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1.
JCI Insight ; 9(13)2024 Jun 04.
Article in English | MEDLINE | ID: mdl-38833310

ABSTRACT

Patients with autoimmune diseases are at higher risk for severe infection due to their underlying disease and immunosuppressive treatments. In this real-world observational study of 463 patients with autoimmune diseases, we examined risk factors for poor B and T cell responses to SARS-CoV-2 vaccination. We show a high frequency of inadequate anti-spike IgG responses to vaccination and boosting in the autoimmune population but minimal suppression of T cell responses. Low IgG responses in B cell-depleted patients with multiple sclerosis (MS) were associated with higher CD8 T cell responses. By contrast, patients taking mycophenolate mofetil (MMF) exhibited concordant suppression of B and T cell responses. Treatments with highest risk for low anti-spike IgG response included B cell depletion within the last year, fingolimod, and combination treatment with MMF and belimumab. Our data show that the mRNA-1273 (Moderna) vaccine is the most effective vaccine in the autoimmune population. There was minimal induction of either disease flares or autoantibodies by vaccination and no significant effect of preexisting anti-type I IFN antibodies on either vaccine response or breakthrough infections. The low frequency of breakthrough infections and lack of SARS-CoV-2-related deaths suggest that T cell immunity contributes to protection in autoimmune disease.


Subject(s)
Autoimmune Diseases , COVID-19 Vaccines , COVID-19 , SARS-CoV-2 , Humans , COVID-19/immunology , COVID-19/prevention & control , Female , SARS-CoV-2/immunology , Male , Autoimmune Diseases/immunology , Middle Aged , Adult , COVID-19 Vaccines/immunology , Immunosuppressive Agents/therapeutic use , Immunoglobulin G/immunology , Immunoglobulin G/blood , 2019-nCoV Vaccine mRNA-1273/immunology , 2019-nCoV Vaccine mRNA-1273/administration & dosage , Antibodies, Viral/immunology , Antibodies, Viral/blood , Mycophenolic Acid/therapeutic use , Aged , Vaccination , B-Lymphocytes/immunology , Antibodies, Monoclonal, Humanized/therapeutic use , CD8-Positive T-Lymphocytes/immunology , Spike Glycoprotein, Coronavirus/immunology
2.
Nat Commun ; 15(1): 5058, 2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38871682

ABSTRACT

In this study, high-performance organic photodetectors are presented which utilize a pristine chlorinated subphthalocyanine photoactive layer. Optical and optoelectronic analyses indicate that the device photocurrent is primarily generated through direct charge generation within the chlorinated subphthalocyanine layer, rather than exciton separation at layer interfaces. Molecular modelling suggests that this direct charge generation is facilitated by chlorinated subphthalocyanine high octupole moment (-80 DÅ2), which generates a 200 meV shift in molecular energetics. Increasing the thickness of chlorinated subphthalocyanine leads to faster response time, correlated with a decrease in trap density. Notably, photodetectors with a 50 nm thick chlorinated subphthalocyanine photoactive layer exhibit detectivities approaching 1013 Jones, with a dark current below 10-7 A cm-2 up to -5 V. Based on these findings, we conclude that high octupole moment molecular semiconductors are promising materials for high-performance organic photodetectors employing single-component photoactive layer.

