Aralar Sequesters GABA into Hyperactive Mitochondria, Causing Social Behavior Deficits.

Social impairment is frequently associated with mitochondrial dysfunction and altered neurotransmission. Although mitochondrial function is crucial for brain homeostasis, it remains unknown whether mitochondrial disruption contributes to social behavioral deficits. Here, we show that Drosophila mutants in the homolog of the human CYFIP1, a gene linked to autism and schizophrenia, exhibit mitochondrial hyperactivity and altered group behavior. We identify the regulation of GABA availability by mitochondrial activity as a biologically relevant mechanism and demonstrate its contribution to social behavior. Specifically, increased mitochondrial activity causes gamma aminobutyric acid (GABA) sequestration in the mitochondria, reducing GABAergic signaling and resulting in social deficits. Pharmacological and genetic manipulation of mitochondrial activity or GABA signaling corrects the observed abnormalities. We identify Aralar as the mitochondrial transporter that sequesters GABA upon increased mitochondrial activity. This study increases our understanding of how mitochondria modulate neuronal homeostasis and social behavior under physiopathological conditions.

A neural circuit mechanism integrating motivational state with memory expression in Drosophila.

Behavioral expression of food-associated memory in fruit flies is constrained by satiety and promoted by hunger, suggesting an influence of motivational state. Here, we identify a neural mechanism that integrates the internal state of hunger and appetitive memory. We show that stimulation of neurons that express neuropeptide F (dNPF), an ortholog of mammalian NPY, mimics food deprivation and promotes memory performance in satiated flies. Robust appetitive memory performance requires the dNPF receptor in six dopaminergic neurons that innervate a distinct region of the mushroom bodies. Blocking these dopaminergic neurons releases memory performance in satiated flies, whereas stimulation suppresses memory performance in hungry flies. Therefore, dNPF and dopamine provide a motivational switch in the mushroom body that controls the output of appetitive memory.

First Dark Matter Search Results from the LUX-ZEPLIN (LZ) Experiment.

The LUX-ZEPLIN experiment is a dark matter detector centered on a dual-phase xenon time projection chamber operating at the Sanford Underground Research Facility in Lead, South Dakota, USA. This Letter reports results from LUX-ZEPLIN's first search for weakly interacting massive particles (WIMPs) with an exposure of 60 live days using a fiducial mass of 5.5 t. A profile-likelihood ratio analysis shows the data to be consistent with a background-only hypothesis, setting new limits on spin-independent WIMP-nucleon, spin-dependent WIMP-neutron, and spin-dependent WIMP-proton cross sections for WIMP masses above 9 GeV/c^{2}. The most stringent limit is set for spin-independent scattering at 36 GeV/c^{2}, rejecting cross sections above 9.2×10^{-48} cm at the 90% confidence level.

Genome-wide association mapping of resistance to the sorghum aphid in Sorghum bicolor.

Since 2013, the sorghum aphid (SA), Melanaphis sorghi (Theobald), has been a serious pest that hampers all types of sorghum production in the U.S. Known sorghum aphid resistance in sorghum is limited to a few genetic regions on SBI-06. In this study, a subset of the Sorghum Association Panel (SAP) was used along with some additional lines to identify genomic regions that confer sorghum aphid resistance. SAP lines were grown in the field and visually evaluated for SA resistance during the growing seasons of 2019 and 2020 in Tifton, GA. In 2020, the SAP accessions were also evaluated for SA resistance in the field using drone-based high throughput phenotyping (HTP). Flowering time was recorded in the field to confirm that our methods were sufficient for identifying known quantitative trait loci (QTL). This study combined phenotypic data from field-based visual ratings and reflectance data to identify genome-wide associated (GWAS) marker-trait associations (MTA) using genotyping-by-sequencing (GBS) data. Several MTAs were identified for SA-related traits across the genome, with a few common markers that were consistently identified on SBI-08 and SBI-10 for aphid count and plant damage, as well as loci for reflectance-based traits on SBI-02, SBI-03, and SBI-05. Candidate genes encoding leucine-rich repeats (LRR), Avr proteins, lipoxygenases (LOXs), calmodulins (CAM) dependent protein kinase, WRKY transcription factors, flavonoid biosynthesis genes, and 12-oxo-phytodienoic acid reductase were identified near SNPs that had significant associations with different SA traits. In this study, flowering time-related genes were also identified as a positive control for the methods. The total phenotypic variation explained by significant SNPs across SA-scored traits, reflectance data, and flowering time ranged from 6 to 61%, while the heritability value ranged from 4 to 69%. This study identified three new sources of resistant lines to sorghum aphid. These results supported the existing literature, and also revealed several new loci. Markers identified in this study will support marker-assisted breeding for sorghum aphid resistance.

