Engaging Alkenes in Metallaphotoredox: A Triple Catalytic, Radical Sorting Approach to Olefin-Alcohol Cross-Coupling.

Metallaphotoredox cross-coupling is a well-established strategy for generating clinically privileged aliphatic scaffolds via single-electron reactivity. Correspondingly, expanding metallaphotoredox to encompass new C(sp3)-coupling partners could provide entry to a novel, medicinally relevant chemical space. In particular, alkenes are abundant, bench-stable, and capable of versatile C(sp3)-radical reactivity via metal-hydride hydrogen atom transfer (MHAT), although metallaphotoredox methodologies invoking this strategy remain underdeveloped. Importantly, merging MHAT activation with metallaphotoredox could enable the cross-coupling of olefins with feedstock partners such as alcohols, which undergo facile open-shell activation via photocatalysis. Herein, we report the first C(sp3)-C(sp3) coupling of MHAT-activated alkenes with alcohols by performing deoxygenative hydroalkylation via triple cocatalysis. Through synergistic Ir photoredox, Mn MHAT, and Ni radical sorting pathways, this branch-selective protocol pairs diverse olefins and methanol or primary alcohols with remarkable functional group tolerance to enable the rapid construction of complex aliphatic frameworks.

Exploiting the Marcus inverted region for first-row transition metal-based photoredox catalysis.

Second- and third-row transition metal complexes are widely employed in photocatalysis, whereas earth-abundant first-row transition metals have found only limited use because of the prohibitively fast decay of their excited states. We report an unforeseen reactivity mode for productive photocatalysis that uses cobalt polypyridyl complexes as photocatalysts by exploiting Marcus inverted region behavior that couples increases in excited-state energies with increased excited-state lifetimes. These cobalt (III) complexes can engage in bimolecular reactivity by virtue of their strong redox potentials and sufficiently long excited-state lifetimes, catalyzing oxidative C(sp2)-N coupling of aryl amides with challenging sterically hindered aryl boronic acids. More generally, the results imply that chromophores can be designed to increase excited-state lifetimes while simultaneously increasing excited-state energies, providing a pathway for the use of relatively abundant metals as photoredox catalysts.

Metallaphotoredox: The Merger of Photoredox and Transition Metal Catalysis.

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

Executive Function and Self-Regulation: Bi-Directional Longitudinal Associations and Prediction of Early Academic Skills.

Despite a tendency to study executive function (EF) and self-regulation (SR) separately, parallel lines of research suggest considerable overlap between the two abilities. Specifically, both show similar developmental trajectories (i.e., develop rapidly in the early years), predict a broad range of overlapping outcomes across the lifespan (e.g., academic success, mental and physical health, and social competence), and have overlapping neural substrates (e.g., prefrontal cortex). While theoretical frameworks diverge in how they reconcile EF and SR - ranging from treating the two as functionally synonymous, to viewing them as related yet distinct abilities - there is no consensus and limited empirical evidence on the nature of their relationship and how this extends developmentally. The current study examined bi-directional longitudinal associations between early EF and SR, and their longitudinal associations with subsequent early academic skills, in a sample of 199 3- to 5-year-old pre-school children. The adopted measures permitted EF and SR to be modelled as composite indices for these analyses, thereby decreasing task-specific components of these associations. Early academic skills were captured by a standardized direct assessment. Bi-directional associations between EF and SR were found, with both accounting for unique variance in early academic skills 7 and 19months later. The current results provide important evidence to distinguish between EF and SR abilities, yet also for their reciprocal influence in situ and across early development.

Correction: Improving Physical Task Performance with Counterfactual and Prefactual Thinking.

[This corrects the article DOI: 10.1371/journal.pone.0168181.].

In limbo: A systematic review of psychological responses and coping among people with a missing loved one.

OBJECTIVE: This review explored psychological responses and coping among loved ones left behind when a person is missing. METHOD: A systematic search identified 42 studies that reported data gathered among people with a missing loved one regarding psychological symptoms and/or coping strategies. Studies were arranged according to context of disappearance: forced (a result of war/conflict, abduction, forced separation) or unclear (reason unknown)/unspecified circumstances. RESULTS: The most consistent findings for psychological symptoms were reports of depression, anxiety, posttraumatic stress, and prolonged grief reactions. When the disappearance was unclear/unspecified, people more often reported use of cognitive avoidance and continuing a bond as coping strategies. When the disappearance was forced, people more often reported use of informal support seeking. CONCLUSIONS: Further research is warranted to clarify (a) the generalizability of findings to those left behind under circumstances where the ambiguity may be greater and (b) the acceptability of various targeted psychological interventions.

