bluuebunny/crossref_metadata_2025 huggingface dataset:
Depression is associated with delirium after cardiac surgery—a population-based cohort study
Authors: Falk Anna , Kåhlin Jessica , Nymark Carolin , Hultgren Rebecka , Stenman Malin
Published: May 2022

OBJECTIVES

Depression is common in patients with cardiac disease, and preoperative depression is associated with worse outcomes after cardiac surgery. Depression is also correlated with postoperative delirium (POD) after major surgery. However, the association between preoperative depression and POD after cardiac surgery is sparsely studied. The aim of this study was to investigate depression as a predictor for POD in cardiac surgery patients.

METHODS

This population-based cohort study included 1133 cardiac surgery patients in Stockholm 2013–2016. Depression was defined by the Patient Health Questionnaire-9, and POD was evaluated by assessing medical records for symptoms of POD according to Diagnostic and Statistical Manual of Mental Disorders criteria. The association between depression and POD was determined through multivariable logistic regression analysis.

RESULTS

A total of 162 (14%) individuals reported depressive symptoms preoperatively. The incidence of POD was 26% and highest among elderly patients. Among patients with depression, 34% developed POD. In the group of non-depressed patients, 24% developed POD. The overall adjusted odds of delirium were 2.19 times higher in individuals with depressive symptoms compared to controls (95% confidence interval 1.43–3.34). The onset of delirium was most common on Days 0–2 after surgery.

CONCLUSIONS

This unique population-based study in patients undergoing cardiac surgery shows that preoperative depression is associated with POD in a large proportion of treated patients. The findings support the need for improved preoperative screening for depression, especially in younger patients, and enhanced clinical surveillance in the early postoperative period for all patients.
A Distinct Dexamethasone-Dependent Gene Expression Profile in the Lungs of COVID-19 Patients
Authors: Fahnøe Ulrik , Ronit Andreas , Berg Ronan M G , Jørgensen Sofie E , Mogensen Trine H , Underwood Alexander P , Scheel Troels K H , Bukh Jens , Plovsing Ronni R
Published: May 2022

The effects of dexamethasone (DXM) treatment on pulmonary immunity in COVID-19–associated acute respiratory distress syndrome (CARDS) remain insufficiently understood. We performed transcriptomic RNA-seq analysis of bronchoalveolar lavage fluid from 20 mechanically ventilated patients: 12 with CARDS (with or without DXM) and 8 non–COVID-19 critically ill controls. CARDS with DXM was characterized by upregulation of genes related to B-cell and complement pathway activation, antigen presentation, phagocytosis, and FC-γ receptor signaling. Most interferon-stimulated genes were upregulated in CARDS, particularly in CARDS without DXM. In conclusion, DXM treatment was not associated with regulation of proinflammatory pathways in CARDS but with regulation of other local immune responses.

Clinical Trials Registration. NCT04354584.
A randomized controlled trial comparing perioperative vs. postoperative mFOLFOX6 for lower rectal cancer with suspected lateral pelvic lymph node metastasis (JCOG1310): a phase II/III randomized controlled trial
Authors: Ohue Masayuki , Iwasa Satoru , Mizusawa Junki , Kanemitsu Yukihide , Shiozawa Manabu , Nishizawa Yusuke , Ueno Hideki , Katsumata Kenji , Yasui Masayoshi , Tsukamoto Shunsuke , Katayama Hiroshi , Fukuda Haruhiko , Shimada Yasuhiro
Published: May 2022

Objective

The optimal perioperative chemotherapy for lower rectal cancer with lateral pelvic lymph node metastasis remains unclear. We evaluated the efficacy and safety of perioperative mFOLFOX6 in comparison with postoperative mFOLFOX6 for rectal cancer patients undergoing total mesorectal excision with lateral lymph node dissection.

Methods

We conducted an open label randomized phase II/III trial in 18 Japanese institutions. We enrolled patients with histologically proven lower rectal adenocarcinoma with clinical pelvic lateral lymph node metastasis who were randomly assigned (1:1) to receive postoperative mFOLFOX6 (12 courses of intravenous oxaliplatin [85 mg/m2] with L-leucovorin [200 mg/m2] followed by 5-fluorouracil [400 mg/m2, bolus and 2400 mg/m2, continuous infusion, repeated every 2 weeks]) or perioperative mFOLFOX6 (six courses each preoperatively and postoperatively). The primary endpoint was overall survival (OS). The trial is registered with Japan Registry of Clinical Trials, number jRCTs031180230.

Results

Between May 2015, and May 2019, 48 patients were randomized to the postoperative arm (n = 26) and the perioperative arm (n = 22). The trial was terminated prematurely due to poor accrual. The 3-year OS in the postoperative and perioperative groups were 66.1 and 84.4%, respectively (HR 0.58, 95% CI [0.14–2.45], one-sided P = 0.23). The pathological complete response rate in the perioperative group was 9.1%. Grade 3 postoperative surgical complications were more frequently observed in the perioperative arm (50.0 vs. 12.0%). One treatment-related death due to sepsis from pelvic infection occurred in the postoperative group.

