bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of COVID-19 coinfection with increased mortality among patients with Pseudomonas aeruginosa bloodstream infection in the Veterans Health Administration system
Authors: Hojat Leila S. , Wilson Brigid M. , Perez Federico , Mojica Maria F. , Singer Mendel E. , Bonomo Robert A. , Epstein Lauren H.
Published: December 2023

Objective:

Pseudomonas aeruginosa bloodstream infection (PA-BSI) and COVID-19 are independently associated with high mortality. We sought to demonstrate the impact of COVID-19 coinfection on patients with PA-BSI.

Design:

Retrospective cohort study.

Setting:

Veterans Health Administration.

Patients:

Hospitalized patients with PA-BSI in pre-COVID-19 (January 2009 to December 2019) and COVID-19 (January 2020 to June 2022) periods. Patients in the COVID-19 period were further stratified by the presence or absence of concomitant COVID-19 infection.

Methods:

We characterized trends in resistance, treatment, and mortality over the study period. Multivariable logistic regression and modified Poisson analyses were used to determine the association between COVID-19 and mortality among patients with PA-BSI. Additional predictors included demographics, comorbidities, disease severity, antimicrobial susceptibility, and treatment.

Results:

A total of 6,714 patients with PA-BSI were identified. Throughout the study period, PA resistance rates decreased. Mortality decreased during the pre-COVID-19 period and increased during the COVID-19 period. Mortality was not significantly different between pre-COVID-19 (24.5%, 95% confidence interval [CI] 23.3–28.6) and COVID-19 period/COVID-negative (26.0%, 95% CI 23.5–28.6) patients, but it was significantly higher in COVID-19 period/COVID-positive patients (47.2%, 35.3–59.3). In the modified Poisson analysis, COVID-19 coinfection was associated with higher mortality (relative risk 1.44, 95% CI 1.01–2.06). Higher Charlson Comorbidity Index, higher modified Acute Physiology and Chronic Health Evaluation score, and no targeted PA-BSI treatment within 48 h were also predictors of higher mortality.

Conclusions:

Higher mortality was observed in patients with COVID-19 coinfection among patients with PA-BSI. Future studies should explore this relationship in other settings and investigate potential SARS-CoV-2 and PA synergy.
In vitro activity of clindamycin, doxycycline, and trimethoprim/sulfamethoxazole against clinical isolates of β-hemolytic Streptococcus spp. via BD Phoenix and broth microdilution
Authors: Cho Christian , Shields Ryan K , Kline Ellen G , Walsh Thomas L. , Jones Chelsea E. , Kasarda Karen , Stefano Kelly , Moffa Matthew A. , Bremmer Derek N.
Published: December 2023

We tested 85 isolates of β-hemolytic Streptococcus spp. against trimethoprim/sulfamethoxazole (TMP/SMX), clindamycin, and doxycycline by broth microdilution (BMD) and BD Phoenix. Susceptibility rates via BMD for TMP/SMX, clindamycin, and doxycycline were 100%, 85.5%, and 56.6%, respectively. TMP/SMX is a potential monotherapy agent for β-hemolytic Streptococcus skin and soft tissue infections.
Counting geodesics of given commutator length
Authors: Erlandsson Viveka , Souto Juan
Published: December 2023

Let$\Sigma $be a closed hyperbolic surface. We study, for fixedg, the asymptotics of the number of those periodic geodesics in$\Sigma $having at most lengthLand which can be written as the product ofgcommutators. The basic idea is to reduce these results to being able to count critical realizations of trivalent graphs in$\Sigma $. In the appendix, we use the same strategy to give a proof of Huber’s geometric prime number theorem.
Shallow current of viscous fluid flowing between diverging or converging walls
Authors: Liu Ming-Shau , Huppert Herbert E.
Published: December 2023

We investigate the shallow flow of viscous fluid into and out of a channel whose gap width increases as a power law (

$x^n$

), where

$x$

is the downstream axis. The fluid flows slowly, while injected at a rate in the form of

$t^\alpha$

, where

$t$

is time and

$\alpha$

is a constant. The invading fluid has a higher viscosity than the ambient fluid, thus avoiding Saffman–Taylor instability. Similarity solutions of the first kind for the outflow problem are found using approximations of lubrication theory. Zheng et al. (J. Fluid Mech., vol. 747, 2014, pp. 218–246) studied the deep-channel case and found divergent behaviour of the similarity variable as

$n\rightarrow 1$

and

$n\rightarrow 3$

, when fluid flows into and out of the channel, respectively. No divergence is found in the shallow case presented here up to the breakdown of the geometric assumption. The characteristic equilibration time for the numerically simulated constant-volume flow to converge to the similarity solution is calculated assuming an inverse dependence on the ratio disagreement between the current front using the method of lines. An inverse power dependence between equilibration time and ratio disagreement is found for channels of different powers. A similarity solution of the second kind for the inflow problem is found using the phase-plane formalism and the bisection method. An exponential decay relationship is found between

$n$

and the degree

$\delta$

of the similarity variable

$xt^{-\delta }$

, which does not show any divergent behaviour for large

$n$

. An asymptotic behaviour is found for

$\delta$

that approaches

$1/2$

for

$n\gg 1$

.
Droplet jumping by modulated electrowetting
Authors: Vo Quoc , Tran Tuan
Published: December 2023

