A tale of two twists: mesentero-axial and organo-axial sigmoid volvulus.

INTRODUCTION: Sigmoid volvulus is a potentially devastating and life-threatening condition associated with sigmoid colon redundancy. Many of the classical radiological signs are considered to represent the two adjacent loops of bowel in a mesentero-axial volvulus. However, limited case reports and series have reported on an organo-axial subtype of sigmoid volvulus. This clinical entity is not widely understood. In this study, we assess the radiological and clinical features of mesentero-axial and organo-axial sigmoid volvulus. METHODS: After institutional board approval (CH62/6/2016-228), all computed tomography (CT) studies from 2011 to 2017 reported as sigmoid volvulus at a single institution were reviewed. The cases were reviewed by three radiologists retrospectively and the course of the bowel followed with a focus on assessing its rotational axis. In each case, the sigmoid volvulus was independently subclassified as mesentero-axial or organo-axial volvulus based on the axis of rotation of the volvulus. In addition, X-ray signs including disproportionate sigmoid dilatation, distended inverted 'U' in sigmoid, coffee bean sign, opposed wall sign, direction of apex of sigmoid loop, liver overlap sign, northern exposure sign and proximal colonic dilatation and CT features including whirl sign, 'X' marks the spot sign, split wall sign and number of transition points were reported for each case. The clinical management and outcomes including morbidity, mortality, endoscopic decompression and need for surgery were also evaluated. The subtype of volvulus was correlated with the above X-ray signs, CT features and clinical management and outcomes. Statistical analysis was conducted using Stata/MP, version 15 (StataCorp LP, College Station, TX, USA). RESULTS: A total of 38 scans were reviewed. There were 19 patients identified. Of these, six (32%) were reported as mesentero-axial and 13 (68%) as organo-axial volvulus. No X-ray signs were able to distinguish the two types of volvulus. The number of transition points on CT was predictive of volvulus subtype (OR 25, 95% CI: 1.30-1295.30, P = 0.01). Within the limitations of a small cohort, there was no statistically significant difference in unsuccessful endoscopic decompression, need for colectomy, repeated admissions or mortality between the groups. CONCLUSION: This study has demonstrated that organo-axial sigmoid volvulus may be as common as mesentero-axial volvulus. Distinguishing organo-axial from mesentero-axial volvulus can be achieved on CT, but not on abdominal X-ray. The number of transition points (two for mesentero-axial and one for organo-axial) may be used as a diagnostic feature for differentiating the two forms of volvulus.

Relation of blood lead levels and lead in gasoline: an updated systematic review.

BACKGROUND: Millions of tons of lead were added to gasoline worldwide beginning in 1922, and leaded gasoline has been a major source of population lead exposure. In 1960s, lead began to be removed from automotive gasoline. Removal was completed in 2021. OBJECTIVES: To determine whether removal of lead from automotive gasoline is associated with declines in population mean blood lead levels (BPb). METHODS: We examined published studies that reported population blood leaded levels for two or more years, and we calculated average concentrations of lead in gasoline corresponding to the years and locations of the blood lead level measurements. RESULTS: Removal of lead from gasoline is associated with declines in BPb in all countries examined. In some countries, BPb continues to fall after lead has been eliminated from gasoline. Following elimination of lead from gasoline, BPb less than 1 µg/dL have been observed in several European and North American countries, and BPb less than 3 µg/dL have been documented in several studies from South America. DISCUSSION: There remain many countries for which no multi-year studies of populations BPb have been identified, including all of Central America, high population countries including Pakistan and Indonesia, and major lead producers including Australia and Russia. CONCLUSION: Removal of lead from gasoline has been a public health success. Elimination of lead from gasoline has enabled many countries to achieve population mean BPb levels of 1 µg/dL or lower. These actions have saved lives, increased children's intelligence and created great economic benefit in countries worldwide.

Differential dependencies of human RNA polymerase II promoters on TBP, TAF1, TFIIB and XPB.