Conclusions

Perioperative mFOLFOX6 may be an insufficient treatment to improve survival of lower rectal cancer with lateral pelvic lymph node metastasis.
The Gulf Coast Tick,Amblyomma maculatum(Ixodida: Ixodidae), and Spotted Fever GroupRickettsiain the Highly Urbanized Northeastern United States
Authors: Bajwa Waheed I , Tsynman Leonid , Egizi Andrea M , Tokarz Rafal , Maestas Lauren P , Fonseca Dina M
Published: May 2022

We report the multi-year collection of the Gulf Coast tick, Amblyomma maculatum Koch (Acaridae: Ixodida: Ixodidae) in Staten Island, New York City (NYC) as well as their detection in Brooklyn, NYC, and in Atlantic and Cumberland counties in southern New Jersey, USA. The first and most common detections were of adults, however in Freshkills Park on Staten Island larvae were also collected in a following year. The presence of larvae indicates that adults are successfully finding hosts in Staten Island. While it is still unknown how A. americanum reached Staten Island, immatures of this species often parasitize migratory birds, which are now often seen in Freshkills Park. We describe the landscape features of the area in Staten Island where populations were highest and larvae were detected, which could have facilitated the establishment of A. maculatum. Notably, we also report the presence of human pathogens Rickettsia parkeri in 5/10 (50%) of adults tested and R. felis in 1/24 (4.17%) of larvae tested. In addition to established populations in Staten Island we found evidence of A. maculatum in NJ and other NYC boroughs, suggesting current or future establishment is possible. The failure thus far to detect established populations in these areas may be due to inherent difficulties in detecting low density, spatially heterogeneous incipient populations, which could require targeted surveillance efforts for this species. We discuss the consequences to public health of the establishment of A. maculatum and detection of two additional rickettsial pathogens in the densely populated northeastern United States.
Prevalence of Knock-Down Resistance F1534S Mutations in Aedes albopictus (Skuse) (Diptera: Culicidae) in North Carolina
Authors: Abernathy Haley A , Hollingsworth Brandon D , Giandomenico Dana A , Moser Kara A , Juliano Jonathan J , Bowman Natalie M , George Phillip J , Reiskind Michael H , Boyce Ross M
Published: May 2022

Knock-down resistance (kdr) mutations in the voltage-gated sodium channel gene of Aedes species mosquitoes are biomarkers for resistance to pyrethroid insecticides. In the United States, few studies have reported kdr mutations among Aedes albopictus (Skuse) (Diptera: Culicidae) populations. In this study, we sought to compare the presence of kdr alleles among Ae. albopictus mosquitoes collected from Fort Bragg and Wake County, North Carolina. We collected 538 Ae. albopictus mosquitoes, including 156 from 4 sites at Fort Bragg, North Carolina and 382 from 15 sites in Wake County, North Carolina to compare the prevalence of kdr mutations. Of those successfully sequenced, we identified 12 (3.0%) mosquitoes with kdr mutations, all of which were attributed to variants at position 1534 within domain 3. All mutations were found in mosquitoes collected at Wake County sites; no mutations were identified in collections from Fort Bragg. There was a focus of mutations observed at the Wake County sites with approximately 92% (11 of 12) of the mosquitoes with the mutation coming from one site, where kdr mutations represented 24.4% (11 of 45) of all mosquitoes collected. We observed highly focal resistance in a suburban area of Raleigh, which may be attributable to peri-domestic mosquito control activities that involve area dispersal of pyrethroid insecticides. More robust surveillance is needed to monitor the emergence and spread of resistance.
Description of Larva and Pupa ofPsorophora(Grabhamia)dimidiata(Diptera: Culicidae) and Redescription of the Adult Female and Male
Authors: Stein Marina , Bangher Débora , Laurito Magdalena , Visintín Andrés , Rossi Gustavo C , Almirón Walter
Published: May 2022

Psorophora (Grabhamia) dimidiata Cerqueira (1943) was described based on the adult female and male. Later, descriptions of the male and female genitalia were published by Lane (in Neotropical Culicidae, vols. I & II. Editora da Universidade de São Paulo, S. P., Brazil, 1953) and Guedes et al. (in Catalogo ilustrado dos mosquitos da coleção do Instituto Nacional de Endemias Rurais. I. Gênero Psorophora Robineau-Desvoidy, 1827. Rev. Bras. Malariol. Doencas Trop. 12: 3–24; 1965), respectively. Here we describe the pupa and fourth-instar larva and redescribe the adult male and female genitalia and female cibarium. All stages (except the egg) are illustrated. Unambiguous recognition is provided. Distinctions from Ps. cingulata (Fabricius) and possible phylogenetic relationships are discussed.
Malaria parasite classification framework using a novel channel squeezed and boosted CNN
Authors: Khan Saddam Hussain , Shah Najmus Saher , Nuzhat Rabia , Majid Abdul , Alquhayz Hani , Khan Asifullah
Published: May 2022

Malaria is a life-threatening infection that infects the red blood cells and gradually grows throughout the body. The plasmodium parasite is transmitted by a female Anopheles mosquito bite and severely affects numerous individuals within the world every year. Therefore, early detection tests are required to identify parasite-infected cells. The proposed technique exploits the learning capability of deep convolutional neural network (CNN) to distinguish the parasite-infected patients from healthy individuals using thin blood smear. In this regard, the detection is accomplished using a novel STM-SB-RENet block-based CNN that employs the idea of split–transform–merge (STM) and channel squeezing–boosting (SB) in a modified fashion. In this connection, a new convolutional block-based STM is developed, which systematically implements region and edge operations to explore the parasitic infection pattern of malaria related to region homogeneity, structural obstruction and boundary-defining features. Moreover, the diverse boosted feature maps are achieved by incorporating the new channel SB and transfer learning (TL) idea in each STM block at abstract, intermediate and target levels to capture minor contrast and texture variation between parasite-infected and normal artifacts. The malaria input images for the proposed models are initially transformed using discrete wavelet transform to generate enhanced and reduced feature space. The proposed architectures are validated using hold-out cross-validation on the National Institute of Health Malaria dataset. The proposed methods outperform training from scratch and TL-based fine-tuned existing techniques. The considerable performance (accuracy: 97.98%, sensitivity: 0.988, F-score: 0.980 and area under the curve: 0.996) of STM-SB-RENet suggests that it can be utilized to screen malaria-parasite-infected patients.

