Transcriptome dynamics of CD4+ T cells during malaria maps gradual transit from effector to memory.

The dynamics of CD4+ T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4+ T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (TH1) and follicular helper T (TFH) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated TH1 and TFH trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between TFH and central memory were revealed, with antimalarials modulating these responses and boosting TH1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4+ T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene-gene correlations ( http://haquelab.mdhs.unimelb.edu.au/cd4_memory/ ).

The Ufd1 cofactor determines the linkage specificity of polyubiquitin chain engagement by the AAA+ ATPase Cdc48.

The AAA+ ATPase Cdc48 utilizes the cofactor Ufd1/Npl4 to bind and thread polyubiquitinated substrates for their extraction from complexes or membranes and often for subsequent proteasomal degradation. Previous studies indicated that Cdc48 engages polyubiquitin chains through the Npl4-mediated unfolding of an initiator ubiquitin; yet, the underlying principles remain largely unknown. Using FRET-based assays, we revealed the mechanisms and kinetics of ubiquitin unfolding, insertion into the ATPase, and unfolding of the ubiquitin-attached substrate. We found that Cdc48 uses Ufd1's UT3 domain to bind a K48-linked ubiquitin on the initiator's proximal side of the chain, thereby directing the initiator toward rapid unfolding by Npl4 and engagement by Cdc48. Ubiquitins on the initiator's distal side increase substrate affinity and facilitate unfolding but impede substrate release from Cdc48-Ufd1/Npl4 in the absence of additional cofactors. Our findings explain how Cdc48-UN efficiently processes substrates with K48-linked chains of 4-6 ubiquitins, which represent most cellular polyubiquitinated proteins.

Neurological Improvement by One-Thirds Is Associated With Early Recanalization in Stroke With Large Vessel Occlusion.

BACKGROUND: A proportion of large vessel occlusion strokes demonstrate early recanalization, obviating the initial intention to proceed to endovascular thrombectomy. Neurological improvement is a possible surrogate marker for reperfusion. We aimed to determine the optimal threshold of neurological improvement, as defined by the National Institutes of Health Stroke Scale (NIHSS), which best associates with early recanalization. METHODS: We retrospectively analyzed consecutive patients with large vessel occlusion transferred from primary stroke centers to a tertiary comprehensive stroke center in Melbourne, Australia, for possible endovascular thrombectomy from January 2018 to December 2022. Absolute and percentage changes in NIHSS between transfer, as well as other definitions of neurological improvement, were compared using receiver operating characteristic curve analysis for association with recanalization as defined by the absence of occlusion in the internal carotid artery, middle cerebral artery (M1 or M2 segments), or basilar artery on repeat vascular imaging. RESULTS: Six hundred and fifty-four transferred patients with large vessel occlusion were included in the analysis: mean age was 68.8±14.0 years, 301 (46.0%) were women, and 338 (52%) received intravenous thrombolytics. The proportion of extracranial internal carotid artery, intracranial internal carotid artery, M1, proximal M2, and basilar artery occlusion was 18.8%, 13.6%, 48.3%, 15.0%, and 4.3%, respectively, on initial computed tomography angiogram. Median NIHSSprimary stroke center and NIHSScomprehensive stroke center scores were 15 (interquartile range, 9-18) and 13 (interquartile range, 8-19), respectively. Early recanalization occurred in 82 (13%) patients. NIHSS reduction of ≥33% was the best tradeoff between sensitivity (64%) and specificity (83%) for identifying recanalization. NIHSS reduction of ≥33% had the highest discriminative ability to predict recanalization (area under the curve, 0.735) in comparison with other definitions of neurological improvement. CONCLUSIONS: One-third neurological improvement between the primary hospital and tertiary center was the best predictor of early recanalization.

Phase I Trial Characterizing the Pharmacokinetic Profile of N-803, a Chimeric IL-15 Superagonist, in Healthy Volunteers.

The oncotherapeutic promise of IL-15, a potent immunostimulant, is limited by a short serum t 1/2 The fusion protein N-803 is a chimeric IL-15 superagonist that has a >20-fold longer in vivo t 1/2 versus IL-15. This phase 1 study characterized the pharmacokinetic (PK) profile and safety of N-803 after s.c. administration to healthy human volunteers. Volunteers received two doses of N-803, and after each dose, PK and safety were assessed for 9 d. The primary endpoint was the N-803 PK profile, the secondary endpoint was safety, and immune cell levels and immunogenicity were measures of interest. Serum N-803 concentrations peaked 4 h after administration and declined with a t 1/2 of ∼20 h. N-803 did not cause treatment-emergent serious adverse events (AEs) or grade ≥3 AEs. Injection site reactions, chills, and pyrexia were the most common AEs. Administration of N-803 was well tolerated and accompanied by proliferation of NK cells and CD8+ T cells and sustained increases in the number of NK cells. Our results suggest that N-803 administration can potentiate antitumor immunity.