The effects of rapid acute depletion of components of RNA polymerase II (Pol II) general transcription factors (GTFs) that are thought to be critical for formation of preinitiation complexes (PICs) and initiation in vitro were quantified in HAP1 cells using precision nuclear run-on sequencing (PRO-Seq). The average dependencies for each factor across >70 000 promoters varied widely even though levels of depletions were similar. Some of the effects could be attributed to the presence or absence of core promoter elements such as the upstream TBP-specificity motif or downstream G-rich sequences, but some dependencies anti-correlated with such sequences. While depletion of TBP had a large effect on most Pol III promoters only a small fraction of Pol II promoters were similarly affected. TFIIB depletion had the largest general effect on Pol II and also correlated with apparent termination defects downstream of genes. Our results demonstrate that promoter activity is combinatorially influenced by recruitment of TFIID and sequence-specific transcription factors. They also suggest that interaction of the preinitiation complex (PIC) with nucleosomes can affect activity and that recruitment of TFIID containing TBP only plays a positive role at a subset of promoters.

Survival outcomes associated with Lynch syndrome colorectal cancer and metachronous rate after subtotal/total versus segmental colectomy: Meta-analysis.

BACKGROUND: Lynch syndrome is associated with the most common form of heritable bowel cancer. There remains limited level 1 evidence on survival outcomes and rate of metachronous tumor associated with Lynch syndrome colorectal cancer. METHODS: A systematic literature search of original studies was performed on Ovid searching MEDLINE, Embase, Cochrane Database of Systematic Reviews, American College of Physicians ACP Journal Club, Database of Abstracts of Reviews of Effects DARE, and Clinical Trials databases from inception of database to February 2021. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guideline was followed. The data were pooled using a random-effects model. All of the P values were 2-tailed, and statistical analysis was performed using RevMan v. 5.3 Cochrane Collaboration. RESULTS: From 1,942 studies, 15 studies met the inclusion criteria and were included for qualitative and quantitative synthesis. The five-year overall survival was 89.5% (82.0-94.1%), P < .01; I2 = 89%. The ten-year overall survival was 80.5% (68.7-88.6%), P < .01; I2 = 81%. The fifteen-year overall survival was 70% (33.7%-91.5%), P < .01; I2 = 93%. Univariate meta-regression analysis showed no statistically significant difference in 5-year overall survival by sex, age, MLH1, MSH2, MSH6, nor tumor location (right versus left colon). The metachronous tumor rate was 12% to 33% with a follow-up period of up to 15 years, significantly lower in patients who underwent subtotal/total colectomy (0-6%). CONCLUSION: The overall survival of patients with colorectal cancer with Lynch syndrome was approximately 90% at 5 years, 80% at 10 years, and 70% at 15 years. The metachronous tumor rate was approximately 10% to 30% at up to 15 years, significantly improved by subtotal/total colectomy.

3D mesenteric angiogram-based assessment of Arc of Riolan crossing the inferior mesenteric vein: important considerations in high ligation during splenic flexure takedown in anterior resection.

BACKGROUND: Recent studies have described the finding of the Arc of Riolan (AoR) crossing the inferior mesenteric vein (IMV) seen during high ligation of IMV while performing minimally invasive colectomies. However, the AoR usually has a medial course, and this variant AoR anatomic course and the clinical importance of its preservation during splenic flexure takedown in anterior resection remains controversial. METHODS: After institutional approval (QA-5775), radiological identification of and mapping of the vessel horizontally crossing the IMV under the pancreas, when present, was performed at a single institution (Westmead Hospital, New South Wales, Australia). One hundred consecutive computed tomographic (CT) mesenteric angiograms conducted in 2018 were reviewed retrospectively to determine the presence of a vessel horizontally crossing the IMV. 3D reconstructions were used to map out its course to understand its origin and full course. Baseline characteristics, including demographic and comorbidity data, were obtained from the medical record. RESULTS: On 3D mesenteric angiogram reconstructions, a vessel crossing anterior to the IMV was present in 11 of 98 cases (11.2%). Two cases were excluded as the presence of this vessel was indeterminate. Eight of 11 patients (72.7%) were male, and the mean age was 49.3 years (range: 21-80 years). There was no statistically significant difference in age and comorbidities between the groups. Importantly, in all 11 cases, there was an arterial vessel crossing the IMV originating from the SMA and communicating with the IMA or a branch of the IMA, proving definitively that this vessel was by definition the AoR. CONCLUSION: This 3D mesenteric angiogram mapping study has shown definitively that the vessel horizontally crossing anterior to the IMV and inferior to the pancreas is an arterial vessel from the SMA to IMA, and by definition the Arc of Riolan. When present, identification and preservation of this collateral arterial vessel during splenic flexure takedown in anterior resection may be important in reducing the risk of post-operative bowel ischaemia.