3.
Transplant Rev (Orlando) ; 38(3): 100858, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38729062

ABSTRACT

INTRODUCTION: Persistent findings suggest women and patients identified as "female" are less likely to receive a kidney transplant. Furthermore, the limited research on transplantation among transgender and gender diverse people suggests this population is susceptible to many of the same psychosocial and systemic barriers. OBJECTIVE: This review sought to 1) highlight terminology used to elucidate gender disparities, 2) identify barriers present along the steps to transplantation, and 3) summarize contributors to gender disparities across the steps to transplantation. METHODS: A systematic review of gender and sex disparities in the steps towards kidney transplantation was conducted in accordance with PRISMA guidelines across four social science and public health databases from 2005 to 23. RESULTS: The search yielded 1696 initial results, 33 of which met inclusion criteria. A majority of studies followed a retrospective cohort design (n = 22, 66.7%), inconsistently used gender and sex related terminology (n = 21, 63.6%), and reported significant findings for gender and sex disparities within the steps towards transplantation (n = 28, 84.8%). Gender disparities among the earlier steps were characterized by patient-provider communication and perception of medical suitability whereas disparities in the later steps were characterized by differential outcomes based on older age, an above average BMI, and Black racial identity. Findings for transgender patients pointed to issues computing eGFR and the need for culturally tailored care. DISCUSSION: Providers should be encouraged to critically examine the diagnostic criteria used to determine transplant eligibility and adopt practices that can be culturally tailored to meet the needs of patients.


Subject(s)
Healthcare Disparities , Kidney Transplantation , Humans , United States , Female , Male , Sex Factors , Kidney Failure, Chronic/surgery
4.
J Am Chem Soc ; 146(22): 15376-15392, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38771156

ABSTRACT

Couplings between vibrational motions are driven by electronic interactions, and these couplings carry special significance in vibrational energy transfer, multidimensional spectroscopy experiments, and simulations of vibrational spectra. In this investigation, the many-body contributions to these couplings are analyzed computationally in the context of clathrate-like alkali metal cation hydrates, including Cs+(H2O)20, Rb+(H2O)20, and K+(H2O)20, using both analytic and quantum-chemistry potential energy surfaces. Although the harmonic spectra and one-dimensional anharmonic spectra depend strongly on these many-body interactions, the mode-pair couplings were, perhaps surprisingly, found to be dominated by one-body effects, even in cases of couplings to low-frequency modes that involved the motion of multiple water molecules. The origin of this effect was traced mainly to geometric distortion within water monomers and cancellation of many-body effects in differential couplings, and the effect was also shown to be agnostic to the identity of the ion. These outcomes provide new understanding of vibrational couplings and suggest the possibility of improved computational methods for the simulation of infrared and Raman spectra.

5.
Nat Commun ; 15(1): 4560, 2024 May 29.
Article in English | MEDLINE | ID: mdl-38811556

ABSTRACT

Gene drive systems could be a viable strategy to prevent pathogen transmission or suppress vector populations by propagating drive alleles with super-Mendelian inheritance. CRISPR-based homing gene drives convert wild type alleles into drive alleles in heterozygotes with Cas9 and gRNA. It is thus desirable to identify Cas9 promoters that yield high drive conversion rates, minimize the formation rate of resistance alleles in both the germline and the early embryo, and limit somatic Cas9 expression. In Drosophila, the nanos promoter avoids leaky somatic expression, but at the cost of high embryo resistance from maternally deposited Cas9. To improve drive efficiency, we test eleven Drosophila melanogaster germline promoters. Some achieve higher drive conversion efficiency with minimal embryo resistance, but none completely avoid somatic expression. However, such somatic expression often does not carry detectable fitness costs for a rescue homing drive targeting a haplolethal gene, suggesting somatic drive conversion. Supporting a 4-gRNA suppression drive, one promoter leads to a low drive equilibrium frequency due to fitness costs from somatic expression, but the other outperforms nanos, resulting in successful suppression of the cage population. Overall, these Cas9 promoters hold advantages for homing drives in Drosophila species and may possess valuable homologs in other organisms.


