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Despite being one of the most destructive invasive species of ants, only two natural enemies are known currently for Wasmannia auropunctata, commonly known as the electric ant or little fire ant. Because viruses can be effective biological control agents against many insect pests, including ants, a metagenomics/next-generation sequencing approach was used to facilitate discovery of virus sequences from the transcriptomes of W. auropunctata. Five new and complete positive sense, single-stranded RNA virus genomes, and one new negative sense, single-stranded RNA virus genome were identified, sequenced, and characterized from W. auropunctata collected in Argentina by this approach, including a dicistrovirus (Electric ant dicistrovirus), two polycipiviruses (Electric ant polycipivirus 1; Electric ant polycipivirus 2), a solinvivirus (Electric ant solinvivirus), a divergent genome with similarity to an unclassified group in the Picornavirales (Electric ant virus 1), and a rhabdovirus (Electric ant rhabdovirus). An additional virus genome was detected that is likely Solenopsis invicta virus 10 (MH727527). The virus genome sequences were absent from the transcriptomes of W. auropunctata collected in the USA (Hawaii and Florida). Additional limited field surveys corroborated the absence of these viruses in regions where the electric ant is invasive (the USA and Australia). The replicative genome strand of four of the viruses (Electric ant polycipivirus 2, Electric ant solinvivirus, Electric ant virus 1, and Solenopsis invicta virus 10 (in the electric ant) was detected in Argentinean-collected W. auropunctata indicating that the ant is a host for these viruses. These are the first virus discoveries to be made from W. auropunctata.

As rectal cancer survival increases, more patients survive with potentially severe, long-term gastrointestinal and genitourinary complications from radiotherapy. The burden of these complications for patients and healthcare services is unclear, which this review aims to quantify.Systematic search of Medline and Embase for randomized-controlled trials (RCTs) and multicentre observational studies published since 2000, reporting hospitalization/procedural intervention for long-term (6 months post-treatment) gastrointestinal or genitourinary complications after radiotherapy and surgery for rectal cancer. Prevalence values were pooled in a meta-analysis assuming random effects. Organ-preservation patients were excluded.4044 records screened; 24 reports from 23 studies included (15 RCTs, 8 Observational), encompassing 15 438 patients. Twenty-one studies (median follow-up 60 months) reported gastrointestinal complications post-radiotherapy: pooled prevalence 11% (95% confidence interval (95% CI) 8-14%). Thirteen reported small bowel obstruction: prevalence 9% (95% CI 6-12%), a 58% increased risk compared with surgery alone (RR 1.58, 95% CI 1.26-1.98, n = 5 studies). Seven reported fistulas: prevalence 1% (95% CI 1-2%). Thirteen reported genitourinary complications: prevalence 4% (95% CI 1-6%); RR 1.10 (95% CI 0.88-1.38, n = 3 studies) compared with surgery alone.Over 10% of patients are hospitalized for long-term complications following rectal cancer radiotherapy. Serious gastrointestinal complications are commonplace; late small bowel obstruction is more common in patients having radiotherapy and surgery compared with surgery alone. Patients and clinicians need to be aware of these risks.

The cholesterol-dependent cytolysins (CDCs) are a major family of bacterial pore-forming proteins secreted as virulence factors by Gram-positive bacterial species. CDCs are produced as soluble, monomeric proteins that bind specifically to cholesterol-rich membranes, where they oligomerize into ring-shaped pores of more than 30 monomers. Understanding the details of the steps the toxin undergoes in converting from monomer to a membrane-spanning pore is a continuing challenge. In this review we summarize what we know about CDCs and highlight the remaining outstanding questions that require answers to obtain a complete picture of how these toxins kill cells.

