bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variable antiviral activity of islatravir against M184I/V mutant HIV-1 selected during antiretroviral therapy
Authors: Aulicino Paula C , Sharma Suman , Truong Khanghy , Kukunoor Vindhya , Ghei Karm , Arazi-Caillaud Solange , Taicz Moira , Bologna Rosa , Mangano Andrea , Kimata Jason T 
Published: December 2023

Abstract

Background
Islatravir is a new antiretroviral drug that inhibits the reverse transcriptase (RT) of HIV-1 through multiple mechanisms. It is proposed to be used in combination with doravirine, a new NNRTI. M184V/I mutations have been shown to reduce the in vitro antiviral activity of islatravir, but their effect when pre-selected during ART has not been investigated.

Methods
HIV-1 rt sequences were obtained from four individuals of the Garrahan HIV cohort prior to, or during virological failure to ART. HIV-1 infectious molecular clones were constructed on an NL4-3 backbone, and infectious viruses were produced by transfection of 293T cells. Fold-changes in IC50 were calculated for each mutant versus the NL4-3 WT. HIV-1 phenotypic drug resistance was tested in vitro against NRTIs and NNRTIs.

Results
In all the cases, M184I/V, either alone or in the presence of other mutations, was associated with reduced susceptibility to islatravir, abacavir and lamivudine. Viruses carrying M184V/I showed variable levels of resistance to islatravir (4.8 to 33.8-fold). The greatest reduction in susceptibility was observed for viruses carrying the mutations M184V + V106I (33.8-fold resistance) or M184V + I142V (25.2-fold resistance). For NNRTIs, the presence of V106I alone did not affect susceptibility to doravirine or etravirine, but showed a modest reduction in susceptibility to efavirenz (6-fold). Susceptibility to doravirine was slightly reduced only for one of the mutants carrying V106I in combination with Y181C and M184V.

Conclusions
Mutations and polymorphisms selected in vivo together with M184V/I depend on the viral genetic context and on ART history, and could affect the efficacy of islatravir once available for use in the clinic.
Streptococcus suis serotype 9 in Italy: genomic insights into high-risk clones with emerging resistance to penicillin
Authors: Massacci Francesca Romana , Cucco Lucilla , Panicciá Marta , Luppi Andrea , Albini Elisa , Peruzzo Arianna , Ferroni Laura , Ustulin Martina , Orsini Massimiliano , Magistrali Chiara Francesca 
Published: December 2023

Abstract

Background
Streptococcus suis is an important pig pathogen and an emerging zoonotic agent. In a previous study, we described a high proportion of penicillin-resistant serotype 9 S. suis (SS9) isolates on pig farms in Italy.

Objectives
We hypothesized that resistance to penicillin emerged in some SS9 lineages characterized by substitutions at the PBPs, contributing to the successful spread of these lineages in the last 20 years.

Methods
Sixty-six SS9 isolates from cases of streptococcosis in pigs were investigated for susceptibility to penicillin, ceftiofur and ampicillin. The isolates were characterized for ST, virulence profile, and antimicrobial resistance genes through WGS. Multiple linear regression models were employed to investigate the associations between STs, year of isolation, substitutions at the PBPs and an increase in MIC values to β-lactams.

Results
MIC values to penicillin increased by 4% each year in the study period. Higher MIC values for penicillin were also positively associated with ST123, ST1540 and ST1953 compared with ST16. The PBP sequences presented a mosaic organization of blocks. Within the same ST, substitutions at the PBPs were generally more frequent in recent isolates. Resistance to penicillin was driven by substitutions at PBP2b, including K479T, D512E and K513E, and PBP2x, including T551S, while reduced susceptibility to ceftiofur and ampicillin were largely dependent on substitutions at PBP2x.

Conclusions
Here, we identify the STs and substitutions at the PBPs responsible for increased resistance of SS9 to penicillin on Italian pig farms. Our data highlight the need for monitoring the evolution of S. suis in the coming years.
Usefulness of inclusion of ertapenem and temocillin screening breakpoints in the EUCAST rapid antimicrobial susceptibility testing (RAST) for rapid detection of OXA-48-producing Klebsiella pneumoniae directly from positive blood cultures
Authors: Fernández-Caso Belén , Lumbreras-Iglesias Pilar , Rodicio M Rosario , Fernández Javier , Rodríguez-Lucas Carlos 
Published: December 2023

Abstract

Objectives
The aims of this study were: (i) to assess the ability of the meropenem screening breakpoint as part of the screening rapid antimicrobial susceptibility testing (sRAST) of EUCAST for the detection of OXA-48 carbapenemase-producing Klebsiella pneumoniae directly from positive blood cultures (BCs); and (ii) to evaluate the inclusion of ertapenem and temocillin discs into the sRAST to enhance the detection of OXA-48-producing isolates.