Evaluation of A3 cytoplasmic male sterile forage sorghum lines for resistance to sugarcane aphid.

MAIN CONCLUSION: Three known sugarcane aphid-resistant pollinator parents were sterilized in A3 cytoplasmic male sterility and were confirmed in this study to be resistant to sugarcane aphid allowing for the development of sugarcane aphid-resistant forage hybrids. We utilized A3 cytoplasmic male sterility and converted known sugarcane aphid-resistant sorghum TX 2783, and newly released R. LBK1 (Reg. No. GP-865, PI 687244) and R. LBK2 (Reg. No. GP-866, PI 687245) into A3 sterility to determine if the sterile counterparts would also equally express tolerance and or antibiosis to sugarcane aphid. Free-choice flat screen trials and life-table demographic studies were utilized and compared to know susceptible/fertile entries KS 585, and TX 7000, and known resistant/fertile entries TX 2783 and DKS 37-07. The R. LBK1 fertile entry was more tolerant than the known susceptible entries KS 585 and TX 7000, but was not as resistant as the other resistant entries, sustaining a damage rating of 6.0 across two different screen trials. The sterile A3 R. LBK2 showed a greater tolerance and expressed higher levels of antibiosis during aphid reproductive studies when compared to the known resistant and fertile TX 2783. All other fertile (R. LBK2, TX2783) and the A3 male sterile counterparts (A3 R. LBK2, A3 TX2783) were very similar in expression of high levels of tolerance and exhibited statistically similar damage ratings of 3.3-4.3 when exposed to sugarcane aphids. No entry, either fertile or sterile, was as tolerant as DKS 37-07, a known resistant commercial hybrid. Other plant measurements including percent loss in chlorophyll content, difference in plant height, and number of true leaves for sugarcane aphid infested versus non-infested were very consistent and highly correlated with damage ratings. Antibiosis was also exhibited in both fertile and sterile versions of the resistant lines. There was a 2 × reduction in fecundity between the R. LBK1 fertile and its sterile A3 R. LBK1 when compared to the susceptible KS 585 and TX 7000; however, the remaining fertile and sterile entries had 3.8 × to 5.8 × decrease in fecundity when compared to the susceptible KS 585 and TX 7000. Other measurements in life-table statistics such as nymphs produced/female/d, and the intrinsic rates of increased were significantly lower for all fertile and sterile lines, showing that antibiosis significantly affected sugarcane aphid reproduction. In conclusion, the A3 cytoplasmic male sterility shows consistency for maintaining the single dominant trait SCA-resistant trait of TX 2783 for expressing both antibiosis and tolerance, and great utility in the development of sugarcane aphid-resistant forage sorghums.

Melanoma secretion of transforming growth factor-ß2 leads to loss of epidermal AMBRA1 threatening epidermal integrity and facilitating tumour ulceration.

