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This work demonstrates the dominance of a Ni(0/II/III) cycle for Ni-photoredox amide arylation, which contrasts with other Ni-photoredox C-heteroatom couplings that operate via Ni(I/III) self-sustained cycles. The kinetic data gathered when using different Ni precatalysts supports an initial Ni(0)-mediated oxidative addition into the aryl bromide. Using NiCl2 as the precatalyst resulted in an observable induction period, which was found to arise from a photochemical activation event to generate Ni(0) and to be prolonged by unproductive comproportionation between the Ni(II) precatalyst and the in-situ generated Ni(0) active species. Ligand exchange after oxidative addition yields a Ni(II) aryl amido complex, which was identified as the catalyst resting state for the reaction. Stoichiometric experiments showed that oxidation of this Ni(II) aryl amido intermediate was required to yield functionalized amide products. The kinetic data presented supports a rate-limiting photochemically-mediated Ni(II/III) oxidation to enable C-N reductive elimination. An alternative Ni(I/III) self-sustained manifold was discarded based on EPR and kinetic measurements. The mechanistic insights uncovered herein will inform the community on how subtle changes in Ni-photoredox reaction conditions may impact the reaction pathway, and have enabled us to include aryl chlorides as coupling partners and to reduce the Ni loading by 20-fold without any reactivity loss.

This paper describes a mild strategy to promote amide arylations. Photoinduced oxidation of a Ni(II) aryl amido intermediate is proposed to facilitate the challenging C-N reductive elimination step at moderate temperatures. Notably, the mildly basic conditions employed facilitate access to a broad scope including protected amino acids, heterocycles, phenols, and sterically hindered substituents. Hence, this work presents an attractive strategy to enable late-stage functionalization of pre-existing amide moieties in commercial drugs and natural products.

White spruce is a commercially important tree species in Canadaâs boreal forest, and studies are underway to determine the best conditions for planting nursery grown seedlings in the field. Here, we studied effects of low thinning (1/3 harvested), shelterwood (2/3 harvested), and clear-cut harvesting on soil chemical properties, on the growth and nutrition of white spruce seedlings, and on diffuse non-intercepted (DIFN) light levels at 75 cm above the soil surface. The study was conducted on a nutrient-rich clayey soil in the Abitibi region of Québec. DIFN light was lowest in non-harvested control plots and increased curvilinearly with basal area removal. Thus, DIFN light in clear-cut plots was more than twice the amount in shelterwood plots. At three years post-planting, significant linear relationships were found between DIFN light and seedling growth parameters, which were significantly higher in clear-cut than in other treatment plots. Harvesting treatments had no significant effects on soil chemical properties or on four indices of mineral N availability. Needle mass increased with harvesting intensity. Mg and K concentrations in current-year needles were lower in clear-cut than in other treatment plots. In previous-year needles, Ca concentration was higher and Mg concentrations lower in clear-cut plots, whereas as K concentration was higher in non-harvested control plots. Nutrient concentrations were nearly all sufficient in all harvesting treatments according to diagnostic norms established for white spruce. Relative nutrient content (mg nutrient needleâ1) of current-year late-summer needles increased, whereas relative nutrient concentration (mg nutrient mgâ1 needle) varied slightly, with increasing harvesting intensity, indicating that all nutrients were sufficient in all treatments. There were significant linear relationships between seedling growth and needle Ca, Mg and K concentrations. We conclude that light availability, rather than nutrient limitations, is the main determinant of white spruce seedling growth on these fertile soils.

Most eukaryotes harbor two distinct pre-mRNA splicing machineries: the major spliceosome, which removes >99% of introns, and the minor spliceosome, which removes rare, evolutionarily conserved introns. Although hypothesized to serve important regulatory functions, physiologic roles of the minor spliceosome are not well understood. For example, the minor spliceosome component ZRSR2 is subject to recurrent, leukemia-associated mutations, yet functional connections among minor introns, hematopoiesis and cancers are unclear. Here, we identify that impaired minor intron excision via ZRSR2 loss enhances hematopoietic stem cell self-renewal. CRISPR screens mimicking nonsense-mediated decay of minor intron-containing mRNA species converged on LZTR1, a regulator of RAS-related GTPases. LZTR1 minor intron retention was also discovered in the RASopathy Noonan syndrome, due to intronic mutations disrupting splicing and diverse solid tumors. These data uncover minor intron recognition as a regulator of hematopoiesis, noncoding mutations within minor introns as potential cancer drivers and links among ZRSR2 mutations, LZTR1 regulation and leukemias.

Many of the most highly conserved elements in the human genome are "poison exons," alternatively spliced exons that contain premature termination codons and permit post-transcriptional regulation of mRNA abundance through induction of nonsense-mediated mRNA decay (NMD). Poison exons are widely assumed to be highly conserved due to their presumed importance for organismal fitness, but this functional importance has never been tested in the context of a whole organism. Here, we report that a poison exon in Smndc1 is conserved across mammals and plants and plays a molecular autoregulatory function in both kingdoms. We generated mouse and A. thaliana models lacking this poison exon to find its loss leads to deregulation of SMNDC1 protein levels, pervasive alterations in mRNA processing, and organismal size restriction. Together, these models demonstrate the importance of poison exons for both molecular and organismal phenotypes that likely explain their extraordinary conservation. Author summary: Poison exons are highly conserved elements in the human genome and are known for their roles in regulating mRNA abundance. Despite their assumed importance for organismal fitness, their functional significance has not been tested in whole organisms. Our study focuses on a poison exon in the Smndc1 gene. We discovered that this poison exon is conserved between mammals and plants and sought to test its functional importance. We generated mouse and plant models lacking this specific poison exon. The loss of this exon led to dysregulated SMNDC1 protein levels and widespread disruptions in RNA processing. These molecular changes resulted in a noticeable reduction in organismal size, underscoring the physiological impact of poison exon loss. Our findings demonstrate that poison exons are crucial for maintaining proper protein levels and mRNA processing homeostasis, which may partially explain their remarkable evolutionary conservation. This study highlights the importance of poison exons in both molecular regulation and overall organismal health, providing insights into their conservation across diverse species. [ABSTRACT FROM AUTHOR]