R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline.

Accumulation of DNA-RNA hybrids in the form of R-loops can result in replication-transcription conflict that leads to the formation of DNA double strand breaks (DSBs). Using null mutants for the two Caenorhabditis elegans genes encoding for RNaseH1 and RNaseH2, we identify novel effects of R-loop accumulation in the germline. R-loop accumulation leads, as expected, to replication stress, followed by the formation of DSBs. A subset of these DSBs are irreparable. However, unlike irreparable DSBs generated in other systems, which trigger permanent cell cycle arrest, germline irreparable DSBs are propagated to oocytes. Despite DNA damage checkpoint activation in the stem cell niche, the signaling cannot be sustained and nuclei with irreparable DNA damage progress into meiosis. Moreover, unlike other forms of DNA damage that increase germline apoptosis, R-loop-generated DSBs remain undetected by the apoptotic checkpoint. This coincides with attenuation of ATM/ATR signaling in mid-to-late meiotic prophase I. These data altogether indicate that in the germline, DSBs that are generated by R-loops can lead to irreparable DSBs that evade cellular machineries designed for damage recognition. These studies implicate germline R-loops as an especially dangerous driver of germline mutagenesis.

The Widened Pipe Model of plant hydraulic evolution.

Shaping global water and carbon cycles, plants lift water from roots to leaves through xylem conduits. The importance of xylem water conduction makes it crucial to understand how natural selection deploys conduit diameters within and across plants. Wider conduits transport more water but are likely more vulnerable to conduction-blocking gas embolisms and cost more for a plant to build, a tension necessarily shaping xylem conduit diameters along plant stems. We build on this expectation to present the Widened Pipe Model (WPM) of plant hydraulic evolution, testing it against a global dataset. The WPM predicts that xylem conduits should be narrowest at the stem tips, widening quickly before plateauing toward the stem base. This universal profile emerges from Pareto modeling of a trade-off between just two competing vectors of natural selection: one favoring rapid widening of conduits tip to base, minimizing hydraulic resistance, and another favoring slow widening of conduits, minimizing carbon cost and embolism risk. Our data spanning terrestrial plant orders, life forms, habitats, and sizes conform closely to WPM predictions. The WPM highlights carbon economy as a powerful vector of natural selection shaping plant function. It further implies that factors that cause resistance in plant conductive systems, such as conduit pit membrane resistance, should scale in exact harmony with tip-to-base conduit widening. Furthermore, the WPM implies that alterations in the environments of individual plants should lead to changes in plant height, for example, shedding terminal branches and resprouting at lower height under drier climates, thus achieving narrower and potentially more embolism-resistant conduits.

Posterior National Institutes of Health Stroke Scale Improves Prognostic Accuracy in Posterior Circulation Stroke.

BACKGROUND AND PURPOSE: The National Institutes of Health Stroke Scale (NIHSS) underestimates clinical severity in posterior circulation stroke and patients presenting with low NIHSS may be considered ineligible for reperfusion therapies. This study aimed to develop a modified version of the NIHSS, the Posterior NIHSS (POST-NIHSS), to improve NIHSS prognostic accuracy for posterior circulation stroke patients with mild-moderate symptoms. METHODS: Clinical data of consecutive posterior circulation stroke patients with mild-moderate symptoms (NIHSS <10), who were conservatively managed, were retrospectively analyzed from the Basilar Artery Treatment and Management registry. Clinical features were assessed within 24 hours of symptom onset; dysphagia was assessed by a speech therapist within 48 hours of symptom onset. Random forest classification algorithm and constrained optimization were used to develop the POST-NIHSS in the derivation cohort. The POST-NIHSS was then validated in a prospective cohort. Poor outcome was defined as modified Rankin Scale score ≥3 at 3 months. RESULTS: We included 202 patients (mean [SD] age 63 [14] years, median NIHSS 3 [interquartile range, 1-5]) in the derivation cohort and 65 patients (mean [SD] age 63 [16] years, median NIHSS 2 [interquartile range, 1-4]) in the validation cohort. In the derivation cohort, age, NIHSS, abnormal cough, dysphagia and gait/truncal ataxia were ranked as the most important predictors of functional outcome. POST-NIHSS was calculated by adding 5 points for abnormal cough, 4 points for dysphagia, and 3 points for gait/truncal ataxia to the baseline NIHSS. In receiver operating characteristic analysis adjusted for age, POST-NIHSS area under receiver operating characteristic curve was 0.80 (95% CI, 0.73-0.87) versus NIHSS area under receiver operating characteristic curve, 0.73 (95% CI, 0.64-0.83), P=0.03. In the validation cohort, POST-NIHSS area under receiver operating characteristic curve was 0.82 (95% CI, 0.69-0.94) versus NIHSS area under receiver operating characteristic curve 0.73 (95% CI, 0.58-0.87), P=0.04. CONCLUSIONS: POST-NIHSS showed higher prognostic accuracy than NIHSS and may be useful to identify posterior circulation stroke patients with NIHSS <10 at higher risk of poor outcome.