Human Cytomegalovirus IE2 Both Activates and Represses Initiation and Modulates Elongation in a Context-Dependent Manner.

Human cytomegalovirus (HCMV) immediate-early 2 (IE2) protein is a multifunctional transcription factor that is essential for lytic HCMV infection. IE2 functions as an activator of viral early genes, negatively regulates its own promoter, and is required for viral replication. The mechanisms by which IE2 executes these distinct functions are incompletely understood. Using PRO-Seq, which profiles nascent transcripts, and a recently developed DFF-chromatin immunoprecipitation (DFF-ChIP; employs chromatin digestion by the endonuclease DNA fragmentation factor prior to IP) approach that resolves occupancy and local chromatin environment, we show that IE2 controls viral gene transcription in three distinct capacities during late HCMV infection and reveal mechanisms that involve direct binding of IE2 to viral DNA. IE2 represses a subset of viral promoters by binding within their core promoter regions and blocking the assembly of preinitiation complexes (PICs). Remarkably, IE2 forms a repressive complex at the major immediate-early promoter region involving direct association of IE2 with nucleosomes and TBP. IE2 stimulates transcription by binding nearby, but not within, core promoter regions. In addition, IE2 functions as a direct roadblock to transcription elongation. At one locus, this function of IE2 appears to be important for the synthesis of a spliced viral RNA. Consistent with the minimal observed effects of IE2 depletion on host gene transcription, IE2 does not functionally engage the host genome. Our results reveal mechanisms of transcriptional control by IE2, uncover a previously unknown function of IE2 as a Pol II elongation modulator, and demonstrate that DFF-ChIP is a useful tool for probing transcription factor occupancy and interactions between transcription factors and nucleosomes at high resolution. IMPORTANCE HCMV infects more than half of the world population and persists lifelong in its hosts. Although generally asymptomatic, HCMV infection can lead to life-threating disease in immunosuppressed individuals. Moreover, HCMV is the leading infectious cause of birth defects in the United States. As there are no vaccines effective against HCMV and antiviral drugs exhibit toxicity and are undermined by resistant HCMV variants, other vulnerabilities in HCMV must be explored. Here, we characterize the mechanism by which IE2 controls transcription during late HCMV infection. We demonstrate that IE2 engages numerous consensus sites across the HCMV genome and functions as an activator, repressor, or elongation modulator depending on the context of IE2 binding sites in relation to Pol II initiation and elongation complexes. Our findings have important implications for the ongoing exploration of IE2 as an antiviral drug target.

Attitudes towards Enhanced Recovery after Surgery (ERAS) interventions in colorectal surgery: nationwide survey of Australia and New Zealand colorectal surgeons.

BACKGROUND: Whilst Enhanced Recovery after Surgery (ERAS) has been widely accepted in the international colorectal surgery community, there remains significant variations in ERAS programme implementations, compliance rates and best practice recommendations in international guidelines. METHODS: A questionnaire was distributed to colorectal surgeons from Australia and New Zealand after ethics approval. It evaluated specialist attitudes towards the effectiveness of specific ERAS interventions in improving short term outcomes after colorectal surgery. The data were analysed using a rating scale and graded response model in item response theory (IRT) on Stata MP, version 15 (StataCorp LP, College Station, TX). RESULTS: Of 300 colorectal surgeons, 95 (31.7%) participated in the survey. Of eighteen ERAS interventions, this study identified eight strategies as most effective in improving ERAS programmes alongside early oral feeding and mobilisation. These included pre-operative iron infusion for anaemic patients (IRT score = 7.82 [95% CI: 6.01-9.16]), minimally invasive surgery (IRT score = 7.77 [95% CI: 5.96-9.07]), early in-dwelling catheter removal (IRT score = 7.69 [95% CI: 5.83-9.01]), pre-operative smoking cessation (IRT score = 7.68 [95% CI: 5.49-9.18]), pre-operative counselling (IRT score = 7.44 [95% CI: 5.58-8.88]), avoiding drains in colon surgery (IRT score = 7.37 [95% CI: 5.17-8.95]), avoiding nasogastric tubes (IRT score = 7.29 [95% CI: 5.32-8.8]) and early drain removal in rectal surgery (IRT score = 5.64 [95% CI: 3.49-7.66]). CONCLUSIONS: This survey has demonstrated the current attitudes of colorectal surgeons from Australia and New Zealand regarding ERAS interventions. Eight of the interventions assessed in this study including pre-operative iron infusion for anaemic patients, minimally invasive surgery, early in-dwelling catheter removal, pre-operative smoking cessation, pre-operative counselling, avoidance of drains in colon surgery, avoiding nasogastric tubes and early drain removal in rectal surgery should be considered an important part of colorectal ERAS programmes.