Summary Commercial cigarettes were analyzed for harmful and potentially harmful constituents (HPHCs) in tobacco and smoke to investigate temporal product variability independent of analytical variability over one week, one year, and three years. Cigarettes from the worldwide market with various design features were collected over a 3-year period, stored, and tested concurrently for HPHCs to minimize analytical variability; repeat testing of reference cigarette 3R4F was included as an analytical control for the study design. Physical parameters were found to be relatively consistent. No trends in variability were noted based on blend type, smoke analyte matrix, or magnitude of an HPHC's yield. Combustion-related HPHCs generally showed low variation. Long-term batch-to-batch variability was found to be higher than short-term variability for tobacco-related compounds that have the potential to vary over time due to weather and agronomic practices. “Tar”, nicotine, and carbon monoxide were tested in multiple labs and showed greater lab-to-lab variability than batch-to-batch variability across all phases. Based on the results of this study, commercial cigarette products appear to have relatively low product variability. The low analyte variability noted in this study with products tested under unconventionally controlled analytical conditions serves to indicate that analytical variability may be a significant contributor to overall variability for general product testing over time and in interlaboratory studies. Laboratory controls and using a matched reference product across studies and between laboratories are important to assess testing differences and variability.

Sociolegal barriers to cancer care are defined as health-related social needs like affordable healthy housing, stable utility service, and food security that may be remedied by public policy, law, regulation, or programming. Legal support has not been studied in cancer care.The authors conducted a randomized controlled trial of patients who had newly diagnosed cancer at a safety-net medical center in Boston from 2014 through 2017, comparing standard patient navigation versus enhanced navigation partnered with legal advocates to identify and address sociolegal barriers. English-speaking, Spanish-speaking, or Haitian Creole-speaking patients with breast and lung cancer were eligible within 30 days of diagnosis. The primary outcome was timely treatment within 90 days of diagnosis. Secondary outcomes included patient-reported outcomes (distress, cancer-related needs, and satisfaction with navigation) at baseline and at 6 months.In total, 201 patients with breast cancer and 19 with lung cancer enrolled (response rate, 78%). The mean patient age was 55 years, 51% of patients were Black and 22% were Hispanic, 20% spoke Spanish and 8% spoke Haitian Creole, 73% had public health insurance, 77% reported 1 or more perceived sociolegal barrier, and the most common were barriers to housing and employment. Ninety-six percent of participants with breast cancer and 73% of those with lung cancer initiated treatment within 90 days. No significant effect of enhanced navigation was observed on the receipt of timely treatment among participants with breast cancer (odds ratio, 0.88; 95% CI, 0.17-4.52) or among those with lung cancer (odds ratio, 4.00; 95% CI, 0.35-45.4). No differences in patient-reported outcomes were observed between treatment groups.Navigation enhanced by access to legal consultation and support had no impact on timely treatment, patient distress, or patient needs. Although most patients reported sociolegal barriers, few required intensive legal services that could not be addressed by navigators.In patients with cancer, the experience of sociolegal barriers to care, such as unstable housing, utility services, or food insecurity, is discussed. Addressing these barriers through legal information and assistance may improve care. This study compares standard patient navigation versus enhanced navigation partnered with legal advocates for patients with breast and lung cancers. Almost all patients in both navigation groups received timely care and also reported the same levels of distress, needs, and satisfaction with navigation. Although 75% of patients in the study had at least 1 sociolegal barrier identified, few required legal advocacy beyond what a navigator who received legal information and coaching could provide.

Aminoacyl transfer RNA (tRNA) synthetases (aaRSs) are attractive drug targets, and we present class I and II aaRSs as previously unrecognized targets for adenosine 5′-monophosphate–mimicking nucleoside sulfamates. The target enzyme catalyzes the formation of an inhibitory amino acid–sulfamate conjugate through a reaction-hijacking mechanism. We identified adenosine 5′-sulfamate as a broad-specificity compound that hijacks a range of aaRSs and ML901 as a specific reagent a specific reagent that hijacks a single aaRS in the malaria parasite Plasmodium falciparum , namely tyrosine RS ( Pf YRS). ML901 exerts whole-life-cycle–killing activity with low nanomolar potency and single-dose efficacy in a mouse model of malaria. X-ray crystallographic studies of plasmodium and human YRSs reveal differential flexibility of a loop over the catalytic site that underpins differential susceptibility to reaction hijacking by ML901.

Fig. S5. Representative sphere images for sorted PDX tumor subpopulations grown in non-adherent serum-free culture conditions. Scale bar = 200 µm.