We investigate jumping of sessile droplets from a solid surface in ambient oil using modulated electrowetting actuation. We focus on the case in which the electrowetting effect is activated to cause droplet spreading and then deactivated exactly at the moment the droplet reaches its maximum deformation. By systematically varying the control parameters such as the droplet radius, liquid viscosity and applied voltage, we provide detailed characterisation of the resulting behaviours including a comprehensive phase diagram separating detachment from non-detachment behaviours, as well as how the detach velocity and detach time, i.e. duration leading to detachment, depend on the control parameters. We then construct a theoretical model predicting the detachment condition using energy conservation principles. We finally validate our theoretical analysis by experimental data obtained in the explored ranges of the control parameters.
The Achilles Heel of Constitutional Jurisprudence: Conceptualization of Minority Rights by Constitutional Courts in Central and Eastern Europe
Authors: Korhecz Tamás , Nagy Noémi
Published: December 2023

The minority question has long been a hot topic in Central and Eastern Europe. Whereas most CEE countries guarantee the privileged position of the dominant nation, they also recognize the existence of national minorities and provide special rights for them. Hence there is an apparent contradiction between the values of the nation-states: unity and diversity. This article proposes that to resolve this contradiction, it is necessary to define the concept, scope and limitations of group-specific minority rights, as well as their relationship with other human rights and the nation-state. Constitutional courts are appropriate candidates for this task. However, based on our analysis of the relevant constitutional jurisprudence of five CEE countries – Croatia, Hungary, Romania, Serbia, and Slovenia – it seems that constitutional courts in the region have failed to properly conceptualize minority rights. Instead of developing appropriate tests for assessing the constitutionality of legal regulations, they have only superficially touched upon the conceptual issues of minority rights, using incidental, case-by-case arguments to justify the (un)constitutionality of the legal provisions. Therefore, this article also attempts to outline a constitutionality test that may be suitable for constitutional courts to consistently evaluate submissions that challenge the constitutionality of laws on minority rights.
Places of Body: On Authors, Lives, and Agency
Authors: Aboul-Ela Hosam
Published: December 2023

Edward Said’s life’s work illustrated the very argument for individual agency that became a theoretical focus for him beginning with his classic 1978 study, Orientalism.
Kant on Free Speech: Criticism, Enlightenment, and the Exercise of Judgement in the Public Sphere
Authors: Sweet Kristi
Published: December 2023

In this article, I offer a novel and in-depth account of how, for Kant, free speech is the mechanism that moves a society closer to justice. I argue that the criticism of the legislator preserved by free speech must also be the result of collective agreement. I further argue that structural features of judgements of taste and the sensus communis give guidance for how we should communicate publicly to succeed at the aims Kant has laid out, as judgements of taste, like politics, belong fundamentally to a transitional sphere between nature and freedom.
“The Best Songs Came from the Gutters”: Tin Pan Alley and the Birth of Manhattan Mass Culture
Authors: Backer Samuel E.
Published: December 2023

In the early twentieth century, the publishers of Tin Pan Alley revolutionized American music. Focused on the dissemination of a constantly changing set of attention-grabbing songs, leading companies dramatically expanded the market for popular compositions, generating hits that sold millions of copies of sheet music to customers across the country. While publishers aimed at this continental audience, their output was shaped by the urban context in which their businesses first emerged. During these years, local popularity was crucial to national success. As a result, firms sought to engage with new audiences throughout Manhattan, incorporating a host of social and ethnic groups into the structures of commercial entertainment. Over time, Tin Pan Alley’s relationship to these groups—and the distinctive leisure spaces in which they gathered—would define its musical production. It was not simply that publishers molded songs to fit public taste. Rather, the industry and the broader world of commercial entertainment developed together. By exploring this business-influenced process of cultural change, it is possible to gain new perspective on the emergence of American popular song, as well as the consumption-driven dynamics remaking society in the Progressive Era in the United States.
“Speculative Imaginations”: Listening to 1889, Then and Now
Authors: Stephens Carlene E.
Published: December 2023

In an examination of three cylinder recordings from 1889, this essay compares the context for their original production with the experience of hearing them again in 2019, thanks to IRENE, a twenty-first century suite of state-of-the-art techniques and equipment designed to recover sound from old recordings otherwise considered unplayable. This pairing offers an opportunity to examine how each period envisioned the technical opportunities and social purpose of these new sound technologies in their respective times. Inspired by the work of Sheila Jasanoff and others who have developed the concept of “sociotechnical imaginaries,” this analysis focuses on the role of listeners’ imaginations and asks how their notions shaped the meaning, use, and material aspects of recorded sound and playback. As a contribution to sound studies, this comparative look manifests the field’s attention to both sonic phenomena and the means by which we come to know and experience those phenomena.
Beobachtungsverfahren zur Erfassung der Interaktionsqualität in Kindertageseinrichtungen
Authors: Oppermann Elisa , Barenthien Julia , Burghardt Lars , Steffensky Mirjam , Anders Yvonne
Published: December 2023