Graphical Abstract
The Development of Global Cancer Research at the United States National Cancer Institute
Authors: Parascandola Mark , Pearlman Paul C , Eldridge Linsey , Gopal Satish
Published: May 2022

International research and collaboration has been a part of the National Cancer Institute’s (NCI) mission since its creation in 1937. Early on, efforts were limited to international exchange of information to ensure that US cancer patients could benefit from advances in other countries. As NCI’s research grant portfolio grew in the 1950s, it included a modest number of grants to foreign institutions, primarily in the United Kingdom and Europe. In the 1960s, the development of geographic pathology, which aimed to study cancer etiology through variations in cancer incidence and risk factors, led to an increase in NCI-funded international research, including research in low- and middle-income countries. In this paper, we review key international research programs, focusing particularly on the first 50 years of NCI history. The first NCI-led overseas research programs, established in the 1960s in Ghana and Uganda, generated influential research but also struggled with logistical challenges and political instability. The 1971 National Cancer Act was followed by the creation of a number of bilateral agreements with foreign governments, including China, Japan, and Russia, to support cooperation in technology and medicine. Although these agreements were broad without specific scientific goals, they provided an important mechanism for sustained collaborations in specific areas. With the creation of the NCI Center for Global Health in 2011, NCI’s global cancer research efforts gained sustained focus. Because the global cancer burden has evolved over time, increasingly impacting low- and middle-income countries, NCI’s role in global cancer research remains more important than ever.
‘A man greatly beloved’ and Immortalized in opus sectile Powell & Sons, Monument to Robert Claudius Billing (1899)
Authors: Allen Jasmine
Published: May 2022

The alabaster wall monument to Robert Claudius Billing, Suffragan Bishop of Bedford, placed in the crypt of St Paul’s Cathedral, commemorates the life and service of a Victorian cleric known for his work in the overcrowded parishes of east London. Supplied by Powell and Sons, a London-based glassmaking firm that made stained glass and mosaics as well as reredoses and tablets, the monument echoes the architectural style and decoration of the iconic building in which it is placed, as well as showcasing a new vitreous mosaic material known as opus sectile that the firm innovated and marketed as suitable for both wall and floor decoration. The striking opus sectile portrait of Billing preserves an image of the deceased, and together with the accompanying epitaph demonstrates the affection and high esteem in which he was held in the Diocese of London and beyond.
No slip gravity in light of LISA standard sirens
Authors: Allahyari Alireza , Nunes Rafael C , Mota David F
Published: May 2022

Standard sirens (SS) are the gravitational wave analogue of the astronomical standard candles, and can provide powerful information about the dynamics of the Universe up to very high z values. In this work, we generate three mock SS catalogues based on the merger of massive black hole binaries which are expected to be observed in the LISA operating frequency band. Then, we perform an analysis to test modifications of general relativity (GR) inspired by the no slip gravity framework. We find that in the best scenarios, we can constrain the free parameters which quantify deviations from GR to 21 per cent accuracy, while the Hubble parameter can be simultaneously fit to 6 per cent accuracy. In combination with CMB information, we find a 15 per cent accuracy on the modified gravity free parameters and 0.7 per cent accuracy on the Hubble parameter. The SS events at very large cosmological distances to be observed in LISA band will provide a unique way to test nature of gravity, but in the context of the analysis performed here, it will not be possible to distinguish the no slip gravity from GR.
BUDDI-MaNGA II: the star-formation histories of bulges and discs of S0s
Authors: Johnston Evelyn J , Häußler Boris , Jegatheesan Keerthana , Fraser-McKelvie Amelia , Coccato Lodovico , Cortesi Arianna , Jaffé Yara , Galaz Gaspar , Mora Marcelo , Ordenes-Briceño Yasna
Published: May 2022

Many processes have been proposed to explain the quenching of star formation in spiral galaxies and their transformation into S0s. These processes affect the bulge and disc in different ways, and so by isolating the bulge and disc spectra, we can look for these characteristic signatures. In this work, we used buddi to cleanly extract the spectra of the bulges and discs of 78 S0 galaxies in the MaNGA Survey. We compared the luminosity and mass weighted stellar populations of the bulges and discs, finding that bulges are generally older and more metal rich than their discs. When considering the mass and environment of each galaxy, we found that the galaxy stellar mass plays a more significant role on the formation of the bulges. Bulges in galaxies with masses $\ge 10^{10}\, {\rm M}_\odot$ built up the majority of their mass rapidly early in their lifetimes, while those in lower mass galaxies formed over more extended time-scales and more recently. No clear difference was found in the formation or quenching processes of the discs as a function of galaxy environment. We conclude that more massive S0 galaxies formed through an inside-out scenario, where the bulge formed first and evolved passively while the disc underwent a more extended period of star formation. In lower mass S0s, the bulges and discs either formed together from the same material, or through an outside-in scenario. Our results therefore imply multiple formation mechanisms for S0 galaxies, the pathway of which is chiefly determined by a galaxy’s current stellar mass.
Constraints on interacting dark energy models from time-delay cosmography with seven lensed quasars
Authors: Wang Ling-Feng , Zhang Jie-Hao , He Dong-Ze , Zhang Jing-Fei , Zhang Xin
Published: May 2022