Happiness and counterfactual thinking at the 2016 Summer Olympic Games.

The purpose of this study was to investigate potential differences in emotional expression and counterfactual thought between bronze and silver Olympic medallists. In Study 1, 468 photographs (156 gold medallists, 156 silver medallists, 156 bronze medallists) were obtained of Olympic medal winners standing on the podium at the 2016 Summer Olympic Games, and 20 students rated the level of expressed happiness in each photograph. The students were blind to the outcome of the event and an average score for each photograph was used in data analysis. Results showed that gold medallists displayed greater levels of happiness than silver medallists but that silver and bronze medallists showed little difference in their expressed happiness. In Study 2, 192 quotations from bronze and silver medallists were obtained from news outlets, and 20 students rated the expression of counterfactual thought in each quotation. Results showed that compared to bronze medallists, silver medallists had more counterfactual thoughts overall, more counterfactual thoughts about how things could have gone better, and more counterfactual thoughts about their opponents' behaviour. Overall, findings indicate that counterfactual thoughts differ between bronze and silver medallists, but that differences in expressed emotion are likely to be trivial or negligible.

π-Facial Selectivities in Hydride Reductions of Hindered Endocyclic Iminium Ions.

The origins of π-facial selectivities in the borohydride reduction of endocyclic iminium ions have been elucidated by density functional theory calculations. In reductions of conjugated ("thermodynamic") iminium ions, the π-facial preference of the hydride attack was found to be due to torsional steering. Attack at the favored π-face leads to a lower-energy "half-chair"-like conformation of the tetrahydropyridine product, whereas attack at the other π-face results in an unfavorable "twist-boat" conformation. In reductions of nonconjugated ("kinetic") iminium ions, torsional distinction is small between the top- and bottom-face attacks, and the π-facial selectivity of the hydride approach is primarily due to steric hindrance.

An Informatics Approach to Implement Support for Shared Decision Making for Primary Prevention Statin Therapy.

Background. Shared decision making (SDM) is recommended prior to initiation of statin therapy for primary prevention but is underutilized. We designed an informatics decision-support tool to facilitate use of the Mayo Clinic Statin Choice decision aid at the point-of-care and evaluated its impact. Methods. Using an iterative approach, we designed and implemented a single-click decision-support tool embedded within the electronic health records (EHRs) to automate the calculation of 10-year atherosclerotic cardiovascular disease (ASCVD) risk and populate the Statin Choice decision aid. We surveyed primary care providers at two clinics regarding their attitudes about SDM before and after deployment of intervention, as well as their usage of and perceived competence regarding SDM for primary prevention statin therapy. Three-month web traffic to the Statin Choice website was calculated before and after deployment of the intervention. Results. Pre-post surveys were completed by 60 primary care providers (24 [40%] attending physicians and 36 [60%] housestaff physicians). After deployment of the EHR tool, respondents were more aware of the Statin Choice decision aid (P < 0.001), reported being more competent regarding SDM (P = 0.047), and reported using decision aids more often when considering statin initiation (P = 0.043). There was no significant change in attitudes about SDM as measured through the Patient Provider Orientation Scale (pre 4.23 ± 0.40 v. post 4.16 ± 0.38, P = 0.11) and the SDM belief scale (pre 21.4 ± 2.1 v. post 21.1 ± 2.0, P = 0.35). Web-based usage rates for the Statin Choice decision aid increased from 3.4 to 5.2 per 1,000 outpatient clinic visits (P = 0.002). Conclusions. Implementation of a point-of-care decision-support tool increased the usage of decision aids for primary prevention statin therapy. This effect does not appear to be mediated by any concomitant changes in physician attitude toward SDM.

Assessing children's cognitive flexibility with the Shape Trail Test.

In this paper we report an initial validation of the Shape Trail Test-Child Version (STT-CV) with a non-clinical sample of children aged 6 to 9 years. The STT-CV has been developed as an age-appropriate and culturally fair direct downward extension of the Trail Making Test (TMT) for the assessment of cognitive flexibility. Children completed the STT-CV and four established measures of executive functions that assessed working memory, inhibitory control and task switching. Results showed the expected age-based differences in completion times for both parts of the STT-CV (Trail A and Trail B). Children's performance on the STT-CV correlated significantly with all four measures of executive functions. After controlling for the effects of chronological age, completion times for Trail B remained correlated with most other measures of executive functions. These findings provide emerging evidence for the utility of the STT-CV, and highlight the need for designing and using appropriate variants of the TMT in the behavioural assessment of cognitive flexibility in developmentally and culturally diverse populations.

FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation.

Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc- or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.

Improving Physical Task Performance with Counterfactual and Prefactual Thinking.

Counterfactual thinking (reflecting on "what might have been") has been shown to enhance future performance by translating information about past mistakes into plans for future action. Prefactual thinking (imagining "what might be if…") may serve a greater preparative function than counterfactual thinking as it is future-orientated and focuses on more controllable features, thus providing a practical script to prime future behaviour. However, whether or not this difference in hypothetical thought content may translate into a difference in actual task performance has been largely unexamined. In Experiment 1 (n = 42), participants performed trials of a computer-simulated physical task, in between which they engaged in either task-related hypothetical thinking (counterfactual or prefactual) or an unrelated filler task (control). As hypothesised, prefactuals contained more controllable features than counterfactuals. Moreover, participants who engaged in either form of hypothetical thinking improved significantly in task performance over trials compared to participants in the control group. The difference in thought content between counterfactuals and prefactuals, however, did not yield a significant difference in performance improvement. Experiment 2 (n = 42) replicated these findings in a dynamic balance task environment. Together, these findings provide further evidence for the preparatory function of counterfactuals, and demonstrate that prefactuals share this same functional characteristic.

Genetic basis of persistent red blood cell microcytosis in the Chinese unexplained by phenotypical testing.

AIMS: Hypochromic microcytic anaemia is the hallmark phenotype of thalassaemia. Current phenotypical tests do not provide a diagnosis in a small proportion of patients with red blood cell microcytosis. We aim to evaluate the genetic basis of red cell microcytosis in these cases in our Chinese population. METHODS: We identified from a large cohort of 1684 unselected requests for thalassaemia testing 23 Chinese subjects who had unexplained microcytosis after phenotypical iron and haemoglobin studies. In 18 of these subjects with available DNA, extensive genotypical analysis of the α and ß globin gene cluster was performed, including gap-PCR, multiplex amplification-refractory mutation system, Sanger sequencing and multiplex ligation-dependent probe amplification. RESULTS: Occult single and double α globin gene (HBA1, HBA2) deletions and α thalassaemic haemoglobinopathies (Haemoglobin Quong Sze, Haemoglobin Constant Spring) were the genetic basis for the microcytosis. Occult ß globin gene (HBB) mutations and δ globin gene (HBD) abnormalities masking ß thalassaemia are not seen. CONCLUSIONS: A cost-effective genotyping approach for the detection of these occult globin gene mutations can be proposed. The identification of these mutations is important for making a diagnosis and for the provision of accurate genetic counselling. (This paper adds to our understanding of the genetic basis of red blood cell microcytosis in clinical practice, and it provides a cost-effective approach for genotyping in diagnostic laboratories).

Novel point mutation of the α2-globin gene (HBA2) and a rare 2.4 kb deletion of the α1-globin gene (HBA1), identified in two chinese patients with Hb H disease.

Two Chinese patients with mild and moderate Hb H disease were investigated for rare mutations on the α-globin genes (HBA1, HBA2) in addition to the - -(SEA) deletion. One patient was a 41-year old man with mild anemia (Hb 11.3 g/dL). Multiplex ligation-dependent probe amplification (MLPA) revealed a rare 2392 bp deletion involving the entire HBA1 gene. Mapping by gap-polymerase chain reaction (gap-PCR) defined the exact breakpoints of this deletion (HBA1: g36859_39252del2392) and confirmed its identity with a recently reported HBA1 deletion found in a Southern Chinese. The other patient was a 53-year old man with moderate anemia (Hb 9.5 g/dL). Automated direct nucleotide (nt) sequencing identified a novel single nt deletion at codon 40 (HBA2: c.123delG). This leads to a frameshift that modifies the C-terminal sequence to (40)Lys-Pro-Thr-Ser-Arg-Thr-Ser-Thr(47)COOH and the introduction of a stop codon TGA 23 nts downstream. These two cases demonstrate the power of MLPA and direct nt sequencing to detect and characterize rare and novel mutations. They also highlight the differential effect of HBA1 and HBA2 gene mutations on an α-thalassemia (α-thal) phenotype due to their different transcriptional activity.

Treatment of erythropoietin deficiency in mice with systemically administered siRNA.

