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KRAS mutations are the earliest events found in approximately 90% of pancreatic ductal adenocarcinomas (PDACs). However, little is known as to why KRAS mutations preferentially occur in PDACs and what processes/factors generate these mutations. While abnormal carbohydrate metabolism is associated with a high risk of pancreatic cancer, it remains elusive whether a direct relationship between KRAS mutations and sugar metabolism exists. Here, we show that under high-glucose conditions, cellular O-GlcNAcylation is significantly elevated in pancreatic cells that exhibit lower phosphofructokinase (PFK) activity than other cell types. This post-translational modification specifically compromises the ribonucleotide reductase (RNR) activity, leading to deficiency in dNTP pools, genomic DNA alterations with KRAS mutations, and cellular transformation. These results establish a mechanistic link between a perturbed sugar metabolism and genomic instability that induces de novo oncogenic KRAS mutations preferentially in pancreatic cells.

The premier paradigm of offender rehabilitation is the Risk-Need-Responsivity (RNR) model and several training programs for community corrections officers to better apply the RNR principles have been developed. This article summarizes and critiques three major training models: STICS, EPICS, and STARR. Furthermore, lessons are drawn from the research to guide further improvements in the training of community correctional staff. The community supervision of persons in conflict with the law is one of the most widely used correctional sanctions in North America and yet, its effectiveness in reducing recidivism is questionable. The review of training programs that capitalize on the RNR model shows that community supervision can lead to changes in officer behavior and reduced recidivism. However, to achieve promising results modifications to the training and to the agencies that adopt such training programs are necessary. [ABSTRACT FROM AUTHOR]

Forensic mental health care primarily focuses on aspects of safety. Treatment is involuntary, and personal rights are highly restricted. Both direct and indirect coercion and significant power imbalances can impede not only the psychological state of inpatients but also their treatment motivation and the therapeutic process in general. However, successful treatment is essential to enable patients to regain their freedom. Therefore, the question arises whether and how health professionals, without disregarding the potential risks, can enable forensic psychiatric patients to experience meaningfulness and self-efficacy in their lives. In offender rehabilitation, the Risk-Need-Responsivity (RNR) model and Good Lives Model (GLM) are widely established theories. The RNR model focuses not only on the risk of recidivism but also on those needs of a person that provoke or prevent criminal behavior and the individual's ability to respond to various kinds of interventions. In contrast, the GLM aims to reduce the risk of re-offending by enabling an individual to live a "good life," i.e., a meaningful and fulfilling life. Originally developed in correctional services, i.e., for offenders without severe mental disorders, both the RNR model and the GLM have also been tested in forensic psychiatric treatment contexts. The Recovery Model is based on the concept of personal recovery in mental health care and is understood as the development of a sense of purpose and mastery in one's own life during the process of coping with the sequelae of a mental disorder. It is a central element of rehabilitation in general, but is also being increasingly applied in forensic psychiatric treatment settings. This review aims to compare the central concepts of the three models, in particular regarding personal development, and the current evidence for their efficacy in mentally disordered offenders. [ABSTRACT FROM AUTHOR]

Abstract Background Deficiency in thymidine kinase 2 (TK2) or p53 inducible ribonucleotide reductase small subunit (p53R2) is associated with tissue specific mitochondrial DNA (mtDNA) depletion. To understand the mechanisms of the tissue specific mtDNA depletion we systematically studied key enzymes in dTMP synthesis in mitochondrial and cytosolic extracts prepared from adult rat tissues. Results In addition to mitochondrial TK2 a cytosolic isoform of TK2 was characterized, which showed similar substrate specificity to the mitochondrial TK2. Total TK activity was highest in spleen and lowest in skeletal muscle. Thymidylate synthase (TS) was detected in cytosols and its activity was high in spleen but low in other tissues. TS protein levels were high in heart, brain and skeletal muscle, which deviated from TS activity levels. The p53R2 proteins were at similar levels in all tissues except liver where it was ~ 6-fold lower. Our results strongly indicate that mitochondria in most tissues are capable of producing enough dTTP for mtDNA replication via mitochondrial TK2, but skeletal muscle mitochondria do not and are most likely dependent on both the salvage and de novo synthesis pathways. Conclusion These results provide important information concerning mechanisms for the tissue dependent variation of dTTP synthesis and explained why deficiency in TK2 or p53R2 leads to skeletal muscle dysfunctions. Furthermore, the presence of a putative cytosolic TK2-like enzyme may provide basic knowledge for the understanding of deoxynucleoside-based therapy for mitochondrial disorders.

