bluuebunny/crossref_metadata_2025_split huggingface dataset:
18F-Fluciclovine PET Detected Early Tumor Recurrence in Prostatectomy Bed With Low PSA of 0.3 ng/mL But Negative on 18F-PSMA PET Scan
Authors: Nguyen Trinh T. , Bhosale Priya R. , Lu Yang 
Published: August 2022

Abstract
A 58-year-old man with metastatic prostate cancer was treated with prostatectomy, radiation therapy to bone metastasis, and androgen deprivation therapy plus abiraterone. He had posttreatment nadir PSA of 0.1 ng/mL. A follow-up 18F-fluciclovine PET performed with PSA of 0.3 ng/mL showed a focal tracer-avid lesion in the left prostatectomy bed. This lesion was negative on 18F-DCFPyL PET/CT, but with typical MRI features for disease recurrence. Minimal urinary activity of fluciclovine helped detection of local disease recurrence in the prostatectomy bed.
Melon pan-genome and multi-parental framework for high-resolution trait dissection
Authors: Oren Elad , Dafna Asaf , Tzuri Galil , Halperin Ilan , Isaacson Tal , Elkabetz Meital , Meir Ayala , Saar Uzi , Ohali Shachar , La Thuy , Romay Cinta , Tadmor Yaakov , Schaffer Arthur A , Buckler Edward S , Cohen Roni , Burger Joseph , Gur Amit 
Published: August 2022

AbstractLinking between genotype and phenotype is a fundamental goal in biology and requires robust data for both layers. The prominent increase in plant genome sequencing and comparisons of multiple related individuals, exposed the abundance of structural genomic variation and suggest that a single reference genome cannot represent the complete sequence diversity of a crop species, leading to the expansion of the pan-genome concept. For high-resolution forward genetics, this unprecedented access to genomic variation should be paralleled by availability and phenotypic characterization of genetic diversity, and effective integration between these layers. Here, we describe a multi-parental framework for trait dissection in melon, leveraging a novel pan-genome constructed for this crop. Melon (Cucumis melo L.) is an important crop from the Cucurbitaceae family, which display extensive phenotypic variation available for breeding. A diverse core set of 25 founder lines (MelonCore25) was sequenced using a combination of short and long-read technologies and their genomes were assembled de novo. The construction of a melon pan-genome exposed substantial variation in genome size and structure, including detection of ~300,000 structural variants and ~9 million SNPs. A half-diallel derived set of 300 F2 populations representing all possible MelonCore25 parental combinations was constructed as framework for trait dissection through integration with the pan-genome. We demonstrate the potential of this unified framework for genetic analysis of various melon traits, including rind color and mottling pattern, fruit sugar content and resistance to fungal diseases. We anticipate that utilization of this integrated resource will enhance genetic dissection of important traits and accelerate melon breeding.Significance statementPan-genomes aim to address the abundance of genome structural variation within species for improved genomic analyses. New pan-genome, constructed from de novo genome assemblies of 25 diverse melon (Cucumis melo L.) accessions is integrated with a half-diallel derived set of 300 F2 populations representing all possible parental combinations. The potential of this unified multi-parental trait dissection framework for melon genetics and breeding is presented.
Platelet-derived transcription factors license human monocyte inflammation
Authors: Hawwari Ibrahim , Rossnagel Lukas , Reyes Nathalia Sofia Rosero , Maasewerd Salie , Jentzsch Marius , Demczuk Agnieszka , Teichmann Lino L , Meffert Lisa , Ribeiro Lucas S. , Kallabis Sebastian , Meissner Felix , Rivas Magali Noval , Arditi Moshe , Bertheloot Damien , Franklin Bernardo S. 
Published: August 2022

