Morphomechanical Innovation Drives Explosive Seed Dispersal.

How mechanical and biological processes are coordinated across cells, tissues, and organs to produce complex traits is a key question in biology. Cardamine hirsuta, a relative of Arabidopsis thaliana, uses an explosive mechanism to disperse its seeds. We show that this trait evolved through morphomechanical innovations at different spatial scales. At the organ scale, tension within the fruit wall generates the elastic energy required for explosion. This tension is produced by differential contraction of fruit wall tissues through an active mechanism involving turgor pressure, cell geometry, and wall properties of the epidermis. Explosive release of this tension is controlled at the cellular scale by asymmetric lignin deposition within endocarp b cells-a striking pattern that is strictly associated with explosive pod shatter across the Brassicaceae plant family. By bridging these different scales, we present an integrated mechanism for explosive seed dispersal that links evolutionary novelty with complex trait innovation. VIDEO ABSTRACT.

PLEKHS1 drives PI3Ks and remodels pathway homeostasis in PTEN-null prostate.

The PIP3/PI3K network is a central regulator of metabolism and is frequently activated in cancer, commonly by loss of the PIP3/PI(3,4)P2 phosphatase, PTEN. Despite huge research investment, the drivers of the PI3K network in normal tissues and how they adapt to overactivation are unclear. We find that in healthy mouse prostate PI3K activity is driven by RTK/IRS signaling and constrained by pathway feedback. In the absence of PTEN, the network is dramatically remodeled. A poorly understood YXXM- and PIP3/PI(3,4)P2-binding PH domain-containing adaptor, PLEKHS1, became the dominant activator and was required to sustain PIP3, AKT phosphorylation, and growth in PTEN-null prostate. This was because PLEKHS1 evaded pathway-feedback and experienced enhanced PI3K- and Src-family kinase-dependent phosphorylation of Y258XXM, eliciting PI3K activation. hPLEKHS1 mRNA and activating Y419 phosphorylation of hSrc correlated with PI3K pathway activity in human prostate cancers. We propose that in PTEN-null cells receptor-independent, Src-dependent tyrosine phosphorylation of PLEKHS1 creates positive feedback that escapes homeostasis, drives PIP3 signaling, and supports tumor progression.

An mTORC1-to-CDK1 Switch Maintains Autophagy Suppression during Mitosis.

Since nuclear envelope breakdown occurs during mitosis in metazoan cells, it has been proposed that macroautophagy must be inhibited to maintain genome integrity. However, repression of macroautophagy during mitosis remains controversial and mechanistic detail limited to the suggestion that CDK1 phosphorylates VPS34. Here, we show that initiation of macroautophagy, measured by the translocation of the ULK complex to autophagic puncta, is repressed during mitosis, even when mTORC1 is inhibited. Indeed, mTORC1 is inactive during mitosis, reflecting its failure to localize to lysosomes due to CDK1-dependent RAPTOR phosphorylation. While mTORC1 normally represses autophagy via phosphorylation of ULK1, ATG13, ATG14, and TFEB, we show that the mitotic phosphorylation of these autophagy regulators, including at known repressive sites, is dependent on CDK1 but independent of mTOR. Thus, CDK1 substitutes for inhibited mTORC1 as the master regulator of macroautophagy during mitosis, uncoupling autophagy regulation from nutrient status to ensure repression of macroautophagy during mitosis.

NANOGP1, a tandem duplicate of NANOG, exhibits partial functional conservation in human naïve pluripotent stem cells.

Gene duplication events can drive evolution by providing genetic material for new gene functions, and they create opportunities for diverse developmental strategies to emerge between species. To study the contribution of duplicated genes to human early development, we examined the evolution and function of NANOGP1, a tandem duplicate of the transcription factor NANOG. We found that NANOGP1 and NANOG have overlapping but distinct expression profiles, with high NANOGP1 expression restricted to early epiblast cells and naïve-state pluripotent stem cells. Sequence analysis and epitope-tagging revealed that NANOGP1 is protein coding with an intact homeobox domain. The duplication that created NANOGP1 occurred earlier in primate evolution than previously thought and has been retained only in great apes, whereas Old World monkeys have disabled the gene in different ways, including homeodomain point mutations. NANOGP1 is a strong inducer of naïve pluripotency; however, unlike NANOG, it is not required to maintain the undifferentiated status of human naïve pluripotent cells. By retaining expression, sequence and partial functional conservation with its ancestral copy, NANOGP1 exemplifies how gene duplication and subfunctionalisation can contribute to transcription factor activity in human pluripotency and development.

