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Primary hepatocellular carcinoma (HCC) and colorectal liver metastases (CRLM) represent the two most common malignant neoplasms of the liver. The objective of this study was to assess outcomes of surgical approaches to liver ablation comparing laparoscopic versus percutaneous microwave ablation (MWA), and MWA versus radiofrequency ablation (RFA) in patients with HCC or CRLM lesions smaller than 5 cm.A systematic review was conducted across seven databases, including PubMed, Embase, and Cochrane, to identify all comparative studies between 1937 and 2021. Two independent reviewers screened for eligibility, extracted data for selected studies, and assessed study bias using the modified Newcastle Ottawa Scale. Random effects meta-analyses were subsequently performed on all available comparative data.From 1066 records screened, 11 studies were deemed relevant to the study and warranted inclusion. Eight of the 11 studies were at high or uncertain risk for bias. Our meta-analyses of two studies revealed that laparoscopic MW ablation had significantly higher complication rates compared to a percutaneous approach (risk ratio = 4.66; 95% confidence interval = [1.23, 17.22]), but otherwise similar incomplete ablation rates, local recurrence, and oncologic outcomes. The remaining nine studies demonstrated similar efficacy of MWA and RFA, as measured by incomplete ablation, complication rates, local/regional recurrence, and oncologic outcomes, for both HCC and CRLM lesions less than 5 cm (p 0.05 for all outcomes). There was no statistical subgroup interaction in the analysis of tumors 3 cm.The available comparative evidence regarding both laparoscopic versus percutaneous MWA and MWA versus RFA is limited, evident by the few studies that suffer from high/uncertain risk of bias. Additional high-quality randomized trials or statistically matched cohort studies with sufficient granularity of patient variables, institutional experience, and physician specialty/training will be useful in informing clinical decision making for the ablative treatment of HCC or CRLM.

Drawing on an existing typology, this study used latent transition profile analysis (LTPA) to examine changes in the striving and wellbeing profiles among teachers from their early until mid-career. Five profiles were identified (Sparing, Good health, Ambitious, Burnout and Wornout) among a longitudinal sample of 414 Australian secondary and primary teachers. LTPA showed that 28% of teachers were movers over time. Most movers from maladaptive types underwent a recovery transition to a more adaptive profile by mid-career, although initial Burnout and Wornout profiles were overrepresented among those who subsequently quit teaching. Perceived excessive work demands and supportive leadership were significant covariates: perceived excessive work demands decreased the likelihood of transitioning to Good health or Ambitious profiles; supportive leadership increased the likelihood of transitioning to Ambitious. Profiles were associated with teachers' professional engagement; the Wornout profile exhibited the lowest, and the Ambitious and Good health profiles the highest professional engagement by mid-career. Implications for theory and policy to support teachers' development and wellbeing are discussed.

Women and non-white racial and ethnic groups remain underrepresented in science, technology, engineering, and math (STEM). To achieve a more diverse and equitable STEM workforce, the recruitment and retention of these historically marginalized communities in postsecondary education will also need to increase. Recently, the lens has turned to pedagogy and how creating a more inclusive classroom environment can foster STEM identity in previously marginalized communities. This work focuses on developing and piloting systems biology education modules designed to promote an inclusive learning environment in a summer outreach program for high school students by (1) utilizing a hybrid of unplugged activities with coded simulation and (2) a female-oriented problem statement. Based on initial findings in our pilot program, we anticipate that these techniques will enable students with limited prior computational experience to feel more comfortable and able to complete tasks, thereby increasing their self-efficacy and STEM identity. These modules could be a valuable tool for practitioners teaching high school or early college-level computational courses who instruct students with varied coding experience. Additionally, our analysis of the use of a female-oriented problem statement on female-identifying students’ self-efficacy provides potential evidence of the usefulness of representative problem statements in engaging underrepresented student populations. We believe these techniques could be adapted to address a variety of contexts across STEM disciplines and other fields to foster inclusive learning environments.

