Execution: the Critical “What’s Next?” in Strategic Human Resource Management

The Human Resource Planning Society’s 1999 State of the Art/Practice (SOTA/P) study was conducted by a virtual team of researchers who interviewed and surveyed 232 human resource and line executives, consultants, and academics worldwide. Looking three to five years ahead, the study probed four basic topics: (1) major emerging trends in external environments, (2) essential organizational capabilities, (3) critical people issues, and (4) the evolving role of the human resource function. This article briefly reports some of the study’s major findings, along with an implied action agenda – the “gotta do’s for the leading edge. Cutting through the complexity, the general tone is one of urgency emanating from the intersection of several underlying themes: the increasing fierceness of competition, the rapid and unrelenting pace of change, the imperatives of marketplace and thus organizational agility, and the corresponding need to buck prevailing trends by attracting and, especially, retaining and capturing the commitment of world-class talent. While it all adds up to a golden opportunity for human resource functions, there is a clear need to get to get on with it – to get better, faster, and smarter – or run the risk of being left in the proverbial dust. Execute or be executed

Transcriptional profiles of genes related to electrophysiological function in Scn5a+/− murine hearts

The Scn5a gene encodes the major pore-forming Nav1.5 (α) subunit, of the voltage-gated Na+ channel in cardiomyocytes. The key role of Nav1.5 in action potential initiation and propagation in both atria and ventricles predisposes organisms lacking Scn5a or carrying Scn5a mutations to cardiac arrhythmogenesis. Loss-of-function Nav1.5 genetic abnormalities account for many cases of the human arrhythmic disorder Brugada syndrome (BrS) and related conduction disorders. A murine model with a heterozygous Scn5a deletion recapitulates many electrophysiological phenotypes of BrS. This study examines the relationships between its Scn5a+/− genotype, resulting transcriptional changes, and the consequent phenotypic presentations of BrS. Of 62 selected protein-coding genes related to cardiomyocyte electrophysiological or homeostatic function, concentrations of mRNA transcribed from 15 differed significantly from wild type (WT). Despite halving apparent ventricular Scn5a transcription heterozygous deletion did not significantly downregulate its atrial expression, raising possibilities of atria-specific feedback mechanisms. Most of the remaining 14 genes whose expression differed significantly between WT and Scn5a+/− animals involved Ca2+ homeostasis specifically in atrial tissue, with no overlap with any ventricular changes. All statistically significant changes in expression were upregulations in the atria and downregulations in the ventricles. This investigation demonstrates the value of future experiments exploring for and clarifying links between transcriptional control of Scn5a and of genes whose protein products coordinate Ca2+ regulation and examining their possible roles in BrS

Transcriptional profiles of genes related to electrophysiological function in Scn5a+/- murine hearts.

The Scn5a gene encodes the major pore-forming Nav 1.5 (α) subunit, of the voltage-gated Na+ channel in cardiomyocytes. The key role of Nav 1.5 in action potential initiation and propagation in both atria and ventricles predisposes organisms lacking Scn5a or carrying Scn5a mutations to cardiac arrhythmogenesis. Loss-of-function Nav 1.5 genetic abnormalities account for many cases of the human arrhythmic disorder Brugada syndrome (BrS) and related conduction disorders. A murine model with a heterozygous Scn5a deletion recapitulates many electrophysiological phenotypes of BrS. This study examines the relationships between its Scn5a+/- genotype, resulting transcriptional changes, and the consequent phenotypic presentations of BrS. Of 62 selected protein-coding genes related to cardiomyocyte electrophysiological or homeostatic function, concentrations of mRNA transcribed from 15 differed significantly from wild type (WT). Despite halving apparent ventricular Scn5a transcription heterozygous deletion did not significantly downregulate its atrial expression, raising possibilities of atria-specific feedback mechanisms. Most of the remaining 14 genes whose expression differed significantly between WT and Scn5a+/- animals involved Ca2+ homeostasis specifically in atrial tissue, with no overlap with any ventricular changes. All statistically significant changes in expression were upregulations in the atria and downregulations in the ventricles. This investigation demonstrates the value of future experiments exploring for and clarifying links between transcriptional control of Scn5a and of genes whose protein products coordinate Ca2+ regulation and examining their possible roles in BrS

Itaconate Links Inhibition of Succinate Dehydrogenase with Macrophage Metabolic Remodeling and Regulation of Inflammation

