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يقدم الكتاب الطريقة الأمثل للتعامل في بورصات الأسهم وهي التي استطاع من خلالها وارن بافيت تحقيق أرباح قدرها 42 مليار دولار ويمكن تلخيص تلك الطريق في تحديد الشركات شديدة التميز ذات التاريخ الطويل في تحقيق الأرباح والتى تديرها إدارات قوية ومتميزة وانتظار تدهور أسعار أسهم تلك الشركات مع الهبوط الشديد في الأسواق وعندئذ يتم شرائها … ثم الانتظار لبضعة سنوات لحين ارتفاع البورصه وعندئذ يتم البيع وفي ذلك الحين تكون قيمة الأسهم تضاعفت عدة مرات.

Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early-phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR/Cas9 screens implicated decreased translation initiation as protective following GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to the effects of GSPT1 degradation. We defined 2 Crbn amino acids that prevent Gspt1 degradation in mice, generated a knockin mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant acute myeloid leukemia.

Background The Northern Territory (NT) has the highest levels of alcohol consumption and harms in Australia. Since the creation of the NT Liquor Act 1978, which came into effect in 1979, numerous legislated alcohol policies have been introduced to attempt to address these harms. We present a narrative historical overview of alcohol policies implemented in the NT from 1979 to 2021. Methods Using scoping review methodology, databases were searched from 1979 to 2021. Of 506 articles screened, 34 met inclusion criteria. Reference lists of all included articles were searched, resulting in the inclusion of another 41 articles and reports, totalling 75 final documents. Policies were organised using Babor and colleagues (2010) established framework: 1. pricing/ taxation; 2. regulating physical availability; 3. modifying drinking environments; 4. drink-driving countermeasures; 5. restrictions on marketing; 6. education/persuasion; 7. treatment/early intervention. Results Two pricing/taxation policies have been implemented, Living With Alcohol (LWA) and Minimum Unit Price, both demonstrating evidence of positive effects on health and consumption outcomes. Eight policies approaches have focused on regulating physical availability, implemented at both individual and local area levels. Several of these policies have varied by location and been amended over time. There is some evidence demonstrating reduction in harms attributable to Liquor Supply Plans, localised restrictions, and General Restricted Areas, although these have been site specific. Of the three policies which targeted modifying the drinking environment; one was evaluated, finding a relocation of social harms, rather than a reduction. The literature outlines a range of controversies, particularly regarding policies in domain 2–3, including racial discrimination and a lack of policy stability. No policies relating to restricting marketing or education/persuasion programs were found. The only drink-driving legislated policy was considered to have contributed to the success of the LWA program. Three policies relating to treatment were described; two were not evaluated and evidence showed no ongoing benefits of Alcohol Mandatory Treatment. Discussion The NT has implemented a large number of alcohol policies, several of which have evidence of positive effects. However, these policies have often existed in a context of clear politicisation of alcohol policy, frequently with an implicit focus on Aboriginal people’s consumption.

PPM1D encodes a serine/threonine phosphatase that regulates numerous pathways including the DNA damage response and p53. Activating mutations and amplification of PPM1D are found across numerous cancer types. GSK2830371 is a potent and selective allosteric inhibitor of PPM1D, but its mechanism of binding and inhibition of catalytic activity are unknown. Here we use computational, biochemical and functional genetic studies to elucidate the molecular basis of GSK2830371 activity. These data confirm that GSK2830371 binds an allosteric site of PPM1D with high affinity. By further incorporating data from hydrogen deuterium exchange mass spectrometry and sedimentation velocity analytical ultracentrifugation, we demonstrate that PPM1D exists in an equilibrium between two conformations that are defined by the movement of the flap domain, which is required for substrate recognition. A hinge region was identified that is critical for switching between the two conformations and was directly implicated in the high-affinity binding of GSK2830371 to PPM1D. We propose that the two conformations represent active and inactive forms of the protein reflected by the position of the flap, and that binding of GSK2830371 shifts the equilibrium to the inactive form. Finally, we found that C-terminal truncating mutations proximal to residue 400 result in destabilization of the protein via loss of a stabilizing N- and C-terminal interaction, consistent with the observation from human genetic data that nearly all PPM1D mutations in cancer are truncating and occur distal to residue 400. Taken together, our findings elucidate the mechanism by which binding of a small molecule to an allosteric site of PPM1D inhibits its activity and provides insights into the biology of PPM1D. In this work, the authors report a sophisticated combination of genetic, biophysical, and biochemical analyses to identifies the cycling conformational states of PPM1D. The findings reveal how an allosteric inhibitor locks the protein into a conformationally inactive state, and explain the distribution of PPM1D activating mutations in cancer.

To investigate awareness of short‐term and long‐term consequences of alcohol use among a sample of Australian adult drinkers. Demographic correlates of the awareness of each consequence were also explored. Participants aged 18–45 years (n=1,061; mean age=33.2 years) drawn from an online panel completed a web‐based survey assessing demographics, awareness of alcohol warning labels, and awareness of seven short‐term and 12 long‐term consequences of alcohol use. The level of awareness of short‐ and long‐term consequences ranged from 16% (breast cancer) to 69% (low coordination and slower reflexes). The study found consistent differences in awareness of consequences by gender, with some differences for specific consequences by age, education, SES, rurality and awareness of alcohol warning labels. Most consumers lack a sufficient understanding of the potential consequences of alcohol use. Particular subgroups of drinkers may not equate drinking with negative consequences. Front‐of‐label alcohol warnings on all products and public health and education campaigns presenting messages targeting subgroups of drinkers could increase awareness of short‐ and long‐term negative health and social effects of alcohol use.