BACKGROUND: For patients with early American Joint Committee on Cancer (AJCC)-stage melanoma the combined loss of the autophagy regulatory protein AMBRA1 and the terminal differentiation marker loricrin in the peritumoral epidermis is associated with a significantly increased risk of metastasis. OBJECTIVES: The aim of the present study was to evaluate the potential contribution of melanoma paracrine transforming growth factor (TGF)-ß signalling to the loss of AMBRA1 in the epidermis overlying the primary tumour and disruption of epidermal integrity. METHODS: Immunohistochemistry was used to analyse AMBRA1 and TGF-ß2 in a cohort of 109 AJCC all-stage melanomas, and TGF-ß2 and claudin-1 in a cohort of 30 or 42 AJCC stage I melanomas, respectively, with known AMBRA1 and loricrin (AMLo) expression. Evidence of pre-ulceration was analysed in a cohort of 42 melanomas, with TGF-ß2 signalling evaluated in primary keratinocytes. RESULTS: Increased tumoral TGF-ß2 was significantly associated with loss of peritumoral AMBRA1 (P < 0·05), ulceration (P < 0·001), AMLo high-risk status (P < 0·05) and metastasis (P < 0·01). TGF-ß2 treatment of keratinocytes resulted in downregulation of AMBRA1, loricrin and claudin-1, while knockdown of AMBRA1 was associated with decreased expression of claudin-1 and increased proliferation of keratinocytes (P < 0·05). Importantly, we show loss of AMBRA1 in the peritumoral epidermis was associated with decreased claudin-1 expression (P < 0·05), parakeratosis (P < 0·01) and cleft formation in the dermoepidermal junction (P < 0·05). CONCLUSIONS: Collectively, these data suggest a paracrine mechanism whereby TGF-ß2 causes loss of AMBRA1 overlying high-risk AJCC early-stage melanomas and reduced epidermal integrity, thereby facilitating erosion of the epidermis and tumour ulceration.

A mixed methods investigation of the relationship between blood donor policy, interest in donation, and willingness to donate among gay, bisexual, and other men who have sex with men in Ontario, Canada.

BACKGROUND: As of 2019, men who have sex with men (MSM) in Canada are ineligible to donate blood if they have had oral or anal sex with another man in the last 3 months. Deferral policies targeting MSM are largely interpreted as unjust by gay, bisexual, and other men who have sex with men (GBMSM) - shaping their desire to donate blood and engage with blood operators. This mixed methods study explores interest in blood donation among GBMSM as well as willingness (and eligibility) to donate under four different deferral policies. METHODS: We surveyed 447 GBMSM who were recruited from the Ontario-wide #iCruise study. Participants were asked whether they were interested in blood donation and if they were willing to donate under each of our four deferral policies. We also completed interviews with 31 of these GBMSM. Participants were asked to describe their feelings about blood donation, their views on our different deferral policies, the impact of a policy change, as well as other means of redress. RESULTS: Most participants (69%) indicated that they were interested in donating blood. Despite this, an interpretation of the MSM deferral policy as discriminatory was common among all participants. Our mixed methods findings indicate that, among those who were interested in blood donation, the adoption of one of the alternative policies presented in this study (specifically Policy 2 or Policy 3) would significantly increase the number of participants willing to donate and be viewed as "a step in the right direction." However, many participants who were not interested in blood donation argued that a gender-neutral deferral policy would need to be implemented for them to donate. Participants recommended that blood operators consider efforts to repair relations with GBMSM beyond policy change, including pop-up clinics in predominantly queer areas and diversity sensitivity training for staff. CONCLUSION: We argue that the most impactful policy shift would be the implementation of an individual risk-based deferral policy that is applied to all donors regardless of sexual orientation or gender identity. However, given MSM's historical exclusion from blood donations, blood operators should pair this policy shift with community relationship-building efforts.

Cognitive stimulation has potential for brain activation in individuals with Rett syndrome.

BACKGROUND: Knowledge regarding neuropsychological training in Rett syndrome (RS) is scarce. The aim of this study was to assess the outcome and the duration of the effect of cognitive stimulation on topographic electroencephalography (EEG) data in RS. METHODS: Twenty female children diagnosed with RS were included in the analysis. Girls with RS conducted a cognitive task using an eye-tracker designed to evaluate access and choice skills. EEG data were acquired during the experimental procedure including two 10-min baseline stages before and after the task. Topographical changes of several EEG spectral markers including absolute and relative powers, Brain Symmetry Index and entropy were assessed. RESULTS: Topographic significance probability maps suggested statistical decreases on delta activity and increases on beta rhythm associated with the cognitive task. Entropy increased during and after the task, likely related to more complex brain activity. A significant positive interaction was obtained between Brain Symmetry Index and age showing that the improvement of interhemispheric symmetry was higher in younger girls (5-10 years). CONCLUSIONS: According to our findings, significant alterations of brain rhythms were observed during and after cognitive stimulation, suggesting that cognitive stimulation may have effects on brain activity beyond the stimulation period. Finally, our promising results also showed an increase brain symmetry that was especially relevant for the younger group. This could suggest an interaction of the eye-tracking cognitive task; however, further studies in this field are needed to assess the relation between brain asymmetries and age.