Subject(s)
CRISPR-Cas Systems , Drosophila Proteins , Drosophila melanogaster , Gene Drive Technology , Germ Cells , Promoter Regions, Genetic , RNA, Guide, CRISPR-Cas Systems , Animals , Promoter Regions, Genetic/genetics , Drosophila melanogaster/genetics , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Gene Drive Technology/methods , Germ Cells/metabolism , RNA, Guide, CRISPR-Cas Systems/genetics , Animals, Genetically Modified , CRISPR-Associated Protein 9/metabolism , CRISPR-Associated Protein 9/genetics , Alleles , Female , Male , RNA-Binding Proteins
6.
J Am Chem Soc ; 146(13): 8895-8903, 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38511265

ABSTRACT

Actin is one of the most abundant proteins in eukaryotic cells and is a key component of the cytoskeleton. A range of small molecules has emerged that interfere with actin dynamics by either binding to polymeric F-actin or monomeric G-actin to stabilize or destabilize filaments or prevent their formation and growth, respectively. Among these, the latrunculins, which bind to G-actin and affect polymerization, are widely used as tools to investigate actin-dependent cellular processes. Here, we report a photoswitchable version of latrunculin, termed opto-latrunculin (OptoLat), which binds to G-actin in a light-dependent fashion and affords optical control over actin polymerization. OptoLat can be activated with 390-490 nm pulsed light and rapidly relaxes to its inactive form in the dark. Light activated OptoLat induced depolymerization of F-actin networks in oligodendrocytes and budding yeast, as shown by fluorescence microscopy. Subcellular control of actin dynamics in human cancer cell lines was demonstrated via live cell imaging. Light-activated OptoLat also reduced microglia surveillance in organotypic mouse brain slices while ramification was not affected. Incubation in the dark did not alter the structural and functional integrity of the microglia. Together, our data demonstrate that OptoLat is a useful tool for the elucidation of G-actin dependent dynamic processes in cells and tissues.


Subject(s)
Actin Cytoskeleton , Actins , Animals , Mice , Humans , Actins/chemistry , Actin Cytoskeleton/metabolism , Cytoskeleton/metabolism , Cell Line , Microtubules/metabolism
7.
JCI Insight ; 9(5)2024 Mar 08.
Article in English | MEDLINE | ID: mdl-38456511

ABSTRACT

Understanding the immune responses to SARS-CoV-2 vaccination is critical to optimizing vaccination strategies for individuals with autoimmune diseases, such as systemic lupus erythematosus (SLE). Here, we comprehensively analyzed innate and adaptive immune responses in 19 patients with SLE receiving a complete 2-dose Pfizer-BioNTech mRNA vaccine (BNT162b2) regimen compared with a control cohort of 56 healthy control (HC) volunteers. Patients with SLE exhibited impaired neutralizing antibody production and antigen-specific CD4+ and CD8+ T cell responses relative to HC. Interestingly, antibody responses were only altered in patients with SLE treated with immunosuppressive therapies, whereas impairment of antigen-specific CD4+ and CD8+ T cell numbers was independent of medication. Patients with SLE also displayed reduced levels of circulating CXC motif chemokine ligands, CXCL9, CXCL10, CXCL11, and IFN-γ after secondary vaccination as well as downregulation of gene expression pathways indicative of compromised innate immune responses. Single-cell RNA-Seq analysis reveals that patients with SLE showed reduced levels of a vaccine-inducible monocyte population characterized by overexpression of IFN-response transcription factors. Thus, although 2 doses of BNT162b2 induced relatively robust immune responses in patients with SLE, our data demonstrate impairment of both innate and adaptive immune responses relative to HC, highlighting a need for population-specific vaccination studies.


Subject(s)
COVID-19 , Lupus Erythematosus, Systemic , Humans , BNT162 Vaccine , COVID-19 Vaccines , SARS-CoV-2 , COVID-19/prevention & control , Vaccination
8.
Am J Obstet Gynecol ; 2024 Mar 01.
Article in English | MEDLINE | ID: mdl-38432418