Zusammenfassung: Die Qualität pädagogischer Interaktionen in Kindertageseinrichtungen gilt als ausschlaggebend für die kindliche Entwicklung. Methodische Zugänge zur Interaktionsqualität sind daher von hoher Bedeutsamkeit für Forschung und Praxis. Ziel des vorliegenden Beitrags ist eine inhaltliche Diskussion und empirische Analyse der internationalen Beobachtungsverfahren zur Erfassung der Interaktionsqualität CLASS Pre-K (Classroom Assessment Scoring System; Pianta et al., 2008 ) und SSTEW (Sustained Shared Thinking and Emotional Wellbeing Scale; Siraj-Blatchford et al., 2015 ; für die deutsche Version, vgl. Anders et al., 2017 ). Inhaltlich zeigen sich viele Überschneidungen der beiden Instrumente; unterschiedliche Schwerpunktsetzungen lassen sich insbesondere im Bereich der kognitiven Anregungsqualität feststellen. Das Muster der mittleren Ausprägungen der Qualitätsratings mit der CLASS Pre-K und der SSTEW war ähnlich. Die inhaltlichen Überschneidungen sowie konzeptionellen Unterschiede der Instrumente zeigten sich auch empirisch in bivariaten Korrelationen. Implikationen für Forschung und Praxis werden diskutiert.
Inequalities in Air Pollution Exposure and Attributable Mortality in a Low Carbon Future
Authors: Reddington C. L. , Turnock S. T. , Conibear L. , Forster P. M. , Lowe J. A. , Ford L. Berrang , Weaver C. , van Bavel B. , Dong H. , Alizadeh M. R. , Arnold S. R.
Published: December 2023

Understanding the costs and benefits of climate change mitigation and adaptation options is crucial to justify and prioritize future decarbonization pathways to achieve net zero. Here, we quantified the co‐benefits of decarbonization for air quality and public health under scenarios that aim to limit end‐of‐century warming to 2°C and 1.5°C. We estimated the mortality burden attributable to ambient PM2.5 exposure using population attributable fractions of relative risk, incorporating projected changes in population demographics. We found that implementation of decarbonization scenarios could produce substantial global reductions in population exposure to PM2.5 pollution and associated premature mortality, with maximum health benefits achieved in Asia around mid‐century. The stringent 1.5ºC‐compliant decarbonization scenario (SSP1‐1.9) could reduce the PM2.5‐attributable mortality burden by 29% in 2050 relative to a middle‐of‐the‐road scenario (SSP2‐4.5), averting around 2.9 M annual deaths worldwide. While all income groups were found to benefit from improved air quality through a combination of decarbonization and air pollution controls, the smallest health benefits are experienced by the low‐income population. The disparity in PM2.5 exposure across income groups is projected to reduce by 2100, but a 30% disparity between high‐ and low‐income groups persists even in the strongest mitigation scenario. Further, without additional and targeted air quality measures, low‐ and lower‐middle‐income populations (predominantly in Africa and Asia) will continue to experience PM2.5 exposures that are over three times the World Health Organization Air Quality Guideline.
Unprecedented Human‐Perceived Heat Stress in 2021 Summer Over Western North America: Increasing Intensity and Frequency in a Warming Climate
Authors: Jeong Dae Il , Yu Bin , Cannon Alex J.
Published: December 2023

The unprecedented 2021 June‐July heatwave in Western North America resulted in record‐breaking human‐perceived heat stress across the region, measured by the humidex considering both air temperature and humidity. During extended summer (June‐September), both 95th percentiles of daily maximum humidex (HX95) and air temperature (TX95) have increased over the 1940–2022 period, with even faster intensification in the last two decades (2001–2022). HX95 has increased more than TX95 because of the positive monotonic nonlinear relationship between humidex and air temperature at a given level of relative humidity. The Canadian Earth System Model version 5 (CanESM5) projects a larger increase in human‐perceived heat stress than air temperature across the region under low to high emission scenarios (HX95 increases 4.40–7.04°C and TX95 increases 2.92–4.65°C between 1981–2010 and 2041–2060). Moreover, CanESM5 projects significant increases in the frequency of HX and TX conditions that exceed the levels reached in 2021 under intermediate and high emission scenarios.
Planetary Wave Modulation of Gravity Waves Over the Andes in 2016
Authors: France Jeff , Hervig Mark , Thurairajah Brentha , Randall Cora E. , Harvey V. Lynn , Forbes Jeffrey M. , Bailey Scott
Published: December 2023

The Andes account for the largest source of orographic gravity waves (GWs) in the middle atmosphere. This results from persistent, strong zonal winds at the surface encountering the north‐south mountain chain, producing strong orographic lift, and resulting GWs. Here, we consider GWs in the stratosphere and mesosphere above the Andes as observed by the Cloud Imaging and Particle Size instrument, the Solar Occultation for Ice Experiment on the AIM satellite, and the Sounding of the Atmosphere using Broadband Emission Radiometry instrument onboard the Thermosphere Ionosphere Mesosphere Energetics and Dynamics satellite. GW variability is considered in the context of the location of the stratospheric wintertime westerly jet and planetary wave (PW) amplitude and phase. The occurrence of GWs in the middle and upper atmosphere depends not only on tropospheric sources, like the Andes, but also on the background winds through which they propagate. Results suggest that the propagation of GWs into the mesosphere is well correlated with winds throughout the middle and upper stratosphere. PWs cause the westerly jet to move over the Andes, resulting in an increase in GW amplitude throughout the middle and upper stratosphere. The evolution and variability of GWs are tied closely to the phase of the PW‐1 and are linked to PW‐2 when the PW amplitudes are sufficiently large. GW amplitude, as observed by all three data sets, increases in the upper stratosphere and lower mesosphere when the trough of the PW‐1 in the stratosphere is over the Andes.
Space Weather in the Popular Media, and the Opportunities the Upcoming Solar Maximum Brings
Authors: Carter Brett A. , Lugaz Noé , Morley Steven K. , Gannon Jennifer , Zou Shasha , Liu Huixin
Published: December 2023