Supplementary Methods, References, Figure Legends, and Tables.

Purpose: Salivary gland cancers (SGC) frequently present with distant metastases many years after diagnosis, suggesting a cancer stem cell (CSC) subpopulation that initiates late recurrences; however, current models are limited both in their availability and suitability to characterize these rare cells.Experimental Design: Patient-derived xenografts (PDX) were generated by engrafting patient tissue onto nude mice from one acinic cell carcinoma (AciCC), four adenoid cystic carcinoma (ACC), and three mucoepidermoid carcinoma (MEC) cases, which were derived from successive relapses from the same MEC patient. Patient and PDX samples were analyzed by RNA-seq and Exome-seq. Sphere formation potential and in vivo tumorigenicity was assessed by sorting for Aldefluor (ALDH) activity and CD44-expressing subpopulations.Results: For successive MEC relapses we found a time-dependent increase in CSCs (ALDH+CD44high), increasing from 0.2% to 4.5% (P=0.033), but more importantly we observed an increase in individual CSC sphere formation and tumorigenic potential. A 50% increase in mutational burden was documented in subsequent MEC tumors, and this was associated with increased expression of tumor-promoting genes (MT1E, LGR5, and LEF1), decreased expression of tumor-suppressor genes (CDKN2B, SIK1, and TP53), and higher expression of CSC-related proteins such as SOX2, MYC, and ALDH1A1. Finally, genomic analyses identified a novel NFIB–MTFR2 fusion in an ACC tumor and confirmed previously reported fusions (NTRK3–ETV6 and MYB–NFIB).Conclusions: Sequential MEC PDX models preserved key patient features and enabled the identification of genetic events putatively contributing to increases in both CSC proportion and intrinsic tumorigenicity, which mirrored the patient's clinical course. Clin Cancer Res; 24(12); 2935–43. ©2018 AACR.

Excel file containing deferentially expressed genes (RNA-seq) for comparisons of CUSG006, -007, and -012 tumors.

The solar atmosphere is known to be replete with magneto-hydrodynamic wave modes, and there has been significant investment in understanding how these waves propagate through the Sun's atmopshere and deposit their energy into the plasma. The waves' journey is made interesting by the vertical variation in plasma quantities that define the solar atmosphere. In addition to this large-scale inhomogeneity, a wealth of fine-scale structure through the chromosphere and corona has been brought to light by high-resolution observations over the last couple of decades. This fine-scale sturcture represents inhomogeneity that is thought to be perpendicular to the local magnetic fields. The implications of this form of inhomogeneity on wave propagation is still being uncovered, but is known to fundamentally change the nature of MHD wave modes. It also enables interesting physics to arise including resonances, turbulence and instabilities. Here we review some of the key insights into how the inhomogeneity influences Alfvénic wave propagation through the Sun's atmosphere, discussing both inhomogeneities parallel and perpendicular to the magnetic field., Accepted in Journal of Modern Plasma Physics

This paper describes the design, fabrication, and record performance of a new class of ultra-wideband wavelength tuning, ultra-low noise semiconductor laser, the Integrated Coherent Tunable Laser (ICTL). The ICTL device is designed for, and fabricated in, a CMOS foundry based Silicon Photonics platform, utilizing heterogeneous integration of III-V material to create the integrated gain section of the laser - enabling high-volume mass-market manufacturing at low cost and with high reliability. The ICTL incorporates three or more ultra-low loss micro-ring resonators, with large ring size, in a Sagnac loop reflector geometry, creating exceptional laser reflector performance, plus an extended laser cavity length that enables highly-coherent output; ultra-low linewidth and phase noise. This paper describes record integrated laser performance; 118 nm wavelength tuning, covering S-, C- and L-bands, with Lorentzian linewidth

Testing for SARS-CoV-2 is one of the most important assets in COVID-19 management and mitigation. At the onset of the pandemic, SARS-CoV-2 testing was uniquely performed in central laboratories using RT-qPCR. RT-qPCR relies on trained personnel operating complex instrumentation, while time-to-result can be lengthy (