Anemia linked to a relative deficiency of renal erythropoietin production is a significant cause of morbidity and medical expenditures in the developed world. Recombinant erythropoietin is expensive and has been linked to excess cardiovascular events. Moreover, some patients become refractory to erythropoietin because of increased production of factors such as hepcidin. During fetal life, the liver, rather than the kidney, is the major source of erythropoietin. In the present study, we show that it is feasible to reactivate hepatic erythropoietin production and suppress hepcidin levels using systemically delivered siRNAs targeting the EglN prolyl hydroxylases specifically in the liver, leading to improved RBC production in models of anemia caused by either renal insufficiency or chronic inflammation with enhanced hepcidin production.

Hb A2 Hong Kong - A novel δ-globin variant in a Chinese family masks the diagnosis of ß-thalassemia trait.

A 42-year-old Chinese woman (FP) was the mother of a patient with ß-thalassemia major (ß-TM) due to a compound heterozygosity for ß(0)-thalassemia (ß(0)-thal) mutations. She was also found to have a low Hb A(2) level of 1.6% by high performance liquid chromatography (HPLC) despite being a heterozygous carrier of the codons 41/42 (-TCTT) (HBB:c.126_129delCTTT) ß(0)-thal mutation. Doubling the amount of hemolysate loaded for chromatography revealed a widened Hb A(2) peak and raised the level to 4.1%, consistent with ß-thal trait. Direct nucleotide sequencing detected a novel δ-globin gene mutation at codon 29 (HBD:c.89G>A), which leads to a glycine to aspartic acid substitution. A homologous mutation at codon 29 in the ß-globin gene [Hb Lufkin or ß29(B11)Gly→Asp] has been reported in Black families. This report highlights the importance of genotype-phenotype correlation and the potential pitfall of relying on Hb A(2) level for phenotypic diagnosis of ß(0)-thal trait.

Haemoglobin Bonn in a Chinese family as a cause of spurious hypoxaemia measured by pulse oximetry.

Haemoglobin (Hb) Bonn is a newly described benign Hb variant that causes falsely depressed oxygen saturation as measured by pulse oximetry. It was found to be associated with mild haemolysis. Since its first report in a German family, no further cases have been documented in the literature. We report the first Chinese family with this Hb variant and confirm its unusual clinical presentation. No evidence of haemolysis was seen. The absence of consistent abnormalities in routine Hb tests such as high-performance liquid chromatography and gel electrophoresis means that spurious hypoxaemia is the only clue to its presence, and genotypic analysis is the preferred method for definitive diagnosis. Its positive identification is important for counselling and will help to avoid unnecessary investigation and treatment for this benign condition.

Double heterozygosity for Hb New York [beta 113 GTG-->GAG; VAL-->GLU] and beta degrees-thalassemia mutations manifests as a thalassemia trait.

An extended family with three individuals affected by two different forms of double heterozygosity for beta-thalassemia and Hb New York is reported. Double heterozygosity of Hb New York [beta 113 GTG-->GAG; VAL-->GLU] and beta degrees codon 17 was detected in a fetus following prenatal screening for thalassemia. The father and a paternal aunt were also found to be heterozygous for Hb New York and beta degrees IVSII-654. Both adults had clinical and hematological features consistent with beta-thalassemia trait. The affected child was followed up after birth and manifested the typical course of a thalassemia trait, with no signs of organomegaly or overt hemolysis. Observations strongly suggest that double heterozygosity of Hb New York and beta degrees thalassemia has mild, if any, clinical symptoms, and is not an indication of therapeutic abortion when detected antenatally.

Folate deprivation increases tau phosphorylation by homocysteine-induced calcium influx and by inhibition of phosphatase activity: Alleviation by S-adenosyl methionine.

Several recent studies have indicated that increased levels of homocysteine (HC), including that resulting from deficiency in folate, increases tau phosphorylation. Some studies indicate that this is accomplished via HC-dependent activation of NMDA channels and resultant activation of calcium-dependent kinase pathways, while others suggest that the increase in tau phosphorylation is derived via HC-dependent inhibition of methylation of phosphatases and resultant inhibition of phosphatase activity. We demonstrate herein in SH-SY-5Y human neuroblastoma that both of these phenomena contribute to the increase in phospho-tau immunoreactivity following folate deprivation, and that supplementation with S-adenosyl methionine (SAM) prevents both the increase in kinase activity and the decrease in phosphatase activity. These findings demonstrate that the divergent neuropathological consequences of folate deprivation includes multiple pathways that converge upon tau phosphorylation, and further support the notion that dietary supplementation with SAM may reduce or delay neurodegeneration.