Current Perspectives on the Importance of Pathological Features in Prognostication and Guidance of Adjuvant Chemotherapy in Colon Cancer.

There is not a clear consensus on which pathological features and biomarkers are important in guiding prognosis and adjuvant therapy in colon cancer. The Pathology in Colon Cancer, Prognosis and Uptake of Adjuvant Therapy (PiCC UP) Australia and New Zealand questionnaire was distributed to colorectal surgeons, medical oncologists and pathologists after institutional board approval. The aim of this study was to understand current specialist attitudes towards pathological features in the prognostication of colon cancer and adjuvant therapy in stage II disease. A 5-scale Likert score was used to assess attitudes towards 23 pathological features for prognosis and 18 features for adjuvant therapy. Data were analysed using a rating scale and graded response model in item response theory (IRT) on STATA (Stata MP, version 15; StataCorp LP). One hundred and sixty-four specialists (45 oncologists, 86 surgeons and 33 pathologists) participated. Based on IRT modelling, the most important pathological features for prognosis in colon cancer were distant metastases, lymph node metastases and liver metastases. Other features seen as important were tumour rupture, involved margin, radial margin, CRM, lymphovascular invasion and grade of differentiation. Size of tumour, location, lymph node ratio and EGFR status were considered less important. The most important features in decision making for adjuvant therapy in stage II colon cancer were tumour rupture, lymphovascular invasion and microsatellite instability. BRAF status, size of tumour, location, tumour budding and tumour infiltrating lymphocytes were factored as lesser importance. Biomarkers such as CDX2, EGFR, KRAS and BRAF status present areas for further research to improve precision oncology. This study provides the most current status on the importance of pathological features in prognostication and recommendations for adjuvant therapy in Australia and New Zealand. Results of this nationwide study may be useful to help in guiding prognosis and adjuvant treatment in colon cancer.

Episodic Plate Tectonics on Europa: Evidence for Widespread Patches of Mobile-Lid Behavior in the Antijovian Hemisphere.

A nearly pole-to-pole survey near 140°E longitude on Europa revealed many areas that exhibit past lateral surface motions, and these areas were examined to determine whether the motions can be described by systems of rigid plates moving across Europa's surface. Three areas showing plate-like behavior were examined in detail to determine the sequence of events that deformed the surface. All three areas were reconstructed to reveal the original pre-plate motion surfaces by performing multi-stage rotations of plates in spherical coordinates. Several motions observed along single plate boundaries were also noted in previous works, but this work links together isolated observations of lateral offsets into integrated systems of moving plates. Not all of the surveyed surface could be described by systems of rigid plates. There is evidence that the plate motions did not all happen at the same time, and that they are not happening today. We conclude that plate tectonic-like behavior on Europa occurs episodically, in limited regions, with less than 100 km of lateral motion accommodated along any particular boundary before plate motions cease. Europa may represent a world perched on the theoretical boundary between stagnant and mobile lid convective behavior, or it may represent an additional example of the wide variations in possible planetary convective regimes. Differences in observed strike-slip sense and plate rotation directions between the northern and southern hemispheres raise the question of whether tidal forces may influence plate motions.

Pathological Features and Prognostication in Colorectal Cancer.