Methods
BC bottles were spiked with a total of 117 K. pneumoniae isolates, including 77 previously characterized OXA-48 producers and 40 non-OXA-48 producers. Disc diffusion assays were directly performed from positive BCs with meropenem (10 µg), ertapenem (10 µg) and temocillin (30 µg) discs, and inhibition zones were manually measured after 4, 6 and 8 h of incubation. The screening cut-off values of sRAST were applied to evaluate their capability in detecting OXA-48-producing isolates. Receiver operating characteristic curves were constructed to illustrate the performance efficacy of the disc diffusion assays to detect OXA-48 producers.

Results
The meropenem cut-off values of sRAST only detected 90.91% of the OXA-48-producing isolates after 6 and 8 h of incubation. With the proposed cut-off points for ertapenem [&lt;19 mm (4/6 h) and &lt;20 mm (8 h)] and temocillin [&lt;10 mm (4 h) and &lt;11 mm (6/8 h)], all OXA-48-positive isolates were detected without any false-positive results at any reading time.

Conclusions
In healthcare settings with a high prevalence of OXA-48 producers, the inclusion of ertapenem and temocillin discs in the sRAST procedure may improve the detection of OXA-48-producing K. pneumoniae isolates directly from positive BCs, providing reliable results after only a 4 h incubation period.
Gene Regulatory Network that Shaped the Evolution of Larval Apical Organ in Cnidaria
Authors: Gilbert Eleanor , Craggs Jamie , Modepalli Vengamanaidu 
Published: December 2023

AbstractAmong non-bilaterian animals, a larval apical sensory organ with integrated neurons is only found in cnidarians. Within cnidarians, an apical organ with a ciliary tuft is mainly found in Actiniaria. Whether this apical tuft has evolved independently in Actiniaria or alternatively originated in the common ancestor of Cnidaria and Bilateria and was lost in specific groups is uncertain. To test this hypothesis, we generated transcriptomes of the apical domain during the planula stage of four species representing three key groups of cnidarians: Aurelia aurita (Scyphozoa), Nematostella vectensis (Actiniaria), and Acropora millepora and Acropora tenuis (Scleractinia). We showed that the canonical genes implicated in patterning the apical domain of N. vectensis are largely absent in A. aurita. In contrast, the apical domain of the scleractinian planula shares gene expression pattern with N. vectensis. By comparing the larval single-cell transcriptomes, we revealed the apical organ cell type of Scleractinia and confirmed its homology to Actiniaria. However, Fgfa2, a vital regulator of the regionalization of the N. vectensis apical organ, is absent in the scleractinian genome. Likewise, we found that FoxJ1 and 245 genes associated with cilia are exclusively expressed in the N. vectensis apical domain, which is in line with the presence of ciliary apical tuft in Actiniaria and its absence in Scleractinia and Scyphozoa. Our findings suggest that the common ancestor of cnidarians lacked a ciliary apical tuft, and it could have evolved independently in the Actiniaria.
Harmonin homology domain-mediated interaction of RTEL1 helicase with RPA and DNA provides insights into its recruitment to DNA repair sites
Authors: Kumar Niranjan , Taneja Arushi , Ghosh Meenakshi , Rothweiler Ulli , Sundaresan Nagalingam Ravi , Singh Mahavir 
Published: December 2023

