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Acute myeloid leukemia (AML) is fueled by leukemic stem cells (LSC) whose determinants are challenging to discern from hematopoietic stem cells (HSC) or uncover by approaches focused on general cell properties. We have identified a set of RNA-binding proteins (RBP) selectively enriched in human AML LSCs. Using an in vivo two-step CRISPR-Cas9 screen to assay stem cell functionality, we found 32 RBPs essential for LSCs in MLL-AF9;NrasG12D AML. Loss-of-function approaches targeting key hit RBP ELAVL1 compromised LSC-driven in vivo leukemic reconstitution, and selectively depleted primitive malignant versus healthy cells. Integrative multiomics revealed differentiation, splicing, and mitochondrial metabolism as key features defining the leukemic ELAVL1–mRNA interactome with mitochondrial import protein, TOMM34, being a direct ELAVL1-stabilized target whose repression impairs AML propagation. Altogether, using a stem cell–adapted in vivo CRISPR screen, this work demonstrates pervasive reliance on RBPs as regulators of LSCs and highlights their potential as therapeutic targets in AML. Significance: LSC-targeted therapies remain a significant unmet need in AML. We developed a stem-cell–adapted in vivo CRISPR screen to identify key LSC drivers. We uncover widespread RNA-binding protein dependencies in LSCs, including ELAVL1, which we identify as a novel therapeutic vulnerability through its regulation of mitochondrial metabolism. This article is highlighted in the In This Issue feature, p. 171

A promising direction in the research on Alzheimer’s Disease (AD) is the identification of biomarkers that better inform the disease progression of AD. However, the performance of amyloid-based biomarkers in predicting cognitive performance has been shown to be suboptimal. We hypothesise that neuronal loss could better inform cognitive impairment. We have utilised the 5xFAD transgenic mouse model that displays AD pathology at an early phase, already fully manifested after 6 months. We have evaluated the relationships between cognitive impairment, amyloid deposition, and neuronal loss in the hippocampus in both male and female mice. We observed the onset of disease characterized by the emergence of cognitive impairment in 6-month-old 5xFAD mice coinciding with the emergence of neuronal loss in the subiculum, but not amyloid pathology. We also showed that female mice exhibited significantly increased amyloid deposition in the hippocampus and entorhinal cortex, highlighting sex-related differences in the amyloid pathology of this model. Therefore, parameters based on neuronal loss might more accurately reflect disease onset and progression compared to amyloid-based biomarkers in AD patients. Moreover, sex-related differences should be considered in studies involving 5xFAD mouse models.

Lithium metal anode holds great promises for next-generation battery technologies but is notoriously difficult to work with. The key to solving this challenge is believed to lie in the ability of forming stable solid-electrolyte interphase (SEI) layers. To further address potential safety issues, it is critical to achieve this goal in nonflammable electrolytes. Building upon previous successes in forming stable SEI in conventional carbonate-based electrolytes, here we report that reversible Li stripping/plating could be realized in triethyl phosphate (TEP), a known flame retardant. The critical enabling factor of our approach was the introduction of oxygen, which upon electrochemical reduction induces the initial decomposition of TEP and produces Li3 PO4 and poly-phosphates. Importantly, the reaction was self-limiting, and the resulting material regulated Li plating by limiting dendrite formation. In effect, we obtained a functional SEI on Li metal in a nonflammable electrolyte. When tested in a symmetric Li∥Li cell, more than 300 cycles of stripping/plating were measured at a current density of 0.5 mA cm-2 . Prototypical Li-O2 and Li-ion batteries were also fabricated and tested to further support the effectiveness of this strategy. The mechanism by which the SEI forms was studied by density functional theory (DFT), and the predictions were corroborated by the successful detection of the intermediates and products.

The incompatibility between the anode and the cathode chemistry limits the used of Mg as an anode. This issue may be addressed by separating the anolyte and the catholyte with a membrane that only allows for Mg2+ transport. Mg-MOF-74 thin films were used as the separator for this purpose. It was shown to meet the needs of low-resistance, selective Mg2+ transport. The uniform MOF thin films supported on Au substrate with thicknesses down to ca. 202 nm showed an intrinsic resistance as low as 6.4 Ω cm2 , with the normalized room-temperature ionic conductivity of ca. 3.17×10-6 S cm-1 . When synthesized directly onto a porous anodized aluminum oxide (AAO) support, the resulting films were used as a standalone membrane to permit stable, low-overpotential Mg striping and plating for over 100 cycles at a current density of 0.05 mA cm-2 . The film was effective in blocking solvent molecules and counterions from crossing over for extended period of time.