ABSTRACT

OBJECTIVE: This study aimed to systematically review objective and subjective success and surgical outcomes of suburethral sling surgery for female patients with stress or mixed urinary incontinence using synthetic vs nonsynthetic material with corresponding surgical approaches (retropubic or transobturator). DATA SOURCES: We systematically searched Medline, Embase, EBM Reviews, ClinicalTrials.gov, and Web of Science Core Collection using standardized Medical Subject Headings (MeSH) without date restrictions (PROSPERO-registered). We double-screened studies and used backward citation chaining. STUDY ELIGIBILITY CRITERIA: We included peer-reviewed randomized controlled trials and prospective or retrospective comparative studies examining outcomes of retropubic or transobturator synthetic vs nonsynthetic (autologous, allograft, or xenograft) slings for female stress or mixed urinary incontinence, with available English or French full texts. We excluded minislings (single insertion point). We allowed slings for recurrent stress or mixed urinary incontinence, and slings concomitant with prolapse surgery, with at least 6 weeks of postoperative follow-up. We excluded systematic reviews, meta-analyses, review studies, case-control studies, case reports, studies that did not describe surgical approach or material, and studies of combination slings. METHODS: We evaluated study quality using RoB, the Cochrane risk-of-bias tool for randomized controlled trials, and the Newcastle-Ottawa scale for observational studies. We used pooled relative risk with 95% confidence intervals to estimate the effect of sling material type on each outcome through meta-analysis and meta-regression, as appropriate. RESULTS: We screened 4341 abstracts, assessed 104 full texts, and retained 35 articles (30 separate studies). For retropubic synthetic vs nonsynthetic slings, there was no difference in the number of objectively or subjectively continent patients. The rates of reoperation for stress urinary incontinence and overall were higher with nonautologous retropubic slings than with synthetic slings. Compared with autologous slings, retropubic synthetic slings were associated with higher subjective continence in populations with ≥25% recurrent stress urinary incontinence (relative risk, 1.27; 95% confidence interval, 1.12-1.43). There were no differences in continence between transobturator synthetic and nonsynthetic slings. Subjective satisfaction was better in the transobturator synthetic group than in the autologous sling group (relative risk, 1.42; 95% confidence interval, 1.03-1.94). CONCLUSION: Synthetic and nonsynthetic slings have comparable objective and subjective success, with synthetic materials generally showing better operative outcomes and fewer complications.

9.
Pediatr Cardiol ; 45(2): 361-367, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38062259

ABSTRACT

Sinus node dysfunction (SND) with junctional rhythm (JR) is common after the Fontan operation. Atrial pacing (AP) restores atrioventricular (AV) synchrony, but the placement of a pacemaker carries significant morbidity. To study the impact of AP on echocardiographic parameters of function in Fontan patients with SND and JR. Nine Fontan patients with AP for SND and JR were prospectively studied with echocardiography in the following conditions-baseline paced rhythm, underlying JR and, if possible, slow-paced rhythm below their baseline paced rate (~ 10 bpm faster than their JR rate). Cardiac index was significantly lower in JR (3 ± 1.1 L/min/m2) vs AP (4.2 ± 1.4 L/min/m2; p = 0.002). Diastolic function also significantly worsened with increased ratio of early diastolic systemic AV valve inflow velocity to early diastolic systemic AV valve annulus velocity (E/e' ratio) by tissue Doppler imaging (TDI) in JR (11.6 ± 4.6) vs AP (8.8 ± 2.2, p = 0.016). Pulmonary venous flow reversal was present in 7/9 patients in JR vs 0/9 in AP (p = 0.016). There were no significant differences in these echocardiographic measurements between the paced and slow-paced conditions. When compared to AP, JR was associated with a significant reduction in cardiac output and diastolic function, and an increased prevalence of pulmonary vein flow reversal. There were no differences between paced and slow-paced conditions, suggesting that AV synchrony rather than heart rate was primarily contributing to cardiac output. Further studies are needed to understand the chronic impact of JR on Fontan outcomes.


