bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of the DNA Methyltransferase Variant DNMT3b3 in DNA Methylation
Authors: Weisenberger Daniel J. , Velicescu Mihaela , Cheng Jonathan C. , Gonzales Felicidad A. , Liang Gangning , Jones Peter A. 
Published: May 2022

Abstract
Several alternatively spliced variants of DNA methyltransferase (DNMT) 3b have been described. Here, we identified new murine Dnmt3b mRNA isoforms and found that mouse embryonic stem (ES) cells expressed only Dnmt3b transcripts that contained exons 10 and 11, whereas the Dnmt3b transcripts in somatic cells lacked these exons, suggesting that this region is important for embryonic development. DNMT3b2 and 3b3 were the major isoforms expressed in human cell lines and the mRNA levels of these isoforms closely correlated with their protein levels. Although DNMT3b3 may be catalytically inactive, it still may be biologically important because D4Z4 and satellites 2 and 3 repeat sequences, all known DNMT3b target sequences, were methylated in cells that predominantly expressed DNMT3b3. Treatment of cells with the mechanism-based inhibitor 5-aza-2′-deoxycytidine (5-Aza-CdR) caused a complete depletion of DNMT1, 3a, 3b1, and 3b2 proteins. Human DNMT3b3 and the murine Dnmt3b3-like isoform, Dnmt3b6, were also depleted although less efficiently, suggesting that DNMT3b3 also may be capable of DNA binding. Moreover, de novo methylation of D4Z4 in T24 cancer cells after 5-Aza-CdR treatment only occurred when DNMT3b3 was expressed, reinforcing its role as a contributing factor of DNA methylation. The expression of either DNMT3b2 or 3b3, however, was not sufficient to explain the abnormal methylation of DNMT3b target sequences in human cancers, which may therefore be dependent on factors that affect DNMT3b targeting. Methylation analyses of immunodeficiency, chromosomal instabilities, and facial abnormalities cells revealed that an Alu repeat sequence was highly methylated, suggesting that Alu sequences are not DNMT3b targets.
Bcl-2 Overexpression Leads to Increases in Suppressor of Cytokine Signaling-3 Expression in B Cells and De novo Follicular Lymphoma
Authors: Vanasse Gary J. , Winn Robert K. , Rodov Sofya , Zieske Arthur W. , Li John T. , Tupper Joan C. , Tang Jingjing , Raines Elaine W. , Peters Mette A. , Yeung Ka Yee , Harlan John M. 
Published: May 2022

Abstract
The t(14;18)(q32;q21), resulting in deregulated expression of B-cell-leukemia/lymphoma-2 (Bcl-2), represents the genetic hallmark in human follicular lymphomas. Substantial evidence supports the hypothesis that the t(14;18) and Bcl-2 overexpression are necessary but not solely responsible for neoplastic transformation and require cooperating genetic derangements for neoplastic transformation to occur. To investigate genes that cooperate with Bcl-2 to influence cellular signaling pathways important for neoplastic transformation, we used oligonucleotide microarrays to determine differential gene expression patterns in CD19+ B cells isolated from Eμ-Bcl-2 transgenic mice and wild-type littermate control mice. Fifty-seven genes were induced and 94 genes were repressed by ≥2-fold in Eμ-Bcl-2 transgenic mice (P &lt; 0.05). The suppressor of cytokine signaling-3 (SOCS3) gene was found to be overexpressed 5-fold in B cells from Eμ-Bcl-2 transgenic mice. Overexpression of Bcl-2 in both mouse embryo fibroblast-1 and hematopoietic cell lines resulted in induction of SOCS3 protein, suggesting a Bcl-2-associated mechanism underlying SOCS3 induction. Immunohistochemistry with SOCS3 antisera on tissue from a cohort of patients with de novo follicular lymphoma revealed marked overexpression of SOCS3 protein that, within the follicular center cell region, was limited to neoplastic follicular lymphoma cells and colocalized with Bcl-2 expression in 9 of 12 de novo follicular lymphoma cases examined. In contrast, SOCS3 protein expression was not detected in the follicular center cell region of benign hyperplastic tonsil tissue. These data suggest that Bcl-2 overexpression leads to the induction of activated signal transducer and activator of transcription 3 (STAT3) and to the induction of SOCS3, which may contribute to the pathogenesis of follicular lymphoma.
Cyclooxygenase-2 Inhibitor Induces Apoptosis in Breast Cancer Cells in an In vivo Model of Spontaneous Metastatic Breast Cancer
Authors: Basu Gargi D. , Pathangey Latha B. , Tinder Teresa L. , LaGioia Michelle , Gendler Sandra J. , Mukherjee Pinku 
Published: May 2022