Measurements of time-delay cosmography of lensed quasars can provide an independent probe to explore the expansion history of the late-time Universe. In this paper, we employ the time-delay cosmography measurements from seven lenses (here abbreviated as the TD data) to constrain interacting dark energy (IDE) models. We mainly focus on the scenario of vacuum energy (with w = −1) interacting with cold dark matter, and consider four typical cases of the interaction form Q. When the TD data alone are employed, we find that the IDE models with Q ∝ ρde seem to have an advantage in relieving the H0 tension between the cosmic microwave background (CMB) and TD data. When the TD data are added to the CMB+BAO+SN+H0 data, we find that (i) the coupling parameter β in all the considered IDE models is positive within 1σ range, implying a mild preference for the case of cold dark matter decaying into dark energy; (ii) the IDE model with Q = βH0ρc slightly relieves the S8 tension, but the other considered IDE models further aggravate this tension; (iii) the Akaike information criteria of the IDE models with Q ∝ ρc are lower than that of the ΛCDM model, indicating that these IDE models are more preferred by the current mainstream data. We conclude that the considered IDE models have their own different advantages when the TD data are employed, and none of them can achieve good scores in all aspects.
High time resolution search for prompt radio emission from the long GRB 210419A with the Murchison Widefield Array
Authors: Tian J , Anderson G E , Hancock P J , Miller-Jones J C A , Sokolowski M , Swainston N A , Rowlinson A , Williams A , Kaplan D L , Hurley-Walker N , Morgan J , Bhat N D R , Ung D , Tingay S , Bannister K W , Bell M E , Meyers B W , Walker M
Published: May 2022

We present a low-frequency (170–200 MHz) search for prompt radio emission associated with the long GRB 210419A using the rapid-response mode of the Murchison Widefield Array (MWA), triggering observations with the Voltage Capture System for the first time. The MWA began observing GRB 210419A within 89 s of its detection by Swift, enabling us to capture any dispersion delayed signal emitted by this gamma-ray burst (GRB) for a typical range of redshifts. We conducted a standard single pulse search with a temporal and spectral resolution of $100\, \mu$s and 10 kHz over a broad range of dispersion measures from 1 to $5000\, \text{pc}\, \text{cm}^{-3}$, but none were detected. However, fluence upper limits of 77–224 Jy ms derived over a pulse width of 0.5–10 ms and a redshift of 0.6 < z < 4 are some of the most stringent at low radio frequencies. We compared these fluence limits to the GRB jet–interstellar medium interaction model, placing constraints on the fraction of magnetic energy (ϵB ≲ [0.05–0.1]). We also searched for signals during the X-ray flaring activity of GRB 210419A on minute time-scales in the image domain and found no emission, resulting in an intensity upper limit of $0.57\, \text{Jy}\, \text{beam}^{-1}$, corresponding to a constraint of ϵB ≲ 10−3. Our non-detection could imply that GRB 210419A was at a high redshift, there was not enough magnetic energy for low-frequency emission, or the radio waves did not escape from the GRB environment.
Evolution of Plasmid Mobility: Origin and Fate of Conjugative and Nonconjugative Plasmids
Authors: Coluzzi Charles , Garcillán-Barcia Maria Pilar , de la Cruz Fernando , Rocha Eduardo P.C.
Published: May 2022

Conjugation drives the horizontal transfer of adaptive traits across prokaryotes. One-fourth of the plasmids encode the functions necessary to conjugate autonomously, the others being eventually mobilizable by conjugation. To understand the evolution of plasmid mobility, we studied plasmid size, gene repertoires, and conjugation-related genes. Plasmid gene repertoires were found to vary rapidly in relation to the evolutionary rate of relaxases, for example, most pairs of plasmids with 95% identical relaxases have fewer than 50% of homologs. Among 249 recent transitions of mobility type, we observed a clear excess of plasmids losing the capacity to conjugate. These transitions are associated with even greater changes in gene repertoires, possibly mediated by transposable elements, including pseudogenization of the conjugation locus, exchange of replicases reducing the problem of incompatibility, and extensive loss of other genes. At the microevolutionary scale of plasmid taxonomy, transitions of mobility type sometimes result in the creation of novel taxonomic units. Interestingly, most transitions from conjugative to mobilizable plasmids seem to be lost in the long term. This suggests a source-sink dynamic, where conjugative plasmids generate nonconjugative plasmids that tend to be poorly adapted and are frequently lost. Still, in some cases, these relaxases seem to have evolved to become efficient at plasmid mobilization in trans, possibly by hijacking multiple conjugative systems. This resulted in specialized relaxases of mobilizable plasmids. In conclusion, the evolution of plasmid mobility is frequent, shapes the patterns of gene flow in bacteria, the dynamics of gene repertoires, and the ecology of plasmids.
Evidence for TET-mediated DNA demethylation as an epigenetic alteration in cumulus granulosa cells of women with polycystic ovary syndrome
Authors: Sagvekar Pooja , Shinde Gayatri , Mangoli Vijay , Desai Sadhana K , Mukherjee Srabani
Published: May 2022