Remodeling of the tricarboxylic acid (TCA) cycle is a metabolic adaptation accompanying inflammatory macrophage activation. During this process, endogenous metabolites can adopt regulatory roles that govern specific aspects of inflammatory response, as recently shown for succinate, which regulates the pro-inflammatory IL-1β-HIF-1α axis. Itaconate is one of the most highly induced metabolites in activated macrophages, yet its functional significance remains unknown. Here, we show that itaconate modulates macrophage metabolism and effector functions by inhibiting succinate dehydrogenase-mediated oxidation of succinate. Through this action, itaconate exerts anti-inflammatory effects when administered in vitro and in vivo during macrophage activation and ischemia-reperfusion injury. Using newly generated Irg1(−/−) mice, which lack the ability to produce itaconate, we show that endogenous itaconate regulates succinate levels and function, mitochondrial respiration, and inflammatory cytokine production during macrophage activation. These studies highlight itaconate as a major physiological regulator of the global metabolic rewiring and effector functions of inflammatory macrophages

Genetic engineering of potato cultivars for potato tuber moth resistance

Potato tuber moth Phthorimaea operculella (Zeller) is a major insect pest of potato (Solanum tuberosum L) throughout the world, including New Zealand. This thesis investigates two genetic engineering strategies to develop potato cultivars resistant to this pest using cry genes and genes encoding biotin-binding proteins. The crystal proteins of Bacillus thuringiensis are specifically toxic to larvae of certain Lepidoptera, Coleoptera and Diptera. Two cry genes (cry1Ac9 and cry9Aa2), with a series of modifications to their codon use, have been transferred to a range of potato cultivars by an Agrobacterium-mediated transformation system. The transformation efficiency of recovered putative transgenic lines determined that cultivars Iwa and Red Rascal are both highly amenable for transformation and regeneration response. Molecular analysis and larvae feeding trials on potato lines transgenic for either the modified cry1Ac9 or cry9Aa2 genes identified 38 and 31 transgenic lines respectively with normal phenotypic appearance in a containment greenhouse and significantly less leaf damage compared with the non-transgenic controls. To investigate an alternative approach for PTM resistance a chimeric avidin gene, with the expressed protein targeted to the vacuoles of plant cells using a signal peptide from the PPI-I gene from potato, was transformed using three explant sources from cultivars Iwa and Red Rascal. This identified leaf explants as the most convenient and productive explants source for potato transformation relative to stems and roots. Complete larvae mortality was observed in 65% from potato lines transgenic for the avidin gene. A great effect on the phenotypic appearance of the transgenic lines expressing the avidin gene was evident. Avidin concentrations >0.8 nmole/gm of fresh weight, as determined by ELISA, either markedly inhibited larval growth rates or induced complete larval mortality. The field evaluation of 84 potato lines transgenic for either the modified cry1Ac9 and cry9Aa2 genes identified 15 phenotypically normal potato lines transgenic for the cry1Ac9 and 21 for cry9Aa2 genes with significantly reduced larval growth and similar tuber yield to nontransgenic controls

The Post-translational Regulation of Transcription Factor EB (TFEB) in Health and Disease

Transcription factor EB (TFEB) is a basic helix-loop-helix leucine-zipper transcription factor that acts as a master regulator of lysosomal biogenesis, lysosomal exocytosis, and macro-autophagy. TFEB contributes to a wide range of physiological functions, including mitochondrial biogenesis, and innate and adaptive immunity. As such, TFEB is an essential component of cellular adaptation to stressors, ranging from nutrient deprivation to pathogenic invasion. The activity of TFEB depends on its subcellular localisation, turnover, and DNA-binding capacity, all of which are regulated at the post-translational level. Pathological states are characterised by a specific set of stressors, which elicit post-translational modifications that promote gain or loss of TFEB function in the affected tissue. In turn, the resulting increase or decrease in survival of the tissue in which TFEB is more or less active, respectively, may either benefit or harm the organism as a whole. In this way, the post-translational modifications of TFEB account for its otherwise paradoxical protective and deleterious effects on organismal fitness in diseases ranging from neurodegeneration to cancer. In this review, we describe how the intracellular environment characteristic of different diseases alters the post-translational modification profile of TFEB, enabling cellular adaptation to a particular pathological state.We are grateful for funding from the UK Dementia Research Institute (funded by the MRC, Alzheimer’s Research UK and the Alzheimer’s Society), and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). M.T. is funded by the Rosetrees Trust and the Cambridge University School of Clinical Medicine (James Baird Fund and F.E. Elmore Fund). S.K. is funded by the Cambridge Commonwealth, European & International Trust, the Nehru Trust for Cambridge University, and the Trinity-Henry Barlow Scholarship