Subject(s)
Cardiac Pacing, Artificial , Echocardiography , Humans , Prospective Studies , Cardiac Pacing, Artificial/methods , Heart Atria/diagnostic imaging , Arrhythmias, Cardiac , Sick Sinus Syndrome
10.
Cancer ; 130(3): 344-355, 2024 02 01.
Article in English | MEDLINE | ID: mdl-37962199

ABSTRACT

Fertility is a top concern for many survivors of cancer diagnosed as children, adolescents and young adults (CAYA). Fertility preservation (FP) treatments are effective, evidence-based interventions to support their family building goals. Fertility discussions are a part of quality oncology care throughout the cancer care continuum. For nearly 2 decades, clinical guidelines recommend counseling patients about the possibility of infertility promptly at diagnosis and offering FP options and referrals as indicated. Multiple guidelines now recommend post-treatment counseling. Infertility risks differ by cancer treatments and age, rendering risk stratification a central part of FP care. To support FP decision-making, online tools for female risk estimation are available. At diagnosis, females can engage in mature oocyte/embryo cryopreservation, ovarian tissue cryopreservation, ovarian suppression with GnRH agonists, in vitro oocyte maturation, and/or conservative management for gynecologic cancers. Post-treatment, several populations may consider undergoing oocyte/embryo cryopreservation. Male survivors' standard of care FP treatments center on sperm cryopreservation before cancer treatment and do not have the same post-treatment indication for additional gamete cryopreservation. In practice, FP care requires systemized processes to routinely screen for FP needs, bridge oncology referrals to fertility, offer timely fertility consultations and access to FP treatments, and support financial navigation. Sixteen US states passed laws requiring health insurers to provide insurance benefits for FP treatments, but variation among the laws and downstream implementation are barriers to accessing FP treatments. To preserve the reproductive futures of CAYA survivors, research is needed to improve risk stratification, FP options, and delivery of FP care.


Subject(s)
Fertility Preservation , Genital Neoplasms, Female , Infertility , Neoplasms , Child , Humans , Male , Female , Adolescent , Young Adult , Semen , Cryopreservation , Neoplasms/complications , Neoplasms/therapy , Neoplasms/psychology , Infertility/etiology , Infertility/prevention & control
11.
IUBMB Life ; 76(2): 72-87, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37731280

ABSTRACT

Mitochondria are essential for normal cellular function and have emerged as key aging determinants. Indeed, defects in mitochondrial function have been linked to cardiovascular, skeletal muscle and neurodegenerative diseases, premature aging, and age-linked diseases. Here, we describe mechanisms for mitochondrial protein and organelle quality control. These surveillance mechanisms mediate repair or degradation of damaged or mistargeted mitochondrial proteins, segregate mitochondria based on their functional state during asymmetric cell division, and modulate cellular fitness, the response to stress, and lifespan control in yeast and other eukaryotes.


Subject(s)
Mitochondrial Proteins , Saccharomycetales , Mitochondrial Proteins/genetics , Mitochondrial Proteins/metabolism , Saccharomycetales/genetics , Saccharomycetales/metabolism , Mitochondria/metabolism , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae/metabolism , Quality Control , Reactive Oxygen Species/metabolism
12.
Heliyon ; 9(12): e22688, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38058434

ABSTRACT

Machine learning (ML) and citizen science (CS) are increasingly prevalent and rapidly evolving approaches to studying and managing environmental challenges. Municipal and other governance actors can benefit from technology advances in ML and public engagement benefits of CS but must also address validity and other quality assurance concerns in their application to particular management contexts. In this article, we take up the pervasive challenge of urban litter to demonstrate how ML can support CS by providing quality assurance in the regulatory context of California's stormwater program. We gave quantitative CS-collected data to five ML models to compare their predictions of a qualitative, site-specific, multiclass "Litter Index" score, an important regulatory metric typically only assessed by trained experts. XGBoost had the best outcome, with scores of 0.98 for accuracy, precision, recall and F-1. These strong results show that ML can provide a reliable complement to CS assessments and increase quality assurance in a regulatory context. To date, ML and CS have each contributed to litter management in novel ways and we find that their integration can provide important synergies with additional applications in other environmental management domains.