Peripheral and tissue-specific alterations in global DNA methylation (5-methylcytosine (5mC)) and DNA hydroxymethylation (5-hydroxymethylcytosine (5hmC)) profiles have been identified as both biomarkers for disease prediction and as hallmarks of dysregulated localized gene networks. Global and gene-specific epigenetic alterations in the 5mC profiles have shown widespread implications in the etiology of polycystic ovary syndrome (PCOS). However, there has been no study in PCOS that integrates the quantification of 5mC and 5hmC signatures alongside the expression levels of DNA methylating and demethylating enzymes as respective indicators of methylation and demethylation pathways. Having previously shown that the 5mC signatures are not substantially altered in PCOS, we assessed the global 5hmC levels in peripheral blood leukocytes and cumulus granulosa cells (CGCs) of 40 controls and 40 women with PCOS. This analysis revealed higher 5hmC levels in CGCs of PCOS women, indicating a more dominant demethylation pathway. Furthermore, we assessed the transcript and protein expression levels of DNA demethylating and methylating enzymes, i.e. ten-eleven translocation methylcytosine dioxygenases (TET1, TET2, TET3) and DNA methyltransferases (DNMT1, DNMT3A and DNMT3B), respectively, in CGCs. The relative transcript and protein expression levels of all three TETs were found to be higher in women with PCOS, and the TET mRNA expression profiles were positively correlated with 5hmC levels in CGCs. Also, all three DNMT genes showed altered transcript expression in PCOS, although only the downregulated DNMT3A transcript was correlated with decreasing 5mC levels. At the protein level, the expression of DNMT1 (maintenance methylation enzyme) was higher, while that of DNMT3A (de novo methylation enzyme) was found to be lower in PCOS compared to controls. Overall, these results indicate that DNA methylation changes in CGCs of PCOS women may arise partly due to intrinsic alterations in the transcriptional regulation of TETs and DNMT3A.
Ribosomal protein eL39 is important for maturation of the nascent polypeptide exit tunnel and proper protein folding during translation
Authors: Micic Jelena , Rodríguez-Galán Olga , Babiano Reyes , Fitzgerald Fiona , Fernández-Fernández José , Zhang Yunyang , Gao Ning , Woolford John L , de la Cruz Jesús
Published: May 2022

During translation, nascent polypeptide chains travel from the peptidyl transferase center through the nascent polypeptide exit tunnel (NPET) to emerge from 60S subunits. The NPET includes portions of five of the six 25S/5.8S rRNA domains and ribosomal proteins uL4, uL22, and eL39. Internal loops of uL4 and uL22 form the constriction sites of the NPET and are important for both assembly and function of ribosomes. Here, we investigated the roles of eL39 in tunnel construction, 60S biogenesis, and protein synthesis. We show that eL39 is important for proper protein folding during translation. Consistent with a delay in processing of 27S and 7S pre-rRNAs, eL39 functions in pre-60S assembly during middle nucleolar stages. Our biochemical assays suggest the presence of eL39 in particles at these stages, although it is not visualized in them by cryo-electron microscopy. This indicates that eL39 takes part in assembly even when it is not fully accommodated into the body of pre-60S particles. eL39 is also important for later steps of assembly, rotation of the 5S ribonucleoprotein complex, likely through long range rRNA interactions. Finally, our data strongly suggest the presence of alternative pathways of ribosome assembly, previously observed in the biogenesis of bacterial ribosomal subunits.
Mutations compensating for the fitness cost of rifampicin resistance inEscherichia coliexert pleiotropic effect on RNA polymerase catalysis
Authors: Kurepina Natalia , Chudaev Maxim , Kreiswirth Barry N , Nikiforov Vadim , Mustaev Arkady
Published: May 2022

The spread of drug-resistant bacteria represents one of the most significant medical problems of our time. Bacterial fitness loss associated with drug resistance can be counteracted by acquisition of secondary mutations, thereby enhancing the virulence of such bacteria. Antibiotic rifampicin (Rif) targets cellular RNA polymerase (RNAP). It is potent broad spectrum drug used for treatment of bacterial infections. We have investigated the compensatory mechanism of the secondary mutations alleviating Rif resistance (Rifr) on biochemical, structural and fitness indices. We find that substitutions in RNAP genes compensating for the growth defect caused by βQ513P and βT563P Rifr mutations significantly enhanced bacterial relative growth rate. By assaying RNAP purified from these strains, we show that compensatory mutations directly stimulated basal transcriptional machinery (2–9-fold) significantly improving promoter clearance step of the transcription pathway as well as elongation rate. Molecular modeling suggests that compensatory mutations affect transcript retention, substrate loading, and nucleotidyl transfer catalysis. Strikingly, one of the identified compensatory substitutions represents mutation conferring rifampicin resistance on its own. This finding reveals an evolutionary process that creates more virulent species by simultaneously improving the fitness and augmenting bacterial drug resistance.
Functional editing of endogenous genes through rapid selection of cell pools (Rapid generation of endogenously tagged genes in Drosophila ovarian somatic sheath cells)
Authors: Meng Qingcai , Stoyko Daniel , Andrews Celine Marlin , Konstantinidou Parthena , Genzor Pavol , O Timothy , Elchert Alexandra R , Benner Leif , Sobti Sushil , Katz Esther Y , Haase Astrid D
Published: May 2022

The combination of genome-editing and epitope tagging provides a powerful strategy to study proteins with high affinity and specificity while preserving their physiological expression patterns. However, stably modifying endogenous genes in cells that do not allow for clonal selection has been challenging. Here, we present a simple and fast strategy to generate stable, endogenously tagged alleles in a non-transformed cell culture model. At the example of piwi in Drosophila ovarian somatic sheath cells, we show that this strategy enables the generation of an N-terminally tagged protein that emulates the expression level and subcellular localization of the wild type protein and forms functional Piwi–piRNA complexes. We further present a concise workflow to establish endogenously N-terminally and C-terminally tagged proteins, and knockout alleles through rapid selection of cell pools in fly and human models.
Cooperation between intrinsically disordered and ordered regions of Spt6 regulates nucleosome and Pol II CTD binding, and nucleosome assembly
Authors: Kasiliauskaite Aiste , Kubicek Karel , Klumpler Tomas , Zanova Martina , Zapletal David , Koutna Eliska , Novacek Jiri , Stefl Richard
Published: May 2022