Bayesian sample size determination for diagnostic accuracy studies.

The development of a new diagnostic test ideally follows a sequence of stages which, among other aims, evaluate technical performance. This includes an analytical validity study, a diagnostic accuracy study, and an interventional clinical utility study. In this article, we propose a novel Bayesian approach to sample size determination for the diagnostic accuracy study, which takes advantage of information available from the analytical validity stage. We utilize assurance to calculate the required sample size based on the target width of a posterior probability interval and can choose to use or disregard the data from the analytical validity study when subsequently inferring measures of test accuracy. Sensitivity analyses are performed to assess the robustness of the proposed sample size to the choice of prior, and prior-data conflict is evaluated by comparing the data to the prior predictive distributions. We illustrate the proposed approach using a motivating real-life application involving a diagnostic test for ventilator associated pneumonia. Finally, we compare the properties of the approach against commonly used alternatives. The results show that, when suitable prior information is available, the assurance-based approach can reduce the required sample size when compared to alternative approaches.

Variation in cloud immersion, not precipitation, drives leaf trait plasticity and water relations in vascular epiphytes during an extreme drought.

PREMISE: Epiphytes are abundant in ecosystems such as tropical montane cloud forests where low-lying clouds are often in contact with vegetation. Climate projections for these regions include more variability in rainfall and an increase in cloud base heights, which would lead to drier conditions in the soil and atmosphere. While recent studies have examined the effects of drought on epiphytic water relations, the influence that atmospheric moisture has, either alone or in combination with drought, on the health and performance of epiphyte communities remains unclear. METHODS: We conducted a 10-week drought experiment on seven vascular epiphyte species in two shadehouses, one with warmer and drier conditions and another that was cooler and more humid. We measured water relations across control and drought-treatment groups and assessed functional traits of leaves produced during drought conditions to evaluate trait plasticity. RESULTS: Epiphytes exposed to drought and drier atmospheric conditions had a significant reduction in stomatal conductance and leaf water potential and an increase in leaf dry matter. Nonsucculent epiphytes from the drier shadehouse had the greatest shifts in functional traits, whereas succulent epiphytes released stored leaf water to maintain water status. CONCLUSIONS: Individuals in the drier shadehouse had a substantial reduction in performance, whereas drought-treated individuals that experienced cloud immersion displayed minimal changes in water status. Our results indicate that projected increases in the cloud base height will reduce growth and performance of epiphytic communities and that nonsucculent epiphytes may be particularly vulnerable.

Utility of Severity-Based Prehospital Triage for Endovascular Thrombectomy: ACT-FAST Validation Study.