The prognostication of colorectal cancer (CRC) has traditionally relied on staging as defined by the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM staging classifications. However, clinically, there appears to be differences in survival patterns independent of stage, suggesting a complex interaction of stage, pathological features, and biomarkers playing a role in guiding prognosis, risk stratification, and guiding neoadjuvant and adjuvant therapies. Histological features such as tumour budding, perineural invasion, apical lymph node involvement, lymph node yield, lymph node ratio, and molecular features such as MSI, KRAS, BRAF, and CDX2 may assist in prognostication and optimising adjuvant treatment. This study provides a comprehensive review of the pathological features and biomarkers that are important in the prognostication and treatment of CRC. We review the importance of pathological features and biomarkers that may be important in colorectal cancer based on the current evidence in the literature.

Optimal Isolation Protocols for Examining and Interrogating Mononuclear Phagocytes From Human Intestinal Tissue.

The human intestine contains numerous mononuclear phagocytes (MNP), including subsets of conventional dendritic cells (cDC), macrophages (Mf) and monocytes, each playing their own unique role within the intestinal immune system and homeostasis. The ability to isolate and interrogate MNPs from fresh human tissue is crucial if we are to understand the role of these cells in homeostasis, disease settings and immunotherapies. However, liberating these cells from tissue is problematic as many of the key surface identification markers they express are susceptible to enzymatic cleavage and they are highly susceptible to cell death. In addition, the extraction process triggers immunological activation/maturation which alters their functional phenotype. Identifying the evolving, complex and highly heterogenous repertoire of MNPs by flow cytometry therefore requires careful selection of digestive enzyme blends that liberate viable cells and preserve recognition epitopes involving careful selection of antibody clones to enable analysis and sorting for functional assays. Here we describe a method for the anatomical separation of mucosa and submucosa as well as isolating lymphoid follicles from human jejunum, ileum and colon. We also describe in detail the optimised enzyme digestion methods needed to acquire functionally immature and biologically functional intestinal MNPs. A comprehensive list of screened antibody clones is also presented which allows for the development of high parameter flow cytometry panels to discriminate all currently identified human tissue MNP subsets including pDCs, cDC1, cDC2 (langerin+ and langerin-), newly described DC3, monocytes, Mf1, Mf2, Mf3 and Mf4. We also present a novel method to account for autofluorescent signal from tissue macrophages. Finally, we demonstrate that these methods can successfully be used to sort functional, immature intestinal DCs that can be used for functional assays such as cytokine production assays.

Association between physiological performance and short temporal changes in habitat utilisation modulated by environmental factors.

Temporal environmental variability causes behavioural and physiological responses in organisms that can affect their spatial location in time, and ultimately drive changes in population and community dynamics. Linking ecological changes with underlying environmental drivers is a complex task that can however be facilitated through the integration of physiology. Our overarching aim was to investigate the association between physiological performance and habitat utilisation patterns modulated by short temporal fluctuations in environmental factors. We used in situ monitoring data from a system experiencing extreme environmental fluctuations over a few hours and we selected four fish species with different habitat utilisation patterns across dissolved oxygen (DO) fluctuations: two commonly observed species (Siganus lineatus and Acanthopagrus pacificus), including at low DO (40 and 50% saturation, respectively), and two reef species (Heniochus acuminatus and Chaetodon vagabundus) never recorded below 70% saturation. We hypothesised that these patterns were associated to species' physiological performance in hypoxia. Therefore, we measured different metabolic variables (O2crit, incipient lethal oxygen (ILO), time to ILO, index of cumulative ambient oxygen deficit (O2deficit), maximum oxygen supply capacity (α)) using respirometry. Physiological performance differed among species and was intrinsically associated to habitat use patterns. S. lineatus had a lower O2crit than H. acuminatus, A. pacificus and C. vagabundus (13, 18.7, 20 and 20.2% saturation respectively). Additionally, S. lineatus and A. pacificus displayed better capacity for survival below O2crit than C. vagabundus and H. acuminatus (lower ILO, higher O2deficit and longer time to ILO) and higher α. Field monitoring data revealed that DO temporarily falls below species' O2crit and even ILO on most days, suggesting that short temporal variability in DO likely forces species to temporarily avoid harmful conditions, driving important changes in ecosystem structure over a few hours. Our results support the hypothesis that organismal physiology can provide insights into ecological changes occurring over a few hours as a result of environmental variability. Consequently, integrating physiology with ecological data at relevant temporal scales may help predict temporal shifts in ecosystems structure and functions to account for ecological patterns often overlooked and difficult to identify.