Transcription elongation factor Spt6 associates with RNA polymerase II (Pol II) and acts as a histone chaperone, which promotes the reassembly of nucleosomes following the passage of Pol II. The precise mechanism of nucleosome reassembly mediated by Spt6 remains unclear. In this study, we used a hybrid approach combining cryo-electron microscopy and small-angle X-ray scattering to visualize the architecture of Spt6 from Saccharomyces cerevisiae. The reconstructed overall architecture of Spt6 reveals not only the core of Spt6, but also its flexible N- and C-termini, which are critical for Spt6’s function. We found that the acidic N-terminal region of Spt6 prevents the binding of Spt6 not only to the Pol II CTD and Pol II CTD-linker, but also to pre-formed intact nucleosomes and nucleosomal DNA. The N-terminal region of Spt6 self-associates with the tSH2 domain and the core of Spt6 and thus controls binding to Pol II and nucleosomes. Furthermore, we found that Spt6 promotes the assembly of nucleosomes in vitro. These data indicate that the cooperation between the intrinsically disordered and structured regions of Spt6 regulates nucleosome and Pol II CTD binding, and also nucleosome assembly.
USP16-mediated histone H2A lysine-119 deubiquitination during oocyte maturation is a prerequisite for zygotic genome activation
Authors: Rong Yan , Zhu Ye-Zhang , Yu Jia-li , Wu Yun-Wen , Ji Shu-Yan , Zhou Yong , Jiang Yu , Jin Jin , Fan Heng-Yu , Shen Li , Sha Qian-Qian
Published: May 2022

Maternal-to-zygotic transition (MZT) is the first and key step in the control of animal development and intimately related to changes in chromatin structure and histone modifications. H2AK119ub1, an important epigenetic modification in regulating chromatin configuration and function, is primarily catalyzed by PRC1 and contributes to resistance to transcriptional reprogramming in mouse embryos. In this study, the genome-wide dynamic distribution of H2AK119ub1 during MZT in mice was investigated using chromosome immunoprecipitation and sequencing. The results indicated that H2AK119ub1 accumulated in fully grown oocytes and was enriched at the TSSs of maternal genes, but was promptly declined after meiotic resumption at genome-wide including the TSSs of early zygotic genes, by a previously unidentified mechanism. Genetic evidences indicated that ubiquitin-specific peptidase 16 (USP16) is the major deubiquitinase for H2AK119ub1 in mouse oocytes. Conditional knockout of Usp16 in oocytes did not impair their survival, growth, or meiotic maturation. However, oocytes lacking USP16 have defects when undergoing zygotic genome activation or gaining developmental competence after fertilization, potentially associated with high levels of maternal H2AK119ub1 deposition on the zygotic genomes. Taken together, H2AK119ub1 level is declined during oocyte maturation by an USP16-dependent mechanism, which ensures zygotic genome reprogramming and transcriptional activation of essential early zygotic genes.
Changes in E-cigarette Use Among Youth and Young Adults During the COVID-19 Pandemic: Insights Into Risk Perceptions and Reasons for Changing Use Behavior
Authors: Bennett Morgane , Speer Jessica , Taylor Nathaniel , Alexander Tesfa
Published: May 2022

Introduction

This study assessed changes in e-cigarette use since the COVID-19 pandemic began and reasons for these changes among US youth and young adults.

Aims and Methods

We combined data from two cross-sectional samples of youth and young adult (15–24 years) participants of a monthly surveillance study (data collected in April and June 2021). Analyses were restricted to past-year e-cigarette users who reported using e-cigarettes before the pandemic (n = 1762). Participants reported changes in e-cigarette use since the pandemic began, reasons for changing their behavior, and their perceptions around COVID-19 risk related to e-cigarette use. Multinomial logistic regression models assessed associations between demographics and COVID vaping risk perceptions and changes in e-cigarette use.

Results

Over a third of the sample (37.9%) reported increasing e-cigarette use, while 28.9% reported decreasing use, and 33.1% reported no change. Analyses revealed associations between change in e-cigarette use and age, race and ethnicity, e-cigarette use status, and COVID vaping risk perceptions. The most common reason for increasing use was managing stress (36%); the most common reasons for decreasing use included fewer social interactions (22%) and concerns over general health (18%). Results also indicated differences in reasons for decreasing use by race and ethnicity, and differences in reasons for both increasing and decreasing use by age.

Conclusions

This study provides recent data on how the ongoing and evolving COVID-19 pandemic has impacted youth and young adults’ e-cigarette use. Findings identify subpopulations that may benefit from e-cigarette prevention interventions, as well as insights that may inform the content and delivery of such interventions.

Implications

This study provides recent insights into if and why the ongoing COVID-19 pandemic has impacted e-cigarette use behavior among youth and young adults. Findings contribute to the understanding of the role e-cigarettes play in young people’s lives—insights that can inform youth and young adult prevention efforts.
Evaluating Treatment Mechanisms of Varenicline: Mediation by Affect and Craving
Authors: Tonkin Sarah S , Colder Craig , Mahoney Martin C , Swan Gary E , Cinciripini Paul , Schnoll Robert , George Tony P , Tyndale Rachel F , Hawk Larry W
Published: May 2022

Introduction

Negative reinforcement models posit that relapse to cigarette smoking is driven in part by changes in affect and craving during the quit attempt. Varenicline may aid cessation by attenuating these changes; however, this mediational pathway has not been formally evaluated in placebo-controlled trials. Thus, trajectories of negative affect (NA), positive affect (PA), and craving were tested as mediators of the effect of varenicline on smoking cessation.