In Saccharomyces cerevisiae, absence of the checkpoint kinase Mec1 (ATR) is viable upon mutations that increase the activity of the ribonucleotide reductase (RNR) complex. Whether this pathway is conserved in mammals remains unknown. Here we show that cells from mice carrying extra alleles of the RNR regulatory subunit RRM2 (Rrm2(TG)) present supraphysiological RNR activity and reduced chromosomal breakage at fragile sites. Moreover, increased Rrm2 gene dosage significantly extends the life span of ATR mutant mice. Our study reveals the first genetic condition in mammals that reduces fragile site expression and alleviates the severity of a progeroid disease by increasing RNR activity.

To conduct an umbrella review of Risk-Need-Responsivity (RNR) principles by synthesizing and appraising the consistency and quality of the underlying evidence base of RNR. Following PRISMA guidelines, we searched three bibliographic databases, the Cochrane Library, and grey literature from 2002 to 2022 for systematic reviews and meta-analysis on RNR principles. We summarized effect sizes, including as odds ratios and Area Under the Curve (AUC) statistic. We evaluated the quality of review evidence by examining risk of bias, excess statistical significance, between-study heterogeneity, and calculated prediction intervals for reported effect sizes. We identified 26 unique meta-anlayses that examined RNR principles. These meta-analyses indicate inconsistent statistical support for the individual components of RNR. For the risk principle, there were links with recidivism (OR = 1.6, 95% CI [1.1, 2.3]). For the need principle, although there were associations between adherence to intervention programs and recidivism, risk assessment tools reflecting this principle had low predictive accuracy (AUCs 0.62–0.64). The general and specific responsivity principles received some support. However, the overall quality of the evidence was poor as indicated by potential authorship bias, lack of transparency, substandard primary research, limited subgroup analyses, and conflation of prediction with causality. The prevalent poor quality evidence and identified biases suggests that higher quality research is needed to determine whether current RNR claims of being evidence-based are justified. • The underlying evidence for RNR principles is mixed and mostly of low quality. • This evidence shows authorship bias and often lacks transparency. • All reviews that tested the risk principle were rated as low quality. • Higher quality research is needed to support the claims about the RNR principles. [ABSTRACT FROM AUTHOR]

The effective use of the core treatment principles from the Risk-Need-Responsivity (RNR) model has the potential to reduce criminal recidivism significantly. A pilot trial of the RNR-based model Krimstics in the Swedish probation service showed increased RNR adherence but no effects on recidivism. The subsequent implementation of Krimstics involved the training and clinical support of more than 700 probation officers working with community supervision. In parallel, an implementation evaluation examining RNR adherence was undertaken, collecting and coding audio-recorded supervision sessions and case file data. Findings showed that Krimstics-trained probation officers (N = 96) used cognitive behavioral therapy-based techniques in supervision sessions while demonstrating moderate-to-high levels of relationship building skills. However, adherence to the risk principle was lacking and key cognitive behavioral techniques showed poor quality. Although Krimstics has increased RNR adherence in a Swedish context, challenges with implementing theory into practice may obscure the assessment of the service's effectiveness. [ABSTRACT FROM AUTHOR]

Abstract Manganese plays multiple role in many biological redox reactions in which it exists in different oxidation states from Mn(II) to Mn(IV). Among them the high-valent manganese-oxo intermediate plays important role in the activity of certain enzymes and lessons from the natural system provide inspiration for new developments of artificial systems for a sustainable energy supply and various organic conversions. This review describes recent advances and key lessons learned from the nature on high-valent Mn-oxo intermediates. Also we focus on the elemental science developed from the natural system, how the novel strategies are realised in nano particles and molecular sites at heterogeneous and homogeneous reaction conditions respectively. Finally, perspectives on the utilisation of the high-valent manganese-oxo species towards other organic reactions are proposed.