The media interest/coverage of space weather has been increasing as we approach solar maximum and the private space industry has grown significantly since the last significant solar maximum in 2000–2002. It is not uncommon for space weather media coverage to use hyperbole with frequent references to the infamous “Carrington event.” The implications of associating each of the many upcoming moderate‐to‐severe storms with the Carrington event are discussed, and we encourage the curbing of hyperbole whenever possible. While there is an excellent but small cohort of space weather researchers actively engaging with the media, we urge more (particularly early‐to‐mid career) to take advantage of media training resources and to join in. We also call for these efforts to be broadly supported by peers and institutions for the benefit of space weather as a discipline.
The impact of thrombosis on probabilities of death and disease progression in polycythemia vera: a multistate transition analysis of 1,545 patients
Authors: Barbui Tiziano , Carobbio Alessandra , Thiele Juergen , Gangat Naseema , Rumi Elisa , Rambaldi Alessandro , Vannucchi Alessandro M. , Tefferi Ayalew ,   IWG-MRT group, Jeryczynski Georg , Müllauer Leonhard , Vaidya Rakhee , Sulai Nanna H. , Pardanani Animesh , Larson Dirk R. , Cazzola Mario , Casetti Ilaria , Finazzi Guido , Pieri Lisa , Gisslinger Heinz , Gisslinger Bettina , Rodeghiero Francesco , Ruggeri Marco , Randi Maria Luigia , Bertozzi Irene , Passamonti Francesco
Published: December 2023

We applied a parametric Markov five-state model, on a well-characterized international cohort of 1,545 patients with polycythemia vera (PV; median age 61 years; females 51%), in order to examine the impact of incident thrombosis on the trajectory of death or disease progression. At a median follow-up of 6.9 years, 347 (23%) deaths, 50 (3%) blast phase (BP), and 138 (9%) fibrotic (post-PV MF) transformations were recorded. Incident thrombosis occurred at a rate of 2.62% pt/yr (arterial 1.59% and venous 1.05%). The probability of death, in the first 10 years, for 280 (18%) patients who developed thrombosis during follow-up was 40%, which was two-fold higher than that seen in the absence of thrombosis or any other transition state (20%; p < 0.01); the adverse impact from thrombosis was more apparent for arterial (HR 1.74; p < 0.01) vs venous thrombosis (p=NS) and was independent of other fixed (i.e., age, prior venous thrombosis, leukocytosis) or time-dependent (i.e., progression to BP or MF) risk variables. The transition probability to post-PV MF increased over time, in a linear fashion, with a rate of 5% capped at 5 and 10 years, in patients with or without incident thrombosis, respectively. The impact of thrombosis on transition probability to death or post-PV MF tapered off beyond 10 years and appeared to reverse direction of impact on MF evolution at the 12-year time point. These observations suggest thrombosis in PV to be a marker of aggressive disease biology or a disease-associated inflammatory state that is consequential to both thrombosis and disease progression.
Identification of 5-HT2A receptor signaling pathways associated with psychedelic potential
Authors: Wallach Jason , Cao Andrew B. , Calkins Maggie M. , Heim Andrew J. , Lanham Janelle K. , Bonniwell Emma M. , Hennessey Joseph J. , Bock Hailey A. , Anderson Emilie I. , Sherwood Alexander M. , Morris Hamilton , de Klein Robbin , Klein Adam K. , Cuccurazzu Bruna , Gamrat James , Fannana Tilka , Zauhar Randy , Halberstadt Adam L. , McCorvy John D.
Published: December 2023

Serotonergic psychedelics possess considerable therapeutic potential. Although 5-HT2A receptor activation mediates psychedelic effects, prototypical psychedelics activate both 5-HT2A-Gq/11 and β-arrestin2 transducers, making their respective roles unclear. To elucidate this, we develop a series of 5-HT2A-selective ligands with varying Gq efficacies, including β-arrestin-biased ligands. We show that 5-HT2A-Gq but not 5-HT2A-β-arrestin2 recruitment efficacy predicts psychedelic potential, assessed using head-twitch response (HTR) magnitude in male mice. We further show that disrupting Gq-PLC signaling attenuates the HTR and a threshold level of Gq activation is required to induce psychedelic-like effects, consistent with the fact that certain 5-HT2A partial agonists (e.g., lisuride) are non-psychedelic. Understanding the role of 5-HT2A Gq-efficacy in psychedelic-like psychopharmacology permits rational development of non-psychedelic 5-HT2A agonists. We also demonstrate that β-arrestin-biased 5-HT2A receptor agonists block psychedelic effects and induce receptor downregulation and tachyphylaxis. Overall, 5-HT2A receptor Gq-signaling can be fine-tuned to generate ligands distinct from classical psychedelics.
A single C-terminal residue controls SARS-CoV-2 spike trafficking and incorporation into VLPs
Authors: Dey Debajit , Qing Enya , He Yanan , Chen Yihong , Jennings Benjamin , Cohn Whitaker , Singh Suruchi , Gakhar Lokesh , Schnicker Nicholas J. , Pierce Brian G. , Whitelegge Julian P. , Doray Balraj , Orban John , Gallagher Tom , Hasan S. Saif
Published: December 2023