13.
J Chem Phys ; 159(20)2023 Nov 28.
Article in English | MEDLINE | ID: mdl-38010326

ABSTRACT

Simulations of anharmonic vibrational motion rely on computationally expedient representations of the governing potential energy surface. The n-mode representation (n-MR)-effectively a many-body expansion in the space of molecular vibrations-is a general and efficient approach that is often used for this purpose in vibrational self-consistent field (VSCF) calculations and correlated analogues thereof. In the present analysis, a lack of convergence in many VSCF calculations is shown to originate from negative and unbound potentials at truncated orders of the n-MR expansion. For cases of strong anharmonic coupling between modes, the n-MR can both dip below the true global minimum of the potential surface and lead to effective single-mode potentials in VSCF that do not correspond to bound vibrational problems, even for bound total potentials. The present analysis serves mainly as a pathology report of this issue. Furthermore, this insight into the origin of VSCF non-convergence provides a simple, albeit ad hoc, route to correct the problem by "painting in" the full representation of groups of modes that exhibit these negative potentials at little additional computational cost. Somewhat surprisingly, this approach also reasonably approximates the results of the next-higher n-MR order and identifies groups of modes with particularly strong coupling. The method is shown to identify and correct problematic triples of modes-and restore SCF convergence-in two-mode representations of challenging test systems, including the water dimer and trimer, as well as protonated tropine.

14.
Nat Commun ; 14(1): 6941, 2023 10 31.
Article in English | MEDLINE | ID: mdl-37907556

ABSTRACT

Circumstantial evidence suggests that B cells may instruct T cells to break tolerance. Here, to test this hypothesis, we used a murine model in which a single B cell clone precipitates an autoreactive response resembling systemic lupus erythematosus (SLE). The initiating clone did not need to enter germinal centers to precipitate epitope spreading. Rather, it localized to extrafollicular splenic bridging channels early in the response. Autoantibody produced by the initiating clone was not sufficient to drive the autoreactive response. Subsequent epitope spreading depended on antigen presentation and was compartmentalized by major histocompatibility complex (MHC). B cells carrying two MHC haplotypes could bridge the MHC barrier between B cells that did not share MHC. Thus, B cells directly relay autoreactivity between two separate compartments of MHC-restricted T cells, leading to inclusion of distinct B cell populations in germinal centers. Our findings demonstrate that B cells initiate and propagate the autoimmune response.


Subject(s)
Antigen Presentation , Lupus Erythematosus, Systemic , Mice , Animals , Epitopes , Histocompatibility Antigens Class II/genetics , B-Lymphocytes , Major Histocompatibility Complex , Histocompatibility Antigens
15.
Semin Perinatol ; 47(8): 151838, 2023 12.
Article in English | MEDLINE | ID: mdl-37858459

ABSTRACT

Increased fossil fuel usage and extreme climate change events have led to global increases in greenhouse gases and particulate matter with 99% of the world's population now breathing polluted air that exceeds the World Health Organization's recommended limits. Pregnant women and neonates with exposure to high levels of air pollutants are at increased risk of adverse health outcomes such as maternal hypertensive disorders, postpartum depression, placental abruption, low birth weight, preterm birth, infant mortality, and adverse lung and respiratory effects. While the exact mechanism by which air pollution exerts adverse health effects is unknown, oxidative stress as well as epigenetic and immune mechanisms are thought to play roles. Comprehensive, global efforts are urgently required to tackle the health challenges posed by air pollution through policies and action for reducing air pollution as well as finding ways to protect the health of vulnerable populations in the face of increasing air pollution.