Mechanism and spectrum of inhibition of a 4'-cyano modified nucleotide analog against diverse RNA polymerases of prototypic respiratory RNA viruses.

The development of safe and effective broad-spectrum antivirals that target the replication machinery of respiratory viruses is of high priority in pandemic preparedness programs. Here, we studied the mechanism of action of a newly discovered nucleotide analog against diverse RNA-dependent RNA polymerases (RdRps) of prototypic respiratory viruses. GS-646939 is the active 5'-triphosphate metabolite of a 4'-cyano modified C-adenosine analog phosphoramidate prodrug GS-7682. Enzyme kinetics show that the RdRps of human rhinovirus type 16 (HRV-16) and enterovirus 71 incorporate GS-646939 with unprecedented selectivity; GS-646939 is incorporated 20-50-fold more efficiently than its natural ATP counterpart. The RdRp complex of respiratory syncytial virus and human metapneumovirus incorporate GS-646939 and ATP with similar efficiency. In contrast, influenza B RdRp shows a clear preference for ATP and human mitochondrial RNA polymerase does not show significant incorporation of GS-646939. Once incorporated into the nascent RNA strand, GS-646939 acts as a chain terminator although higher NTP concentrations can partially overcome inhibition for some polymerases. Modeling and biochemical data suggest that the 4'-modification inhibits RdRp translocation. Comparative studies with GS-443902, the active triphosphate form of the 1'-cyano modified prodrugs remdesivir and obeldesivir, reveal not only different mechanisms of inhibition, but also differences in the spectrum of inhibition of viral polymerases. In conclusion, 1'-cyano and 4'-cyano modifications of nucleotide analogs provide complementary strategies to target the polymerase of several families of respiratory RNA viruses.

CDS2 expression regulates de novo phosphatidic acid synthesis.

CDS enzymes (CDS1 and 2 in mammals) convert phosphatidic acid (PA) to CDP-DG, an essential intermediate in the de novo synthesis of PI. Genetic deletion of CDS2 in primary mouse macrophages resulted in only modest changes in the steady-state levels of major phospholipid species, including PI, but substantial increases in several species of PA, CDP-DG, DG and TG. Stable isotope labelling experiments employing both 13C6- and 13C6D7-glucose revealed loss of CDS2 resulted in a minimal reduction in the rate of de novo PI synthesis but a substantial increase in the rate of de novo PA synthesis from G3P, derived from DHAP via glycolysis. This increased synthesis of PA provides a potential explanation for normal basal PI synthesis in the face of reduced CDS capacity (via increased provision of substrate to CDS1) and increased synthesis of DG and TG (via increased provision of substrate to LIPINs). However, under conditions of sustained GPCR-stimulation of PLC, CDS2-deficient macrophages were unable to maintain enhanced rates of PI synthesis via the 'PI cycle', leading to a substantial loss of PI. CDS2-deficient macrophages also exhibited significant defects in calcium homeostasis which were unrelated to the activation of PLC and thus probably an indirect effect of increased basal PA. These experiments reveal that an important homeostatic response in mammalian cells to a reduction in CDS capacity is increased de novo synthesis of PA, likely related to maintaining normal levels of PI, and provides a new interpretation of previous work describing pleiotropic effects of CDS2 deletion on lipid metabolism/signalling.

Inducing ipsilateral motor-evoked potentials in the biceps brachii muscle in healthy humans.