ObjectiveThe objective of this investigation was to demonstrate thatin vivoinduction of hypertension (HTN) andin vitrocyclic stretch of aortic VSMCs can cause SGK-1-dependent production of cytokines to promote macrophage accumulation as agents of vascular remodeling.MethodsHTN was induced in C57Bl/6 mice with AngiotensinII (AngII) infusion (1.46mg/kg/day x 21 days) with or without systemic infusion of EMD638683 (2.5mg/kg/day x 21 days), a selective SGK-1 inhibitor. Systolic blood pressure (SBP) was recorded on days 0 and 21. At terminal study, abdominal aortas were harvested to quantify SGK-1 activity (pSGK-1:SGK-1) by immunoblot. Additional replicates were digested and analyzed by flow cytometry for abundance of CD11b+/F4-80+cells (macrophages). Plasma was analyzed by ELISA to quantify IL-6 and MCP-1. Aortic VSMCs from wild-type (WT) mice were subjected to 12% biaxial cyclic stretch for 3 or 12 hours +/- EMD638683 (10μM) and +/- SGK-1siRNA with subsequent QPCR for IL-6 and MCP-1 expression. Culture media was analyzed by ELISA for IL-6 and MCP-1. Aortic VSMCs from SGK-1flox+/+mice were transfected with Cre-Adenovirus to knockout SGK-1 (SGK-1KO VSMCs) and underwent parallel tension experimentation. Computational modeling was employed to simulate VSMC signaling due to mechanical strain and AngII. Statistical analysis included ANOVA with significance at pResultsSGK-1 activity (pSGK-1:SGK-1) was upregulated in the abdominal aorta of mice with HTN and significantly reduced by treatment with EMD638683. Concurrently, increased CD11b+/F4-80+cells and plasma IL-6 levels in the HTN group and reduction with EMD638683 was observed. This mirrored the increased abundance of IL-6 in media from Stretch WT VSMCs, and attenuation of the effect with EMD638683. Treating WT VSMCs with SGK-1siRNA likewise inhibited IL-6 expression. MCP-1 also demonstrated increased expression and secretion into the media in WT VSMCs with Stretch. Further supporting the integral role of mechanical signaling through SGK-1, target gene expression and cytokine secretion was unchanged in SGK-1KO VSMCs with Stretch, and computer modeling confirmed SGK-1 as an intersecting node of signaling due to mechanical strain and AngII. In summation, this data suggests a biomechanical link between aortic VSMC mechanotransduction and cytokine production to promote macrophage accumulation, mediated in-part by SGK-1 activation.ConclusionMechanotransduction through SGK-1 is instrumental in pro-inflammatory cytokine production and aortic macrophage accumulation in systemic HTN, therefore further investigation into targeting this kinase may present opportunities to modulate hypertensive vascular remodeling.

Despite mediating several essential processes in the brain, including during development, cyclin-dependent kinase-like 5 (CDKL5) remains a poorly characterized human protein kinase. Accordingly, its substrates, functions, and regulatory mechanisms have not been fully described. We realized that availability of a potent and selective small molecule probe targeting CDKL5 could enable illumination of its roles in normal development as well as in diseases where it has become aberrant due to mutation. We prepared analogs of AT-7519, a known inhibitor of several cyclin dependent and cyclin-dependent kinase-like kinases that has been advanced into Phase II clinical trials. We identified analog2as a highly potent and cell-active chemical probe for CDKL5/GSK3 (glycogen synthase kinase 3). Evaluation of its kinome-wide selectivity confirmed that analog2demonstrates excellent selectivity and only retains GSK3α/β affinity. As confirmation that our chemical probe is a high-quality tool to use in directed biological studies, we demonstrated inhibition of downstream CDKL5 and GSK3α/β signaling and solved a co-crystal structure of analog2bound to CDKL5. A structurally similar analog (4) proved to lack CDKL5 affinity and maintain potent and selective inhibition of GSK3α/β. Finally, we used our chemical probe pair (2and4) to demonstrate that inhibition of CDKL5 and/or GSK3α/β promotes the survival of human motor neurons exposed to endoplasmic reticulum (ER) stress. We have demonstrated a neuroprotective phenotype elicited by our chemical probe pair and exemplified the utility of our compounds to characterize the role of CDKL5/GSK3 in neurons and beyond.

Transcription factors are the primary regulators of gene expression and recognize specific DNA sequences under diverse physiological conditions. Although they are vital for many important cellular processes, it remains unclear when and how transcription factors and DNA interact. The antitoxin from a toxin–antitoxin system is an example of negative transcriptional autoregulation: during expression of the cognate toxin it is suppressed through binding to a specific DNA sequence. In the present study, the antitoxin HigA2 from Mycobacterium tuberculosis M37Rv was structurally examined. The crystal structure of M. tuberculosis HigA2 comprises three sections: an N-terminal autocleavage region, an α-helix bundle which contains an HTH motif, and a C-terminal β-lid. The N-terminal region is responsible for toxin binding, but was shown to cleave spontaneously in its absence. The HTH motif performs a key role in DNA binding, with the C-terminal β-lid influencing the interaction by mediating the distance between the motifs. However, M. tuberculosis HigA2 exhibits a unique coordination of the HTH motif and no DNA-binding activity is detected. Three crystal structures of M. tuberculosis HigA2 show a flexible alignment of the HTH motif, which implies that the motif undergoes structural rearrangement to interact with DNA. This study reveals the molecular mechanisms of how transcription factors interact with partner proteins or DNA.