Cytomegalovirus late transcription factor target sequence diversity orchestrates viral early to late transcription.

Beta- and gammaherpesviruses late transcription factors (LTFs) target viral promoters containing a TATT sequence to drive transcription after viral DNA replication has begun. Human cytomegalovirus (HCMV), a betaherpesvirus, uses the UL87 LTF to bind both TATT and host RNA polymerase II (Pol II), whereas the UL79 LTF has been suggested to drive productive elongation. Here we apply integrated functional genomics (dTag system, PRO-Seq, ChIP-Seq, and promoter function assays) to uncover the contribution of diversity in LTF target sequences in determining degree and scope to which LTFs drive viral transcription. We characterize the DNA sequence patterns in LTF-responsive and -unresponsive promoter populations, determine where and when Pol II initiates transcription, identify sites of LTF binding genome-wide, and quantify change in nascent transcripts from individual promoters in relation to core promoter sequences, LTF loss, stage of infection, and viral DNA replication. We find that HCMV UL79 and UL87 LTFs function concordantly to initiate transcription from over half of all active viral promoters in late infection, while not appreciably affecting host transcription. Both LTFs act on and bind to viral early-late and late kinetic-class promoters. Over one-third of these core promoters lack the TATT and instead have a TATAT, TGTT, or YRYT. The TATT and non-TATT motifs are part of a sequence block with a sequence code that correlates with promoter transcription level. LTF occupancy of a TATATA palindrome shared by back-to-back promoters is linked to bidirectional transcription. We conclude that diversity in LTF target sequences shapes the LTF-transformative program that drives the viral early-to-late transcription switch.

Non-operative management of small post-appendicectomy intra-abdominal abscess is safe and effective.

BACKGROUND: Intra-abdominal abscess (IAA) post-appendicectomy occurs in 1.4-4.4% of cases. Non-operative management of small (<4 cm) post-appendicectomy IAA in children is well established, but minimal evidence exists in adults. Percutaneous catheter drainage is considered standard treatment for IAA, yet outcome data for post-appendicectomy IAA are sparse. The aims of this study were to assess the effectiveness of non-operative management of small (<4 cm diameter) IAA and the outcomes of percutaneous drainage for larger (>4 cm) IAA post-appendicectomy. METHODS: A retrospective case note review of a series of patients with a post-appendicectomy IAA between 2006 and 2017 was conducted. IAAs were treated selectively; small (<4 cm) IAAs were managed non-operatively and larger IAAs were managed with percutaneous drainage . RESULTS: A total of 4901 patients had an appendicectomy. Forty-two (0.9%) developed a post-operative IAA. Sixteen (38%) had a percutaneous drainage and 26 (62%) had non-operative management. The percutaneous drainage group had a higher proportion of complicated appendicitis (75%) compared to the non-operative group (42%, P = 0.04). The percutaneous drainage group had a significantly higher leucocytosis (P = 0.01) and C-reactive protein (P = 0.02). All patients managed non-operatively resolved without the need for invasive procedures. In the percutaneous drainage group, six had aspiration alone, nine had a percutaneous drain and one was abandoned. Three required repeat percutaneous drainage and four (25%) required operative drainage. Seven patients (34%) of the percutaneous drainage group had grade II or III complications. CONCLUSION: This case series study provides support that small (<4 cm) IAA post-appendicectomy can be safely and effectively managed non-operatively.

Human cytomegalovirus IE2 drives transcription initiation from a select subset of late infection viral promoters by host RNA polymerase II.