Aims and Methods

Secondary data analysis was conducted on 828 adults assigned to either varenicline or placebo in a randomized controlled trial for smoking cessation (NCT01314001). Self-reported NA, PA, and craving were assessed 1-week pre-quit, on the target quit day (TQD), and 1 and 4 weeks post-TQD.

Results

Across time, NA peaked 1-week post-quit, PA did not change, and craving declined. Less steep rises in NA (indirect effect 95% CI: .01 to .30) and lower mean craving at 1-week post-quit (CI: .06 to .50) were mediators of the relationship between varenicline and higher cessation rates at the end of treatment. PA was associated with cessation but was not a significant mediator.

Conclusions

These results partially support the hypothesis that varenicline improves smoking cessation rates by attenuating changes in specific psychological processes and supported NA and craving as plausible treatment mechanisms of varenicline.

Implications

The present research provides the first evidence from a placebo-controlled randomized clinical trial that varenicline’s efficacy is due, in part, to post-quit attenuation of NA and craving. Reducing NA across the quit attempt and craving early into the attempt may be important treatment mechanisms for effective interventions. Furthermore, post-quit NA, PA, and craving were all associated with relapse and represent treatment targets for future intervention development.
Mutations in the chloroplast inner envelope protein TIC100 impair and repair chloroplast protein import and impact retrograde signaling
Authors: Loudya Naresh , Maffei Douglas P F , B�dard Jocelyn , Ali Sabri Mohd , Devlin Paul F , Jarvis R Paul , L�pez-Juez Enrique
Published: May 2022

Chloroplast biogenesis requires synthesis of proteins in the nucleocytoplasm and the chloroplast itself. Nucleus-encoded chloroplast proteins are imported via multiprotein translocons in the organelle’s envelope membranes. Controversy exists around whether a 1-MDa complex comprising TIC20, TIC100, and other proteins constitutes the inner membrane TIC translocon. The Arabidopsis thaliana cue8 virescent mutant is broadly defective in plastid development. We identify CUE8 as TIC100. The tic100cue8 mutant accumulates reduced levels of 1-MDa complex components and exhibits reduced import of two nucleus-encoded chloroplast proteins of different import profiles. A search for suppressors of tic100cue8 identified a second mutation within the same gene, tic100soh1, which rescues the visible, 1 MDa complex-subunit abundance, and chloroplast protein import phenotypes. tic100soh1 retains but rapidly exits virescence and rescues the synthetic lethality of tic100cue8 when retrograde signaling is impaired by a mutation in the GENOMES UNCOUPLED 1 gene. Alongside the strong virescence, changes in RNA editing and the presence of unimported precursor proteins show that a strong signaling response is triggered when TIC100 function is altered. Our results are consistent with a role for TIC100, and by extension the 1-MDa complex, in the chloroplast import of photosynthetic and nonphotosynthetic proteins, a process which initiates retrograde signaling.
The host exocyst complex is targeted by a conserved bacterial type-III effector that promotes virulence
Authors: Michalopoulou Vassiliki A , Mermigka Glykeria , Kotsaridis Konstantinos , Mentzelopoulou Andriani , Celie Patrick H N , Moschou Panagiotis N , Jones Jonathan D G , Sarris Panagiotis F
Published: May 2022

For most Gram-negative bacteria, pathogenicity largely depends on the type-III secretion system that delivers virulence effectors into eukaryotic host cells. The subcellular targets for the majority of these effectors remain unknown. Xanthomonas campestris, the causal agent of black rot disease of crucifers such as Brassica spp., radish, and turnip, delivers XopP, a highly conserved core-effector protein produced by X. campestris, which is essential for virulence. Here, we show that XopP inhibits the function of the host–plant exocyst complex by direct targeting of Exo70B, a subunit of the exocyst complex, which plays a significant role in plant immunity. XopP interferes with exocyst-dependent exocytosis and can do this without activating a plant NOD-like receptor that guards Exo70B in Arabidopsis. In this way, Xanthomonas efficiently inhibits the host’s pathogen-associated molecular pattern (PAMP)-triggered immunity by blocking exocytosis of pathogenesis-related protein-1A, callose deposition, and localization of the FLAGELLIN SENSITIVE2 (FLS2) immune receptor to the plasma membrane, thus promoting successful infection. Inhibition of exocyst function without activating the related defenses represents an effective virulence strategy, indicating the ability of pathogens to adapt to host defenses by avoiding host immunity responses.
The transcription factor ZmMYB69 represses lignin biosynthesis by activating ZmMYB31/42 expression in maize
Authors: Qiang Zhiquan , Sun Honghua , Ge Fanghui , Li Wei , Li Changjiang , Wang Shuwei , Zhang Baocai , Zhu Lei , Zhang Shuaisong , Wang Xiqing , Lai Jinsheng , Qin Feng , Zhou Yihua , Fu Ying
Published: May 2022

A MYB family transcription factor ZmMYB69 is a transcriptional activator at the upper level of ZmMYB31 and ZmMYB42 in the hierarchical network that controls lignin biosynthesis in maize.
An Arabidopsis Retention and Splicing complex regulates root and embryo development through pre-mRNA splicing
Authors: Xiong Feng , Ren Jing-Jing , Wang Yu-Yi , Zhou Zhou , Qi Hao-Dong , Otegui Marisa S , Wang Xiu-Ling
Published: May 2022