The spike (S) protein of SARS-CoV-2 is delivered to the virion assembly site in the ER-Golgi Intermediate Compartment (ERGIC) from both the ER and cis-Golgi in infected cells. However, the relevance and modulatory mechanism of this bidirectional trafficking are unclear. Here, using structure-function analyses, we show that S incorporation into virus-like particles (VLP) and VLP fusogenicity are determined by coatomer-dependent S delivery from the cis-Golgi and restricted by S-coatomer dissociation. Although S mimicry of the host coatomer-binding dibasic motif ensures retrograde trafficking to the ERGIC, avoidance of the host-like C-terminal acidic residue is critical for S-coatomer dissociation and therefore incorporation into virions or export for cell-cell fusion. Because this C-terminal residue is the key determinant of SARS-CoV-2 assembly and fusogenicity, our work provides a framework for the export of S protein encoded in genetic vaccines for surface display and immune activation.
BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state
Authors: Xiao Muran , Kondo Shinji , Nomura Masaki , Kato Shinichiro , Nishimura Koutarou , Zang Weijia , Zhang Yifan , Akashi Tomohiro , Viny Aaron , Shigehiro Tsukasa , Ikawa Tomokatsu , Yamazaki Hiromi , Fukumoto Miki , Tanaka Atsushi , Hayashi Yasutaka , Koike Yui , Aoyama Yumi , Ito Hiromi , Nishikawa Hiroyoshi , Kitamura Toshio , Kanai Akinori , Yokoyama Akihiko , Fujiwara Tohru , Goyama Susumu , Noguchi Hideki , Lee Stanley C. , Toyoda Atsushi , Hinohara Kunihiko , Abdel-Wahab Omar , Inoue Daichi
Published: December 2023

ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.
MYOD-SKP2 axis boosts tumorigenesis in fusion negative rhabdomyosarcoma by preventing differentiation through p57Kip2 targeting
Authors: Pomella Silvia , Cassandri Matteo , D’Archivio Lucrezia , Porrazzo Antonella , Cossetti Cristina , Phelps Doris , Perrone Clara , Pezzella Michele , Cardinale Antonella , Wachtel Marco , Aloisi Sara , Milewski David , Colletti Marta , Sreenivas Prethish , Walters Zoë S. , Barillari Giovanni , Di Giannatale Angela , Milano Giuseppe Maria , De Stefanis Cristiano , Alaggio Rita , Rodriguez-Rodriguez Sonia , Carlesso Nadia , Vakoc Christopher R. , Velardi Enrico , Schafer Beat W. , Guccione Ernesto , Gatz Susanne A. , Wasti Ajla , Yohe Marielle , Ignatius Myron , Quintarelli Concetta , Shipley Janet , Miele Lucio , Khan Javed , Houghton Peter J. , Marampon Francesco , Gryder Berkley E. , De Angelis Biagio , Locatelli Franco , Rota Rossella
Published: December 2023

Rhabdomyosarcomas (RMS) are pediatric mesenchymal-derived malignancies encompassing PAX3/7-FOXO1 Fusion Positive (FP)-RMS, and Fusion Negative (FN)-RMS with frequent RAS pathway mutations. RMS express the master myogenic transcription factor MYOD that, whilst essential for survival, cannot support differentiation. Here we discover SKP2, an oncogenic E3-ubiquitin ligase, as a critical pro-tumorigenic driver in FN-RMS. We show that SKP2 is overexpressed in RMS through the binding of MYOD to an intronic enhancer. SKP2 in FN-RMS promotes cell cycle progression and prevents differentiation by directly targeting p27Kip1 and p57Kip2, respectively. SKP2 depletion unlocks a partly MYOD-dependent myogenic transcriptional program and strongly affects stemness and tumorigenic features and prevents in vivo tumor growth. These effects are mirrored by the investigational NEDDylation inhibitor MLN4924. Results demonstrate a crucial crosstalk between transcriptional and post-translational mechanisms through the MYOD-SKP2 axis that contributes to tumorigenesis in FN-RMS. Finally, NEDDylation inhibition is identified as a potential therapeutic vulnerability in FN-RMS.
Comparing outcomes between coronary artery bypass grafting and percutaneous coronary intervention in octogenarians with left main or multivessel disease
Authors: Kirov Hristo , Caldonazo Tulio , Riedel Leoni Lu , Tasoudis Panagiotis , Moschovas Alexandros , Diab Mahmoud , Färber Gloria , Doenst Torsten
Published: December 2023

Mechanisms of coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) differ as CABG provides surgical collateralization and may prolong life by preventing future myocardial infarctions (MI). However, CABG benefits are unclear in octogenarians, where surgical risk is often perceived as higher and PCI is chosen more liberally. We performed a meta-analysis of studies comparing outcomes in octogenarians with left main or multivessel disease who underwent CABG or PCI. Primary outcome was late mortality (> 5 years). Secondary outcomes were perioperative mortality, MI, re-revascularization (R-R), acute renal failure (ARF), and stroke. Fourteen studies with 17,942 patients were included. CABG was associated with lower late mortality (hazard ratio, HR: 1.23, 95% confidence interval: CI 1.05–1.44, p < 0.01). In the pooled Kaplan–Meier analysis CABG showed significantly lower risk of death in the follow-up compared to PCI (HR: 1.08, 95%CI 1.02–1.41, p = 0.005). Landmark analyses confirmed the survival advantage of CABG over PCI after 21.5 months of follow-up (HR: 1.31, 1.19–1.44, p < 0.0001), but suggested advantage of PCI over CABG in the first 30-days (HR: 0.72, 0.64–0.82, p < 0.0001) and comparable survival from 1 to 21.5 months (HR: 0.98, 0.92–1.05, p = 0.652). We found lower risk for MI and R-R after CABG but higher perioperative mortality and no differences in ARF and stroke. CABG appears superior to PCI over time in octogenarians with complex CAD. This survival advantage is associated with fewer events of MI and R-R; however, it comes with an increased risk in perioperative mortality.
Two independent LAMP assays for rapid identification of the serpentine leafminer, Liriomyza huidobrensis (Blanchard, 1926) (Diptera: Agromyzidae) in Australia
Authors: Zhu Xiaocheng , Gopurenko David , Holloway Joanne C. , Duff John D. , Malipatil Mallik B.
Published: December 2023