ABSTRACTCD14+monocytes, the predominant population in human blood, are primarily engaged in host defense and pro-inflammatory cytokine responses. Aberrant monocyte activity causes life-threatening cytokine storms, while dysfunctional monocytes lead to ’immunoparalysis.’ Understanding the mechanisms controlling monocyte functions is therefore paramount. Here, we reveal platelets’ vital role in human monocytes’ pro-inflammatory responses. Low platelet counts in immune thrombocytopenia (ITP) patients, or platelet depletion in healthy monocytes result in monocyte immunoparalysis, characterized by reduced pro-inflammatory gene expression and weakened cytokine responses to immune challenge. Remarkably, adding fresh platelets reverses monocyte immunoparalysis. In mice, thrombocytopenia results in down-regulation of myeloid innate immune genes, and compromised host defense transcriptional programs in monocytes despite normal responses to LPS. Platelets control monocyte cytokines independently of traditional cross-talk pathways, acting as reservoirs of transcription factors like NFκB and MAPK p38. We pinpointed megakaryocyte-derived NFκB2 transfer to human monocytes by mass spectrometry-based proteomics. Functionally, platelets proportionally restored impaired cytokine secretion in human monocytes lacking p38a and NFκB. We unveil the intercellular transfer of inflammatory regulators, positioning platelets as central checkpoints in monocyte-mediated inflammation.Key PointsPlatelets are essential to TLR and NLR cytokine responses of human monocytes,Immune thrombocytopenia leads to monocyte immunoparalysis;Platelet supplementation reverses monocyte immunoparalysis;Platelets transfer NFκB that reactivates cytokine production in genetically deficient monocytes.
The dissemination of Rift Valley fever virus to the eye and sensory neurons of zebrafish larvae is stat1 dependent
Authors: ter Horst S. , Siekierska A. , De Meulemeester AS. , Cuvry A. , Cools L. , Neyts J. , de Witte P. , Rocha-Pereira J. 
Published: August 2022

AbstractThe Rift Valley fever virus (RVFV) is listed by the WHO as priority disease and causes haemorrhagic fever, encephalitis, and permanent blindness. To study RVFV pathogenesis and identify small-molecule antivirals, we established a novel in vivo model using zebrafish larvae. Pericardial injection of RVFV resulted in ~4 log10 viral RNA copies/larva, which was inhibited by antiviral 2′-fluoro-2′-deoxycytidine. The optical transparency of the larvae allowed detection of RVFVeGFP in the liver and sensory nervous system, including the optic tectum and retina, but not the brain or spinal cord. Thus, RVFV-induced blindness likely occurs due to direct damage to the eye and peripheral neurons, rather than the brain. Treatment with JAK-inhibitor ruxolitinib, as well as knockout of stat1a but not stat1b, enhanced RVFV replication to ~6 log10 viral RNA copies/larva and ultra-bright livers, although without dissemination to sensory neurons or the eye, hereby confirming the critical role of stat1 in RVFV pathogenesis.
Neisseria gonorrhoeae diagnostic escape from a gyrA-based test for ciprofloxacin susceptibility can lead to increased zoliflodacin resistance
Authors: Rubin Daniel H. F. , Mortimer Tatum D. , Grad Yonatan H. 
Published: August 2022

AbstractThe etiologic agent of gonorrhea, Neisseria gonorrhoeae, has become resistant to each of the first line antibiotics used to treat it. However, most isolates in the US remain susceptible to ciprofloxacin, leading to the hypothesis that a diagnostic that accurately reports susceptibility to ciprofloxacin may allow its reintroduction into clinical use. One diagnostic approach is to identify codon 91 in gyrA, where coding for the wildtype serine is associated with ciprofloxacin susceptibility and phenylalanine with resistance. Here, we found that escape from this diagnostic method can occur through gyrA F91S reversion and expansion of pre-existing ciprofloxacin non-susceptible N. gonorrhoeae lineages with gyrA 91S. Furthermore, we found that mutations conferring ciprofloxacin resistance in gyrA 91S isolates led to cross-resistance with zoliflodacin, an antibiotic in phase 3 trial for treatment of gonorrhea. These findings define N. gonorrhoeae mutations that should be monitored via surveillance systems, particularly in populations and regions deploying gyrA 91-based diagnostics, and demonstrate how diagnostics that guide antibiotic therapy can have unintended consequences.
A lone spike in blood glucose can enhance the thrombo-inflammatory response in cortical vessels
Authors: Shaked Iftach , Foo Conrad , Liu Rui , Cui Yingying , Ji Xiang , Broggini Thomas , Mächler Philipp , Sundd Prithu , Devor Anna , Friedman Beth , Kleinfeld David 
Published: August 2022