Abstract
Cyclooxygenase-2 (COX-2) inhibitors are rapidly emerging as a new generation of therapeutic drug in combination with chemotherapy or radiation therapy for the treatment of cancer. The mechanisms underlying its antitumor effects are not fully understood and more thorough preclinical trials are needed to determine if COX-2 inhibition represents a useful approach for prevention and/or treatment of breast cancer. The purpose of this study was to evaluate the growth inhibitory mechanism of a highly selective COX-2 inhibitor, celecoxib, in an in vivo oncogenic mouse model of spontaneous breast cancer that resembles human disease. The oncogenic mice carry the polyoma middle T antigen driven by the mouse mammary tumor virus promoter and develop primary adenocarcinomas of the breast. Results show that oral administration of celecoxib caused significant reduction in mammary tumor burden associated with increased tumor cell apoptosis and decreased proliferation in vivo. In vivo apoptosis correlated with significant decrease in activation of protein kinase B/Akt, a cell survival signaling kinase, with increased expression of the proapoptotic protein Bax and decreased expression of the antiapoptotic protein Bcl-2. In addition, celecoxib treatment reduced levels of proangiogenic factor (vascular endothelial growth factor), suggesting a role of celecoxib in suppression of angiogenesis in this model. Results from these preclinical studies will form the basis for assessing the feasibility of celecoxib therapy alone or in combination with conventional therapies for treatment and/or prevention of breast cancer.
Sequential Single-Cell Transcriptional and Protein Marker Profiling Reveals TIGIT as a Marker of CD19 CAR-T Cell Dysfunction in Patients with Non-Hodgkin Lymphoma
Authors: Jackson Zachary , Hong Changjin , Schauner Robert , Dropulic Boro , Caimi Paolo F. , de Lima Marcos , Giraudo Maria Florencia , Gupta Kalpana , Reese Jane S. , Hwang Tae Hyun , Wald David N. 
Published: May 2022

Abstract

Chimeric antigen receptor T-cell (CAR-T cell) therapy directed at CD19 produces durable remissions in the treatment of relapsed/refractory non-Hodgkin lymphoma (NHL). Nonetheless, many patients receiving CD19 CAR-T cells fail to respond for unknown reasons. To reveal changes in 4-1BB–based CD19 CAR-T cells and identify biomarkers of response, we used single-cell RNA sequencing and protein surface marker profiling of patient CAR-T cells pre- and postinfusion into patients with NHL. At the transcriptional and protein levels, we note the evolution of CAR-T cells toward a nonproliferative, highly differentiated, and exhausted state, with an enriched exhaustion profile in CAR-T cells of patients with poor response marked by TIGIT expression. Utilizing in vitro and in vivo studies, we demonstrate that TIGIT blockade alone improves the antitumor function of CAR-T cells. Altogether, we provide evidence of CAR-T cell dysfunction marked by TIGIT expression driving a poor response in patients with NHL.

Significance:
This is the first study investigating the mechanisms linked to CAR-T patient responses based on the sequential analysis of manufactured and infused CAR-T cells using single-cell RNA and protein expression data. Furthermore, our findings are the first to demonstrate an improvement of CAR-T cell efficacy with TIGIT inhibition alone.
This article is highlighted in the In This Issue feature, p. 1825
Abstract 70: Females With Acute Myocardial Infarction Are Still Undertreated
Authors: Cordova Sanchez Andres , Chaudhuri Debanik 
Published: May 2022

Objective:
To identify differences in management and outcomes in males versus females with acute myocardial infarction(AMI) presenting to our institution.

Methods:
Retrospective analysis of patients between the ages of 18 to 89 years old presenting to SUNY Upstate Medical University with a diagnosis of AMI defined as either STEMI or NSTEMI from March 2021 to September 2021. Patients with diagnosis of demand ischemia were excluded.

Results:
From a total of 236 patients, 44.1% (104 out of 236) were females. The age in both groups was similar with mean of 63.64 (SD 14.5) years old in males and 66.36(SD 14.2).

Only 53.8% (56 of 104) Females were admitted to intensive care level of service versus 72% (95 of 132) males (P 0.004 OR 0.264-0.781).
Cardiac catheterizations were done more frequently in males than females 78.8% (104 of 132) and 67.3% (71 of 104) respectively (P0.047). Between patients who underwent cardiac catheterization 45.7% (33 of 70) females and 66.3% (69 of 104) males received PCI. More males had depressed left ventricular ejection fraction 50.8% (64 of 132) versus 32% (31 of 104) females. Although not statistically significant, 30-day mortality was more frequent in women 10.6% (11 of 104) compared to males 6.8% (9 of 132).

