Orchestration of the S-phase and DNA damage checkpoint pathways by replication forks from early origins

The S-phase checkpoint activated at replication forks coordinates DNA replication when forks stall because of DNA damage or low deoxyribonucleotide triphosphate pools. We explore the involvement of replication forks in coordinating the S-phase checkpoint using dun1Δ cells that have a defect in the number of stalled forks formed from early origins and are dependent on the DNA damage Chk1p pathway for survival when replication is stalled. We show that providing additional origins activated in early S phase and establishing a paused fork at a replication fork pause site restores S-phase checkpoint signaling to chk1Δ dun1Δ cells and relieves the reliance on the DNA damage checkpoint pathway. Origin licensing and activation are controlled by the cyclin–Cdk complexes. Thus, oncogene-mediated deregulation of cyclins in the early stages of cancer development could contribute to genomic instability through a deficiency in the forks required to establish the S-phase checkpoint

Defects in intracellular trafficking of fungal cell wall synthases lead to aberrant host immune recognition

Acknowledgments We acknowledge Jeanette Wagener and Louise Walker for performing the HPAEC-PAD analysis and Neil Gow for providing access to the Dionex HPAEC-PAD instrumentation. We thank Mike Cook and the Duke University Cancer Center Flow Cytometry Shared Resource for assistance with the flow cytometry. We also acknowledge Michelle Plue and the Duke University Shared Materials Institute Facility for performing the transmission electron microscopy. We thank Marcel Wu¨thrich for providing the MyD88-/-and TLR2/4-/- mice, and Mari Shinohara and Elizabeth Deerhake for providing the Dectin-1-/- mice. Funding: These experiments were supported by a National Institutes of Health grant awarded to JAA and FLW, Jr. (R01 AI074677, https://grants.nih.gov/grants/oer.html). CM and colleagues Jeanette Wagener, Louise Walker, Neil Gow were supported by the Wellcome Trust Strategic Award in Medical Mycology and Fungal Immunology (097377, https://wellcome.ac.uk), Wellcome Trust Senior Investigator Award (101873) and the MRC Centre for Medical Mycology (MR/N006364/1, https://www.abdn.ac.uk/cmm/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Maximizing as a predictor of job satisfaction and performance: A tale of three scales

Research on individual differences in maximizing (versus satisficing) has recently proliferated in the Judgment and Decision Making literature, and high scores on this construct have been linked to lower life satisfaction as well as, in some cases, to worse decision-making performance. The current study exported this construct to the organizational domain and evaluated the utility of the three most widely used measures of maximizing in predicting several criteria of interest to organizational researchers: job satisfaction, intentions to quit the organization, performance in the job role, and income. Moreover, this study used relative weight analyses to determine the relative importance of maximizing and two dispositional variables (conscientiousness and core self-evaluations) that are traditionally used to predict these criteria in the organizational literature. Results indicate that relationships between maximizing and these criteria are influenced by the way in which maximizing is measured. Yet, regardless of how it is measured, maximizing is not a particularly strong predictor of these criteria compared to traditional organizational predictors. Limitations and future research directions are discussed

Improved control strategy of DFIG-based wind turbines using direct torque and direct power control techniques

This paper presents different control strategies for a variable-speed wind energy conversion system (WECS), based on a doubly fed induction generator. Direct Torque Control (DTC) with Space-Vector Modulation is used on the rotor side converter. This control method is known to reduce the fluctuations of the torque and flux at low speeds in contrast to the classical DTC, where the frequency of switching is uncontrollable. The reference for torque is obtained from the maximum power point tracking technique of the wind turbine. For the grid-side converter, a fuzzy direct power control is proposed for the control of the instantaneous active and reactive power. Simulation results of the WECS are presented to compare the performance of the proposed and classical control approaches.Peer reviewedFinal Accepted Versio

Self-report dieting and long-term changes in body mass index and waist circumference