To assess reticulospinal tract excitability, high-intensity transcranial magnetic stimulation (TMS) has been used to elicit ipsilateral motor-evoked potentials (iMEPs). However, there is no consensus on robust and valid methods for use in human studies. The present study proposes a standardized method for eliciting and analysing iMEPs in the biceps brachii. Twenty-four healthy young adults participated in this study. Electromyography (EMG) electrodes recorded contralateral MEPs (cMEPs) from the right and iMEPs from the left biceps brachii. A dynamic preacher curl task was used with ~15% of the subject's one-repetition maximum load. The protocol included maximal compound action potential (M-max) determination of the right biceps brachii muscle, TMS hotspot determination, and four sets of five repetitions where 100% stimulator output was delivered at an elbow angle of 110° of flexion. We normalized cMEP amplitude by M-max (% M-max) and iMEP by cMEP amplitude ratio (ICAR). Clear iMEPs above background EMG were observed in 21 subjects (88%, ICAR = .31 ± .19). Good-to-excellent agreement (intraclass correlation coefficient [ICC] = .795-1.000) and low bias (.01-.08 mV and .60-1.11 ms) were demonstrated when comparing two different analysis methods (i.e. fixed time-window vs. manual onset detection) to determine the cMEP and iMEP amplitude and latency, respectively. Most subjects demonstrated clear iMEPs above background EMG triggered at a pre-determined joint angle during a light-load dynamic preacher curl exercise. Similar results were obtained when comparing a single-trial manual identification of iMEP and a semi-automated time-window data analysis approach.

Strength-trained adults demonstrate greater corticoreticular activation versus untrained controls.

The rapid increase in strength following strength-training involves neural adaptations, however, their specific localisation remains elusive. Prior focus on corticospinal responses prompts this study to explore the understudied cortical/subcortical adaptations, particularly cortico-reticulospinal tract responses, comparing healthy strength-trained adults to untrained peers. Fifteen chronically strength-trained individuals (≥2 years of training, mean age: 24 ± 7 years) were compared with 11 age-matched untrained participants (mean age: 26 ± 8 years). Assessments included maximal voluntary force (MVF), corticospinal excitability using transcranial magnetic stimulation (TMS), spinal excitability (cervicomedullary stimulation), voluntary activation (VA) and reticulospinal tract (RST) excitability, utilizing StartReact responses and ipsilateral motor-evoked potentials (iMEPs) for the flexor carpi radialis muscle. Trained participants had higher normalized MVF (6.4 ± 1.1 N/kg) than the untrained participants (4.8 ± 1.3 N/kg) (p = .003). Intracortical facilitation was higher in the strength-trained group (156 ± 49%) (p = .02), along with greater VA (98 ± 3.2%) (p = .002). The strength-trained group displayed reduced short-interval-intracortical inhibition (88 ± 8.0%) compared with the untrained group (69 ± 17.5%) (p < .001). Strength-trained individuals exhibited a greater normalized rate of force development (38.8 ± 10.1 N·s-1/kg) (p < .009), greater reticulospinal gain (2.5 ± 1.4) (p = .02) and higher ipsilateral-to-contralateral MEP ratios compared with the untrained group (p = .03). Strength-trained individuals displayed greater excitability within the intrinsic connections of the primary motor cortex and the RST. These results suggest greater synaptic input from the descending cortico-reticulospinal tract to α-motoneurons in strength-trained individuals, thereby contributing to the observed increase in VA and MVF.

Social Decision-Making Analysis: A General Approach to Inform Decisions on Resources in the Public Sector.

OBJECTIVES: Public expenditure aims to achieve social objectives by improving a range of socially valuable attributes of benefit (arguments in a social welfare function). Public expenditure is typically allocated to public sector budgets, where budget holders are tasked with meeting a subset of social objectives. METHODS: Decision makers require an evidence-based assessment of whether a proposed investment is likely to be worthwhile given existing levels of public expenditure. However, others also require some assessment of whether the overall level and allocation of public expenditure are appropriate. This article proposes a more general theoretical framework for economic evaluation that addresses both these questions. RESULTS: Using a stylized example of the economic evaluation of a new intervention in a simplified UK context, we show that this more general framework can support decisions beyond the approval or rejection of single projects. It shows that broader considerations about the level and allocation of public expenditure are possible and necessary when evaluating specific investments, which requires evidence of the range of benefits offered by marginal changes in different types of public expenditure and normative choices of how the attributes of benefit gained and forgone are valued. CONCLUSIONS: The proposed framework shows how to assess the value of a proposed investment and whether and how the overall level of public expenditure and its allocation across public sector budgets might be changed. It highlights that cost-benefit analysis and cost-effectiveness analysis can be viewed as special cases of this framework, identifying the weakness with each.

Providing medically assisted dying in Canada: a qualitative study of emotional and moral impact.