Abstract
The regulator of telomere elongation helicase 1 (RTEL1) plays roles in telomere DNA maintenance, DNA repair, and genome stability by dismantling D-loops and unwinding G-quadruplex structures. RTEL1 comprises a helicase domain, two tandem harmonin homology domains 1&2 (HHD1 and HHD2), and a Zn2+-binding RING domain. In vitro D-loop disassembly by RTEL1 is enhanced in the presence of replication protein A (RPA). However, the mechanism of RTEL1 recruitment at non-telomeric D-loops remains unknown. In this study, we have unravelled a direct physical interaction between RTEL1 and RPA. Under DNA damage conditions, we showed that RTEL1 and RPA colocalise in the cell. Coimmunoprecipitation showed that RTEL1 and RPA interact, and the deletion of HHDs of RTEL1 significantly reduced this interaction. NMR chemical shift perturbations (CSPs) showed that RPA uses its 32C domain to interact with the HHD2 of RTEL1. Interestingly, HHD2 also interacted with DNA in the in vitro experiments. HHD2 structure was determined using X-ray crystallography, and NMR CSPs mapping revealed that both RPA 32C and DNA competitively bind to HHD2 on an overlapping surface. These results establish novel roles of accessory HHDs in RTEL1’s functions and provide mechanistic insights into the RPA-mediated recruitment of RTEL1 to DNA repair sites.
Glycyrrhizin Production in Licorice Hairy Roots Based on Metabolic Redirection of Triterpenoid Biosynthetic Pathway by Genome Editing
Authors: Chiyo Naoki , Seki Hikaru , Kanamoto Takuya , Ueda Hiroshi , Kojoma Mareshige , Muranaka Toshiya 
Published: December 2023

Abstract
Glycyrrhizin, a type of the triterpenoid saponin, is a major active ingredient contained in the roots of the medicinal plant licorice (Glycyrrhiza uralensis, G. glabra and G. inflata), and is used worldwide in diverse applications, such as herbal medicines and sweeteners. The growing demand for licorice threatens wild resources and therefore a sustainable method of supplying glycyrrhizin is required. With the goal of establishing an alternative glycyrrhizin supply method not dependent on wild plants, we attempted to produce glycyrrhizin using hairy root culture. We tried to promote glycyrrhizin production by blocking competing pathways using CRISPR/Cas9-based gene editing. CYP93E3 CYP72A566 double-knockout (KO) and CYP93E3 CYP72A566 CYP716A179 LUS1 quadruple-KO variants were generated, and a substantial amount of glycyrrhizin accumulation was confirmed in both types of hairy root. Furthermore, we evaluated the potential for promoting further glycyrrhizin production by simultaneous CYP93E3 CYP72A566 double-KO and CYP88D6-overexpression. This strategy resulted in a 3-fold increase (∼1.4 mg/g) in glycyrrhizin accumulation in double-KO/CYP88D6-overexpression hairy roots, on average, compared with that of double-KO hairy roots. These findings demonstrate that the combination of blocking competing pathways and overexpression of the biosynthetic gene is important for enhancing glycyrrhizin production in G. uralensis hairy roots. Our findings provide the foundation for sustainable glycyrrhizin production using hairy root culture. Given the widespread use of genome editing technology in hairy roots, this combined with gene knockout and overexpression could be widely applied to the production of valuable substances contained in various plant roots.
Temperature-Regulated Flowering Locus T–Like Gene Coordinates the Spike Initiation in Phalaenopsis Orchid
Authors: Lu Hsiang-Chia , Huang Chiao-Wen , Mimura Tetsuro , Sukma Dewi , Chan Ming-Tsair 
Published: December 2023

Abstract
Phalaenopsis aphrodite can be induced to initiate spike growth and flowering by exposure to low ambient temperatures. However, the factors and mechanisms responsible for spike initiation in P. aphrodite remain largely unknown. In this study, we show that a repressor Flowing Locus T-like (FTL) gene, FTL, can act as a negative regulator of spike initiation in P. aphrodite. The mRNA transcripts of PaFTL are consistently high during high ambient temperature, thereby preventing premature spike initiation. However, during low ambient temperature, PaFTL expression falls while FT expression increases, allowing for spike initiation. Knock-down of PaFTL expression through virus-inducing gene silencing promoted spike initiation at 30/28°C. Moreover, PaFTL interacts with FLOWERING LOCUS D in a similar manner to FT to regulate downstream flowering initiation genes. Transgenic P. aphrodite plants exhibiting high expression of PaFTL do not undergo spike initiation, even when exposed to low ambient temperatures. These findings shed light on the flowering mechanisms in Phalaenopsis and provide new insights into how perennial plants govern spike initiation in response to temperature cues.
Resistance‐only and concurrent exercise induce similar myofibrillar protein synthesis rates and associated molecular responses in moderately active men before and after training
Authors: Lee Matthew J. , Caruana Nikeisha J. , Saner Nicholas J. , Kuang Jujiao , Stokes Tanner , McLeod Jonathan C. , Oikawa Sara Y. , Bishop David J. , Bartlett Jonathan D. , Phillips Stuart M. 
Published: December 2023