Image patch priors become a popular tool for image denoising. The Gaussian mixture model (GMM) is remarkably effective in modelling natural image patches. However, GMM prior learning using the expectation maximisation (EM) algorithm is sensitive to the initialisation, often leading to low convergence rate of parameter estimation. In this study, a novel sampling method called random neighbourhood resampling (RNR) is proposed to improve the accuracy and efficiency of parameter estimation. An enhanced GMM (EGMM) learning algorithm is further developed by incorporating RNR into the EM algorithm to initialise and update the GMM prior. The learned EGMM prior is applied in the expected patch log‐likelihood (EPLL) framework for image denoising. The effectiveness and performance of the proposed RNR and EGMM algorithm are demonstrated via extensive experimental results comparing with the state‐of‐the‐art image denoising methods, the experimental results show the higher PSNR result of the denoised images using the proposed method. Meanwhile, the authors verified that the proposed method can efficiently reduce the time of image denoising compared with the basic EPLL method. [ABSTRACT FROM AUTHOR]

Inactivation of Mec1, the budding yeast ATR, results in a permanent S phase arrest followed by chromosome breakage and cell death during G2/M. The S phase arrest is proposed to stem from a defect in Mec1-mediated degradation of Sml1, a conserved inhibitor of ribonucleotide reductase (RNR), causing a severe depletion in cellular dNTP pools. Here, the casual link between the S phase arrest, Sml1, and dNTP-levels is examined using a temperature sensitive mec1 mutant. In addition to S phase arrest, thermal inactivation of Mec1 leads to constitutively high levels of Sml1 and an S phase arrest. Expression of a novel suppressor, GIS2, a conserved mRNA binding zinc finger protein, rescues the arrest without down-regulating Sml1 levels. The dNTP pool in mec1 is reduced by ∼17% and GIS2 expression restores it, but only partially, to ∼93% of a control. We infer that the permanent S phase block following Mec1 inactivation can be uncoupled from its role in Sml1 down-regulation. Furthermore, unexpectedly modest effects of mec1 and GIS2 on dNTP levels suggest that the S phase arrest is unlikely to result from a severe depletion of dNTP pool as assumed, but a heightened sensitivity to small changes in its availability.

Telomeres, the nucleoprotein complexes at the end of eukaryotic chromosomes, protect them from degradation and ensure the replicative capacity of cells. In most human tumors and in budding yeast, telomere length is maintained by the activity of telomerase, an enzyme that adds dNTPs according to an internal RNA template. The dNTPs are generated with the help of the ribonucleotide reductase (RNR) complex. We have recently generated strains lacking the large subunit of RNR, Rnr1, which were kept viable by the expression of RNR complexes containing the Rnr1 homolog, Rnr3. Interestingly, we found that these Rnr1-deficient strains have short telomeres that are stably maintained, but cannot become efficiently elongated by telomerase. Thus, a basic maintenance of short telomeres is possible under conditions, where Rnr1 activity is absent, but a sustained elongation of short telomeres fully depends on Rnr1 activity. We show that Rnr3 cannot compensate for this telomeric function of Rnr1 even when overall cellular dNTP values are restored. This suggests that Rnr1 plays a role in telomere elongation beyond increasing cellular dNTP levels. Furthermore, our data indicate that telomerase may act in two different modes, one that is capable of coping with the “end-replication problem” and is functional even in the absence of Rnr1 and another required for the sustained elongation of short telomeres, which fully depends on the presence of Rnr1. Supply of dNTPs for telomere elongation is provided by the Mec1ATR checkpoint, both during regular DNA replication and upon replication fork stalling. We discuss the implications of these results on telomere maintenance in yeast and cancer cells. [ABSTRACT FROM AUTHOR]