A well-qualified, well-paid, stable workforce with high psychological and emotional wellbeing is critical to the provision of quality early childhood education and care, yet workforce shortages and high turnover persist in Australia and internationally. This paper uses ecological theory to conceptualise and make sense of findings from research that has investigated the recruitment, retention and wellbeing of early childhood teachers in Australia. The theoretical framing of early childhood teacher workforce issues proffered in the paper highlights the utility of considering these issues from a holistic ecological perspective. Analysis of Australian early childhood workforce studies draws attention to the need for large-scale, longitudinal research that holistically investigates influences on the attracting, retaining and sustaining of early childhood teachers, and the impact of these influences on teacher quality.

While surgical resection has a demonstrated utility for patients with colorectal liver metastases (CRLM), it is unclear whether minimally invasive surgery (MIS) or an open approach should be used. This review sought to assess the efficacy and safety of MIS versus open hepatectomy for isolated, resectable CRLM when performed separately from (Key Question (KQ) 1) or simultaneously with (KQ2) the resection of the primary tumor.PubMed, Embase, Google Scholar, Cochrane CENTRAL, International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov databases were searched to identify both randomized controlled trials (RCTs) and non-randomized comparative studies published during January 2000-September 2020. Two independent reviewers screened literature for eligibility, extracted data from included studies, and assessed internal validity using the Cochrane Risk of Bias 2.0 Tool and the Newcastle-Ottawa Scale. A random-effects meta-analysis was performed using risk ratios (RR) and mean differences (MD).From 2304 publications, 35 studies were included for meta-analysis. For staged resections, three RCTs and 20 observational studies were included. Data from RCTs indicated MIS having similar disease-free survival (DFS) at 1-year (RR 1.03, 95%CI 0.70-1.50), overall survival (OS) at 5-years (RR 1.04, 95%CI 0.84-1.28), fewer complications of Clavien-Dindo Grade III (RR 0.62, 95%CI 0.38-1.00), and shorter hospital length of stay (LOS) (MD -6.6 days, 95%CI -10.2, -3.0). For simultaneous resections, 12 observational studies were included. There was no evidence of a difference between MIS and the open group for DFS-1-year, OS-5-year, complications, R0 resections, blood transfusions, along with lower blood loss (MD -177.35 mL, 95%CI -273.17, -81.53) and shorter LOS (MD -3.0 days, 95%CI -3.82, -2.17).Current evidence regarding the optimal approach for CRLM resection demonstrates similar oncologic outcomes between MIS and open techniques, however MIS hepatectomy had a shorter LOS, lower blood loss and complication rate, for both staged and simultaneous resections.

Correlates of turnover intent among primary (N = 580) and secondary (N = 675), male (N = 254) and female (N = 999) teachers, were examined through the lens of the job demands-resources (JD-R) model. Multigroup structural equation modelling indicated that job demands (workload, student misbehaviour), and the personal demand of work–family conflict, were positively associated with emotional exhaustion—the core dimension of burnout. All demands indirectly related to turnover intent via emotional exhaustion. Among all teacher groups, no significant differences were found in level of emotional exhaustion or turnover intent, and only mild stress was reported as a result of student misbehaviour. Work–family conflict was the strongest predictor of emotional exhaustion for male and female teachers. Results suggest the JD-R as a promising theory for use in explaining job-related outcomes among Australian teachers, and that personal demands should be examined in addition to job demands within it.