Liriomyza huidobrensis is a leafminer fly and significant horticultural pest. It is a quarantine listed species in many countries and is now present as an established pest in Australia. Liriomyza huidobrensis uses a broad range of host plants and has potential for spread into various horticultural systems and regions of Australia. Rapid in-field identification of the pest is critically needed to assist efforts to manage this pest. Morphological identification of the pest is effectively limited to specialist examinations of adult males. Generally, molecular methods such as qPCR and DNA barcoding for identification of Liriomyza species require costly laboratory-based hardware. Herein, we developed two independent and rapid LAMP assays targeted to independently inherited mitochondrial and nuclear genes. Both assays are highly sensitive and specific to L. huidobrensis. Positive signals can be detected within 10 min on laboratory and portable real-time amplification fluorometers. Further, we adapted these assays for use with colorimetric master mixes, to allow fluorometer free in-field diagnostics of L. huidobrensis. Our LAMP assays can be used for stand-alone testing of query specimens and are likely to be essential tools used for rapid identification and monitoring of L. huidobrensis.
Transcription factor-mediated direct cellular reprogramming yields cell-type specific DNA methylation signature
Authors: Horisawa Kenichi , Miura Shizuka , Araki Hiromitsu , Miura Fumihito , Ito Takashi , Suzuki Atsushi
Published: December 2023

Direct reprogramming, inducing the conversion of one type of somatic cell into another by the forced expression of defined transcription factors, is a technology with anticipated medical applications. However, due to the many unresolved aspects of the induction mechanisms, it is essential to thoroughly analyze the epigenomic state of the generated cells. Here, we performed comparative genome-wide DNA methylation analyses of mouse embryonic fibroblasts (MEFs) and cells composing organoids formed by intestinal stem cells (ISCs) or induced ISCs (iISCs) that were directly induced from MEFs. We found that the CpG methylation state was similar between cells forming ISC organoids and iISC organoids, while they differed widely from those in MEFs. Moreover, genomic regions that were differentially methylated between ISC organoid- and iISC organoid-forming cells did not significantly affect gene expression. These results demonstrate the accuracy and safety of iISC induction, leading to the medical applications of this technology.
Scale-dependent power law properties in hashtag usage time series of Weibo
Authors: Jiang Jiwei J. , Yamada Kenta , Takayasu Hideki , Takayasu Misako
Published: December 2023

We analyze the time series of hashtag numbers of social media data. We observe that the usage distribution of hashtags is characterized by a fat-tailed distribution with a size-dependent power law exponent and we find that there is a clear dependency between the growth rate distributions of hashtags and size of hashtags usage. We propose a generalized random multiplicative process model with a theory that explains the size dependency of the fat-tailed distribution. Numerical simulations show that our model reproduces these size-dependent properties nicely. We expect that our model is useful for understanding the mechanism of fat-tailed distributions in various fields of science and technology.
Spatial–temporal distribution and key factors of urban land use ecological efficiency in the Loess Plateau of China
Authors: Zhang Lanyue , Xiao Yi , Guo Yimeng , Qian Xinmeng
Published: December 2023

Urban land use ecological efficiency is crucial to the urbanization process and urban ecosystem sustainability. Cities in ecologically sensitive zones with frequent natural disasters need more complex land use patterns and plans. Achieving the goal of harmonizing economy and ecosystem is key for sustainable development policy makers in these cities. Aiming to explore the urban land use ecological efficiency (LUEE) of ecologically sensitive areas, urban land use ecological efficiency index system of the Loess Plateau was constructed, the SBM-Tobit model was adopted to measure the LUEE and influencing factors from 2009 to 2018, and the characteristics of spatial–temporal evolution was discussed. The results indicated that there were significant spatial differences of LUEE in ecologically sensitive zone. The high-level cities of LUEE were located in the southwest areas, while low-level cities of LUEE were mostly situated in the northeast zones, and the temporal variation trend showed the characteristic of “W” curve. Additionally, the results of key factors identification demonstrated that science and technology expenditure and public transport development had positive effects on urban LUEE, while the land expansion, GDP growth, the second industry and real estate development will limit the improvement of urban LUEE. This study used the scientific evaluation index system and key factors identification method to explore the land use ecological efficiency in ecologically sensitive zones, aiming to provide a case study reference for urban land management and optimization in ecologically fragile areas.
Temporal encoding in deep reinforcement learning agents
Authors: Lin Dongyan , Huang Ann Zixiang , Richards Blake Aaron
Published: December 2023