Herpesvirus late promoters activate gene expression after viral DNA synthesis has begun. Alphaherpesviruses utilize a viral immediate-early protein to do this, whereas beta- and gammaherpesviruses primarily use a 6-member set of viral late-acting transcription factors (LTF) that are drawn to a TATT sequence in the late promoter. The betaherpesvirus, human cytomegalovirus (HCMV), produces three immediate-early 2 protein isoforms, IE2-86, IE2-60, IE2-40, late in infection, but whether they activate late viral promoters is unknown. Here, we quickly degrade the IE2 proteins in late infection using dTag methodology and analyze effects on transcription using customized PRO-Seq and computational methods combined with multiple validation methods. We discover that the IE2 proteins selectively drive RNA Pol II transcription initiation at a subset of viral early-late and late promoters common to different HCMV strains, but do not substantially affect Pol II transcription of the 9,942 expressed host genes. Most of the IE2-activated viral late infection promoters lack the TATT sequence bound by the HCMV UL87-encoded LTF. The HCMV TATT-binding protein is not mechanistically involved in late RNA expression from the IE2-activated TATT-less UL83 (pp65) promoter, as it is for the TATT-containing UL82 (pp71) promoter. While antecedent viral DNA synthesis is necessary for transcription from the late infection viral promoters, continued viral DNA synthesis is unnecessary. We conclude that in late infection the IE2 proteins target a distinct subset of HCMV early-late and late promoters for transcription initiation by RNA Pol II. Commencement of viral DNA replication renders the HCMV genome late promoters susceptible to late-acting viral transcription factors.

Biological Contamination Prevention for Outer Solar System Moons of Astrobiological Interest: What Do We Need to Know?

To ensure that scientific investments in space exploration are not compromised by terrestrial contamination of celestial bodies, special care needs to be taken to preserve planetary conditions for future astrobiological exploration. Significant effort has been made and is being taken to address planetary protection in the context of inner Solar System exploration. In particular for missions to Mars, detailed internationally accepted guidelines have been established. For missions to the icy moons in the outer Solar System, Europa and Enceladus, the planetary protection requirements are so far based on a probabilistic approach and a conservative estimate of poorly known parameters. One objective of the European Commission-funded project, Planetary Protection of Outer Solar System, was to assess the existing planetary protection approach, to identify inherent knowledge gaps, and to recommend scientific investigations necessary to update the requirements for missions to the icy moons.

The NASA Roadmap to Ocean Worlds.

In this article, we summarize the work of the NASA Outer Planets Assessment Group (OPAG) Roadmaps to Ocean Worlds (ROW) group. The aim of this group is to assemble the scientific framework that will guide the exploration of ocean worlds, and to identify and prioritize science objectives for ocean worlds over the next several decades. The overarching goal of an Ocean Worlds exploration program as defined by ROW is to "identify ocean worlds, characterize their oceans, evaluate their habitability, search for life, and ultimately understand any life we find." The ROW team supports the creation of an exploration program that studies the full spectrum of ocean worlds, that is, not just the exploration of known ocean worlds such as Europa but candidate ocean worlds such as Triton as well. The ROW team finds that the confirmed ocean worlds Enceladus, Titan, and Europa are the highest priority bodies to target in the near term to address ROW goals. Triton is the highest priority candidate ocean world to target in the near term. A major finding of this study is that, to map out a coherent Ocean Worlds Program, significant input is required from studies here on Earth; rigorous Research and Analysis studies are called for to enable some future ocean worlds missions to be thoughtfully planned and undertaken. A second finding is that progress needs to be made in the area of collaborations between Earth ocean scientists and extraterrestrial ocean scientists.

Building New York State Centers of Excellence in Children's Environmental Health: A Replicable Model in a Time of Uncertainty.

Public health programs may be seriously affected in periods of federal retrenchment. During these times, state-based strategies provide an alternate pathway for advancing public health.A 12-year campaign to secure state support for a network of Centers of Excellence in Children's Environmental Health (CEH) promoting health of children across New York State is described. It was driven by rising rates of asthma, birth defects, developmental disorders, and other noncommunicable diseases in children; growing evidence associating hazardous environmental exposures with these conditions; and recognition that federal resources in CEH are insufficient.Critical campaign elements were (1) formation of a statewide coalition of academic health centers, health care providers, public health officials, community advocates, and other stakeholders; (2) bipartisan collaborations with legislative champions and government leaders; (3) assessment of the burden of developmental disorders and noncommunicable diseases associated with environmental exposures among children; (4) maps documenting the presence of environmental hazards in every county statewide; (5) iterative charting of a changing political landscape; and (6) persistence. The 2017 award of a 5-year, $10 million contract to establish Centers of Excellence in CEH demonstrates the value of this statewide strategy.