PURPOSE: Medical assistance in dying (MAiD) in Canada places the medical provider at the centre of the process. The MAiD provider holds primary responsibility for determining eligibility and becomes acquainted with patients' inner desires and expressions of suffering. This is followed by the MAiD procedure of administering the lethal agent and being present at the death of eligible patients. We report participants' perceptions of the emotional and moral impacts of this role. METHODOLOGY: Two years after MAiD was legalised in Canada, 22 early-adopting physician providers were interviewed. Data were examined using both phenomenological analysis and a novel ChatGPT-enhanced analysis of an anonymised subset of interview excerpts. FINDINGS: Participants described MAiD as emotionally provocative with both challenges and rewards. Providers expressed a positive moral impact when helping to optimise a patient's autonomy and moral comfort with their role in relieving suffering. Providers experienced tensions around professional duty and balancing self with service to others. Personal choice and patient gratitude enhanced the provider experience, while uncertainty and conflict added difficulty. CONCLUSIONS: Participants described MAiD provision as strongly aligned with a patient-centred ethos of practice. This study suggests that, despite challenges, providing MAiD can be a meaningful and satisfying practice for physicians. Understanding the emotional and moral impact and factors that enhance or detract from the providers' experience allows future stakeholders to design and regulate assisted dying in ways congruent with the interests of patients, providers, families and society.

The Effects of the StartReact on Reaction Time, Rate of Force Development, and Muscle Activity in Biceps Brachii.

The StartReact test, increasingly popular for assessing cortico-reticular functioning, is a valid method to influence the firing of reticulospinal tract neurons noninvasively. However, there remains limited evidence on how different stimuli employed in the StartReact test impact motor output in humans. The present study tested elbow flexor responses of 33 adults (aged 26-48 years) to visual stimuli only (LED light), audio-visual (80 dB) stimuli, and startle-inducing audio-visual (120 dB) stimuli sitting with the arm supinated in an electromechanical dynamometer. Surface electromyogram (EMG) recorded muscle activity from the right biceps brachii muscle. Participants were presented with 20 stimuli for each of the three conditions in pseudorandom order with interstimulus intervals of ~8 s. Reaction times were calculated from the stimulus trigger to the initial rise in the EMG signal above 7 × SD from baseline. Rate of torque development (RTD) and EMG signals were recorded throughout and analyzed over their initial 50 ms and 100 ms time-windows. Reaction times were reduced from visual (169 ± 23) to audio-visual (140 ± 23) and further reduced to startle-inducing audio-visual stimuli (108 ± 19, p < 0.001). While RTD and EMG were consistently greatest following startle-inducing stimuli (p < 0.001), they were also enhanced following all audio-visual stimuli over 100 ms (p < 0.05). It appears that startle-inducing audio-visual stimuli result in shorter reaction times, increased RTD, and enhanced muscle activity within the initial 50 ms, likely from subcortical upregulation. However, the 100 ms time-window suggests cortical upregulation following all audio-visual stimuli considering the longer transmission times.

Two-week step-reduction has limited negative effects on physical function and metabolic health in older adults.

PURPOSE: This study determined the effects of a 2-week step-reduction period followed by 4-week exercise rehabilitation on physical function, body composition, and metabolic health in 70-80-year-olds asymptomatic for injury/illness. METHODS: A parallel-group randomized controlled trial (ENDURE-study, NCT04997447) was used, where 66 older adults (79% female) were randomized to either intervention or control group. The intervention group reduced daily steps to < 2000, monitored by accelerometer, for two weeks (Period I) and then step-reduction requirement was removed with an additional exercise rehabilitation 4 times per week for 4 weeks (Period II). The control group continued their habitual physical activity throughout with no additional exercise intervention. Laboratory tests were performed at baseline, after Period I and Period II. The primary outcome measure was leg lean mass (LLM). Secondary outcomes included total lean and fat mass, blood glucose and insulin concentration, LDL cholesterol and HDL cholesterol concentration, maximal isometric leg press force (MVC), and chair rise and stair climb performance. RESULTS: LLM remained unchanged in both groups and no changes occurred in physical function nor body composition in the intervention group in Period I. HDL cholesterol concentration reduced after Period I (from 1.62 ± 0.37 to 1.55 ± 0.36 mmol·L-1, P = 0.017) and returned to baseline after Period II (1.66 ± 0.38 mmol·L-1) in the intervention group (Time × Group interaction: P = 0.065). MVC improved after Period II only (Time × Group interaction: P = 0.009, Δ% = 15%, P < 0.001). CONCLUSION: Short-term step-reduction in healthy older adults may not be as detrimental to health or physical function as currently thought.