Trends in criminal justice programming can sometimes lead one to question the direction the field is taking related to rehabilitation. This article presents one state’s attempt to evaluate the quality of residential treatment services in the state across a primary and then follow-up outcome evaluation. This article outlines study results specific to treatment effects by risk. The study finds consistent evidence in support of the risk principle across both studies. The article also outlines what the state did with the recommendations from these studies, and how that affected the delivery of correctional programming in that state. [ABSTRACT FROM AUTHOR]

Phoma medicaginis (syn. Ascochyta medicaginicola Qchen & L. Cai) causes spring black stem and leaf spot, an important disease of alfalfa and annual medics. P. medicaginis forms uninucleate conidia in melanized pycnidia and is genetically tractable using Agrobacterium mediated transformation (ATMT), resulting in random integration of T-DNA that occasionally generates pycnidial mutants. The T-DNA tagged mutant, P265 displayed smaller pycnidia and more aerial hyphae than the wild type. A single T-DNA disrupted a putative noncanonical poly(A) RNA polymerase gene, Pmnc pap1 , which in yeast interacts with ribonucleotide reductase (RNR). As in yeast mutants, P265 showed sensitivity to hydroxyurea (HU), a RNR inhibitor. To characterize the role of Pmnc pap1 , targeted ΔPmnc pap1 mutants were created using a hygromycin selectable marker flanked by 1 Kbp regions of Pmnc pap1 . ΔPmnc pap1 mutants possessed similar morphological features to those of P265. The plasmid for rescue of PmncPAP1, pCAM−Nat1 (nourseothricin selection) was constructed and used to introduce full-length PmncPAP1 into mutants. Rescued P265 showed partial recovery of wild type and the original T-DNA was lost due to homologous integration. To our knowledge, this is the first ncPAP to be examined in a filamentous fungus. [ABSTRACT FROM AUTHOR]

Ribosomal biogenesis involves the processing of pre-ribosomal RNA. A deficiency of some ribosomal proteins (RPs) impairs processing and causes Diamond Blackfan anemia (DBA), which is associated with anemia, congenital malformations and cancer. p53 mediates many features of DBA, but the mechanism of p53 activation remains unclear. Another hallmark of DBA is the upregulation of adenosine deaminase (ADA), indicating changes in nucleotide metabolism. In RP-deficient zebrafish, we found activation of both nucleotide catabolism and biosynthesis, which is consistent with the need to break and replace the faulty ribosomal RNA. We also found upregulation of deoxynucleotide triphosphate (dNTP) synthesis – a typical response to replication stress and DNA damage. Both RP-deficient zebrafish and human hematopoietic cells showed activation of the ATR/ATM-CHK1/CHK2/p53 pathway. Other features of RP deficiency included an imbalanced dNTP pool, ATP depletion and AMPK activation. Replication stress and DNA damage in cultured cells in non-DBA models can be decreased by exogenous nucleosides. Therefore, we treated RP-deficient zebrafish embryos with exogenous nucleosides and observed decreased activation of p53 and AMPK, reduced apoptosis, and rescue of hematopoiesis. Our data suggest that the DNA damage response contributes to p53 activation in cellular and zebrafish models of DBA. Furthermore, the rescue of RP-deficient zebrafish with exogenous nucleosides suggests that nucleoside supplements could be beneficial in the treatment of DBA.