Potential risk factors associated with COVID-19 in health care workers.

BACKGROUND: Health care workers (HCWs) have been recognized as being at higher risk for coronavirus disease 2019 (COVID-19) infection; however, relevant factors and magnitude have not been clearly elucidated. AIM: This study was aimed to describe COVID-19 infections among hospital employees at a large tertiary care hospital located in Ontario, Canada from March to July 2020, towards better understanding potential risk factors. METHODS: Data on all HCWs with either a positive COVID test or a high-risk exposure from March to July 2020 were analyzed. HCWs with positive COVID test results and high-risk exposures were described. Those who developed COVID-19 following high-risk exposure were compared to those who did not. Data were also analyzed to determine trends over time. RESULTS: Over the period of observation, 193 staff (2% of total working staff) had a positive COVID-19 test. Incidence of HCW infections closely followed community incidence. Overall, 31% of COVID-19 cases were deemed occupationally acquired. Of these, 41% were acquired from a patient, with the remainder (59%) from fellow staff. Over the same period, 204 staff were identified as having a high-risk exposure. The majority of exposures (55%) were patient-associated, with the remaining (45%) resulting from staff-to-staff contact. Overall, 13% went on to develop COVID-19. Of these cases, 58% were patient-associated and 42% were a result of staff-to-staff transmission. CONCLUSIONS: HCWs are at risk for work-related COVID-19. Given the number of infections attributed to staff-staff transmission, greater attention could be paid to implementing prevention measures in non-clinical areas.

The effect of saline versus air for cuff inflation on the incidence of high intra-cuff pressure in paediatric MicroCuff® tracheal tubes: a randomised controlled trial.

The use of cuffed tracheal tubes in paediatric anaesthesia is now common. The use of nitrous oxide in anaesthesia risks excessive tracheal tube cuff pressures, as nitrous oxide can diffuse into the cuff during the course of surgery. The aim of this single-centre, prospective, randomised controlled trial was to compare the effect of saline versus air for the inflation of tracheal tube cuffs on the incidence of excessive intra-operative cuff pressure in children undergoing balanced anaesthesia with nitrous oxide. Children (age ≤ 16 y) were randomly allocated to receive either saline (saline group) or air (air group) to inflate the cuff of their tracheal tube. The pressure in the tracheal tube cuff was measured during surgery and brought down to the initial inflation level if it breached a safe limit (25 cmH2 O). Post-extubation adverse respiratory events were noted. Data from 48 patients (24 in each group), aged 4 months to 16 y, were analysed. The requirement for reduction in intra-cuff pressure occurred in 1/24 patients in the saline group, compared with 16/24 patients in the air group (p < 0.001). The incidence of extubation-related adverse events was similar in the saline and air groups (15/24 vs. 13/24, respectively; p = 0.770). The use of saline to inflate the cuff of paediatric cuffed tubes reduces the incidence of high intra-cuff pressures during anaesthesia. This may provide a pragmatic extra safety barrier to help reduce the incidence of excessive tracheal cuff pressure when nitrous oxide is used during paediatric anaesthesia.

Nemolizumab is associated with a rapid improvement in atopic dermatitis signs and symptoms: subpopulation (EASI ≥ 16) analysis of randomized phase 2B study.

