The ability of animals to flexibly navigate through complex environments depends on the integration of sensory information with motor commands. The sensory modality most tightly linked to motor ...control is mechanosensation. Adaptive motor control depends critically on an animal’s ability to respond to mechanical forces generated both within and outside the body. The compact neural circuits of insects provide appealing systems to investigate how mechanical cues guide locomotion in rugged environments. Here, we review our current understanding of mechanosensation in insects and its role in adaptive motor control. We first examine the detection and encoding of mechanical forces by primary mechanoreceptor neurons. We then discuss how central circuits integrate and transform mechanosensory information to guide locomotion. Because most studies in this field have been performed in locusts, cockroaches, crickets, and stick insects, the examples we cite here are drawn mainly from these ‘big insects’. However, we also pay particular attention to the tiny fruit fly, Drosophila, where new tools are creating new opportunities, particularly for understanding central circuits. Our aim is to show how studies of big insects have yielded fundamental insights relevant to mechanosensation in all animals, and also to point out how the Drosophila toolkit can contribute to future progress in understanding mechanosensory processing.
This Review discusses how studies of insects have yielded insights into mechanosensation, and also points out how genetic tools in Drosophila can contribute to future progress in the field.
To distinguish between complex somatosensory stimuli, central circuits must combine signals from multiple peripheral mechanoreceptor types, as well as mechanoreceptors at different sites in the body. ...Here, we investigate the first stages of somatosensory integration in Drosophila using in vivo recordings from genetically labeled central neurons in combination with mechanical and optogenetic stimulation of specific mechanoreceptor types. We identify three classes of central neurons that process touch: one compares touch signals on different parts of the same limb, one compares touch signals on right and left limbs, and the third compares touch and proprioceptive signals. Each class encodes distinct features of somatosensory stimuli. The axon of an individual touch receptor neuron can diverge to synapse onto all three classes, meaning that these computations occur in parallel, not hierarchically. Representing a stimulus as a set of parallel comparisons is a fast and efficient way to deliver somatosensory signals to motor circuits.
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•Leg touch receptors project to at least three genetically defined neuron classes•Each class integrates excitation and inhibition to compute a comparison•Comparisons occur within a leg, across legs, and between touch and proprioception•Each of these parallel neural circuits encodes a unique stimulus feature
In vivo electrophysiology and 2-photon calcium imaging reveal that touch signals in Drosophila are sent in parallel to multiple genetically defined neuronal classes in the ventral nerve cord, which integrate excitatory and inhibitory inputs from other touch receptors and proprioceptors to encode unique stimulus features.
For most immune-mediated diseases, the main determinant of patient well-being is not the diagnosis itself but instead the course that the disease takes over time (prognosis). Prognosis may vary ...substantially between patients for reasons that are poorly understood. Familial studies support a genetic contribution to prognosis, but little evidence has been found for a proposed association between prognosis and the burden of susceptibility variants. To better characterize how genetic variation influences disease prognosis, we performed a within-cases genome-wide association study in two cohorts of patients with Crohn's disease. We identified four genome-wide significant loci, none of which showed any association with disease susceptibility. Conversely, the aggregated effect of all 170 disease susceptibility loci was not associated with disease prognosis. Together, these data suggest that the genetic contribution to prognosis in Crohn's disease is largely independent of the contribution to disease susceptibility and point to a biology of prognosis that could provide new therapeutic opportunities.
The objective of this study is to estimate per-contact probability of HIV transmission in homosexual men due to unprotected anal intercourse (UAI) in the era of HAART.
Data were collected from a ...longitudinal cohort study of community-based HIV-negative homosexual men in Sydney, Australia.
A total of 1427 participants were recruited from June 2001 to December 2004. They were followed up with 6-monthly detailed behavioral interviews and annual testing for HIV till June 2007. Data were used in a bootstrapping method, coupled with a statistical analysis that optimized a likelihood function for estimating the per-exposure risks of HIV transmission due to various forms of UAI.
During the study, 53 HIV seroconversion cases were identified. The estimated per-contact probability of HIV transmission for receptive UAI was 1.43% 95% confidence interval (CI) 0.48-2.85 if ejaculation occurred inside the rectum, and it was 0.65% (95% CI 0.15-1.53) if withdrawal prior to ejaculation was involved. The estimated transmission rate for insertive UAI in participants who were circumcised was 0.11% (95% CI 0.02-0.24), and it was 0.62% (95% CI 0.07-1.68) in uncircumcised men. Thus, receptive UAI with ejaculation was found to be approximately twice as risky as receptive UAI with withdrawal or insertive UAI for uncircumcised men and over 10 times as risky as insertive UAI for circumcised men.