ABSTRACTHow transient hyperglycemia contributes to cerebro-vascular disease has been a challenge to study under controlled conditions. We present an approach to model luminal vessel thrombo-inflammation using amplified, ultrashort laser-pulses to physically disrupt brain-venule endothelium. Vessel disruption in conjunction with transient hyperglycemia from a single injection of metabolically activeD-glucose results in real-time responses to venule damage that include rapid serum extravasation, platelet aggregation, and neutrophil recruitment, in normal mice. In contrast, vessel thrombo-inflammation following laser-induced vessel disruption is significantly reduced in mice injected with metabolically inert L-glucose. Thrombo-inflammation is pharmacologically ameliorated by a platelet inhibitor, by a scavenger of reactive oxygen species, or by a nitric oxide donor. For comparison, in diabetic mice injured vessel thrombo-inflammatory responses are also reduced by restoration of normo-glycemia. Our approach provides a controlled method to probe synergies of transient metabolic and physical vascular perturbations and reveals new aspects of brain pathophysiology.
Microstimulation of human somatosensory cortex evokes task-dependent, spatially patterned responses in motor cortex
Authors: Shelchkova Natalya D. , Downey John E. , Greenspon Charles M. , Okorokova Elizaveta V. , Sobinov Anton R. , Verbaarschot Ceci , He Qinpu , Sponheim Caleb , Tortolani Ariana F. , Moore Dalton D. , Kaufman Matthew T. , Lee Ray C. , Satzer David , Gonzalez-Martinez Jorge , Warnke Peter C. , Miller Lee E. , Boninger Michael L. , Gaunt Robert A. , Collinger Jennifer L. , Hatsopoulos Nicholas G. , Bensmaia Sliman J. 
Published: August 2022

AbstractMotor (M1) and somatosensory (S1) cortex play a critical role in motor control but the nature of the signaling between these structures is not known. To fill this gap, we recorded – in three human participants whose hands were paralyzed as a result of a spinal cord injury – the responses evoked in the hand and arm representations of primary motor cortex (M1) while we delivered ICMS to the somatosensory cortex (S1). We found that ICMS of S1 activated some M1 neurons at short, fixed latencies, locked to each pulse in a manner consistent with monosynaptic activation. However, most of the changes in M1 firing rates were much more variable in time, suggesting a more indirect effect of the stimulation. The spatial pattern of M1 activation varied systematically depending on the stimulating electrode: S1 electrodes that elicited percepts at a given hand location tended to activate M1 neurons with movement fields at the same location. However, the indirect effects of S1 ICMS on M1 were strongly context dependent, such that the magnitude and even sign relative to baseline varied across tasks. We tested the implications of these effects for brain-control of a virtual hand, in which ICMS was used to convey tactile feedback about object interactions. While ICMS-evoked activation of M1 disrupted decoder performance, this disruption could be minimized with biomimetic stimulation, which emphasizes contact transients at the onset and offset of grasp, reduces sustained stimulation, and has been shown to convey useful contact-related information.SignificanceMotor (M1) and somatosensory (S1) cortex play a critical role in motor control but the nature of the signaling between these structures is not known. To fill this gap, we recorded from M1 while delivering intracortical microstimulation (ICMS) to S1 of three human participants, whose hands were paralyzed by spinal cord injury. We found that ICMS activates M1 and that the motor fields of activated M1 neurons match the sensory fields of the stimulated S1 electrodes. These findings have important implications for using ICMS to convey tactile feedback for brain-controlled bionic hands. Indeed, the ICMS-evoked M1 activity worsens control of the hand. Fortunately, this effect is minimized by using biomimetic tactile feedback, which emphasizes contact transients and reduces sustained ICMS.
Cryo-EM structure of the Type IV pilus extension ATPase from enteropathogenic Escherichia coli
Authors: Nayak Ashok R. , Singh Pradip K. , Zhao Jinlei , Samsó Montserrat , Donnenberg Michael S. 
Published: August 2022