Subject(s)
Air Pollutants , Air Pollution , Premature Birth , Infant , Female , Infant, Newborn , Pregnancy , Humans , Premature Birth/epidemiology , Placenta , Air Pollution/adverse effects , Air Pollution/analysis , Air Pollutants/toxicity , Air Pollutants/analysis , Particulate Matter/adverse effects , Particulate Matter/analysis , Pregnancy Outcome/epidemiology
16.
Cell ; 186(21): 4632-4651.e23, 2023 10 12.
Article in English | MEDLINE | ID: mdl-37776858

ABSTRACT

The dynamics of immunity to infection in infants remain obscure. Here, we used a multi-omics approach to perform a longitudinal analysis of immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in infants and young children by analyzing blood samples and weekly nasal swabs collected before, during, and after infection with Omicron and non-Omicron variants. Infection stimulated robust antibody titers that, unlike in adults, showed no sign of decay for up to 300 days. Infants mounted a robust mucosal immune response characterized by inflammatory cytokines, interferon (IFN) α, and T helper (Th) 17 and neutrophil markers (interleukin [IL]-17, IL-8, and CXCL1). The immune response in blood was characterized by upregulation of activation markers on innate cells, no inflammatory cytokines, but several chemokines and IFNα. The latter correlated with viral load and expression of interferon-stimulated genes (ISGs) in myeloid cells measured by single-cell multi-omics. Together, these data provide a snapshot of immunity to infection during the initial weeks and months of life.


Subject(s)
COVID-19 , SARS-CoV-2 , Adult , Child , Infant , Humans , Child, Preschool , SARS-CoV-2/metabolism , Multiomics , Cytokines/metabolism , Interferon-alpha , Immunity, Mucosal
17.
J Chem Phys ; 159(8)2023 Aug 28.
Article in English | MEDLINE | ID: mdl-37606324

ABSTRACT

The vibrational self-consistent field (VSCF) method yields anharmonic states and spectra for molecular vibrations, and it serves as the starting point for more sophisticated correlated-vibration methods. Convergence of the iterative, non-linear optimization in VSCF calculations can be erratic or altogether unsuccessful, particularly for chemical systems involving low-frequency motions. In this work, a vibrational formulation of the Direct Inversion of the Iterative Subspace method of Pulay is presented and investigated. This formulation accounts for distinct attributes of the vibrational and electronic cases, including the expansion of each single-mode vibrational wavefunction in its own basis set. The resulting Direct Inversion of the Iterative Subspace method is shown to substantially accelerate VSCF convergence in all convergent cases as well as rectify many cases where Roothaan-based methods fail. Performance across systems ranging from small, rigid molecules to weakly bound molecular clusters is investigated in this analysis.

18.
J Chem Theory Comput ; 19(16): 5572-5585, 2023 Aug 22.
Article in English | MEDLINE | ID: mdl-37555634

ABSTRACT

Ab initio computer simulations of anharmonic vibrational spectra provide nuanced insight into the vibrational behavior of molecules and complexes. The computational bottleneck in such simulations, particularly for ab initio potentials, is often the generation of mode-coupling potentials. Focusing specifically on two-mode couplings in this analysis, the combination of a local-mode representation and multilevel methods is demonstrated to be particularly symbiotic. In this approach, a low-level quantum chemistry method is employed to predict the pairwise couplings that should be included at the target level of theory in vibrational self-consistent field (and similar) calculations. Pairs that are excluded by this approach are "recycled" at the low level of theory. Furthermore, because this low-level pre-screening will eventually become the computational bottleneck for sufficiently large chemical systems, distance-based truncation is applied to these low-level predictions without substantive loss of accuracy. This combination is demonstrated to yield sub-wavenumber fidelity with reference vibrational transitions when including only a small fraction of target-level couplings; the overhead of predicting these couplings, particularly when employing distance-based, local-mode cutoffs, is a trivial added cost. This combined approach is assessed on a series of test cases, including ethylene, hexatriene, and the alanine dipeptide. Vibrational self-consistent field (VSCF) spectra were obtained with an RI-MP2/cc-pVTZ potential for the dipeptide, at approximately a 5-fold reduction in computational cost. Considerable optimism for increased accelerations for larger systems and higher-order couplings is also justified, based on this investigation.