The post‐translational regulation of transcription factor EB ( TFEB ) in health and disease

Funder: Rosetrees Trust (Rosetrees); doi: http://dx.doi.org/10.13039/501100000833Funder: UK Dementia Research Institute (UK DRI); doi: http://dx.doi.org/10.13039/501100017510Funder: MRC; doi: http://dx.doi.org/10.13039/100018645Funder: Alzheimer's Research UKFunder: Alzheimer's Society; doi: http://dx.doi.org/10.13039/501100000320Funder: Cambridge University School of Clinical MedicineFunder: James Baird FundFunder: F.E. Elmore FundFunder: Cambridge CommonwealthFunder: European & International TrustFunder: Nehru Trust for Cambridge UniversityFunder: Trinity‐Henry Barlow ScholarshipTranscription factor EB (TFEB) is a basic helix–loop–helix leucine zipper transcription factor that acts as a master regulator of lysosomal biogenesis, lysosomal exocytosis, and macro‐autophagy. TFEB contributes to a wide range of physiological functions, including mitochondrial biogenesis and innate and adaptive immunity. As such, TFEB is an essential component of cellular adaptation to stressors, ranging from nutrient deprivation to pathogenic invasion. The activity of TFEB depends on its subcellular localisation, turnover, and DNA‐binding capacity, all of which are regulated at the post‐translational level. Pathological states are characterised by a specific set of stressors, which elicit post‐translational modifications that promote gain or loss of TFEB function in the affected tissue. In turn, the resulting increase or decrease in survival of the tissue in which TFEB is more or less active, respectively, may either benefit or harm the organism as a whole. In this way, the post‐translational modifications of TFEB account for its otherwise paradoxical protective and deleterious effects on organismal fitness in diseases ranging from neurodegeneration to cancer. In this review, we describe how the intracellular environment characteristic of different diseases alters the post‐translational modification profile of TFEB, enabling cellular adaptation to a particular pathological state

Ageing and the autonomic nervous system

The vertebrate nervous system is divided into central (CNS) and peripheral (PNS) components. In turn, the PNS is divided into the autonomic (ANS) and enteric (ENS) nervous systems. Ageing implicates time-related changes to anatomy and physiology in reducing organismal fitness. In the case of the CNS, there exists substantial experimental evidence of the effects of age on individual neuronal and glial function. Although many such changes have yet to be experimentally observed in the PNS, there is considerable evidence of the role of ageing in the decline of ANS function over time. As such, this chapter will argue that the ANS constitutes a paradigm for the physiological consequences of ageing, as well as for their clinical implications. [Abstract copyright: © 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.

Ageing and the Autonomic Nervous System

The vertebrate nervous system is divided into central (CNS) and peripheral (PNS) components. In turn, the PNS is divided into the autonomic (ANS) and enteric (ENS) nervous systems. Ageing implicates time-related changes to anatomy and physiology in reducing organismal fitness. In the case of the CNS, there exists substantial experimental evidence of the effects of age on individual neuronal and glial function. Although many such changes have yet to be experimentally observed in the PNS, there is considerable evidence of the role of ageing in the decline of ANS function over time. As such, this chapter will argue that the ANS constitutes a paradigm for the physiological consequences of ageing, as well as for their clinical implications

Carrier prevalence, secondary household transmission and long-term shedding in two districts during the Escherichia coli O104:H4 outbreak in Germany, 2011

Background: From May-July 2011, Germany experienced a large Shiga toxin-producing E. coli (STEC) O104:H4 outbreak. Our objective was to identify the prevalence of STEC O104:H4 carriers in households in highly affected areas, the rate of secondary household transmissions, and the duration of long-term shedding. Methods: In a cross-sectional study, we recruited case and control households to determine STEC household prevalence; we then conducted a prospective cohort study (≥2-persons households with ≥1 case) for rates of household transmission and shedding duration. Results: For part 1, we recruited 57 case households (62 cases and 93 household contacts) and 36 control households (89 household members). We only detected cases in previously known case households and identified 1 possible adult-to-adult household transmission. For part 2, we followed 14 households and 20 carriers. No secondary household transmission was detected in the prospective follow-up. The longest prolonged shedding lasted >7 months, however, median estimated shedding time was 10-14 days (95% CI: 0-33 days). Three carriers showed intermittent shedding. Conclusions: Prevalence of STEC O104:H4 carriers even in highly affected areas appears to be low. Despite prolonged shedding in some patients, secondary adult-to-adult household transmissions seem to be rare events in the post-diarrheal disease phase