ABSTRACTType 4 pili (T4P) are retractable surface appendages found on numerous bacteria and archaea that play essential roles in various microbial functions, including host colonization by pathogens. An ATPase is required for T4P extension, but the mechanism by which chemical energy is transduced to mechanical energy for pilus extension has not been elucidated. Here we report the cryo-electron microscopy (cryo-EM) structure of the BfpD ATPase from enteropathogenic Escherichia coli (EPEC) in the presence of either ADP or a mixture of ADP and AMP-PNP. Both structures, solved at 3 Å resolution, reveal the typical toroid shape of AAA+ ATPases and unambiguous six-fold symmetry. This six-fold symmetry contrasts with the two-fold symmetry previously reported for other T4P extension ATPase structures, all of which were from thermophiles and solved by crystallography. In the presence of the nucleotide mixture, BfpD bound exclusively AMP-PNP and this binding resulted in a modest outward expansion in comparison to the structure in the presence of ADP, suggesting a concerted model for hydrolysis. De novo molecular models reveal a partially open configuration of all subunits where the nucleotide binding site may not be optimally positioned for catalysis. ATPase functional studies reveal modest activity similar to that of other extension ATPases, while calculations indicate that this activity is insufficient to power pilus extension. Our results reveal that, despite similarities in primary sequence and tertiary structure, T4P extension ATPases exhibit divergent quaternary configurations. Our data raise new possibilities regarding the mechanism by which T4P extension ATPases power pilus formation.
Pimavanserin for the Treatment of Alzheimer’s Disease Psychosis: An Evaluation of the Clinical Importance of Efficacy Results
Authors: Ballard Clive , Cummings Jeffrey , Tariot Pierre N , Pathak Sanjeev , Coate Bruce , Stankovic Srdjan 
Published: August 2022

AbstractAlzheimer’s disease psychosis (ADP) is a common and serious condition with substantial unmet need for safe and effective treatments. Pimavanserin is approved in the US to treat Parkinson’s disease hallucinations and delusions. This post-hoc analysis of randomized, double-blind, placebo-controlled, phase 2 trial of nursing-home-residents with ADP evaluated the efficacy of pimavanserin by improvements (least squares mean change) in the Neuropsychiatric Inventory–Nursing Home Version Psychosis Score (NPI-NH PS). The clinical significance of the primary endpoint was assessed using responder analyses (≥ 30% and ≥ 50%); numbers needed to treat (NNT); cumulative response (0-100% improvement); All Patients and Severe Psychosis (NPI-NH PS ≥ 12) subgroups were evaluated; improvements in hallucinations and delusions by NPI-NH-PS frequency (3 or 4 points) and severity (2 or 3 points); and ≥ 50% responder analysis at earlier timepoints (weeks 2 and 4). Among 345 patients screened, 181 patients were randomized to pimavanserin (n = 90) and placebo (n = 91). Patients were elderly (mean age: 86 years) and frail (baseline mean NPI-NH PS scores of 9.5 and 10 for pimavanserin and placebo, respectively). Pimavanserin significantly improved NPI-NH PS relative to placebo (−3.76 versus −1.93, respectively; p = 0.0451). In responder analyses, pimavanserin demonstrated a significantly greater reduction in NPI-NH PS versus placebo at both the ≥ 30% (p = 0.0159) and ≥ 50% (p = 0.0240) thresholds with NNTs of 6 and 7, respectively. Furthermore, pimavanserin demonstrated significantly earlier reductions in NPI-NH PS compared with placebo for the ≥ 30% (p = 0.0336) and ≥ 50% (p = 0.0044) thresholds. The cumulative response analysis demonstrated significantly greater efficacy of pimavanserin for All Patients (p = 0.052) and Severe Psychosis (p = 0.004), and Severe Patients versus All Patients demonstrated a greater reduction in NPI-NH PS (p = 0.011; effect size = 0.73). Pimavanserin also demonstrated numerically greater improvements for the frequency and severity of delusions and hallucinations. Responder analyses at earlier timepoints demonstrated significantly greater response rates with pimavanserin versus placebo at week 2 (p = 0.016) but not 4 (p = 0.051). These findings support pimavanserin as safe and effective in a population of nursing-home-resident patients with ADP.
Rare and common variant analyses of amyotrophic lateral sclerosis in the French-Canadian genome
Authors: Ross Jay P. , Akçimen Fulya , Liao Calwing , Kwan Karina , Phillips Daniel E. , Schmilovich Zoe , Spiegelman Dan , Genge Angela , Dupré Nicolas , Dion Patrick A. , Farhan Sali M.K. , Rouleau Guy A. 
Published: August 2022

