: mdl-39057769

ABSTRACT

Neurodevelopmental outcomes for preschool-age children in the United States with in utero Zika virus (ZIKV) exposure have not yet been reported. We performed a case-control study to assess whether children exposed in utero to ZIKV have abnormal neurodevelopment at age 4-5 years compared to unexposed controls. Thirteen ZIKV-exposed cases that did not have microcephaly or other specific features of congenital Zika syndrome and 12 controls were evaluated between ages 4-5 years. Child neurodevelopment was assessed using the Pediatric Evaluation of Disability Inventory, Behavior Rating Inventory of Executive Function, Peabody Picture Vocabulary Test, Bracken School Readiness Assessment (BSRA), and Movement Assessment Battery for Children (MABC). Caregivers answered questions on the child's medical history and family demographics. Cases and controls were evaluated at mean (SD) ages 4.9 (0.3) and 4.8 (0.4) years, respectively. Caregivers reported more behavior and mood problems in cases than controls. MABC scores showed more gross and fine motor coordination difficulties among cases than controls. Controls trended towards higher performance on concepts underlying school readiness on BSRA. Three cases had a diagnosis of autism spectrum disorder or global developmental delay. Continued follow-up through school age for children with prenatal ZIKV exposure is needed to understand the impact of in utero ZIKV exposure on motor coordination, cognition, executive function, and academic achievement.

17.
Nanomaterials (Basel) ; 14(14)2024 Jul 10.
Article in English | MEDLINE | ID: mdl-39057850

ABSTRACT

Strain-free GaAs cone-shell quantum dots have a unique shape, which allows a wide tunability of the charge-carrier probability densities by external electric and magnetic fields. Here, the influence of a lateral electric field on the optical emission is studied experimentally using simulations. The simulations predict that the electron and hole form a lateral dipole when subjected to a lateral electric field. To evaluate this prediction experimentally, we integrate the dots in a lateral gate geometry and measure the Stark-shift of the exciton energy, the exciton intensity, the radiative lifetime, and the fine-structure splitting (FSS) using single-dot photoluminescence spectroscopy. The respective gate voltage dependencies show nontrivial trends with three pronounced regimes. We assume that the respective dominant processes are charge-carrier deformation at a low gate voltage U, a vertical charge-carrier shift at medium U, and a lateral charge-carrier polarization at high U. The lateral polarization forms a dipole, which can either enhance or compensate the intrinsic FSS induced by the QD shape anisotropy, dependent on the in-plane orientation of the electric field. Furthermore, the data show that the biexciton peak can be suppressed by a lateral gate voltage, and we assume the presence of an additional vertical electric field induced by surface charges.

18.
Ann Thorac Surg ; 2024 Jun 29.
Article in English | MEDLINE | ID: mdl-38950724

ABSTRACT

BACKGROUND: The Society of Thoracic Surgeons General Thoracic Surgery Database (STS-GTSD) previously reported short-term risk models for esophagectomy for esophageal cancer. We sought to update existing models using more inclusive contemporary cohorts, with consideration of additional risk factors based on clinical evidence. METHODS: The study population consisted of adult patients in the STS-GTSD who underwent esophagectomy for esophageal cancer between January 2015 and December 2022. Separate esophagectomy risk models were derived for 3 primary end points: operative mortality, major morbidity, and composite morbidity or mortality. Logistic regression with backward selection was used, with predictors retained in models if P < .10. All derived models were validated using 9-fold cross-validation. Model discrimination and calibration were assessed for the overall cohort and specified subgroups. RESULTS: A total of 18,503 patients from 254 centers underwent esophagectomy for esophageal cancer. Operative mortality, morbidity, and composite morbidity or mortality rates were 3.4%, 30.5%, and 30.9%, respectively. Novel predictors of short-term outcomes in the updated models included body surface area and insurance payor type. Overall discrimination was similar or superior to previous STS-GTSD models for operative mortality (C statistic = 0.72) and for composite morbidity or mortality (C statistic = 0.62), Model discrimination was comparable across procedure- and demographic-specific subcohorts. Model calibration was excellent in all patient subgroups. CONCLUSIONS: The newly derived esophagectomy risk models showed similar or superior performance compared with previous models, with broader applicability and clinical face validity. These models provide robust preoperative risk estimation and can be used for shared decision making, assessment of provider performance, and quality improvement.

19.
J Nat Prod ; 87(7): 1826-1837, 2024 Jul 26.
Article in English | MEDLINE | ID: mdl-38995621

ABSTRACT

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous cancer. Two new prenylated indole 2,5-diketopiperazine alkaloids, brevianamides E1 (1) and E2 (2), were isolated from a Penicillium fungus. Both compounds showed moderate cytotoxic activity against select MCC cell lines (i.e., MCC13, MKL-1, UISO, and WaGa) in the low micromolar range. The relative and absolute configurations of 1 and 2 were determined by combined approaches, including NOESY spectroscopy, DFT ECD and DP4 plus calculations, and Marfey's reaction. Literature research and the comparison of NMR and ECD data led to the structure revision of three previously reported natural analogues, notoamides K and P and asperversiamide L. The structurally unstable 1 and 2 underwent steady interconversion under neutral aqueous conditions. Investigation of the degradation of 2 in acidic methanol solutions led to the identification of a new methoxylated derivative (6) and two new ring-opened products (7 and 8) with the rearranged, elongated, 4-methylpent-3-ene side chain. The facile transformation of 2 to 7 and 8 was promoted by the intrinsic impurity (i.e., formaldehyde) of HPLC-grade methanol through the aza-Cope rearrangement.


Subject(s)
Diketopiperazines , Penicillium , Penicillium/chemistry , Diketopiperazines/pharmacology , Diketopiperazines/chemistry , Molecular Structure , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Drug Screening Assays, Antitumor
20.
Anal Chem ; 96(29): 12049-12056, 2024 Jul 23.
Article in English | MEDLINE | ID: mdl-38975928

ABSTRACT

The diagnosis of bloodborne viral infections (viremia) is currently relegated to central laboratories because of the complex procedures required to detect viruses in blood samples. The development of point-of-care diagnostics for viremia would enable patients to receive a diagnosis and begin treatment immediately instead of waiting days for results. Point-of-care systems for viremia have been limited by the challenges of integrating multiple precise steps into a fully automated (i.e., sample-to-answer), compact, low-cost system. We recently reported the development of thermally responsive alkane partitions (TRAPs), which enable the complete automation of diagnostic assays with complex samples. Here we report the use of TRAPs for the sample-to-answer detection of viruses in blood using a low-cost portable device and easily manufacturable cassettes. Specifically, we demonstrate the detection of SARS-CoV-2 in spiked blood samples, and we show that our system detects viremia in COVID-19 patient samples with good agreement to conventional RT-qPCR. We anticipate that our sample-to-answer system can be used to rapidly diagnose SARS-CoV-2 viremia at the point of care, leading to better health outcomes for patients with severe COVID-19 disease, and that our system can be applied to the diagnosis of other life-threatening bloodborne viral diseases, including Hepatitis C and HIV.


Subject(s)
Alkanes , COVID-19 , SARS-CoV-2 , Viremia , Viremia/diagnosis , Viremia/virology , Humans , SARS-CoV-2/isolation & purification , COVID-19/diagnosis , COVID-19/virology , COVID-19/blood , Alkanes/chemistry , Temperature , Point-of-Care Systems , RNA, Viral/analysis
SELECTION OF CITATIONS
SEARCH DETAIL