Despite the fact that a high proportion of HIV-infected men are on antiretroviral treatment and have undetectable viral load, the per-contact probability of HIV transmission due to UAI is similar to estimates reported from developed country settings in the pre-HAART era.
Introduction
Studies utilizing beta-hydroxy-beta-methylbutyrate (HMB) supplementation in trained populations are limited. No long-term studies utilizing HMB free acid (HMB-FA) have been conducted. ...Therefore, we investigated the effects of 12 weeks of HMB-FA supplementation on skeletal muscle hypertrophy, body composition, strength, and power in trained individuals. We also determined the effects of HMB-FA on muscle damage and performance during an overreaching cycle.
Methods
A three-phase double-blind, placebo- and diet-controlled randomized intervention study was conducted. Phase 1 was an 8-week-periodized resistance-training program; Phase 2 was a 2-week overreaching cycle; and Phase 3 was a 2-week taper. Muscle mass, strength, and power were examined at weeks 0, 4, 8, and 12 to assess the chronic effects of HMB-FA; and assessment of these, as well as cortisol, testosterone, and creatine kinase (CK) was performed at weeks 9 and 10 of the overreaching cycle.
Results
HMB-FA resulted in increased total strength (bench press, squat, and deadlift combined) over the 12-week training (77.1 ± 18.4 vs. 25.3 ± 22.0 kg,
p
< 0.001); a greater increase in vertical jump power (991 ± 168 vs. 630 ± 167 W,
p
< 0.001); and increased lean body mass gain (7.4 ± 4.2 vs. 2.1 ± 6.1 kg,
p
< 0.001) in HMB-FA- and placebo-supplemented groups, respectively. During the overreaching cycle, HMB-FA attenuated increases in CK (−6 ± 91 vs. 277 ± 229 IU/l,
p
< 0.001) and cortisol (−0.2 ± 2.9 vs. 4.5 ± 1.7 μg/dl,
p
< 0.003) in the HMB-FA- and placebo-supplemented groups, respectively.
Conclusions
These results suggest that HMB-FA enhances hypertrophy, strength, and power following chronic resistance training, and prevents decrements in performance following the overreaching.
To estimate population health outcomes with delayed second dose versus standard schedule of SARS-CoV-2 mRNA vaccination.
Simulation agent based modeling study.
Simulated population based on real ...world US county.
The simulation included 100 000 agents, with a representative distribution of demographics and occupations. Networks of contacts were established to simulate potentially infectious interactions though occupation, household, and random interactions.
Simulation of standard covid-19 vaccination versus delayed second dose vaccination prioritizing the first dose. The simulation runs were replicated 10 times. Sensitivity analyses included first dose vaccine efficacy of 50%, 60%, 70%, 80%, and 90% after day 12 post-vaccination; vaccination rate of 0.1%, 0.3%, and 1% of population per day; assuming the vaccine prevents only symptoms but not asymptomatic spread (that is, non-sterilizing vaccine); and an alternative vaccination strategy that implements delayed second dose for people under 65 years of age, but not until all those above this age have been vaccinated.
Cumulative covid-19 mortality, cumulative SARS-CoV-2 infections, and cumulative hospital admissions due to covid-19 over 180 days.
Over all simulation replications, the median cumulative mortality per 100 000 for standard dosing versus delayed second dose was 226
179, 233
207, and 235
236 for 90%, 80%, and 70% first dose efficacy, respectively. The delayed second dose strategy was optimal for vaccine efficacies at or above 80% and vaccination rates at or below 0.3% of the population per day, under both sterilizing and non-sterilizing vaccine assumptions, resulting in absolute cumulative mortality reductions between 26 and 47 per 100 000. The delayed second dose strategy for people under 65 performed consistently well under all vaccination rates tested.
A delayed second dose vaccination strategy, at least for people aged under 65, could result in reduced cumulative mortality under certain conditions.