19.
bioRxiv ; 2023 Jul 19.
Article in English | MEDLINE | ID: mdl-37502978

ABSTRACT

Actin is one of the most abundant proteins in eukaryotic cells and a key component of the cytoskeleton. A range of small molecules have emerged that interfere with actin dynamics by either binding to polymeric F-actin or monomeric G-actin to stabilize or destabilize filaments or prevent their formation and growth, respectively. Amongst these, the latrunculins, which bind to G-actin and affect polymerization, are widely used as tools to investigate actin-dependent cellular processes. Here, we report a photoswitchable version of latrunculin, termed opto-latrunculin (OptoLat), which binds to G-actin in a light-dependent fashion and affords optical control over actin polymerization. OptoLat can be activated with 390 - 490 nm pulsed light and rapidly relaxes to the inactive form in the dark. Light activated OptoLat induced depolymerization of F-actin networks in oligodendrocytes and budding yeast, as shown by fluorescence microscopy. Subcellular control of actin dynamics in human cancer cell lines was demonstrated by live cell imaging. Light-activated OptoLat also reduced microglia surveillance in organotypic mouse brain slices while ramification was not affected. Incubation in the dark did not alter the structural and functional integrity of microglia. Together, our data demonstrate that OptoLat is a useful tool for the elucidation of G-actin dependent dynamic processes in cells and tissues.

20.
J Minim Invasive Gynecol ; 30(12): 961-969, 2023 12.
Article in English | MEDLINE | ID: mdl-37506876

ABSTRACT

STUDY OBJECTIVE: To study the impact of Müllerian anomalies on reproductive outcomes in a recurrent pregnancy loss (RPL) population and to evaluate the effect of surgical correction of uterine septum on the odds of achieving live birth in RPL patients with a septate uterus. DESIGN: A retrospective cohort study. SETTING: A specialized RPL clinic at a tertiary center. PATIENTS: RPL patients with ≥ 2 pregnancy losses before 20 weeks' gestation who attended a specialized RPL clinic. INTERVENTION: We aimed to assess the association between a possible risk factor (Müllerian anomalies) and reproductive outcomes and that between having surgery for septate uterus and achieving a live birth. MEASUREMENTS AND MAIN RESULTS: The primary outcome is live birth rate in RPL patients with Müllerian anomalies compared with those without; secondary outcome measures include rates of full-term live birth, preterm live birth, first and second trimester pregnancy loss, and stillbirth. After adjusting for patient age at the initial RPL visit, the number of pregnancy losses, and the presence of any other abnormal RPL investigation, the odds of achieving live birth were on average 49.4% lower for patients with a septate uterus than those without Müllerian anomalies (odds ratio, 0.51; 95% confidence interval, 0.30-0.86) in the studied cohort (n = 377). A subanalysis of 72 patients with septate uterus demonstrated a higher likelihood of live birth in those who underwent septum resection (46/72; 63.9%) than those who elected to go for expectant management (26/72; 36.1%), yet this study was underpowered to establish a significant difference (52.2% vs 34.6%; p = .22). CONCLUSION: In RPL patients, having a septate uterus significantly decreased the chances of achieving live birth. Patients with septate uterus who received hysteroscopic septum division had a higher tendency to achieve more live births than those who elected expectant management. However, our study was underpowered to detect a statistically significant difference.


Subject(s)
Abortion, Habitual , Premature Birth , Septate Uterus , Pregnancy , Infant, Newborn , Female , Humans , Hysteroscopy/adverse effects , Retrospective Studies , Uterus/surgery , Uterus/abnormalities , Abortion, Habitual/etiology , Premature Birth/epidemiology , Premature Birth/etiology
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