BACKGROUND: Nemolizumab is a humanized anti-IL-31 receptor blocker in phase 3 for atopic dermatitis (AD). OBJECTIVE: Analyse onset of action of nemolizumab 30 mg and compare efficacy and safety vs placebo (SC q4wk plus loading dose) in moderate-to-severe AD. METHODS: Post hoc analysis of patients with Eczema Area and Severity Index (EASI) scores ≥ 16 from a phase 2b trial of moderate-to-severe AD. Endpoints were change in EASI score at week 16, peak pruritus numeric rating scale (PP-NRS), Investigator's Global Assessment (IGA), changes in sleep and responders with ≥ 4-point improvement on PP-NRS. RESULTS: There was a significantly greater itch relief apparent by Day 2 (-22.8% vs -12.3% PP-NRS; P = 0.005) which continued to improve through week 16 (-68.5% vs -30.9% PP-NRS; P < 0.001). At week 16, PP-NRS ≥ 4-point response of itch was observed in 68.0% nemolizumab vs 15.9% placebo patients (P ≤ 0.001). There was also a rapid improvement of sleep disturbance with nemolizumab 30 mg, with a significant separation from placebo by Day 3 (-26.6% vs -9.0%; P < 0.001) which further improved till week 16 (-76.0% vs -36.5%; P < 0.001). Also for the EASI score a separation between groups in favour of nemolizumab was observed by week 1 (P ≤ 0.001), which increased through week 16 (-68.6% vs. -42.6%; P = 0.002). Finally, the degree of response was greater in nemolizumab-treated patients; clinically relevant reductions of 75% EASI were observed in 50.0% of nemolizumab patients versus 15.9% of placebo patients, while 90% reductions were reported for 36.0% and 6.8% of patients, respectively (P < 0.001 for both). IGA success (score of 0/1) was 32.0% for nemolizumab vs 6.8% for placebo (P = 0.002). Nemolizumab was safe and well-tolerated in this population; nasopharyngitis and upper respiratory tract infection were the most common adverse events. CONCLUSIONS: Nemolizumab resulted in very rapid, sustained improvements of inflammation, pruritus and sleep in patients with EASI ≥ 16 at baseline.

Prospective Implementation of a Consultative Store-and-Forward Teledermatology Model at a Single Urban Academic Health System with Real Cost Data Subanalysis.

Background: Teledermatology may increase access to care but has not been widely implemented due, in part, to lack of insurance coverage and reimbursement. We assessed the impact of implementing a consultative store-and-forward teledermatology model on access to care, medical cost, and utilization. Materials and Methods: Prospective implementation of teledermatology occurred at five University of Pennsylvania Health System primary care practices from June 27, 2016, to May 25, 2017. Primary outcomes included time to case completion, proportion of patients completing in-person dermatology visits, and total outpatient costs. Medical and pharmacy claims data were used for utilization and cost subanalysis. Results: The study included 167 patients and 1,962 controls with a 6-month follow-up. Median time to definitive dermatologist response was 0.19 days (interquartile range [IQR]: 0.03-2.92) for intervention and 83.60 days (IQR: 19.74-159.73) for controls. In medical claims subanalysis, no significant differences in mean outpatient costs ($3,366 vs. $2,232, p = 0.1356) or total medical costs ($3,535 vs. $2,654, p = 0.2899) were detected. Conclusions: Implementation of teledermatology improved access to care, and within this small sample, remained comparable in terms of cost and utilization. Thus, these data suggest teledermatology may improve access without increasing utilization or cost.

Regeneration of Dopaminergic Neurons in Adult Zebrafish Depends on Immune System Activation and Differs for Distinct Populations.

Adult zebrafish, in contrast to mammals, regenerate neurons in their brain, but the extent and variability of this capacity is unclear. Here we ask whether the loss of various dopaminergic neuron populations is sufficient to trigger their functional regeneration. Both sexes of zebrafish were analyzed. Genetic lineage tracing shows that specific diencephalic ependymo-radial glial (ERG) progenitor cells give rise to new dopaminergic [tyrosine hydroxylase-positive (TH+)] neurons. Ablation elicits an immune response, increased proliferation of ERG progenitor cells, and increased addition of new TH+ neurons in populations that constitutively add new neurons (e.g., diencephalic population 5/6). Inhibiting the immune response attenuates neurogenesis to control levels. Boosting the immune response enhances ERG proliferation, but not addition of TH+ neurons. In contrast, in populations in which constitutive neurogenesis is undetectable (e.g., the posterior tuberculum and locus ceruleus), cell replacement and tissue integration are incomplete and transient. This is associated with a loss of spinal TH+ axons, as well as permanent deficits in shoaling and reproductive behavior. Hence, dopaminergic neuron populations in the adult zebrafish brain show vast differences in regenerative capacity that correlate with constitutive addition of neurons and depend on immune system activation.SIGNIFICANCE STATEMENT Despite the fact that zebrafish show a high propensity to regenerate neurons in the brain, this study reveals that not all types of dopaminergic neurons are functionally regenerated after specific ablation. Hence, in the same adult vertebrate brain, mechanisms of successful and incomplete regeneration can be studied. We identify progenitor cells for dopaminergic neurons and show that activating the immune system promotes the proliferation of these cells. However, in some areas of the brain this only leads to insufficient replacement of functionally important dopaminergic neurons that later disappear. Understanding the mechanisms of regeneration in zebrafish may inform interventions targeting the regeneration of functionally important neurons, such as dopaminergic neurons, from endogenous progenitor cells in nonregenerating mammals.