To mechanistically characterize the microevolutionary processes active in altering transcription factor (TF) binding among closely related mammals, we compared the genome-wide binding of three ...tissue-specific TFs that control liver gene expression in six rodents. Despite an overall fast turnover of TF binding locations between species, we identified thousands of TF regions of highly constrained TF binding intensity. Although individual mutations in bound sequence motifs can influence TF binding, most binding differences occur in the absence of nearby sequence variations. Instead, combinatorial binding was found to be significant for genetic and evolutionary stability; cobound TFs tend to disappear in concert and were sensitive to genetic knockout of partner TFs. The large, qualitative differences in genomic regions bound between closely related mammals, when contrasted with the smaller, quantitative TF binding differences among Drosophila species, illustrate how genome structure and population genetics together shape regulatory evolution.
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•Earliest steps of regulatory evolution in mammals captured using five mouse species•Interspecies differences in TF binding are rarely caused by DNA variation in motifs•Cobound TFs change their genomic binding cooperatively in closely related mammals•Genetic knockouts revealed the extent of cooperative stabilization in TF binding clusters
Microevolutionary mechanisms create different transcription factor binding patterns between mammals, shedding light on the regulatory mechanisms partially underlying speciation.
Entrectinib is a potent inhibitor of tropomyosin receptor kinase (TRK) A, B, and C, which has been shown to have anti-tumour activity against NTRK gene fusion-positive solid tumours, including CNS ...activity due to its ability to penetrate the blood–brain barrier. We present an integrated efficacy and safety analysis of patients with metastatic or locally advanced solid tumours harbouring oncogenic NTRK1, NTRK2, and NTRK3 gene fusions treated in three ongoing, early-phase trials.
An integrated database comprised the pivotal datasets of three, ongoing phase 1 or 2 clinical trials (ALKA-372-001, STARTRK-1, and STARTRK-2), which enrolled patients aged 18 years or older with metastatic or locally advanced NTRK fusion-positive solid tumours who received entrectinib orally at a dose of at least 600 mg once per day in a capsule. All patients had an Eastern Cooperative Oncology Group performance status of 0–2 and could have received previous anti-cancer therapy (except previous TRK inhibitors). The primary endpoints, the proportion of patients with an objective response and median duration of response, were evaluated by blinded independent central review in the efficacy-evaluable population (ie, patients with NTRK fusion-positive solid tumours who were TRK inhibitor-naive and had received at least one dose of entrectinib). Overall safety evaluable population included patients from STARTRK-1, STARTRK-2, ALKA-372-001, and STARTRK-NG (NCT02650401; treating young adult and paediatric patients aged ≤21 years), who received at least one dose of entrectinib, regardless of tumour type or gene rearrangement. NTRK fusion-positive safety evaluable population comprised all patients who have received at least one dose of entrectinib regardless of dose or follow-up. These ongoing studies are registered with ClinicalTrials.gov, NCT02097810 (STARTRK-1) and NCT02568267 (STARTRK-2), and EudraCT, 2012–000148–88 (ALKA-372-001).
Patients were enrolled in ALKA-372–001 from Oct 26, 2012, to March 27, 2018; in STARTRK-1 from Aug 7, 2014, to May 10, 2018; and in STARTRK-2 from Nov 19, 2015 (enrolment is ongoing). At the data cutoff date for this analysis (May 31, 2018) the efficacy-evaluable population comprised 54 adults with advanced or metastatic NTRK fusion-positive solid tumours comprising ten different tumour types and 19 different histologies. Median follow-up was 12.9 months (IQR 8·77–18·76). 31 (57%; 95% CI 43·2–70·8) of 54 patients had an objective response, of which four (7%) were complete responses and 27 (50%) partial reponses. Median duration of response was 10 months (95% CI 7·1 to not estimable). The most common grade 3 or 4 treatment-related adverse events in both safety populations were increased weight (seven 10% of 68 patients in the NTRK fusion-positive safety population and in 18 5% of 355 patients in the overall safety-evaluable population) and anaemia (8 12% and 16 5%). The most common serious treatment-related adverse events were nervous system disorders (three 4% of 68 patients and ten 3% of 355 patients). No treatment-related deaths occurred.
Entrectinib induced durable and clinically meaningful responses in patients with NTRK fusion-positive solid tumours, and was well tolerated with a manageable safety profile. These results show that entrectinib is a safe and active treatment option for patients with NTRK fusion-positive solid tumours. These data highlight the need to routinely test for NTRK fusions to broaden the therapeutic options available for patients with NTRK fusion-positive solid tumours.
Ignyta/F Hoffmann-La Roche.
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