Background Alcohol-related harm is a substantial burden on the community in Australia and internationally, particularly harm related to risky drinking practices of young people in the night-time economy. This protocol paper describes a study that will report on the changes in a wide range of health and justice outcome measures associated with major policy changes in the state of Queensland, Australia. A key element includes trading hours restrictions for licensed premises to 2 am for the state and 3 am in Safe Night Precincts (SNPs). Other measures introduced include drinks restrictions after midnight, increased patron banning measures for repeat offenders, mandatory ID scanning of patrons in late-night venues, and education campaigns. Methods The primary aim of the study is to evaluate change in the levels of harm due to these policy changes using administrative data (e.g., police, hospital, ambulance, and court data). Other study elements will investigate the impact of the Policy by measuring foot traffic volume in SNPs, using ID scanner data to quantify the volume of people entering venues and measure the effectiveness of banning notices, using patron interviews to quantify the levels of pre-drinking, intoxication and illicit drug use within night-time economy districts, and to explore the impacts of the Policy on business and live music, and costs to the community. Discussion The information gathered through this project aims to evaluate the effectiveness of the Policy and to draw on these findings to inform future prevention and enforcement approaches by policy makers, police, and venue staff.

TP53, which encodes the tumor suppressor p53, is the most frequently mutated gene in human cancer. The selective pressures shaping its mutational spectrum, dominated by missense mutations, are enigmatic, and neomorphic gain-of-function (GOF) activities have been implicated. We used CRISPR-Cas9 to generate isogenic human leukemia cell lines of the most common TP53 missense mutations. Functional, DNA-binding, and transcriptional analyses revealed loss of function but no GOF effects. Comprehensive mutational scanning of p53 single–amino acid variants demonstrated that missense variants in the DNA-binding domain exert a dominant-negative effect (DNE). In mice, the DNE of p53 missense variants confers a selective advantage to hematopoietic cells on DNA damage. Analysis of clinical outcomes in patients with acute myeloid leukemia showed no evidence of GOF for TP53 missense mutations. Thus, a DNE is the primary unit of selection for TP53 missense mutations in myeloid malignancies.

Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets 1 – 3 , but a substantial subset of proteins are resistant to targeted degradation using existing approaches 4 , 5 . Here we report an alternative mechanism of targeted protein degradation, in which a small molecule induces the highly specific, reversible polymerization of a target protein, followed by its sequestration into cellular foci and subsequent degradation. BI-3802 is a small molecule that binds to the Broad-complex, Tramtrack and Bric-à-brac (BTB) domain of the oncogenic transcription factor B cell lymphoma 6 (BCL6) and leads to the proteasomal degradation of BCL6 6 . We use cryo-electron microscopy to reveal how the solvent-exposed moiety of a BCL6-binding molecule contributes to a composite ligand–protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology. Binding of the small molecule BI-3802 to the oncogenic transcription factor B cell lymphoma 6 (BCL6) induces polymerization of BCL6, leading to its ubiquitination by SIAH1 and proteasomal degradation.

Acute alcohol intoxication impairs cognitive and psychomotor abilities leading to various public health hazards such as road traffic accidents and alcohol-related violence. Intoxicated individuals are usually identified by measuring their blood alcohol concentration (BAC) using breathalyzers that are expensive and labor intensive. In this paper, we developed the Audio-based Deep Learning Algorithm to Identify Alcohol Inebriation (ADLAIA) that can instantly predict an individual's intoxication status based on a 12-s recording of their speech. ADLAIA was trained on a publicly available German Alcohol Language Corpus that comprises a total of 12,360 audio clips of inebriated and sober speakers (total of 162, aged 21–64, 47.7% female). ADLAIA's performance was determined by computing the unweighted average recall (UAR) and accuracy of inebriation prediction. ADLAIA was able to identify inebriated speakers – with a BAC of 0.05% or higher – with an UAR of 68.09% and accuracy of 67.67%. ADLAIA had a higher performance (UAR of 75.7%) in identifying intoxicated speakers (BAC > 0.12%). Being able to identify intoxicated individuals solely based on their speech, ADLAIA could be integrated into mobile applications and used in environments (such as bars, sports stadiums) to get instantaneous results about inebriation status of individuals. •ADLAIA can outperform humans in identifying alcohol-inebriated individuals based solely on 12 seconds of their speech.•ADLAIA could be integrated into mobile applications and used as a preliminary tool for identifying alcohol-inebriation.•ADLAIA was able to identify inebriated speakers – with BAC of 0.05% or higher – with an UAR of 68.09% and accuracy of 67.67%.

Monitoring levels of alcohol-related harm in populations requires indicators that are robust to extraneous influence. We investigated the validity of an indicator for police-attributed alcohol-related assault. We summarized offence records from Queensland Police, investigated patterns of missing data, and considered the utility of a surrogate for alcohol-related assault. Of 242 107 assaults from 2004–2014, in 35% of cases the drug used by the offender was recorded as ‘unknown’. Under various assumptions about non-random missingness the proportion of assaults judged to be alcohol-related varied from 30%–65%. We found a sharp increase in missing data from 2007 suggesting the downward trend from that point is artefactual. Conversely, we found a stable and increasing trend using a time-based surrogate. The volume of missing data and other limitations preclude valid estimation of trends using the police indicator, and demonstrate how misleading results can be produced. Our analysis supports the use of an empirically-based surrogate indicator.