Older age and comorbidity are independent mortality predictors in a large cohort of 1305 COVID-19 patients in Michigan, United States.

INTRODUCTION: Higher comorbidity and older age have been reported as correlates of poor outcomes in COVID-19 patients worldwide; however, US data are scarce. We evaluated mortality predictors of COVID-19 in a large cohort of hospitalized patients in the United States. DESIGN: Retrospective, multicenter cohort of inpatients diagnosed with COVID-19 by RT-PCR from 1 March to 17 April 2020 was performed, and outcome data evaluated from 1 March to 17 April 2020. Measures included demographics, comorbidities, clinical presentation, laboratory values and imaging on admission. Primary outcome was mortality. Secondary outcomes included length of stay, time to death and development of acute kidney injury in the first 48-h. RESULTS: The 1305 patients were hospitalized during the evaluation period. Mean age was 61.0 ± 16.3, 53.8% were male and 66.1% African American. Mean BMI was 33.2 ± 8.8 kg m-2 . Median Charlson Comorbidity Index (CCI) was 2 (1-4), and 72.6% of patients had at least one comorbidity, with hypertension (56.2%) and diabetes mellitus (30.1%) being the most prevalent. ACE-I/ARB use and NSAIDs use were widely prevalent (43.3% and 35.7%, respectively). Mortality occurred in 200 (15.3%) of patients with median time of 10 (6-14) days. Age > 60 (aOR: 1.93, 95% CI: 1.26-2.94) and CCI > 3 (aOR: 2.71, 95% CI: 1.85-3.97) were independently associated with mortality by multivariate analyses. NSAIDs and ACE-I/ARB use had no significant effects on renal failure in the first 48 h. CONCLUSION: Advanced age and an increasing number of comorbidities are independent predictors of in-hospital mortality for COVID-19 patients. NSAIDs and ACE-I/ARB use prior to admission is not associated with renal failure or increased mortality.

Differential responses of sorghum genotypes to sugarcane aphid feeding.

MAIN CONCLUSION: The findings of this study suggest that known resistant sorghum genotypes compensate for feeding pressure of sugarcane aphid by maintaining/increasing photosynthetic capacity and/or have higher chlorophyll content than susceptible genotypes. Knowledge of the physiological response of sorghum, (Sorghum bicolor (L.) Moench), to sugarcane aphid (SCA), Melanaphis sacchari (Zehnter) feeding will provide baseline information on defense responses and resistance mechanisms. This study documented the impact of SCA feeding on seven sorghum genotypes by measuring chlorophyll content, photosynthetic rate, stomatal conductance, and carbon assimilation for a 14-d post-infestation evaluation. Carbon assimilation (A/Ci) curves were recorded at 3, 6, 9, and 15 d after aphid infestation to describe the pattern of physiological response of resistant and susceptible sorghums over time. Chlorophyll loss from resistant genotypes was significantly lower (≤ 10% loss) than from susceptible cultivars. Most resistant genotypes compensated for aphid feeding by either increasing or maintaining photosynthetic rate and stomatal conductance. Carbon assimilation curves over time showed that infested resistant plants had delayed photosynthetic decreases, whereas susceptible plants rapidly lost photosynthetic capacity. This research also investigated the influence of aphid density (0, 50, 100, and 200 nymphs/plant) on the photosynthetic rates of 28-d-old resistant and susceptible sorghums measured at 72-h post-infestation. Although there were no visual symptoms in susceptible sorghums, photosynthetic rates were impaired when infested with ≥ 100 SCA. In contrast, resistant plants were able to compensate for SCA feeding. Differences in the physiological responses of susceptible versus resistant sorghums indicate that resistant sorghum plants can tolerate some physiological impacts of SCA feeding and maintain photosynthetic integrity.

Gb8, a new gene conferring resistance to economically important greenbug biotypes in wheat.