Conclusions:
Females with AMI where less likely to be admitted to the ICU or undergo cardiac catheterization. They had either similar or worse 30-day mortality, despite having lower rates of coronary disease requiring intervention. These findings support the fact that despite the efforts taken in the last several years, women with AMI are still being undertreated.
Why Drones Have Not Revolutionized War: The Enduring Hider-Finder Competition in Air Warfare
Authors: Calcara Antonio , Gilli Andrea , Gilli Mauro , Marchetti Raffaele , Zaccagnini Ivan 
Published: May 2022

Abstract
According to the accepted wisdom in security studies, unmanned aerial vehicles, also known as drones, have revolutionizing effects on war and world politics. Drones allegedly tilt the military balance in favor of the offense, reduce existing asymmetries in military power between major and minor actors, and eliminate close combat from modern battlefields. A new theory about the hider-finder competition between air penetration and air defense shows that drones are vulnerable to air defenses and electronic warfare systems, and that they require support from other force structure assets to be effective. This competition imposes high costs on those who fail to master the set of tactics, techniques, procedures, technologies, and capabilities necessary to limit exposure to enemy fire and to detect enemy targets. Three conflicts that featured extensive employment of drones—the Western Libya military campaign of the second Libyan civil war (2019–2020), the Syrian civil war (2011–2021), and the Armenia-Azerbaijan conflict over Nagorno-Karabakh (2020)—probe the mechanisms of the theory. Drones do not by themselves produce the revolutionary effects that many have attributed to them.
Dynamic Incentives in Retirement Earnings-Replacement Benefits
Authors: Dean Andrés , Fleitas Sebastian , Zerpa Mariana 
Published: May 2022

Abstract
We analyze dynamic incentives in pension systems created by the use of a small set of final years of earnings to compute benefits. Using social security records and household surveys from Uruguay, we show that self-employed workers and some employees of small firms respond to these incentives by increasing reported earnings in the benefit calculation window. We find evidence that suggests that these responses are explained by changes in earnings reporting and not in total earnings or labor supply. Back-of-the-envelope calculations indicate that this behavior increases the cost of pensions by about 0.2% of the GDP.
Optimal Vaccine Subsidies for Epidemic Diseases
Authors: Goodkin-Gold Matthew , Kremer Michael , Snyder Christopher M. , Williams Heidi 
Published: May 2022

Abstract
We analyze optimal vaccine subsidies in a model integrating disease epidemiology into a market with rational economic agents. The focus is on an intensive vaccine campaign to quell an epidemic in the short run. Across a range of market structures, positive vaccine externalities and optimal subsidies peak for diseases that spread quickly, but not so quickly that everyone is driven to be vaccinated. We assess the practical relevance of this peak—as well as the existence of increasing social returns to vaccination and optimality of universal vaccination—in calibrations to the COVID-19 pandemic.
Nonrandom pattern of vigilance by preening black-headed gulls
Authors: Novčić Ivana , Vidović Zoran , Hauber Mark E. 
Published: May 2022

Abstract
Classic models of vigilance assume instantaneous and sequential randomness in the scanning process, implying negative exponential distribution of interscan durations and no interdependence among successive interscans. We examined whether vigilance pattern by preening black-headed gulls, Chroicocephalus ridibundus, meets these assumptions. Out of 54 behavioural sequences, 50 departed from the expected negative exponential distribution, whereas the focal interscan duration was significantly affected by the interaction of the preceding scan and the interscan interval. These results reveal departures from randomness in the scanning process by gulls, which may be a consequence of the hunting strategies of their predators or due to the trade-off between the needs for feather maintenance and antipredator vigilance.
Two-Dimensional Wavenumber Spectra on the Horizontal Submesoscale and Vertical Finescale
Authors: Vladoiu Anda , Lien Ren-Chieh , Kunze Eric 
Published: May 2022