Introduction COVID19 has stressed and stretched healthcare resources to the limit, thus the rational deployment of any resource should be necessary and of patient benefit. This retrospective audit aims to ascertain if a policy of two valid group and save tests prior to transurethral prostate surgery is necessary and if this resource can be redistributed safely during the ongoing pandemic. Methods A retrospective review of electronic patient records for patients that underwent transurethral prostate surgery from June 2017 to June 2018. During a single admission for surgery it was identified how many pre-operative group and save tests, and if a post-operative blood transfusion patients underwent. Results 146 patients underwent transurethral prostate surgery between June 2017 to June 2018. 97 patients had two valid group and save tests prior to surgery. 49 patients did not have 2 valid group and save tests. 21 patients had expired tests, 20 had only one valid sample, and 8 had no group and save test at all. No patient underwent a blood transfusion during their admission for transurethral prostate surgery. Conclusion This single centre study illustrates pre-operative group and save tests before transurethral prostate surgery are unnecessary as no patient required an associated blood transfusion during admission; and can safely be omitted. The clinical time and resource could be redirected elsewhere for greater patient benefit. £2855.00 of efficiency savings could be made foregoing unneeded group and save tests. A policy omitting pre-operative group and save before transurethral prostate surgery will be implemented under COVID19 pandemic conditions and re-audited in 6 months.

Background The 2019 coronavirus disease (COVID-19) has become a global pandemic and the published literature describing the virus has grown exponentially. Methods We conducted a systematic review of the literature to identify the symptoms, comorbidities present, radiological features and outcomes for adults testing positive for COVID-19 admitted to hospital. The results across multiple studies were numerically pooled to yield total estimated. Results A total of 45 studies were included in this review with 14 358 adult participants (average age 51 years, male 51%). The pooled findings suggest that the most common symptom among patients was fever (81.2%) followed by cough (62.9%), fatigue (38.0%) and anorexia/loss of appetite (33.7%). The comorbidities that were most prevalent among patients with the virus were hypertension (19.1%), cardiovascular disease (17.9%), endocrine disorder (9.3%) and diabetes (9.2%). Abnormal chest X-ray findings were present in 27.7% of patients and ground-glass opacity was demonstrated on chest computerized tomography in 63.0% of patients. The most frequent adverse outcomes were acute respiratory distress syndrome (27.4%), acute cardiac injury (16.2%) and acute kidney injury (12.6%). Death occurred in 8.2% of patients and 16.3% required intensive care admission and 11.7% had mechanical ventilation. Bacterial or secondary infections affected 8.5% of patients and 6.9% developed shock. Conclusions COVID-19 most commonly presents with fever, cough, fatigue and anorexia and among patients with existing hypertension and cardiovascular disease. It is important as serious adverse outcomes can develop such as acute respiratory distress syndrome, acute cardiac injury, acute kidney injury and death.

Our hospital’s reference range for phosphate is 0.85–1.45 mmol/L. Oral replacement is generally adequate for mild and moderate hypophosphataemia >0.3 mmol/L).[1,2][1] Intravenous (IV) phosphate replacement carries many potential side effects and is therefore given for severe hypophosphataemia (<

Summary Clinical challenges exist in the management of hospitalized patients returning to the UK with potential Middle East respiratory syndrome coronavirus (MERS-CoV) infection, particularly with its clinical overlap with influenza, as demonstrated in this case-series and cost-analysis review of returning Hajj pilgrims. These patients were hospitalized with acute febrile respiratory illness, initially managed as potential MERS-CoV infections, but were eventually diagnosed with influenza. Additional costs were small, yet enhanced infection prevention measures created significant burdens on isolation rooms and staff time. Planning for predictable events such as Hajj is important for resource management. Here, in-house MERS-CoV diagnostic testing would have facilitated earlier diagnosis and discharge.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is a novel epidemic strain of Betacoronavirus that is responsible for the current viral pandemic, coronavirus disease 2019 (COVID-19), a global health crisis. Other epidemic Betacoronaviruses include the 2003 SARS-CoV-1 and the 2009 Middle East Respiratory Syndrome Coronavirus (MERS-CoV), the genomes of which, particularly that of SARS-CoV-1, are similar to that of the 2019 SARS-CoV-2. In this extensive review, we document the most recent information on Coronavirus proteins, with emphasis on the membrane proteins in the Coronaviridae family. We include information on their structures, functions, and participation in pathogenesis. While the shared proteins among the different coronaviruses may vary in structure and function, they all seem to be multifunctional, a common theme interconnecting these viruses. Many transmembrane proteins encoded within the SARS-CoV-2 genome play important roles in the infection cycle while others have functions yet to be understood. We compare the various structural and nonstructural proteins within the Coronaviridae family to elucidate potential overlaps and parallels in function, focusing primarily on the transmembrane proteins and their influences on host membrane arrangements, secretory pathways, cellular growth inhibition, cell death and immune responses during the viral replication cycle. We also offer bioinformatic analyses of potential viroporin activities of the membrane proteins and their sequence similarities to the Envelope (E) protein. In the last major part of the review, we discuss complement, stimulation of inflammation, and immune evasion/suppression that leads to CoV-derived severe disease and mortality. The overall pathogenesis and disease progression of CoVs is put into perspective by indicating several stages in the resulting infection process in which both host and antiviral therapies could be targeted to block the viral cycle. Lastly, we discuss the development of adaptive immunity against various structural proteins, indicating specific vulnerable regions in the proteins. We discuss current CoV vaccine development approaches with purified proteins, attenuated viruses and DNA vaccines.