Neuroscientists have observed both cells in the brain that fire at specific points in time, known as “time cells”, and cells whose activity steadily increases or decreases over time, known as “ramping cells”. It is speculated that time and ramping cells support temporal computations in the brain and carry mnemonic information. However, due to the limitations in animal experiments, it is difficult to determine how these cells really contribute to behavior. Here, we show that time cells and ramping cells naturally emerge in the recurrent neural networks of deep reinforcement learning models performing simulated interval timing and working memory tasks, which have learned to estimate expected rewards in the future. We show that these cells do indeed carry information about time and items stored in working memory, but they contribute to behavior in large part by providing a dynamic representation on which policy can be computed. Moreover, the information that they do carry depends on both the task demands and the variables provided to the models. Our results suggest that time cells and ramping cells could contribute to temporal and mnemonic calculations, but the way in which they do so may be complex and unintuitive to human observers.
Fragment Based Drug Design (FBDD) of an Exemplar Inhibitor Against Spike Glycoprotein of SARS-CoV-2
Authors: Shinde Manjiri S. , Chatale Bandoo C.
Published: December 2023

COVID-19 outbreak has become an unprecedented healthcare crisis. To lessen the havoc of pandemic, several multidisciplinary efforts are continuously taken for treatment and precaution. The Fragment-Based Drug Design (FBDD) branch of Computational Aided Drug Discovery (CADD) was one of the methodologies used in current research, focused on the spike glycoprotein of the coronavirus. Fragments were dismembered from repurposed antivirals (FDA-approved) and the same was docked against PDB ID: 6VXX spike glycoprotein. The final inhibitor was docked against the spike glycoprotein and the dock score was recorded. Top scoring hits were identified and through a combinatorial library an exemplar inhibitor was designed. Affinity of an inhibitor towards protein was also observed, and docking score was recorded. Furthermore, the ADME properties were predicted for future development process. FBDD can be another approach to High Throughput Screening (HTS) for the generation of lead compounds for drug targets. This approach was applied to establish a new design computationally against SARS-CoV-2. Thus, additional research using fragments to create a different inhibitor could be done, saving time from working with, screening through, and filtering all sets of fragments, even in the antivirals section.
In Silico Admet Prediction and Molecular Docking Studies in the Design of New Therapeutic Agents Targeting PIM 1 Kinase
Authors: Sireesha S. Muni , Mudiraj A. Sejal , Varmini A. , Pallavi A. , Farahana Afirin , Jyostna T. Saritha
Published: December 2023

Cancer is a crucial reason for death in almost all emerging nations. Huge anti-cancer agents were recognized are still requiring progress in enduring rates and eminence for cancer-affected life. PIM1 belongs to the serine/threonine kinase family, and has been recognized as a distinct target in oncogenesis. The role of PIM 1 is denotable in survival, cellular senescence, cell cycle regulation, drug resistance, and apoptosis and it appears as a probable biomarker in many human malignancies. Today numerous stimulating inhibitors for PIM1 are expanded and few were withdrawn from clinical trials of phase1 and 2, due to the absence of toxicity and bioavailability. Henceforth the determination of the current work is to invent more effective and to minimize lethal compounds. A sequence of novel 2-oxindoles with dithiocarbamates were outlined as PIM1 inhibitors. All the compounds molecular properties were predicted using softwares like Swiss ADME, Molinspiration, Molsoft and pkCSM that are essential for drug candidate. Additionally, in order to perceive the binding affinity of designed molecules with PIM1 kinase protein and to explain their anticancer activity, molecular docking study was accomplished. Outcomes revealed that all the designed molecules satisfied the drug likeliness and bioavailability conditions with low toxicity. All twenty molecules were docked into the PIM1 kinase active site using AutoDock Vina. The results declared that compounds 16 and 18 exhibit better binding energy values, which are commensurable with formerly reported compounds AZ1208 and SGI1776. This study supports the scholars to get a finer drug for cancer treatment.
Drug Repurposing for Primary Lateral Sclerosis: A Molecular Dynamic Study
Authors: Almeida Shannon D , Pandey Akash Kumar , Mutahir Mohamed , Pai Prakash , Prakruthi SM , Gouravakkanvara Shivaraj , Gosh Rishita , Damodar Nayak A , Pavadai Parasuraman
Published: December 2023

Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system that controls voluntary muscles; characterised by a slowly progressive weakness and stiffness of leg upper motor neuron syndrome. Many effective drugs act by modulating multiple targets, Drug repositioning/Drug repurposing can be used as an alternative methodology for drug discovery, and this ‘poly-pharmacology’ can be a therapeutic requirement for complex diseases. This study focuses on repurposing of FDA approved drugs against Transactive response DNA binding protein of 43 kDa (TDP43) protein of PLS disease by molecular docking and dynamic studies. The ligands were chosen from the FDA-approved chemical list and the target receptor was retrived from protein data bank (PDB ID: 7Q8V). The molecular docking study was carried out using the AutoDock Vina program and the results were visualised through Discovery studio tool. The ADMET features of top 10 drugs were predicted using pkCSM online software. Molecular dynamic study was carried out by Desmond. Several drugs showed extremely high binding free energies for chosen target of TDP43 Protein. The results have led to the discovery of Indinavir, Adapalene, Alclometasone, Amsacrine and other FDA-approved drugs as potential candidates for the treatment of PLS. Molecular dynamic studies were carried out for the best two complexes, complex was found to be stable during molecular dynamic simulation. This study led to the identify of Indinavir and Amsacrine as potential candidates for the treatment of PLS. Hence these drugs can be evaluated further in animal model to establish drug for treating PLS.
Identification, Modelling and Docking Studies on Sert Like Mycobacterial Protein as a Possible Anti TB Drug Target
Authors: Hamem Manal NK , Guruvelli PV Sangeeta , Kurati Sony Priya , Muthyala Murali Krishna Kumar
Published: December 2023