Objective This prospective study explores whether dieting attempts and previous changes in weight predict changes in body mass index (BMI) and waist circumference (WC). Methods The study was based on the representative Finnish Health 2000 Survey and on its follow-up examination 11 years later. The sample included 2,785 participants, aged 30-69. BMI and WC were determined at health examinations. Information on dieting attempts and previous changes in weight was collected using a questionnaire including questions on whether participant had tried to lose weight (no/yes), gained weight (no/yes) or lost weight (no/yes) during the previous year. Results At baseline, 32.8% were dieters. Of these, 28.4% had lost weight during the previous year. Dieters had higher BMI and WC than non-dieters. During the follow-up, the measures increased more in dieters and in persons with previous weight loss. The mean BMI changes in non-dieters versus dieters were 0.74 (standard deviation [SD] 2.13) kg/m(2) and 1.06 (SD 2.77) kg/m(2) (P = 0.002), respectively. The corresponding numbers for those with no previous weight change versus those who had lost weight were 0.65 (SD 2.07) kg/m(2) and 1.52 (SD 2.61) kg/m(2). The increases in BMI and WC were most notable in dieters with initially normal weight. Conclusions The increases in BMI and WC were greater in dieters than in non-dieters, suggesting dieting attempts to be non-functional in the long term in the general population.Peer reviewe

Solutions for humanity on how to conserve insects

The fate of humans and insects intertwine, especially through the medium of plants. Global environmental change, including land transformation and contamination, is causing concerning insect diversity loss, articulated in the companion review Scientists' warning to humanity on insect extinctions. Yet, despite a sound philosophical foundation, recognized ethical values, and scientific evidence, globally we are performing poorly at instigating effective insect conservation. As insects are a major component of the tapestry of life, insect conservation would do well to integrate better with overall biodiversity conservation and climate change mitigation. This also involves popularizing insects, especially through use of iconic species, through more media coverage, and more inclusive education. Insect conservationists need to liaise better with decision makers, stakeholders, and land managers, especially at the conceptually familiar scale of the landscape. Enough evidence is now available, and synthesized here, which illustrates that multiple strategies work at local levels towards saving insects. We now need to expand these locally-crafted strategies globally. Tangible actions include ensuring maintenance of biotic complexity, especially through improving temporal and spatial heterogeneity, functional connectivity, and metapopulation dynamics, while maintaining unique habitats, across landscape mosaics, as well as instigating better communication. Key is to have more expansive sustainable agriculture and forestry, improved regulation and prevention of environmental risks, and greater recognition of protected areas alongside agro-ecology in novel landscapes. Future-proofing insect diversity is now critical, with the benefits far reaching, including continued provision of valuable ecosystem services and the conservation of a rich and impressive component of Earth's biodiversity.Peer reviewe

SLC4A10 mutation causes a neurological disorder associated with impaired GABAergic transmission

SLC4A10 is a plasma-membrane bound transporter which utilizes the Na+ gradient to drive cellular HCO3- uptake, thus mediating acid extrusion. In the mammalian brain, SLC4A10 is expressed in principal neurons and interneurons, as well as in epithelial cells of the choroid plexus, the organ regulating the production of cerebrospinal fluid. Using next generation sequencing on samples from five unrelated families encompassing ten affected individuals, we show that biallelic SLC4A10 loss-of-function variants cause a clinically recognizable neurodevelopmental disorder in humans. The cardinal clinical features of the condition include hypotonia in infancy, delayed psychomotor development across all domains and typically severe intellectual impairment. Affected individuals commonly display traits associated with autistic spectrum disorders including anxiety, hyperactivity and stereotyped movements. In two cases isolated episodes of seizures were reported in the first few years of life, and a further affected child displayed bitemporal epileptogenic discharges on EEG without overt clinical seizures. While occipitofrontal circumference was reported to be normal at birth, progressive postnatal microcephaly evolved in 7 out of 10 affected individuals. Neuroradiological features included a relative preservation of brain volume compared to occipitofrontal circumference, characteristic narrow sometimes 'slit-like' lateral ventricles and corpus callosum abnormalities. Slc4a10 -/- mice, deficient for SLC4A10, also display small lateral brain ventricles and mild behavioral abnormalities including delayed habituation and alterations in the 2-object novel object recognition task. Collapsed brain ventricles in both Slc4a10-/- mice and affected individuals suggests an important role of SLC4A10 in the production of the cerebrospinal fluid. However, it is notable that despite diverse roles of the cerebrospinal fluid in the developing and adult brain, the cortex of Slc4a10-/- mice appears grossly intact. Co-staining with synaptic markers revealed that in neurons, SLC4A10 localizes to inhibitory, but not excitatory, presynapses. These findings are supported by our functional studies which show the release of the inhibitory neurotransmitter GABA is compromised in Slc4a10-/- mice, while the release of the excitatory neurotransmitter glutamate is preserved. Manipulation of intracellular pH partially rescues GABA release. Together our studies define a novel characteristic neurodevelopmental disorder associated with biallelic pathogenic variants in SLC4A10 and highlight the importance of further analyses of the consequences of SLC4A10 loss-of-function for brain development, synaptic transmission and network properties