There is a strong movement toward juvenile justice agencies' use of risk assessment and risk-need-responsivity approaches to improve case management decisions for young offenders. However, little is known about whether adoption of risk assessment actually effectuates any changes in the way young offenders are handled. This was a multisite study of the impact on case processing of implementation of the Structured Assessment of Violence Risk in Youth (SAVRY) or Youth Level of Service/Case Management Inventory in 6 juvenile probation offices using a prepost design and 1,694 propensity score-matched young offenders. Consistent with the risk principle, there were significant changes to at least some areas of case processing in all but 1 site, most notably with respect to decreases in the amount of supervision youth received and in rates of out-of-home placement. The nature and extent of the impact varied as a function of sites' characteristics and implementation quality, not as a function of the risk assessment used. No increases in recidivism were observed in any site, and there was a significant reduction in recidivism in 1 site. The key benefits of implementation of valid risk assessment and case management procedures were improved resource allocation and fewer instances of inappropriate interference in youths' lives without an apparent increased risk to public safety. [ABSTRACT FROM AUTHOR]

The presence of responsivity issues has the potential to interfere with the delivery of interventions to offenders. The current study investigated differences among extra- and intra-familial child molesters, sex offenders against adult victims, violent offenders, and general offenders on four potential areas of responsivity, using psychometric measures. Differences were found between sexual offenders with child victims and violent offenders on antisocial and substance abuse variables. However, offender groups did not differ on intellectual, borderline personality, mental health, and treatment motivation variables, indicating that regardless of the nature of offending, responsivity barriers should be assessed to ensure treatment gains are maximized. [ABSTRACT FROM AUTHOR]

Research supports the effectiveness of the Risk-Needs-Responsivity model for reducing criminal recidivism. Yet programming interests of inmates--one facet of responsivity--remain an understudied phenomenon. In the present study, we explored the programming interests of 753 federal inmates housed across three levels of security. Results suggest that inmates, as a group, prefer specific programs over others, and that some of their interests may differ by security level. We discuss possible implications of these findings. [ABSTRACT FROM AUTHOR]

Background: NR4A nuclear receptors are a conserved, functionally diverse group of nuclear receptors that regulate multiple cellular processes including proliferation and differentiation. The gene nhr-6 encodes the sole Caenorhabditis elegans NR4A nuclear receptor homolog with an essential role in reproduction by regulating morphogenesis of the spermatheca, a somatic gonad organ involved in ovulation and fertilization. Results: Here, we identify the spermatheca cell lineage defects that occur in nhr-6 mutants. Utilizing cell marker analysis, we find that nhr-6 is required for cell cycle progression and that the cell proliferation phenotype is not due to premature cell cycle exit. We also show that loss of the negative cell cycle regulators fzr-1 and lin-35 suppresses the cell proliferation defects. We further demonstrate that NHR-6 activity intersects with Eph receptor signaling during spermatheca cell proliferation. Conclusions: NHR-6 has an essential function in promoting cell cycle progression during G1 phase in a specific spermatheca cell lineage. Genetic suppression of the proliferation phenotype does not affect the differentiation phenotypes observed in nhr-6 mutants, indicating a dualistic role for nhr-6 in regulating cell proliferation and cell differentiation during spermatheca organogenesis. Developmental Dynamics 244:417-430, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The following presents the outcome of an evaluation of family violence prevention programs for male offenders. The moderate and high intensity programs were designed and implemented to conform to the Risk-Needs-Responsivity (RNR) principles. Results showed that program participation significantly reduced attitudes that supported violence against women and improved pro-social skills related to non-abusive relationships; treatment effects were moderate to high. Parole officer feedback generally reported positive changes in behavior and attitude associated with treatment. A post-release follow-up indicated that program completion significantly reduced spousal violence and general violent recidivism. Program participation did not, however, have a significant impact on non-violent crime. Results indicate that domestic violence programs respecting the RNR principles may be effective in reducing partner violence. [ABSTRACT FROM AUTHOR]