C-reactive protein (CRP) is an early-stage acute phase protein and highly upregulated in response to inflammatory reactions. We recently identified a novel mechanism that leads to a conformational change from the native, functionally relatively inert, pentameric CRP (pCRP) structure to a pentameric CRP intermediate (pCRP*) and ultimately to the monomeric CRP (mCRP) form, both exhibiting highly pro-inflammatory effects. This transition in the inflammatory profile of CRP is mediated by binding of pCRP to activated/damaged cell membranes via exposed phosphocholine lipid head groups. We designed a tool compound as a low molecular weight CRP inhibitor using the structure of phosphocholine as a template. X-ray crystallography revealed specific binding to the phosphocholine binding pockets of pCRP. We provide in vitro and in vivo proof-of-concept data demonstrating that the low molecular weight tool compound inhibits CRP-driven exacerbation of local inflammatory responses, while potentially preserving pathogen-defense functions of CRP. The inhibition of the conformational change generating pro-inflammatory CRP isoforms via phosphocholine-mimicking compounds represents a promising, potentially broadly applicable anti-inflammatory therapy.

Neurons in the hypothalamic arcuate nucleus (ARC) that express agouti-related peptide (AgRP) govern a critical aspect of survival: the drive to eat. Equally important to survival is the timing at which food is consumed - seeking or eating food to alleviate hunger in the face of a more pressing threat, like the risk of predation, is clearly maladaptive. To ensure optimal prioritization of behaviors within a given environment, therefore, AgRP neurons must integrate signals of internal need states with contextual environmental cues. In this State-of-the-Art review, we highlight recent advances that extend our understanding of AgRP neurons, including the neural circuits they engage to regulate feeding, energy expenditure, and behavior. We also discuss key findings that illustrate how both classical feedback and anticipatory feed-forward signals regulate this neuronal population and how the integration of these signals may be disrupted in states of energy excess. Finally, we examine both technical and conceptual challenges facing the field moving forward.

SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Vaccination, supported by social and public health measures, has proven efficacious for reducing disease severity and virus spread. However, the emergence of highly transmissible viral variants that escape prior immunity highlights the need for additional mitigation approaches. Heparin binds the SARS-CoV-2 spike protein and can inhibit virus entry and replication in susceptible human cell lines and bronchial epithelial cells. Primary infection predominantly occurs via the nasal epithelium, but the nasal cell biology of SARS-CoV-2 is not well studied. We hypothesized that prophylactic intranasal administration of heparin may provide strain-agnostic protection for household contacts or those in high-risk settings against SARS-CoV-2 infection. Therefore, we investigated the ability of heparin to inhibit SARS-CoV-2 infection and replication in differentiated human nasal epithelial cells and showed that prolonged exposure to heparin inhibits virus infection. Furthermore, we establish a method for PCR detection of SARS-CoV-2 viral genomes in heparin-treated samples that can be adapted for the detection of viruses in clinical studies.

Background Exclusion of left atrial appendage thrombus (LAAT) by transoesophageal echocardiography (TOE) is recommended in patients with inadequate anticoagulation prior to direct cardioversion (DCR) or catheter ablation for atrial fibrillation/flutter (AF/AFL). LAAT risk factors in this population remain poorly defined. Purpose Determine LAAT predictors in AF/AFL patients undergoing pre-procedural TOE. Methods We evaluated available clinical and transthoracic echocardiographic (TTE) parameters in AF/AFL patients undergoing TOE between 1999–2022 in our institution in Melbourne, Australia. Regression analysis identified predictors of LAAT, which were applied to a weighted score developed in the derivation cohort (70%) and validated in the remaining 30%. Results Of 627 patients (age 62±12 years, 27% female, AF 84%,AFL 16%, left ventricular ejection fraction (LVEF) 44±20%), 24% had LAAT and 13.8% dense spontaneous echo contrast precluding DCR. Anticoagulation was NOAC 56.5%, warfarin 32.1% and none in 11.4%. In the LAAT cohort, thrombus resolution occurred in 39% on serial transoesophageal imaging with a median time to resolution of 131 days (IQR 54–398). Diabetes (p=0.004), prior stroke (p=0.009), coronary disease (p=0.015), renal impairment (p2 (73% vs. 55%, p Conclusion A novel LAAT risk model comprising clinical and echocardiographic parameters enhances risk prediction over CHADS2VASc in AF/AFL and may guide the need for pre-procedural TOE imaging. Funding Acknowledgement Type of funding sources: None.