Pre-mRNA splicing is an important step in the posttranscriptional processing of transcripts and a key regulator of development. The heterotrimeric retention and splicing (RES) complex plays vital roles in the growth and development of yeast, zebrafish, and humans by mediating pre-mRNA splicing of multiple genes. However, whether the RES complex is conserved in plants and what specific functions it has remain unknown. In this study, we identified Arabidopsis (Arabidopsis thaliana) BUD13 (AtBUD13), GROWTH, DEVELOPMENT AND SPLICING 1 (GDS1), and DAWDLE (DDL) as the counterparts of the yeast RES complex subunits Bud site selection protein 13 (Bud13), U2 snRNP component Snu17 (Snu17), and Pre-mRNA leakage protein 1, respectively. Moreover, we showed that RES is an ancient complex evolutionarily conserved in eukaryotes. GDS1 directly interacts with both AtBUD13 and DDL in nuclear speckles. The BUD13 domain of AtBUD13 and the RNA recognition motif domain of GDS1 are necessary and sufficient for AtBUD13–GDS1 interaction. Mutants of AtBUD13, GDS1, and DDL failed to properly splice multiple genes involved in cell proliferation and showed defects in early embryogenesis and root development. In addition, we found that GDS1 and DDL interact, respectively, with the U2 small nuclear ribonucleoproteins auxiliary factor AtU2AF65B and the NineTeen Complex-related splicing factor SKIP, which are essential for early steps of spliceosome assembly and recognition of splice sites. Altogether, our work reveals that the Arabidopsis RES complex is important for root and early embryo development by modulating pre-mRNA splicing.
Improved outcomes in rheumatoid arthritis with obesity after a weight loss intervention: randomized trial
Authors: Ranganath Veena K , La Cava Antonio , Vangala Sitaram , Brook Jenny , Kermani Tanaz A , Furst Daniel E , Taylor Mihaela , Kaeley Gurjit S , Carpenter Catherine , Elashoff David A , Li Zhaoping
Published: May 2022

Objective

To examine whether a weight loss intervention programme improves RA disease activity and/or musculoskeletal ultrasound synovitis measures in obese RA patients.

Methods

We conducted a proof-of-concept, 12-week, single-blind, randomized controlled trial of obese RA patients (BMI ≥ 30) with 28-joint DAS (DAS28)  ≥ 3.2 and with evidence of power Doppler synovitis. Forty patients were randomized to the diet intervention (n = 20) or control group (n = 20). Diet intervention consisted of a hypocaloric diet of 1000–1500 kcal/day and high protein meal replacements. Co-primary outcomes included change in DAS28 and power Doppler ultrasound (PDUS)-34. Clinical disease activity, imaging, biomarkers, adipokines and patient-reported outcomes were monitored throughout the trial. Recruitment terminated early. All analyses were based on intent-to-treat for a significance level of 0.05.

Results

The diet intervention group lost an average 9.5 kg/patient, while the control group lost 0.5 kg (P < 0.001). Routine Assessment of Patient Index Data 3 (RAPID3) improved, serum leptin decreased and serum adiponectin increased significantly within the diet group and between the groups (all P < 0.03). DAS28 decreased, 5.2 to 4.2, within the diet group (P < 0.001; −0.51 [95% CI −1.01, 0.00], P = 0.056, between groups). HAQ-Disability Index (HAQ-DI) improved significantly within the diet group (P < 0.04; P = 0.065 between group). Ultrasound measures and the multi-biomarker disease activity score did not differ between groups (PDUS-34 −2.0 [95% CI −7.00, 3.1], P = 0.46 between groups).

Conclusion

Obese RA patients on the diet intervention achieved weight loss. There were significant between group improvements for RAPID3, adiponectin and leptin levels, and positive trends for DAS28 and HAQ-DI. Longer-term, larger weight loss studies are needed to validate these findings, and will allow for further investigative work to improve the clinical management of obese RA patients.

Trial registration

ClinicalTrials.gov, https://clinicaltrials.gov, NCT02881307
Cancer occurrence after SLE: effects of medication-related factors, disease-related factors and survival from an observational study
Authors: Zhao Qing , Liu Huazhen , Yang Wenfang , Zhou Ziyue , Yang Yiying , Jiang Xu , Yang Huaxia , Zhang Fengchun
Published: May 2022

Objectives

To explore the survival and risk factors for cancer occurrence after SLE (SLE-CA).

Methods

Patients with cancer diagnosed after SLE in Peking Union Medical College Hospital between January 2006 and September 2017 were recruited and followed. Data regarding medication-related and disease-related factors and survival were collected and compared with matched controls. Logistic regressions were applied to identify risk factors. The Kaplan–Meier method with a log-rank test was performed to evaluate survival.

Results

Forty-five SLE-CA patients and 128 controls were included, with the most common cancer site being the female genital system. SLE-CA patients were exposed to a higher cumulative dosage of CYC, with less mucocutaneous and haematologic involvement and higher anti-dsDNA positivity. At the time of cancer diagnosis, SLE-CA patients had lower SLEDAI 2000 (SLEDAI-2K), tended to achieve Definitions of Remission in SLE remission and minimal disease activity, but had higher SLICC/ACR Damage Index. Multivariable analysis identified high dosage of CYC [odds ratio (OR) 1.027, 95% CI 1.008, 1.046; P = 0.005] and low SLEDAI-2K at cancer diagnosis (OR 0.756, 95% CI 0.579, 0.986; P = 0.039) as risk factors. Mucocutaneous (OR 0.330, 95% CI 0.110, 0.991; P = 0.048) and haematologic involvement (OR 0.304, 95% CI 0.103, 0.902; P = 0.032) were negatively associated with cancer occurrence after SLE. The 5- and 10-year survival rates in SLE-CA patients were 95.2% and 92.1%, respectively. No significant difference of survival was observed between SLE-CA patients and controls (P = 0.177).

Conclusion

High dosage of CYC and disease-related factors (low SLEDAI-2K, less mucocutaneous and haematologic involvement) were related factors for cancer occurrence after SLE, while no survival difference was observed.