Cortical and spinal responses to short-term strength training and detraining in young and older adults in rectus femoris muscle.

INTRODUCTION: Strength training mitigates the age-related decline in strength and muscle activation but limited evidence exists on specific motor pathway adaptations. METHODS: Eleven young (22-34 years) and ten older (66-80 years) adults underwent five testing sessions where lumbar-evoked potentials (LEPs) and motor-evoked potentials (MEPs) were measured during 20 and 60% of maximum voluntary contraction (MVC). Ten stimulations, randomly delivered, targeted 25% of maximum compound action potential for LEPs and 120, 140, and 160% of active motor threshold (aMT) for MEPs. The 7-week whole-body resistance training intervention included five exercises, e.g., knee extension (5 sets) and leg press (3 sets), performed twice weekly and was followed by 4 weeks of detraining. RESULTS: Young had higher MVC (~ 63 N·m, p = 0.006), 1-RM (~ 50 kg, p = 0.002), and lower aMT (~ 9%, p = 0.030) than older adults at baseline. Young increased 1-RM (+ 18 kg, p < 0.001), skeletal muscle mass (SMM) (+ 0.9 kg, p = 0.009), and LEP amplitude (+ 0.174, p < 0.001) during 20% MVC. Older adults increased MVC (+ 13 N·m, p = 0.014), however, they experienced decreased LEP amplitude (- 0.241, p < 0.001) during 20% MVC and MEP amplitude reductions at 120% (- 0.157, p = 0.034), 140% (- 0.196, p = 0.026), and 160% (- 0.210, p = 0.006) aMT during 60% MVC trials. After detraining, young and older adults decreased 1-RM, while young adults decreased SMM. CONCLUSION: Higher aMT and MEP amplitude in older adults were concomitant with lower baseline strength. Training increased strength in both groups, but divergent modifications in cortico-spinal activity occurred. Results suggest that the primary locus of adaptation occurs at the spinal level.

Time Course of Neuromuscular Fatigue During Different Resistance Exercise Loadings in Power Athletes, Strength Athletes, and Nonathletes.

ABSTRACT: Kotikangas, J, Walker, S, Peltonen, H, and Häkkinen, K. Time course of neuromuscular fatigue during different resistance exercise loadings in power athletes, strength athletes, and nonathletes. J Strength Cond Res 38(7): 1231-1242, 2024-Training background may affect the progression of fatigue and neuromuscular strategies to compensate for fatigue during resistance exercises. Thus, our aim was to examine how training background affects the time course of neuromuscular fatigue in response to different resistance exercises. Power athletes (PA, n = 8), strength athletes (SA, n = 8), and nonathletes (NA, n = 7) performed hypertrophic loading (HL, 5 × 10 × 10RM), maximal strength loadings (MSL, 7 × 3 × 3RM) and power loadings (PL, 7 × 6 × 50% of 1 repetition maximum) in back squat. Average power (AP), average velocity (VEL), surface electromyography (sEMG) amplitude (sEMGRMS), and sEMG mean power frequency (sEMGMPF) were measured within all loading sets. During PL, greater decreases in AP occurred from the beginning of SET1 to SET7 and in VEL to both SET4 and SET7 in NA compared with SA (p < 0.01, g > 1.84). During HL, there were various significant group × repetition interactions in AP within and between sets (p < 0.05, ηp2 > 0.307), but post hoc tests did not indicate significant differences between the groups (p > 0.05, g = 0.01-0.93). During MSL and HL, significant within-set and between-set decreases occurred in AP (p < 0.001, ηp2 > 0.701) and VEL (p < 0.001, ηp2 > 0.748) concurrently with increases in sEMGRMS (p < 0.01, ηp2 > 0.323) and decreases in sEMGMPF (p < 0.01, ηp2 > 0.242) in all groups. In conclusion, SA showed fatigue resistance by maintaining higher AP and VEL throughout PL. During HL, PA tended to have the greatest initial fatigue response in AP, but between-group comparisons were nonsignificant despite large effect sizes (g > 0.8). The differences in the progression of neuromuscular fatigue may be related to differing neural activation strategies between the groups, but further research confirmation is required.

Modulation of H-reflex and V-wave responses during dynamic balance perturbations.