Parent and child relationships continuously evolve, part of an ongoing dialectic that derives from developmental changes in both parent and child. The focus of this study is on changes in the strength of association among four types of parenting behaviors considered important for children’s development: supportive presence, respect for autonomy, stimulation, and hostility. Mother–child interaction was observed for 1229 parent–child dyads at 36 months, 54 months, 1st grade, 3rd grade, and 5th grade using similar observational paradigms. The association between respect for autonomy and supportive presence was strong at age three and continued to be strong over time. The association between respect for autonomy and stimulation was modest but also showed little change from age three to 5th grade. Respect for autonomy was negatively associated with maternal hostility, but the relation was complex. It was stronger at 54 months than 36 months but then became weaker through time. Supportive presence showed a moderate relation with stimulation at age 3 but the association became weaker over time. Supportive presence showed an expected negative association with hostility, a relation that changed little over time. The relation between hostility and stimulation also became weaker over time. In effect, there appears to be a shifting pattern of relations between maternal behaviors during early and middle childhood, one that reflects an evolving dialectic in the mother–child relationship.

AbstractMetamemory involves the ability to correctly judge the accuracy of our memories. The retrieval of memories can be improved using transcranial electrical stimulation (tES) during sleep, but evidence for improvements to metamemory sensitivity is limited. Applying tES can enhance sleep-dependent memory consolidation, which along with metamemory requires the coordination of activity across distributed neural systems, suggesting that examining functional connectivity is important for understanding these processes. Nevertheless, little research has examined how functional connectivity modulations relate to overnight changes in metamemory sensitivity. Here, we developed a closed-loop short-duration tES method, time-locked to up-states of ongoing slow-wave oscillations, to cue specific memory replays in humans. We measured electroencephalographic (EEG) coherence changes following stimulation pulses, and characterized network alterations with graph theoretic metrics. Using machine learning techniques, we show that pulsed tES elicited network changes in multiple frequency bands, including increased connectivity in the theta band and increased efficiency in the spindle band. Additionally, stimulation-induced changes in beta-band path length were predictive of overnight changes in metamemory sensitivity. These findings add new insights into the growing literature investigating increases in memory performance through brain stimulation during sleep, and highlight the importance of examining functional connectivity to explain its effects.

Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10-50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4. DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over 1 year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance. [ABSTRACT FROM AUTHOR]

Transmissible spongiform encephalopathies (TSEs) are a fatal neurogenerative disease that include Creutzfeldt–Jakob disease in humans, scrapie in sheep and goats, bovine spongiform encephalopathy (BSE), and several others as well as the recently described camel prion disease (CPD). CPD originally was documented in 3.1% of camels examined during an antemortem slaughterhouse inspection in the Ouargla region of Algeria. Of three individuals confirmed for CPD, two were sequenced for the exon 3 of the prion protein gene (PRNP) and were identical to sequences previously reported for Camelus dromedarius. Given that other TSEs, such as BSE, are known to be capable of cross–species transmission and that there is household consumption of meat and milk from Camelus, regulations to ensure camel and human health should be a One Health priority in exporting countries. Although the interspecies transmissibility of CPD currently is unknown, genotypic characterization of Camelus PRNP may be used for predictability of predisposition and potential susceptibility to CPD. Herein, eight breeds of dromedary camels from a previous genetic (mitochondrial DNA and microsatellites) and morphological study were genotyped for PRNP and compared to genotypes from CPD–positive Algerian camels. Sequence data from PRNP indicated that Ethiopian camels possessed 100% sequence identity to CPD–positive camels from Algeria. In addition, the camel PRNP genotype is unique compared to other members of the Orders Cetartiodactyla and Perissodactyla and provides an in–depth phylogenetic analysis of families within Cetartiodactyla and Perissodactyla that was used to infer the evolutionary history of the PRNP gene. [ABSTRACT FROM AUTHOR]

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects.

Transcranial direct current stimulation (tDCS) influences performance in many cognitive domains. However, the question of which brain networks are involved in these effects is rarely examined. In prior experiments we identified tDCS protocols that produce a large improvement in category learning. Here we examined which brain regions were involved by modelling and comparing the behavioral effects of different electrode placements. In Experiment 1, we placed electrodes at two cephalic sites found the be most effective in our prior studies (F10 and T5/P7), expecting an increased combined effect. However, no effect was found, suggesting that stimulation of additional far field regions using extracephalic electrodes in our prior studies may have been necessary for producing these effects. In Experiment 2, we used finite element modeling (FEM) to compare the E-fields produced by these montages. One region with large differences and that is accessible to tDCS was the cerebellum. We then tested the involvement of the cerebellum by placing electrodes below the inion vs. the left arm in thirty-six participants who received anodal, cathodal, or sham stimulation during training. Neither anodal nor cathodal cerebellar tDCS led to significant changes when compared with sham. These results suggest that neither far-field stimulation of the cerebellum nor nearby cranial nerves played a large causal role in our previous tDCS studies. To our knowledge, this one of the first studies to systematically compare the behavioral and energetic effects produced by different montages to identify the specific brain regions involved in the behavioral responses to tDCS.