Background Lifestyle risk factors (RFs) are a modifiable target in atrial fibrillation (AF) management. However, the relative contribution of individual lifestyle RFs to AF incidence has not been described. Purpose Development and validation of a novel AF-lifestyle risk score to determine AF risk in the general population. Methods The UK Biobank (UKB) is a large prospective cohort with outcomes measured >10 years. In the UKB, we performed regression analysis of AF lifestyle RFs which were then evaluated in a multivariable model and a weighted score was developed. Next, the risk score was externally validated in the Framingham Heart Study (FHS) population. Kaplan-Meier estimates ascertained the 10-year risk of AF development. Results In the UKB, AF incidence was 5.3% among 302,926 participants, with a median time to AF 7.3 years (IQR 4.3–9.8). Hypertension, sleep apnoea, male sex, age, obesity (BMI>30 kg/m2), alcohol and smoking were predictive variables (all p5 points) was associated with a heightened 10-year AF risk (score 5–9: OR 9.35, score 10–14: OR 33.34). Conclusions The HARMS2-AF score is a novel lifestyle risk score which may help identify individuals at risk of AF and assists in general population screening. Funding Acknowledgement Type of funding sources: None.

Understanding the full process of mammalian folliculogenesis is crucial for improving assisted reproductive technologies in livestock, humans, and endangered species. Research has been mostly limited to antral and large preantral follicles due to difficulty in the isolation of smaller preantral follicles, especially in large mammals such as bovine species. This work presents an efficient approach to retrieve large numbers of small preantral follicles from a single bovine ovary. The cortex of individual bovine ovaries was sliced into 500 µm cubes using a tissue chopper and homogenized for 6 min at 9,000-11,000 rpm using a 10 mm probe. Large debris was separated from the homogenate using a cheese cloth, followed by serial filtration through 300 µm and 40 µm cell strainers. The contents retained in the 40 µm strainer were rinsed into a search dish, where follicles were identified and collected into a drop of medium. The viability of the collected follicles was tested via trypan blue staining. This method enables the isolation of a large number of viable small preantral follicles from a single bovine ovary in approximately 90 min. Importantly, this method is entirely mechanical and avoids the use of enzymes to dissociate the tissue, which may damage the follicles. The follicles obtained using this protocol can be used for downstream applications such as isolation of RNA for RT-qPCR, immunolocalization of specific proteins, and in vitro culture.

Aim Virtual consultations (VC) in breast surgery have been successfully utilised during the COVID pandemic and have potential to reduce the costs of outpatient clinics as well as increase patient satisfaction. We aimed to assess the utility and safety of VC in new patient clinics in women under 30, which are considered a low-risk subgroup. Method Data was prospectively collected on 118 women aged under 30 who were referred from primary care to the breast clinic between December 2020 and April 2021. Clinicopathological data was collected on referrals, imaging and follow up. Results Median age was 24 years (range 17–30). The commonest presenting symptoms were a lump (69%), breast pain (16%) and nipple symptoms (14%). The VC was performed via video in 63 (53%) patients and via telephone alone in 55 (47%). Nineteen patients (16%) were reassured and discharged directly from VC. Ninety-four patients (80%) underwent an outpatient ultrasound with a sonographer trained in clinical palpation. Twenty-six (27%) ultrasounds showed benign pathology with the remainder being normal. Six biopsies were performed, all of which were benign. Seventeen (14%) patients required a face-to-face appointment with a breast surgeon after ultrasound or biopsy. Ninety-four (79%) patients were discharged after VC + ultrasound alone. No patients required surgery. Conclusions Utilising VC, the majority of new referrals in women under 30 did not require face-to-face appointments. VC have potential to reduce burden on new patient clinics whilst improving patient convenience. Early data suggest a low risk of compromising safety in this subgroup.