AbstractAerobic and resistance exercise (RE) induce distinct molecular responses. One hypothesis is that these responses are antagonistic and unfavorable for the anabolic response to RE when concurrent exercise is performed. This thesis may also depend on the participants' training status and concurrent exercise order. We measured free‐living myofibrillar protein synthesis (MyoPS) rates and associated molecular responses to resistance‐only and concurrent exercise (with different exercise orders), before and after training. Moderately active men completed one of three exercise interventions (matched for age, baseline strength, body composition, and aerobic capacity): resistance‐only exercise (RE, n = 8), RE plus high‐intensity interval exercise (RE+HIIE, n = 8), or HIIE+RE (n = 9). Participants trained 3 days/week for 10 weeks; concurrent sessions were separated by 3 h. On the first day of Weeks 1 and 10, muscle was sampled immediately before and after, and 3 h after each exercise mode and analyzed for molecular markers of MyoPS and muscle glycogen. Additional muscle, sampled pre‐ and post‐training, was used to determine MyoPS using orally administered deuterium oxide (D2O). In both weeks, MyoPS rates were comparable between groups. Post‐exercise changes in proteins reflective of protein synthesis were also similar between groups, though MuRF1 and MAFbx mRNA exhibited some exercise order‐dependent responses. In Week 10, exercise‐induced changes in MyoPS and some genes (PGC‐1ɑ and MuRF1) were dampened from Week 1. Concurrent exercise (in either order) did not compromise the anabolic response to resistance‐only exercise, before or after training. MyoPS rates and some molecular responses to exercise are diminished after training.
Effect of Levodopa on Heat Hypersensitivity and Complex Motor Parkinsonism
Authors: Noyes Eric , Rajput Ali H. , Bocking Sarah , Rajput Alex 
Published: December 2023

Objectives
The aim of the study is to report a case with heat intolerance, complex motor fluctuations, and parkinsonism.

Materials and Methods
A male with onset of heat intolerance at the age of 46 years developed left upper limb tremor at the age of 58 years. He was diagnosed with Parkinson disease at the age of 62 years and presented to Movement Disorders Clinic Saskatchewan at the age of 65 years. He reported motor response fluctuations, including WO and dyskinesias. There was no history of dizziness on standing, bladder, or sexual dysfunction. We recorded an asymptomatic drop of orthostatic blood pressure. He reported loss of smell sensation for 5 years and REM behavior disorder characterized by talking in his sleep. He was assessed at the age of 65 years over the course of a day with 4 video recordings of his evolving findings and symptoms with his informed consent.

Results
Initial assessment after levodopa was withheld more than 14 hours revealed him to be ‘off’ with severe dystonic neck flexion and with bradykinesia and rigidity in the limbs. He was anhidrotic, felt hot, and needed a wet towel over his neck. Over the course of 4 hours, he turns “on” with improvement in heat intolerance, neck hypertonicity, and parkinsonian findings and develops evolving dyskinetic movements before turning “off” again. His overall clinical picture was most consistent with multiple system atrophy.

Conclusions
Heat intolerance can precede onset of motor symptoms of parkinsonism by several years and supports a diagnosis of multiple system atrophy. To our knowledge, this is the first documented case of improvement in heat intolerance with levodopa.
The 8C model of vaccination readiness: A common framework to facilitate cross-study comparisons
Authors: Howe Piers , Dearnley Ferron 
Published: December 2023