Recent discovery of potent anti TB activity in sertraline, a popular antidepressant drug which acts via selective serotonin reuptake inhibition, enthused us to search for possible presence of related proteins in Mycobacterium tuberculosis. We used bioinformatic tools and we used Serotonin Reuptake Receptor of 5-HT protein sequence as query and search the Mycobacterium tuberculosis database using protein blast tool. The mycobacterial protein SGC57945.1, a sodium dependant transporter, is selected based on score (identical percentage-25%; similarity-45%) and pursued for homology modelling and binding site prediction. It is interesting to note that, the binding site amino acids of the query were matching with the alignment region. The modeled protein is used for docking simulation to verify binding interactions and also to find possible hits in the DrugBank database. The drugs with highest score were selected and screened against MtbH37rv.
In Silico Design of Natural Compound-Derived Novel Inhibitors Against RdRP OF SARS-CoV-2
Authors: Madala Sanjay , Kiran K S S V , Prasad Burra V L S
Published: December 2023

RNA dependent RNA polymerase (RdRp), an important class of nucleic acid polymerases, encoded by RNA viruses such as SARS-CoV-2, has been a major drug target against viral diseases. Among the twenty-nine SARS-CoV-2 encoded proteins, RdRp is referred to as Non-Structural Protein 12 (Nsp12). Obtaining novel RdRp inhibitors is one of the crucial strategies in developing fast therapeutics against COVID-19. The NCI natural compound database containing 250 thousand small molecules was docked against the available 3D structure of SARS-CoV-2 RdRp (PDB ID: 7BV2). The molecules with best docking scores were assessed for their safety through ADMET predictions. Lead molecules that passed all the parameters of ADMET predictions, were subjected to molecular dynamic simulations and binding affinity analysis. This in silico study gave seven antiviral lead compounds that were having better binding affinities than the remdesivir. Their binding affinities ranged from −8.5 to −11.4 kcal/mol which is significantly higher than remdesivir (−7.59 kcal/mol). Besides, these novel antiviral compounds were found to bind between the Finger and Palm domains, restricting or obstructing the template RNA entry and movement, unlike remdesivir which binds at the 3’ end of the nascent RNA near the palm domain. The data indicates stable structures, favorable binding free energies when compared to remdesivir. Besides having better binding affinity, these leads have easy access to the binding pocket unlike the binding site of remdesivir that is in a deep cleft. These advantages of the identified novel compounds demand for immediate in vitro studies.
Quantification of Daridorexant in Human Plasma Using RPHPLC: A Bioanalytical Method Development and Validation
Authors: Pavani Bonagiri , Malothu Narender , Prasanth D S N B K , Guntupalli Chakravarthi
Published: December 2023

A novel analytical approach for quantifying Daridorexant (DXT) in plasma has been devised using suvorexant as an internal standard (IS), To separate the DXT from the plasma, liquid-liquid extraction (LLE) was utilized, followed by RP-HPLC analysis using a PDA. DXT recovery was tested with several extraction solvents (n-butyl chloride, ether / toluene (1: 1), and methyl t-butyl ether (MTBE)). Analytes were separated on an Inertsil ODS column (250 x 4.6 mm, 5µ) using a 0.5 mM sodium acetate buffer (pH-3.5): methanol (78:22 v/v) as mobile phase pumped at 0.5 mL/min. The temperature in the column was kept constant at 25 °C and drug was monitored at 225 nm. The proposed technique was validated in accordance with the USFDA guidelines. Linearity was established in a range of 0.25 to 10.00 µg/mL. The LOQ was determined to be 0.13 µg/mL. The mean accuracy (% CV) was found to be less than 15% of ranging from 92 to 115% of the nominal concentration. In HQC 8.50 µg/mL and LOQ 0.750 µg/mL, the matrix impact was 2.24 and 4.51%, respectively. Plasma Quality Control (QC) samples were kept at -20° C. After three freeze-thaw cycles, first intraday quality control analysis revealed an accuracy of 4% of nominal with an accuracy (% CV) of 3.8%. QC plasma samples have been demonstrated to stay stable at -20 °C for up to 10 months. The method can be used to support clinical studies and/or bioavailability and bioequivalence studies.
Development and Validation of Stability Indicating Related Substances Method for Montelukast Sodium and Levocetirizine Dihydrochloride Combined Tablets by RP-HPLC
Authors: Ranjith K , Reddy D. Rama Sekhara , Murthy TEGK
Published: December 2023

In this paper authors presented the development and validation of RP-HPLC method for determination of related substances present in Montelukast sodium and Levocetirizine dihydrochloride combined tablets. Chromatographic separation was achieved on Hypersil ODS (150 x 4.6 mm),5 µ column with flow rate 1 mL/min, detection wavelength 238 nm, injection volume 10 µL, column temperature 40°C and run time 75 mins. Gradient programming was used with mobile phase-A (MP-A)-50mM acetate buffer pH 5.5 and mobile phase-B(MP-B)-methanol: MP-A (90:10 %v/v). Developed method was validated as per ICH Q2(R1) guideline. As the method was able to analyse forced degradation samples successfully, it proved to be stability-indicating.