BACKGROUND AND PURPOSE: Severity-based assessment tools may assist in prehospital triage of patients to comprehensive stroke centers (CSCs) for endovascular thrombectomy (EVT), but criticisms regarding diagnostic inaccuracy have not been adequately addressed. This study aimed to quantify the benefits and disadvantages of severity-based triage in a large real-world paramedic validation of the Ambulance Clinical Triage for Acute Stroke Treatment (ACT-FAST) algorithm. METHODS: Ambulance Victoria paramedics assessed the prehospital ACT-FAST algorithm in patients with suspected stroke from November 2017 to July 2019 following an 8-minute training video. All patients were transported to the nearest stroke center as per current guidelines. ACT-FAST diagnostic accuracy was compared with hospital imaging for the presence of large vessel occlusion (LVO) and need for CSC-level care (LVO, intracranial hemorrhage, and tumor). Patient-level time saving to EVT was modeled using a validated Google Maps algorithm. Disadvantages of CSC bypass examined potential thrombolysis delays in non-LVO infarcts, proportion of patients with false-negative EVT, and CSC overburdening. RESULTS: Of 517 prehospital assessments, 168/517 (32.5%) were ACT-FAST positive and 132/517 (25.5%) had LVO. ACT-FAST sensitivity and specificity for LVO was 75.8% and 81.8%, respectively. Positive predictive value was 58.8% for LVO and 80.0% when intracranial hemorrhage and tumor (CSC-level care) were included. Within the metropolitan region, 29/55 (52.7%) of ACT-FAST-positive patients requiring EVT underwent a secondary interhospital transfer. Prehospital bypass with avoidance of secondary transfers was modeled to save 52 minutes (95% CI, 40.0-61.5) to EVT commencement. ACT-FAST was false-positive in 8 patients receiving thrombolysis (8.1% of 99 non-LVO infarcts) and false-negative in 4 patients with EVT requiring secondary transfer (5.4% of 74 EVT cases). CSC bypass was estimated to over-triage 1.1 patients-per-CSC-per-week in our region. CONCLUSIONS: The overall benefits of an ACT-FAST algorithm bypass strategy in expediting EVT and avoiding secondary transfers are estimated to substantially outweigh the disadvantages of potentially delayed thrombolysis and over-triage, with only a small proportion of EVT patients missed.

Anticoagulation prescribing practice following ischaemic strokes in the setting of non-valvular atrial fibrillation.

It is well established that anticoagulation following an ischaemic stroke in the setting of non-valvular atrial fibrillation is an effective means of secondary prevention. However, there is a lack of a solid evidence base to guide both the agent choice and the optimal timing in which to initiate anticoagulation therapy. The decision is complex, and consideration is required to balance the risks between recurrent strokes and potentially causing or exacerbating parenchymal haemorrhages. A clinical audit was performed at a high-volume primary stroke centre looking at anticoagulation prescribing practices among neurologists. We found apixaban was by far the anticoagulation of choice for non-valvular atrial fibrillation. The median time to anticoagulation initiation was Day 1 post transient ischaemic attack, Day 2 post small infarcts, Day 4 post moderate infarcts and Day 5 post large infarcts.

Feminizing effects of exposure to Corexit-enhanced water-accommodated fraction of crude oil in vitro on sex determination in Alligator mississippiensis.

Deepwater Horizon spilled over 200 million gallons of oil into the waters of the Gulf of Mexico in 2010. In an effort to contain the spill, chemical dispersants were applied to minimize the amount of oil reaching coastal shorelines. However, the biological impacts of chemically-dispersed oil are not well characterized, and there is a particular lack of knowledge concerning sublethal long-term effects of exposure. This study examined potential estrogenic effects of CWAF, Corexit 9500-enhanced water-accommodated fraction of oil, by examining its effect on estrogen receptors and sex determination in the American alligator, Alligator mississippiensis. The alligator exhibits temperature-dependent sex determination which is modulated by estrogen signals, and exposure to 17ß-estradiol (E2) and estrogenic compounds in ovo during the thermosensitive period of embryonic development can induce ovarian development at a male-producing temperature (MPT). CWAF induced transactivation up to 50% of the maximum induction by E2 via alligator estrogen receptors in vitro. To determine potential endocrine-disrupting effects of exposure directly on the gonad, gonad-adrenal-mesonephric (GAM) organ complexes were isolated from embryos one day prior to the thermosensitive period and exposed to E2, CWAF, or medium alone in vitro for 8-16 days at MPT. Both CWAF and E2 exposure induced a significant increase in female ratios. CWAF exposure suppressed GAM mRNA abundances of anti-Müllerian hormone (AMH), sex determining region Y-box 9, and aromatase, whereas E2 exposure suppressed AMH and increased Forkhead box protein L2 mRNA abundances in GAM. These results indicate that the observed endocrine-disrupting effects of CWAF are not solely estrogenically mediated, and further investigations are required.

Investigating the Impact of Polymer Functional Groups on the Stability and Activity of Lysozyme-Polymer Conjugates.