Motoneuron excitability is possible to measure using H-reflex and V-wave responses. However, it is not known how the motor control is organized, how the H-reflex and V-wave responses modulate and how repeatable these are during dynamic balance perturbations. To assess the repeatability, 16 participants (8 men, 8 women) went through two, identical measurement sessions with ~ 48 h intervals, where maximal isometric plantar flexion (IMVC) and dynamic balance perturbations in horizontal, anterior-posterior direction were performed. Soleus muscle (SOL) neural modulation during balance perturbations were measured at 40, 70, 100 and 130 ms after ankle movement by using both H-reflex and V-wave methods. V-wave, which depicts the magnitude of efferent motoneuronal output (Bergmann et al. in JAMA 8:e77705, 2013), was significantly enhanced as early as 70 ms after the ankle movement. Both the ratio of M-wave-normalized V-wave (0.022-0.076, p < 0.001) and H-reflex (0.386-0.523, p < 0.001) increased significantly at the latency of 70 ms compared to the latency of 40 ms and remained at these levels at latter latencies. In addition, M-wave normalized V-wave/H-reflex ratio increased from 0.056 to 0.179 (p < 0.001). The repeatability of V-wave demonstrated moderate-to-substantial repeatability (ICC = 0.774-0.912) whereas the H-reflex was more variable showing fair-to-substantial repeatability (ICC = 0.581-0.855). As a conclusion, V-wave was enhanced already at 70 ms after the perturbation, which may indicate that increased activation of motoneurons occurred due to changes in descending drive. Since this is a short time-period for voluntary activity, some other, potentially subcortical responses might be involved for V-wave increment rather than voluntary drive. Our results addressed the usability and repeatability of V-wave method during dynamic conditions, which can be utilized in future studies.

AIM2 Suppresses Inflammation and Epithelial Cell Proliferation during Glomerulonephritis.

Absent in melanoma-2 (AIM2) is an inflammasome-forming innate immune sensor for dsDNA but also exhibits inflammasome-independent functions such as restricting cellular proliferation. AIM2 is expressed in the kidney, but its localization and function are not fully characterized. In normal human glomeruli, AIM2 localized to podocytes. In patients with glomerulonephritis, AIM2 expression increased in CD44+-activated parietal epithelial cells within glomerular crescents. To explore AIM2 effects in glomerular disease, studies in Aim2 -/- mice were performed. Aim2-/- glomeruli showed reduced expression of Wilm tumor gene-1 (WT1), WT1-driven podocyte genes, and increased proliferation in outgrowth assays. In a nephrotoxic serum (NTS)-induced glomerulonephritis model, Aim2-/- (B6) mice exhibited more severe glomerular crescent formation, tubular injury, inflammation, and proteinuria compared with wild-type controls. Inflammasome activation markers were absent in both Aim2 -/- and wild-type kidneys, despite an increased inflammatory transcriptomic signature in Aim2 -/- mice. Aim2 -/- mice also demonstrated dysregulated cellular proliferation and an increase in CD44+ parietal epithelial cells during glomerulonephritis. The augmented inflammation and epithelial cell proliferation in Aim2 -/- (B6) mice was not due to genetic background, as Aim2 -/- (B6.129) mice demonstrated a similar phenotype during NTS glomerulonephritis. The AIM2-like receptor (ALR) locus was necessary for the inflammatory glomerulonephritis phenotype observed in Aim2 -/- mice, as NTS-treated ALR -/- mice displayed equal levels of injury as wild-type controls. Podocyte outgrowth from ALR -/- glomeruli was still increased, however, confirming that the ALR locus is dispensable for AIM2 effects on epithelial cell proliferation. These results identify a noncanonical role for AIM2 in suppressing inflammation and epithelial cell proliferation during glomerulonephritis.

Supporting the revision of the health benefits package in Uganda: A constrained optimisation approach.

This study demonstrates how the linear constrained optimization approach can be used to design a health benefits package (HBP) which maximises the net disability adjusted life years (DALYs) averted given the health system constraints faced by a country, and how the approach can help assess the marginal value of relaxing health system constraints. In the analysis performed for Uganda, 45 interventions were included in the HBP in the base scenario, resulting in a total of 26.7 million net DALYs averted. When task shifting of pharmacists' and nutrition officers' tasks to nurses is allowed, 73 interventions were included in the HBP resulting in a total of 32 million net DALYs averted (a 20% increase). Further, investing only $58 towards hiring additional nutrition officers' time could avert one net DALY; this increased to $60 and $64 for pharmacists and nurses respectively, and $100,000 for expanding the consumable budget, since human resources present the main constraint to the system.