Highlights: [•] Hug1p overexpression sensitizes wild-type cells to DNA damage and hydroxyurea (HU). [•] Expression of Hug1p in response to HU treatment is delayed relative to Rnr3p. [•] MEC1 pathway genes are required for cytoplasmic localization of Hug1p. [•] Hug1p subcellular compartmentalization to the cytoplasm coincides with Rnr2p–Rnr4p. [ABSTRACT FROM AUTHOR]

This study evaluated the Ottawa Community Youth Diversion Program (OCYDP), a diversion program targeting medium-risk youth and structured according to the risk, need, responsivity principles of offender rehabilitation. The recidivism rate of 170 postcharge youth referred to the OCYDP were compared to that of 208 matched youth sentenced to a period of probation. Youth referred to diversion had significantly lower reoffense rates than those referred to probation even when controlling for risk level, age, gender, and nature of the index offense. However, program completion within the diversion program impacted outcomes, with those failing to complete the program showing higher recidivism levels than the probation youth. Results are discussed in terms of the impact of judicial system involvement and the provision of treatment. [ABSTRACT FROM AUTHOR]

Apicomplexa are protist parasites of tremendous medical and economic importance, causing millions of deaths and billions of dollars in losses each year. Apicomplexan-related diseases may be controlled via inhibition of essential enzymes. Ribonucleotide reductase (RNR) provides the only de novo means of synthesizing deoxyribonucleotides, essential precursors for DNA replication and repair. RNR has long been the target of antibacterial and antiviral therapeutics. However, targeting this ubiquitous protein in eukaryotic pathogens may be problematic unless these proteins differ significantly from that of their respective host. The typical eukaryotic RNR enzymes belong to class Ia, and the holoenzyme consists minimally of two R1 and two R2 subunits (αβ). We generated a comparative, annotated, structure-based, multiple-sequence alignment of R2 subunits, identified a clade of R2 subunits unique to Apicomplexa, and determined its phylogenetic position. Our analyses revealed that the apicomplexan-specific sequences share characteristics with both class I R2 and R2lox proteins. The putative radical-harboring residue, essential for the reduction reaction by class Ia R2-containing holoenzymes, was not conserved within this group. Phylogenetic analyses suggest that class Ia subunits are not monophyletic and consistently placed the apicomplexan-specific clade sister to the remaining class Ia eukaryote R2 subunits. Our research suggests that the novel apicomplexan R2 subunit may be a promising candidate for chemotherapeutic-induced inhibition as it differs greatly from known eukaryotic host RNRs and may be specifically targeted. [ABSTRACT FROM AUTHOR]

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Three separate field experiments were conducted during kharif 2008-09 and 2009-10 at Regional Agricultural Research Station (ANGRAU), Palem to study the impact of land configuration, life saving irrigation and intercropping on yield and economics of major rainfed crops (castor and redgram) of Southern Telangana Zone of Andhra Pradesh. Results of pooled analysis of individual experiment revealed that life saving irrigation @ 20 mm with harvested water (from farm pond) through sprinkler method of irrigation was found to have enhanced the castor and redgram seed yield by 21.9 and 28.1%, respectively over purely rainfed crop. It also resulted in additional net returns of ...4118 ha-1 and ...12722 ha-1 in castor and redgram, respectively. Adoption of ridge and furrow method (1058 kg ha-1) of land configuration resulted in 6.54% and 12.3% higher castor bean yield over dead furrow (993 kg ha-1) and flat bed method (942 kg ha-1), respectively. While, it was 6.84 and 18.2 in case of redgram. Ridge and furrow was at par with dead furrow but significantly superior to flat bed with respect to seed yield of castor. On the other hand, ridge furrow was significantly superior to dead furrow and flat bed in case of redgram. Castor + redgram (1:1) intercropping system (1417 kg ha-1) being at par with sole redgram (1382 kg ha-1) recorded significantly higher castor seed equivalent yield and also higher RNR index (1.67). But, sole redgram gave higher net returns (...19026 ha-1) and was closely followed by castor + redgram (1:1) intercropping system (...18117 ha-1 ). [ABSTRACT FROM AUTHOR]