141 Background: PRL-02 (abiraterone decanoate) is a novel, long-acting IM depot prodrug of abiraterone. In non-clinical models, PRL-02 provided high and durable concentrations of prodrug and abiraterone to target tissues including adrenal glands, lymph nodes and bone. Single doses of PRL-02 suppressed testosterone (T) through 14 weeks in a castrate monkey model to concentrations comparable to oral abiraterone acetate (AA) with lower and less variable plasma abiraterone exposures. Clinically, PRL-02 blocks androgens with minimal increases in mineralocorticoids or depletion of glucocorticoids via inhibition of CYP17 lyase and minimal inhibition of CYP17 hydroxylase. PRL-02 has the potential for a superior therapeutic index and safety profile compared to oral AA. Methods: Phase 1 is a standard 3+3 design intended to identify a recommended phase 2 dose (RP2D). Pts with metastatic castrate resistant or sensitive prostate cancer (mCRPC/mCSPC) and a screening T of 2 - 50 ng/dL were administered IM PRL-02 every 12 weeks with daily oral dexamethasone. Results: As of 8Sep22, 17 pts (6 mCRPC, 11 mCSPC) were treated across 5 dose cohorts (180, 360, 720, 1260, 1800mg). Generally, there was a dose-proportional increase in abiraterone concentrations following a single dose of PRL-02 with a Tmax of 14 - 28 days and a plasma half-life of 18.3 days. The median baseline T level was 7.45ng/dL. Among pts dosed at 720mg and above, 9 of 11 had a 90% reduction in T or values ≤ 1ng/dL at day 28, including 2 pts with T≤LLOQ of 0.1 ng/dL, and PSA50 responses were observed in 8 of 10 with post-baseline results. There were no treatment related serious adverse events (AEs) or dose limiting toxicities. G3 AEs related to PRL-02 included hip and shoulder pain. G2 related AEs included fatigue, decreased appetite, insomnia and hot flush; symptoms of mineralocorticoid excess were not reported. Minimal and transient changes in ‘up-stream’ steroids (e.g., progesterone (P) and corticosterone (C)) were observed through the 1800mg dose. Although serial radiology was not prospectively required, there was radiographic improvement in 6 pts with data available. Conclusions: PRL-02 was well tolerated. Dose-dependent T suppression was associated with clinical benefit including PSA responses and radiographic improvement. Based on a historical comparison, the levels of P and C are significantly lower than seen with AA + prednisone which appear to be due to greater CYP17 lyase selectivity. The 1260mg or 1800mg dose will be the RP2D. Clinical trial information: NCT04729114 . [Table: see text]

Introduction: Imaging studies patients with mitral valve prolapse (MVP) have previously shown cross sectional evidence of left ventricular (LV) fibrosis as well as increased risk for sudden cardiac death. This, along with evidence for post-repair ventricular dysfunction in Mitral valve surgery patients support a link between fibrosis and MVP. The development of fibrosis as a result of MVP, however, remains poorly understood. Hypothesis: Regionalized LV Fibrosis in MVP patients is driven by increased mechanical tension through the chordae tendineae by billowing leaflets. Methods: We performed histopathologic analysis on cardiac biopsies of 6 patients who underwent surgical repair for MV prolapse. We additionally performed longitudinal histopathologic analysis on hearts harvested from a mouse modal of human non-syndromic MVP (Dzip1 S14R/+). To assess the cellular response to increased mechanical tension, pathological stretch assays on human cardiac fibroblasts were performed in tandem with RNA seq, as well ATP luminescence assays to assess ATP release from stretched cells. Results: Biopsies from peripapillary regions, inferobasal wall, LV septum, and LV apex demonstrated regionalized myocardial fibrosis that correlated with increased macrophages and myofibroblasts. Our mouse model demonstrated similar regionalized deposition of collagen that increased over time, as well as an increase in macrophages and myofibroblasts. Stretching of human cardiac fibroblasts caused significant changes in 232 transcripts (Bonferroni corrected P value Conclusions: A mouse model of human MVP phenocopied regionalized myocardial fibrosis seen in humans and will provide a useful tool to investigate mechanisms of myocardial fibrosis in MVP patients. Stretch initiates changes in pro-fibrotic gene transcription, and causes ATP release from human cardiac fibroblasts.

Riparian and ground-water dependent ecosystems found in the Great Basin of North America are heavily utilized by livestock and wildlife throughout the year. Due to this constant pressure, grazing can be a major influence on many groundwater dependent resources. It is important for land managers to understand how intensity and timing of grazing affect the temporal availability of these commodities (i.e., biodiversity, water filtration, forage, habitat). Shifts in forage or water availability could potentially be harmful for fauna that rely on them at specific times of the year. Seven meadow communities, each consisting of three distinct vegetative communities, were grazed at three intensities to determine the relationship between grazing management and phenological timing of vegetation. The agreement of on-the-ground measurements, near-surface digital cameras (phenocams), and satellite-based indices of greenness was examined for a two-year period (2019–2020) over these grazing and vegetative community gradients. Field determined phenology, phenocam Green Chromatic Coordinate (GCC), and Landsat Normalized Difference Vegetation Index (NDVI) were all highly correlated and the relationship did not change across the treatments. Timing of growth varied in these ecosystems depending on yearly precipitation and vegetative type. Communities dominated by mesic sedges had growing seasons which stopped earlier in the year. Heavier grazing regimes, however, did not equate to significant changes in growing season. Ultimately, shifts in phenology occurred and were successfully monitored at various spatial and temporal scales.