Abstract
Horizontal and vertical wavenumbers (kx, kz) immediately below the Ozmidov wavenumber (N3/ε)1/2 are spectrally distinct from both isotropic turbulence (kx, kz > 1 cpm) and internal waves as described by the Garrett–Munk (GM) model spectrum (kz < 0.1 cpm). A towed CTD chain, augmented with concurrent Electromagnetic Autonomous Profiling Explorer (EM-APEX) profiling float microstructure measurements and shipboard ADCP surveys, are used to characterize 2D wavenumber (kx, kz) spectra of isopycnal slope, vertical strain, and isopycnal salinity gradient on horizontal wavelengths from 50 m to 250 km and vertical wavelengths of 2–48 m. For kz < 0.1 cpm, 2D spectra of isopycnal slope and vertical strain resemble GM. Integrated over the other wavenumber, the isopycnal slope 1D kx spectrum exhibits a roughly +1/3 slope for kx > 3 × 10−3 cpm, and the vertical strain 1D kz spectrum a −1 slope for kz > 0.1 cpm, consistent with previous 1D measurements, numerical simulations, and anisotropic stratified turbulence theory. Isopycnal salinity gradient 1D kx spectra have a +1 slope for kx > 2 × 10−3 cpm, consistent with nonlocal stirring. Turbulent diapycnal diffusivities inferred in the (i) internal wave subrange using a vertical strain-based finescale parameterization are consistent with those inferred from finescale horizonal wavenumber spectra of (ii) isopycnal slope and (iii) isopycnal salinity gradients using Batchelor model spectra. This suggests that horizontal submesoscale and vertical finescale subranges participate in bridging the forward cascade between weakly nonlinear internal waves and isotropic turbulence, as hypothesized by anisotropic turbulence theory.
Improvement of Mean Wave Period Based on Dispersion Relation Filter Using Shore-Based Coherent S-Band Radar
Authors: Liu Han , Chen Zezong , Zhao Chen , Wu Sitao 
Published: May 2022

Abstract
Wavenumber–frequency spectra obtained with coherent microwave radar at upwind-grazing angle consist of energy along the ocean wave dispersion relation and additional features that lie above this relation labeled as “high-order harmonic” and below this relation known as “group line.” Due to these nonlinear features, low-frequency components appear in the radar-estimated wave spectrum and the energy and peak frequency of the dominant wave spectrum decrease, which are responsible for the overestimation of radar-measured wave period. According to the component distribution in the wavenumber–frequency spectrum, a mean wave period inversion method based on a dispersion relation filter for coherent S-band radar is proposed. The method filters out the “group line” and preserves the high-order harmonic to compensate for the energy loss caused by the decrease of peak frequency of the dominant wave spectrum. A two-dimensional inverse Fourier transform is applied to the filtered wavenumber–frequency spectrum. Then the radar-measured velocity sequence is selected to obtain the velocity spectrum via a one-dimension Fourier transform. The wave height spectrum is estimated from the one-dimensional velocity spectrum by the direct transform relationship between the one-dimensional velocity spectrum and the wave height spectrum. Later, mean wave periods can be derived by the first moment of the wave height spectrum. A 13-day dataset collected with a shore-based coherent S-band radar deployed at Zhelang, China, is reanalyzed and used to retrieve mean wave periods. Comparisons between the measurements of radar and wave buoy are conducted. The results indicate that the proposed method improves the wave period measurement for coherent S-band radar.

Significance Statement
This work provides a mean wave period inversion method for coherent S-band radar. The mean wave period is always overestimated due to the “group line” in the wavenumber–frequency spectrum and the energy loss caused by the decrease of peak frequency of the dominant wave spectrum. Therefore, dealing with these estimation errors is important.
Predicting Peak Wind Gusts during Specific Weather Types with the Meteorologically Stratified Gust Factor Model
Authors: Lang Victoria A. , Turner Teresa J. , Selbig Brandon R. , Harris Austin R. , Kahl Jonathan D. W. 
Published: May 2022

Abstract
Wind gusts present challenges to operational meteorologists, both to forecast accurately and also to verify. Strong wind gusts can damage structures and create costly risks for diverse industrial sectors. The meteorologically stratified gust factor (MSGF) model incorporates site-specific gust factors (the ratio of peak wind gust to mean wind speed) with wind speed and direction forecast guidance. The MSGF model has previously been shown to be a viable operational tool that exhibits skill (improvement over climatology) in forecasting peak wind gusts. This study assesses the performance characteristics of the MSGF model by evaluating peak gust predictions during several types of gust-producing weather phenomena. Peak wind gusts were prepared and verified for seven specific weather conditions over an 8-yr period at 16 sites across the United States. When coupled with two forms of model output statistics (MOS) wind guidance, the MSGF model generally shows skill in predicting peak wind gusts at forecast projections ranging from 6 to 72 h. The model performed best during high pressure and nocturnal conditions and was also skillful during conditions involving snow. The model did not perform well during the “rain with thunder” weather type. The MSGF model is a viable tool for the operational prediction of peak gusts for most gust-producing weather types.