Polymers are often conjugated to proteins to improve stability; however, the impact of polymer chain length and functional groups on protein structure and function is not well understood. Here we use RAFT polymerization to grow polymers of different lengths and functionality from a short acrylamide oligomer with a RAFT end group conjugated to lysozyme. We show by X-ray crystallography that enzyme structure is minimally impacted by modification with the RAFT end group. Significant activity toward the negatively charged Micrococcus lysodeicticus cell wall was maintained when lysozyme was modified with cationic polymers. Thermal and chemical stability of the conjugates was characterized using differential scanning fluorimetry and tryptophan fluorescence. All conjugates had a lower melting temperature; however, conjugates containing ionic or substrate mimicking polymers were more resistant to denaturation by guanidine hydrochloride. Our results demonstrate that tailoring polymer functionality can improve conjugate activity and minimize enzymatic inactivation by denaturants.

Well-Defined Macromolecules Using Horseradish Peroxidase as a RAFT Initiase.

Enzymatic catalysis and control over macromolecular architectures from reversible addition-fragmentation chain transfer polymerization (RAFT) are combined to give a new method of making polymers. Horseradish peroxidase (HRP) is used to catalytically generate radicals using hydrogen peroxide and acetylacetone as a mediator. RAFT is used to control the polymer structure. HRP catalyzed RAFT polymerization gives acrylate and acrylamide polymers with relatively narrow molecular weight distributions. The polymerization is rapid, typically exceeding 90% monomer conversion in 30 min. Complex macromolecular architectures including a block copolymer and a protein-polymer conjugate are synthesized using HRP to catalytically initiate RAFT polymerization.

Hydraulic constraints modify optimal photosynthetic profiles in giant sequoia trees.

Optimality theory states that whole-tree carbon gain is maximized when leaf N and photosynthetic capacity profiles are distributed along vertical light gradients such that the marginal gain of nitrogen investment is identical among leaves. However, observed photosynthetic N gradients in trees do not follow this prediction, and the causes for this apparent discrepancy remain uncertain. Our objective was to evaluate how hydraulic limitations potentially modify crown-level optimization in Sequoiadendron giganteum (giant sequoia) trees up to 90 m tall. Leaf water potential (Ψ l ) and branch sap flow closely followed diurnal patterns of solar radiation throughout each tree crown. Minimum leaf water potential correlated negatively with height above ground, while leaf mass per area (LMA), shoot mass per area (SMA), leaf nitrogen content (%N), and bulk leaf stable carbon isotope ratios (δ(13)C) correlated positively with height. We found no significant vertical trends in maximum leaf photosynthesis (A), stomatal conductance (g s), and intrinsic water-use efficiency (A/g s), nor in branch-averaged transpiration (E L), stomatal conductance (G S), and hydraulic conductance (K L). Adjustments in hydraulic architecture appear to partially compensate for increasing hydraulic limitations with height in giant sequoia, allowing them to sustain global maximum summer water use rates exceeding 2000 kg day(-1). However, we found that leaf N and photosynthetic capacity do not follow the vertical light gradient, supporting the hypothesis that increasing limitations on water transport capacity with height modify photosynthetic optimization in tall trees.

Integrative and comparative reproductive biology: From alligators to xenobiotics.

Dr. Louis J. Guillette Jr. thought of himself as a reproductive biologist. However, his interest in reproductive biology transcended organ systems, life history stages, species, and environmental contexts. His integrative and collaborative nature led to diverse and fascinating research projects conducted all over the world. He doesn't leave us with a single legacy. Instead, he entrusts us with several. The purpose of this review is to highlight those legacies, in both breadth and diversity, and to illustrate Dr. Guillette's grand contributions to the field of reproductive biology. He has challenged the field to reconsider how we think about our data, championed development of novel and innovative techniques to measure endocrine function, helped define the field of endocrine disruption, and lead projects to characterize new endocrine disrupting chemicals. He significantly influenced our understanding of evolution, and took bold and important steps to translate all that he has learned into advances in human reproductive health. We hope that after reading this manuscript our audience will appreciate and continue Dr. Guillette's practice of open-minded and passionate collaboration to understand the basic mechanisms driving reproductive physiology and to ultimately apply those findings to protect and improve wildlife and human health.

Design, synthesis and evaluation of XZH-5 analogues as STAT3 inhibitors.

Inhibition of the signaling pathways of signal transducer and activator of transcription 3 (STAT 3) has shown to be a promising strategy to combat cancer. In this paper we report the design, synthesis and evaluation of a novel class of small molecule inhibitors, that is, XZH-5 and its analogues, as promising leads for further development of STAT3 inhibitors. Preliminary SARs was established for XZH-5 and its derivatives; and the binding modes were predicted by molecular docking. Lead compounds with IC50 as low as 6.5µM in breast cancer cell lines and 7.6µM in pancreatic cancer cell lines were identified.