Achievement Goal Theory has been adapted as a useful framework for studying teacher motivation in terms of their different goal orientations. This paper reports findings from an Australian study with 257 teachers, that explored their mastery, work-avoidance, and relational goal orientations and four dimensions of self-reported classroom behaviours: expectation, structure, autonomy support, and relatedness. Structural equation modelling underscored the importance of mastery and relational goal orientations as adaptive goal orientations that positively predicted teachers’ perceptions about their expectation, structure, and relatedness with students. Interestingly neither of these adaptive goal orientations predicted teachers’ self-reported behavior of autonomy support. The only significant predictor was work-avoidance goal orientations, which negatively predicted teachers’ discernments of supporting student autonomy.

P. aeruginosa (PA) continues to pose a threat to global public health due to its high levels of antimicrobial resistance (AMR). The ongoing AMR crisis has led to an alarming shortage of effective treatments for resistant microbes, and hence there is a pressing demand for the development of novel antimicrobial interventions. The potential use of antivirulence therapeutics to tackle bacterial infections has attracted considerable attention over the past decades as they hamper the pathogenicity of target microbes with reduced selective pressure, minimizing the emergence of resistance. One such approach is to interfere with the PA pqs quorum sensing system which upon the interaction of PqsR, a Lys-R type transcriptional regulator, with its cognate signal molecules 4-hydroxy-2-heptylquinoline (HHQ) and 2-heptyl-3-hydroxy-4-quinolone (PQS), governs multiple virulence traits and host-microbe interactions. In this study, we report the hit identification and optimization of PqsR antagonists using virtual screening coupled with whole cell assay validation. The optimized hit compound 61 ((R)-2-(4-(3-(6-chloro-4-oxoquinazolin-3(4H)-yl)-2-hydroxypropoxy)phenyl)acetonitrile) was found to inhibit the expression of the PA P-pqsA promoter controlled by PqsR with an IC50 of 1 mu M. Using isothermal titration calorimetry, a K-d of 10 nM for the P-qsR ligand binding domain (PqsR(LBD)) was determined for 61. Furthermore, the crystal structure of 61 with PqsR(LBD) was attained with a resolution of 2.65 angstrom. Compound 61 significantly reduced levels of pyocyanin, PQS, and HHQ in PAO1-L, PA14 lab strains and PAK6085 clinical isolate. Furthermore, this compound potentiated the effect of ciprofloxacin in early stages of biofilm treatment and in Galleria mellonella infected with PA. Altogether, this data shows 61 as a potent PqsR inhibitor with potential for hit to lead optimization toward the identification of a PA QS inhibitor which can be advanced into preclinical development.

Attacks against remote workers who are working from home due to the global pandemic has significantly increased. Cyber criminals have realised this and are exploiting users for financial gain and for espionage motives. Criminals are aiming to exploit vulnerable smart homes through Internet of Things and leverage access into corporate networks. This means that home users need to be extra vigilant against this contemporary technique. This paper will address these challenges with robust protocols for organisations to absorb, train, and implement. Additionally, this paper will align organisations expectations with user vulnerabilities to increase organisation resilience.

Cyber warfare is undoubtedly inevitable, since this can be done with low costs, minimal equipment, and it can be performed by attribution which means adversaries are less likely to be counter attacked. Industrial Control Systems (ICS) are a system which was built over thirty years ago, and a system without security in-mind. Therefore, these systems are vulnerable, however they should be protected diligently as these systems are critical to the economic growth, public healthcare and welfare. In this paper, we will look to critically appraise cyber warfare and its effects against ICS, along with robust recommendations with the intention of enhancing national security.

Drones are being utilised in diverse domains all over the world. The latest employment is the utilisation of drones during the global pandemic for crowd dispersal, infection monitoring, facial recognition, and logistical roles. Drones with artificial intelligence are unique devices that enhance the economy and are capable of completing tasks that humans cannot. The issue is that companies have disregarded the security of these machines, making them vulnerable to cyberattacks. Furthermore, a compromised drone can be used as a malicious offensive weapon system for tasks such as illegal imagery, videography, and as a functioning autonomous weapon system. This paper critically analyses the amalgamation of drones and artificial intelligence, reviews the current threat landscape, and studies drone vulnerabilities in regard to attack methods. Finally, a robust framework with secure countermeasures is proposed and therefore recommended for the drone industry to adopt and implement.