Recent studies emphasize how prosocial religious beliefs promote behaviors that lead to success in intergroup competition. We extend this research by introducing the Prosocial Religion as a Resourc...

Recent research on the Uses of the Past and Rhetorical History (Argyres, De Massis, Foss, Frattini, Jones, and Silverman, 2019) has shown that historical narratives can be powerful and persuasive t...

In most cities, taxis play an important role in providing point-to-point transportation service. If the taxi service is reliable, responsive, and cost-effective, past studies show that taxi-like services can be a viable choice in replacing a significant amount of private cars. However, making taxi services efficient is extremely challenging, mainly due to the fact that taxi drivers are self-interested and they operate with only local information. Although past research has demonstrated how recommendation systems could potentially help taxi drivers in improving their performance, most of these efforts are not feasible in practice. This is mostly due to the lack of both the comprehensive data coverage and an efficient recommendation engine that can scale to tens of thousands of drivers. In this paper, we propose a comprehensive working platform called the Driver Guidance System (DGS). With real-time citywide taxi data provided by our collaborator in Singapore, we demonstrate how we can combine real-time data analytics and large-scale optimization to create a guidance system that can potentially benefit tens of thousands of taxi drivers. Via a realistic agent-based simulation, we demonstrate that drivers following DGS can significantly improve their performance over ordinary drivers, regardless of the adoption ratios. We have concluded our system designing and building and have recently entered the field trial phase.

Hemophagocytic lymphohistiocytosis (HLH) is rare and life-threatening medical emergency. Parvovirus infection is rarely associated with HLH. We report a case of parvovirus-related HLH in a patient with alpha thalassaemia (HbH disease). The patient responded well to a course of dexamethasone without the need of etoposide. Based on our literature search, this is the first case of parvovirus related HLH in a patient with HbH disease in the medical literature.

Introduction This study aimed to assess training of Senior House Officer-grade equivalent doctors in postgraduate surgical training or service (SHO-DIPST) in surgical specialties across the United Kingdom (UK), against nationally agreed Joint Committee on Surgical Training Quality Indicators (JCST QIs). Specific recommendations are made, with a view to improving quality of training, workforce retention and recruitment to Higher Surgical Training. Method Prospective, observational, multicentre study conducted by the Association of Surgeons in Training, using the UK National Research Collaborative model. Any centres in the UK providing acute surgical services were eligible. SHO-DIPST with a permanent contract, on out-of-hours ‘on-call rota' were included across four, one-week data capture periods (September to October 2016, February to March 2017). Adherence to five quality indicators was reported using descriptive statistics. P-values were calculated using Student's t-test for continuous data, with a 5% level of significance. Results 2569 SHO-DIPST were included from all ten surgical specialties in 141 NHS trusts across all 16 Local Education and Training Boards in the UK. 960 SHO-DIPST were in registered ‘training' posts (37.3%). The median number of SHO-DIPST per rota was 7.0 (IQR 5.0–9.0). Adherence to the five included JCST QIs ranged from 6.0 to 53.1%. Only four SHO-DIPST posts across the study population met all five JCST QIs (0.3%). The total number of training sessions was higher for those in registered training posts (p Conclusions Only four early years postgraduate surgical training posts in the UK meet nationally approved minimum quality standards. Specific recommendations are made to improve training in this cohort and to bolster recruitment and retention into Higher Surgical Training.

How is rhetorical history used to legitimate new industries that are considered morally dubious or even reprehensible by many stakeholders? This paper seeks to answer this question and in so doing ...

The reaction yields strongly depend on the electronic nature of the aryl sulfonamide as well as of the aryl bromides employed.

Pyruvate kinase M2 (PKM2) is essential for aerobic glycolysis, the dominant metabolic pathway utilized by cancer cells. To determine the association of PKM2 with prostate cancer (PC), we examined 29 primary PC and three lymph node metastatic tumors; elevation of PKM2 was observed in Gleason 8-10 tumors compared to Gleason 6-7 carcinomas. High PKM2 was detected by immunohistochemistry in more aggressive xenograft tumors derived from PC stem-like cells (PCSCs) compared to those produced from non-PCSCs. While PCSCs and non-PCSCs expressed comparable levels of PKM2, distinct posttranslational modifications were observed. Collectively, upregulation and specific modification to PKM2 associate with PC progression.

A regioselective C—H activation approach is used to prepare biologically relevant title compounds.