AbstractSeveral factors can potentially influence an individual’s vaccination readiness. To facilitate cross-study comparisons, it is essential that researchers use a shared framework to measure these factors. This would not only help determine their relative importance cross different contexts but also would aid in tailoring interventions to enhance vaccine uptake. Historically, five psychological antecedents of vaccination were identified: confidence, complacency, constraints, calculation, and collective responsibility. This 5C scale was later expanded to a 7C model by incorporating two additional components: compliance and conspiracy. Building upon this framework, we propose an eighth component, certification, defined as the person’s self-report that, in the past, they have had to provide evidence of vaccination. This component addresses a significant gap in the 7C model, as some individuals reported taking the COVID-19 vaccine primarily to obtain proof of vaccination, a motivation not captured by the 7C model. Our confirmatory factor analysis (N = 406) of a bifactor model of US citizens’ self-reported COVID-19 vaccination status showed that this eighth component had good psychometric properties and the 8C model had slightly higher criterion validity than the 7C model. We present the 8C model as a framework that provides a richer and more complete descriptions of the factors that determine vaccination readiness and encourage future studies of vaccination readiness to utilise it.
Improvements in cardiovascular health over the perinatal period predicts lower postpartum psychological distress
Authors: Donofry Shannon D. , Jouppi Riley J. , Call Christine C. , Conlon Rachel P. Kolko , Levine Michele D. 
Published: December 2023

AbstractBackgroundAdverse cardiovascular events during pregnancy (e.g., pre-eclampsia) occur at higher rates among individuals with pre-pregnancy overweight or obesity (body mass index [BMI]≥25kg/m2) and have been associated with postpartum depression. However, it is unclear whether cardiovascular health (CVH), defined more holistically than the absence of cardiovascular conditions in pregnancy, relates to postpartum psychological functioning. The present study examined whether changes in CVH during the perinatal period predicted postpartum psychological functioning among individuals with pre-pregnancy BMI≥25kg/m2.MethodsIndividuals (N=226; Mage=28.43±5.4 years; MBMI=34.17±7.15kg/m2) were recruited when their pregnancies were 12-20 weeks gestation (M=15.64±2.45 weeks) for a longitudinal study of health and well-being. Participants completed the Center for Epidemiological Studies Depression Scale (CES-D) and Perceived Stress Scale (PSS) and reported on CVH behaviors (dietary intake, physical activity, nicotine exposure, and sleep) at baseline and at 6-months postpartum. BMI and CVH behaviors were coded according to the American Heart Association’s Life’s Essential 8 to create a CVH score at both timepoints. Linear regression analyses were performed to examine whether change in CVH related to postpartum CES-D and PSS scores. Because sleep was only measured in a subset of participants (n=114), analyses were conducted with and without sleep included. Baseline CVH, CES-D and PSS scores, and demographic factors were included as covariates in all models.ResultsImproved CVH was associated with lower postpartum CES-D (β=-0.18,p<0.01) and PSS (β=-0.13,p=0.02) scores when excluding sleep. Compared to those whose CVH improved by >1SD from pregnancy to 6-months postpartum, individuals whose CVH worsened by >1SD scored 6.42 points higher on the CESD (MCESD=15.25±10.92 vs. 8.52±6.90) and 6.12 points higher on the PSS (MPSS=24.45±8.29 vs. 17.83±8.70). However, when including sleep, these relationships were no longer significant (ps>0.4).ConclusionsImprovements in CVH from early pregnancy to 6-months postpartum were associated with lower postpartum depressive symptoms and perceived stress. However, these relationships were no longer significant when including sleep in the CVH metric, potentially due to the large reduction in sample size. These data suggest that intervening during pregnancy to promote CVH may improve postpartum psychological functioning among high-risk individuals.
Gene prioritization in GWAS loci using multimodal evidence
Authors: Schipper Marijn , de Leeuw Christiaan A. , Maciel Bernardo A.P.C. , Wightman Douglas P. , Hubers Nikki , Boomsma Dorret I. , O’Donovan Michael C. , Posthuma Danielle 
Published: December 2023

ABSTRACTGenome-wide association studies (GWAS) yield large numbers of genetic loci associated with traits and diseases. Predicting the effector genes that mediate these locus associations remains challenging. Here we present the FLAMES framework, which predicts the most likely effector gene in a locus. FLAMES integrates machine learning predictions from biological data linking single nucleotide polymorphisms (SNPs) to genes with GWAS-wide convergence of gene interactions. We benchmark FLAMES on gene-locus pairs derived by expert curation, rare variant implication, and domain knowledge of molecular traits. We demonstrate that combining SNP-based and convergence-based modalities outperforms prioritization strategies using a single line of evidence. Applying FLAMES, we resolve theFSHBlocus in the GWAS for dizygotic twinning and further leverage this framework to find novel schizophrenia risk genes that converge with rare coding evidence and are relevant in different stages of life.