Smart wing rotation and trailing-edge vortices enable high frequency mosquito flight.

Mosquitoes exhibit unusual wing kinematics; their long, slender wings flap at remarkably high frequencies for their size (>800 Hz)and with lower stroke amplitudes than any other insect group. This shifts weight support away from the translation-dominated, aerodynamic mechanisms used by most insects, as well as by helicopters and aeroplanes, towards poorly understood rotational mechanisms that occur when pitching at the end of each half-stroke. Here we report free-flight mosquito wing kinematics, solve the full Navier-Stokes equations using computational fluid dynamics with overset grids, and validate our results with in vivo flow measurements. We show that, although mosquitoes use familiar separated flow patterns, much of the aerodynamic force that supports their weight is generated in a manner unlike any previously described for a flying animal. There are three key features: leading-edge vortices (a well-known mechanism that appears to be almost ubiquitous in insect flight), trailing-edge vortices caused by a form of wake capture at stroke reversal, and rotational drag. The two new elements are largely independent of the wing velocity, instead relying on rapid changes in the pitch angle (wing rotation) at the end of each half-stroke, and they are therefore relatively immune to the shallow flapping amplitude. Moreover, these mechanisms are particularly well suited to high aspect ratio mosquito wings.

Epistemic problems with mental health legislation in the doctor-patient relationship.

Mental health legislation that requires patients to accept 'care' has come under increasing scrutiny, prompted primarily by a human rights ethic. Epistemic issues in mental health have received some attention, however, less attention has been paid to the possible epistemic problems of mental health legislation existing. In this manuscript, we examine the epistemic problems that arise from the presence of such legislation, both for patients without a prior experience of being detained under such legislation and for those with this experience. We also examine how the doctor is legally obligated to compound the epistemic problems by the knowledge they prioritise and the failure to generate new knowledge. Specifically, we describe the problems of testimonial epistemic injustice, epistemic silencing, and epistemic smothering, and address the possible justification provided by epistemic paternalism. We suggest that there is no reasonable epistemic justification for mental health legislation that creates an environment that fundamentally unbalances the doctor-patient relationship. Significant positive reasons to counterbalance this are needed to justify the continuation of such legislation.

Contraction intensity modulates spinal excitability during transcranial magnetic stimulation-evoked silent period in rectus femoris muscle.

PURPOSE: Reduced spinal excitability during the transcranial magnetic stimulation (TMS) silent period (SP) has recently been shown to last longer than previously thought in the upper limbs, as assessed via spinal electrical stimulation. Further, there is reason to expect that contraction intensity affects the duration of the reduced spinal excitability. METHODS: This study investigated spinal excitability at different time delays within the TMS-evoked SP in m.rectus femoris. Fifteen participants performed non-fatiguing isometric knee extensions at 25%, 50% and 75% of maximum voluntary contraction (MVC). Lumbar stimulation (LS) induced a lumbar-evoked potential (LEP) of 50% resting M-max. TMS stimulator output induced a SP lasting ~ 200 ms. In each contraction, a LEP (unconditioned) was delivered ~ 2-3 s prior to TMS, which was followed by a second LEP (conditioned) 60, 90, 120 or 150 ms into the silent period. Five contractions were performed at each contraction intensity and for each time delay in random order. RESULTS: Compared to the unconditioned LEP, the conditioned LEP amplitude was reduced (- 28 ± 34%, p = 0.007) only at 60 ms during 25% of MVC. Conditioned LEP amplitudes during 50% and 75% of MVC were reduced at 60 ms (- 37 ± 47%, p = 0.009 and - 37 ± 42%, p = 0.005, respectively) and 150 ms (- 30% ± 37%, p = 0.0083 and - 37 ± 43%, p = 0.005, respectively). LEP amplitude at 90 ms during 50% of MVC also reduced (- 25 ± 35%, p = 0.013). CONCLUSION: Reduced spinal excitability is extended during 50% and 75% of MVC. In future, paired TMS-LS could be a potential method to understand changes in spinal excitability during SP (at different contraction intensities) when testing various neurophysiological phenomena.