ENDOR Spectroscopy and DFT Calculations: Evidence for the Hydrogen-Bond Network Within α2 in the PCET of E. coli Ribonucleotide Reductase

Escherichia coli class I ribonucleotide reductase (RNR) catalyzes the conversion of nucleotides to deoxynucleotides and is composed of two subunits: α2 and β2. β2 contains a stable di-iron tyrosyl radical (Y[subscript 122]•) cofactor required to generate a thiyl radical (C[subscript 439]•) in α2 over a distance of 35 Å, which in turn initiates the chemistry of the reduction process. The radical transfer process is proposed to occur by proton-coupled electron transfer (PCET) via a specific pathway: Y[subscript 122] ⇆ W[subscript 48][?] ⇆ Y[subscript 356] in β2, across the subunit interface to Y[subscript 731] ⇆ Y[subscript 730] ⇆ C[subscript 439] in α2. Within α2 a colinear PCET model has been proposed. To obtain evidence for this model, 3-amino tyrosine (NH2Y) replaced Y[subscript 730] in α2, and this mutant was incubated with β2, cytidine 5′-diphosphate, and adenosine 5′-triphosphate to generate a NH2Y730• in D2O. [[superscript 2]H]-Electron–nuclear double resonance (ENDOR) spectra at 94 GHz of this intermediate were obtained, and together with DFT models of α2 and quantum chemical calculations allowed assignment of the prominent ENDOR features to two hydrogen bonds likely associated with C[subscript 439] and Y[subscript 731]. A third proton was assigned to a water molecule in close proximity (2.2 Å O–H···O distance) to residue 730. The calculations also suggest that the unusual g-values measured for NH[subscript 2]Y[subscript 730]• are consistent with the combined effect of the hydrogen bonds to Cys[subscript 439] and Tyr[subscript 731], both nearly perpendicular to the ring plane of NH[subscript 2]Y[subscript 730]. The results provide the first experimental evidence for the hydrogen-bond network between the pathway residues in α2 of the active RNR complex, for which no structural data are available.National Institutes of Health (U.S.) (NIH GM29595

CEERS: Spatially Resolved UV and mid-IR Star Formation in Galaxies at 0.2 < z < 2.5: The Picture from the Hubble and James Webb Space Telescopes

We present the mid-IR (MIR) morphologies for 64 star-forming galaxies at 0.210^{9}~M_\odot} using JWST MIRI observations from the Cosmic Evolution Early Release Science survey (CEERS). The MIRI bands span the MIR (7.7--21~$\mu$m), enabling us to measure the effective radii ($R_{\rm{eff}}$) and S\'{e}rsic indexes of these SFGs at rest-frame 6.2 and 7.7 $\mu$m, which contains strong emission from Polycyclic aromatic hydrocarbon (PAH) features, a well-established tracer of star formation in galaxies. We define a ``PAH-band'' as the MIRI bandpass that contains these features at the redshift of the galaxy. We then compare the galaxy morphologies in the PAH-bands to those in rest-frame Near-UV (NUV) using HST ACS/F435W or ACS/F606W and optical/near-IR using HST WFC3/F160W imaging from UVCANDELS and CANDELS, where the NUV-band and F160W trace the profile of (unobscured) massive stars and the stellar continuum, respectively. The $R_{\rm{eff}}$ of galaxies in the PAH-band are slightly smaller ($\sim$10\%) than those in F160W for galaxies with $\rm{M_*\gtrsim10^{9.5}~M_\odot}$ at $z\leq1.2$, but the PAH-band and F160W have a similar fractions of light within 1 kpc. In contrast, the $R_{\rm{eff}}$ of galaxies in the NUV-band are larger, with lower fractions of light within 1 kpc compared to F160W for galaxies at $z\leq1.2$. Using the MIRI data to estimate the $\rm{SFR_{\rm{IR}}}$ surface density, we find the correlation between the $\rm{SFR_{\rm{IR}}}$ surface density and stellar mass has a steeper slope than that of the $\rm{SFR_{\rm{UV}}}$ surface density and stellar mass, suggesting more massive galaxies having increasing amounts of obscured fraction of star formation in their inner regions. This paper demonstrates how the high-angular resolution data from JWST/MIRI can reveal new information about the morphology of obscured-star formation.Comment: 28 pages, 11 figures, Accepted by Ap