Growth maximization trumps maintenance of leaf conductance in the tallest angiosperm.

Structural and physiological changes that occur as trees grow taller are associated with increased hydraulic constraints on leaf gas exchange, yet it is unclear if leaf-level constraints influence whole-tree growth as trees approach their maximum size. We examined variation in leaf physiology, leaf area to sapwood area ratio (L/S), and annual aboveground growth across a range of tree heights in Eucalyptus regnans. Leaf photosynthetic capacity did not differ among upper crown leaves of individuals 61.1-92.4 m tall. Maximum daily and integrated diurnal stomatal conductance (g s) averaged 36 and 34% higher, respectively, in upper crown leaves of ~60-m-tall, 80-year-old trees than in ~90-m-tall, 300-year-old trees, with larger differences observed on days with a high vapor pressure deficit (VPD). Greater stomatal regulation in taller trees resulted in similar minimum daily leaf water potentials (Ψ L) in shorter and taller trees over a broad range of VPDs. The long-term stomatal limitation on photosynthesis, as inferred from leaf δ (13)C composition, was also greater in taller trees. The δ (13)C of wood indicated that the bulk of photosynthesis used to fuel wood production in the main trunk and branches occurred in the upper crown. L/S increased with tree height, especially after accounting for size-independent variation in crown structure across 27 trees up to 99.8 m tall. Despite greater stomatal limitation of leaf photosynthesis in taller trees, total L explained 95% of the variation in annual aboveground biomass growth among 15 trees measured for annual biomass growth increment in 2006. Our results support a theoretical model proposing that, in the face of increasing hydraulic constraints with height, whole-tree growth is maximized by a resource trade-off that increases L to maximize light capture rather than by reducing L/S to sustain g s.

Guanylin peptides regulate electrolyte and fluid transport in the Gulf toadfish (Opsanus beta) posterior intestine.

The physiological effects of guanylin (GN) and uroguanylin (UGN) on fluid and electrolyte transport in the teleost fish intestine have yet to be thoroughly investigated. In the present study, the effects of GN, UGN, and renoguanylin (RGN; a GN and UGN homolog) on short-circuit current (Isc) and the transport of Cl-, Na+, bicarbonate (HCO3-), and fluid in the Gulf toadfish (Opsanus beta) intestine were determined using Ussing chambers, pH-stat titration, and intestinal sac experiments. GN, UGN, and RGN reversed the Isc of the posterior intestine (absorptive-to-secretory), but not of the anterior intestine. RGN decreased baseline HCO3- secretion, but increased Cl- and fluid secretion in the posterior intestine. The secretory response of the posterior intestine coincides with the presence of basolateral NKCC1 and apical cystic fibrosis transmembrane conductance regulator (CFTR), the latter of which is lacking in the anterior intestine and is not permeable to HCO3- in the posterior intestine. However, the response to RGN by the posterior intestine is counterintuitive given the known role of the marine teleost intestine as a salt- and water-absorbing organ. These data demonstrate that marine teleosts possess a tissue-specific secretory response, apparently associated with seawater adaptation, the exact role of which remains to be determined.

Reducing the volume of sprint interval training does not diminish maximal and submaximal performance gains in healthy men.

PURPOSE: The present study examined the effect of reducing sprint interval training (SIT) work-interval duration on increases in maximal and submaximal performance. METHODS: Subjects (n = 36) were assigned to one of three training groups: endurance training (ET; 60 min per session for weeks 1-2, increasing to 75 min per session for weeks 3-4), or sprint interval training consisting of either repeated 30 (SIT 30) or 15 (SIT 15) second all-out intervals (starting with 4 bouts per session for weeks 1-2, increasing to 6 intervals per session for weeks 3-4). Training consisted of cycling 3 times per week for 4 weeks. RESULTS: While there was a significant main effect of training on VO2peak such that VO2peak was elevated post-training, no significant difference was observed in the improvements observed between groups (ET ~13%, SIT 30-4%, SIT 15-8%). A significant main effect of training was observed such that lactate threshold and critical power were higher during post-testing across all groups (p < 0.05). There was a main effect of training (p < 0.05) on Wingate peak power with no differences observed between groups at post-training. CONCLUSIONS: Together, these results indicate that reducing SIT work-interval duration from 30 to 15 s had no impact on training-induced increases in aerobic or anaerobic power, or on increases in lactate threshold (absolute) and critical power.