Significance Statement
Wind gusts are an important and potentially costly environmental hazard. Wind gusts affect many industrial sectors, including transportation, power generation, forestry, construction, and insurance, but predicting gusts remains a challenging component of weather forecasting. Recent studies have demonstrated that the meteorologically stratified gust factor (MSGF) model shows skill in predicting peak gusts. This study shows that the MSGF model is skillful at predicting peak gusts during specific types of gust-producing weather phenomena at forecast projections up to 72 h, providing further confirmation that the MSGF model is a viable tool for the operational prediction of peak gusts.
Paradimorphite, β-As4S3, a vintage new mineral from Solfatara di Pozzuoli and Vesuvius, Napoli, Italy
Authors: Campostrini Italo , Castellano Carlo , Demartin Francesco , Rocchetti Ivano , Russo Massimo , Vignola Pietro 
Published: May 2022

AbstractThe new mineral paradimorphite corresponds to the high temperature polymorph of As4S3, whose existence was supposed by Arcangelo Scacchi in 1850 in the fumaroles at the Solfatara di Pozzuoli, Campi Flegrei, near Napoli, Italy.Crystals of paradimorphite are orange yellow, transparent or semitransparent, with adamantine lustre. Habit is prismatic and observed forms are {110}, {101}, {111}, {100}, {010} and {001}. Tenacity is brittle, no distinct cleavage is observed and fracture is conchoidal. The mineral does not fluoresce in long- or shortwave ultraviolet light. No twinning is apparent. The streak is saffron yellow. Hardness (Mohs) = 1–2. The observed density is 3.510(3) g/cm3, calculated density is 3.500 g/cm3. The mineral is orthorhombic, space group Pnma, with a = 9.1577(7), b = 8.0332(6), c = 10.2005(8) Å, V = 750.41(10) Å3 and Z = 4. The eight strongest powder X-ray diffraction lines are [dobs Å(I)(hkl)]: 6.299(48)(011), 5.186(100)(111), 4.174(31)(201), 3.133(34)(022), 3.116(58)(212), 2.980(41)(122), 1.846 (27)(413) and 1.808(23)(134). The structure was refined to R = 0.0229 for 979 reflections with I >2σ(I). Crystals of paradimorphite contain As4S3 molecules, of idealised C3v symmetry, with the four arsenic atoms in a triangular pyramidal arrangement, with sulfur atom bridges on the three adjacent apical edges. Molecular dimensions and conformation are identical within standard uncertainties with those of the low-temperature polymorph dimorphite. No substantial differences, neither in the molecular packing nor in the molecular orientation, could be observed; minor differences being related to intermolecular distances only.
Vogt-Koyanagi-Harada disease: the step-by-step approach to a better understanding of clinicopathology, immunopathology, diagnosis, and management: a brief review
Authors: Urzua Cristhian A. , Herbort Carl P. , Takeuchi Masaru , Schlaen Ariel , Concha-del-Rio Luz E. , Usui Yoshihiko , Cuitino Loreto , Papasavvas Ioannis 
Published: May 2022

Abstract
Background
Appraisals of Vogt-Koyanagi-Harada disease (VKH) have become progressively more complete, since its first description in 1906. The availability of new investigational methods has improved our knowledge of the immunopathology, clinicopathology, diagnosis, and management of VKH disease. This review aimed to describe some of the steps that led to better characterization of VKH as a clinical entity.

Methods
We searched on PubMed for articles that described the history of VKH disease and analyzed the progress in disease appraisal with new investigational and imaging methods. In particular, we searched for articles that investigated the clinicopathology, diagnosis, and management of VKH.

Findings
The following developments were considered essential for improving the appraisal and understanding of VKH: (1) the history of the disease, (2) immunopathological mechanisms, (3) clinicopathology, (4) the importance of distinguishing initial-onset from chronic disease, (5) relevant imaging modalities, among which indocyanine green angiography is crucial, (6) diagnostic criteria that facilitate early diagnosis, and (7) the need for early, prolonged, aggressive treatment that combines steroidal and non-steroidal immunosuppression.

Conclusion
Based on these findings, the definition of VKH has improved. VKH disease starts in the choroidal stroma and later involves other structures when it is not diagnosed and treated early. Indocyanine green angiography and enhanced depth imaging optical coherence tomography facilitate early diagnosis and precise monitoring of choroidal inflammation. ICGA is clearly the gold standard for appraisals and follow-ups in VKH disease, however EDI-OCT should be especially considered in those areas where ICGA is not fully available. These modalities have contributed substantially to a “cure” for VKH, when treatment is introduced within the therapeutic window of opportunity.