KEY MESSAGE: A new greenbug resistance gene Gb8 conferring broad resistance to US greenbug biotypes was identified in hard red winter wheat line PI 595379-1 and was mapped to the terminal region of chromosome 7DL. Greenbug [Schizaphis graminum (Rondani)] is a worldwide insect pest that poses a serious threat to wheat production. New greenbug resistance genes that can be readily used in wheat breeding are urgently needed. The objective of this study was to characterize a greenbug resistance gene in PI 595379-1, a single plant selection from PI 595379. Genetic analysis of response to greenbug biotype E in an F2:3 population derived from a cross between PI 595379-1 and PI 243735 indicated that a single gene, designated Gb8, conditioned resistance. Linkage analysis placed Gb8 in a 2.7-Mb interval in the terminal bin of chromosome 7DL (7DL3-082-1.0), spanning 595.6 to 598.3 Mb in the Chinese Spring IWGSC RefSeq version 1.0 reference sequence. Gb8 co-segregated with a newly developed SSR marker Xstars508, positioned at 596.4 Mb in the reference sequence. Allelism tests showed that Gb8 was different from three permanently named genes on the same chromosome arm and the estimated genetic distance between Gb8 and Gb3 was 15.35 ± 1.35 cM. Gb8 can be directly used in wheat breeding to enhance greenbug resistance.

Epidermal autophagy and beclin 1 regulator 1 and loricrin: a paradigm shift in the prognostication and stratification of the American Joint Committee on Cancer stage I melanomas.

BACKGROUND: The updated American Joint Committee on Cancer (AJCC) staging criteria for melanoma remain unable to identify high-risk stage I tumour subsets. OBJECTIVES: To determine the utility of epidermal autophagy and beclin 1 regulator 1 (AMBRA1)/loricrin (AMLo) expression as a prognostic biomarker for AJCC stage I cutaneous melanoma. METHODS: Peritumoral AMBRA1 expression was evaluated in a retrospective discovery cohort of 76 AJCC stage I melanomas. AMLo expression was correlated with clinical outcomes up to 12 years in two independent powered, retrospective validation and qualification cohorts comprising 379 AJCC stage I melanomas. RESULTS: Decreased AMBRA1 expression in the epidermis overlying primary melanomas in a discovery cohort of 76 AJCC stage I tumours was associated with a 7-year disease-free survival (DFS) rate of 81·5% vs. 100% survival with maintained AMBRA1 (P < 0·081). Following an immunohistochemistry protocol for semi-quantitative analysis of AMLo, analysis was undertaken in validation (n = 218) and qualification cohorts (n = 161) of AJCC stage I melanomas. Combined cohort analysis revealed a DFS rate of 98·3% in the AMLo low-risk group (n = 239) vs. 85·4% in the AMLo high-risk cohort (n = 140; P < 0·001). Subcohort multivariate analysis revealed that an AMLo hazard ratio (HR) of 4·04 [95% confidence interval (CI) 1·69-9·66; P = 0·002] is a stronger predictor of DFS than Breslow depth (HR 2·97, 95% CI 0·93-9·56; P = 0·068) in stage IB patients. CONCLUSIONS: Loss of AMLo expression in the epidermis overlying primary AJCC stage I melanomas identifies high-risk tumour subsets independently of Breslow depth. What's already known about this topic? There is an unmet clinical need for biomarkers of early-stage melanoma. Autophagy and beclin 1 regulator 1 (AMBRA1) is a proautophagy regulatory protein with known roles in cell proliferation and differentiation, and is a known tumour suppressor. Loricrin is a marker of epidermal terminal differentiation. What does this study add? AMBRA1 has a functional role in keratinocyte/epidermal proliferation and differentiation. The combined decrease/loss of peritumoral AMBRA1 and loricrin is associated with a significantly increased risk of metastatic spread in American Joint Committee on Cancer (AJCC) stage I tumours vs. melanomas, in which peritumoral AMBRA1 and loricrin are maintained, independently of Breslow depth. What is the translational message? The integration of peritumoral epidermal AMBRA1/loricrin biomarker expression into melanoma care guidelines will facilitate more accurate, personalized risk stratification for patients with AJCC stage I melanomas, thereby facilitating stratification for appropriate follow-up and informing postdiagnostic investigations, including sentinel lymph node biopsy, ultimately resulting in improved disease outcomes and rationalization of healthcare costs.