ABSTRACTThe genetic etiology of ALS includes few rare, large-effect variants and potentially many common, small-effect variants per case. The genetic risk liability for ALS might require a threshold comprised of a certain amount of variants. Here, we tested the degree to which risk for ALS was affected by rare variants in ALS genes, polygenic risk score, or both. 335 ALS cases and 356 controls from Québec, Canada were concurrently tested by SNP-chip genotyping and targeted sequencing of known ALS genes. ALS GWAS summary statistics were used to estimate an ALS PRS. Cases and controls were subdivided into rare variant carriers and non-carriers. Risk for ALS was significantly associated with PRS and rare variants independently, but the interaction was not significant. ALS PRS affected risk only in those not carrying a rare variant, suggesting that rare variants in ALS genes are generally sufficient for disease risk. Rather than modifying the penetrance of rare variants, ALS PRS is most informative in the absence of these variants.
Estimating the future global dose demand for Measles-Rubella microarray patches
Authors: Ko Melissa , Malvoti Stefano , Cherian Thomas , Mantel Carsten , Biellik Robin , Jarrahian Courtney , Menozzi-Arnaud Marion , Amorij Jean-Pierre , Christiansen Hans , Papania Mark , Meltzer Martin I. , Masresha Balcha Girma , Pastor Desiree , Durrheim David N. , Giersing Birgitte , Hasso-Agopsowicz Mateusz 
Published: August 2022

AbstractBackgroundProgress towards measles and rubella (MR) elimination has stagnated as countries are unable to reach the required 95% vaccine coverage. Microarray patches (MAPs) are anticipated to offer significant programmatic advantages to needle and syringe (N/S) presentation and increase MR vaccination coverage. A demand forecast analysis of the programmatic doses required (PDR) could accelerate MR-MAP development by informing the size and return of the investment required to manufacture MAPs.MethodsUnconstrained global MR-MAP demand for 2030-2040 was estimated for three scenarios, for groups of countries with similar characteristics (archetypes), and four types of uses of MR-MAPs (use cases). The base scenario 1 assumed that MR-MAPs would replace a share of MR doses delivered by N/S, and that MAPs can reach a proportion of previously unimmunised populations. Scenario 2 assumed that MR-MAPs would be piloted in selected countries in each region of the World Health Organization (WHO); and scenario 3 explored introduction of MR-MAPs earlier in countries with the lowest measles vaccine coverage and highest MR disease burden.ResultsFor the base scenario (1), the estimated global PDR for MR-MAPs was forecasted at 30 million doses in 2030 and increased to 220 million doses by 2040. Compared to scenario 1, scenario 2 resulted in an overall decrease in PDR of 18%, and scenario 3 resulted in a 21% increase in PDR between 2030-2040.ConclusionsSignificant demand is expected for MR-MAPs between 2030-2040, however, efforts are required to address remaining data quality, uncertainties and gaps that underpin the assumptions in this analysis.Key pointsthe delivery of measles and rubella vaccines with microarray patches (MR-MAPs) could disrupt the immunization landscape. We estimated the demand for MR-MAPs between 2030-2040 at 4.05 billion doses. This analysis will inform the size of investment required to manufacture MR-MAPs.
Melanonychia and use of nail biopsy to screen for subungual melanoma in a large ethnically diverse pediatric cohort: A cross-sectional study
Authors: Park Helen H. , Lieu Alexander , Conic Rosalynn R.Z. , Metterle Lauren , Zhang Sijia , Toledo Isabella , Hightower George K. 
Published: August 2022

AbstractBackgroundThere are no widely accepted pediatric guidelines on who should undergo biopsy of the nail apparatus to screen for subungual melanoma (SUM). Reported cases of pre-adolescent children diagnosed with SUM presenting as melanonychia remain controversial. Further, observed age differences in the incidence of acral lentiginous melanoma are complicated by reported ethnic differences in adult prevalence and survival rates.MethodsWe conducted a retrospective chart review of Rady Children’s Hospital San Diego, a tertiary hospital system, with over 2 million patients in its electronic health records to identify patients diagnosed with melanonychia younger than 12 years and biopsies in these children, between January 1, 2010, and July 31, 2021.ResultsThere were 623,805 patients younger than 12 years of age seen in the outpatient setting. Average age was 7.2 years for melanonychia diagnosis, and 5.1 years for those biopsied. Nail apparatus biopsies were performed in 22 different individuals and involved the hand 17/22 (77%) and the foot 5/22 (23%). The presence of Hutchinson’s sign was documented in 9/22 (41%) patients. Males were diagnosed with melanonychia and underwent biopsy more often than females. Many of the biopsies were performed in Hispanic/Latino 11/22 (50%) and Asian/Pacific Islander 3/22 (14%) patients.DiscussionRegardless of reported ethnicity, biopsy of nail apparatus is highly unlikely to uncover invasive ALM in children younger than 12 years. Prospective studies are needed to understand how incidence of melanonychia, age, gender, and ethnicity/race influence parental and clinicians’ perceptions of melanoma risk.