Systemic neurophysiological entrainment to behaviorally relevant rhythmic stimuli.

Physiological oscillations, such as those involved in brain activity, heartbeat, and respiration, display inherent rhythmicity across various timescales. However, adaptive behavior arises from the interaction between these intrinsic rhythms and external environmental cues. In this study, we used multimodal neurophysiological recordings, simultaneously capturing signals from the central and autonomic nervous systems (CNS and ANS), to explore the dynamics of brain and body rhythms in response to rhythmic auditory stimulation across three conditions: baseline (no auditory stimulation), passive auditory processing, and active auditory processing (discrimination task). Our findings demonstrate that active engagement with auditory stimulation synchronizes both CNS and ANS rhythms with the external rhythm, unlike passive and baseline conditions, as evidenced by power spectral density (PSD) and coherence analyses. Importantly, phase angle analysis revealed a consistent alignment across participants between their physiological oscillatory phases at stimulus or response onsets. This alignment was associated with reaction times, suggesting that certain phases of physiological oscillations are spontaneously prioritized across individuals due to their adaptive role in sensorimotor behavior. These results highlight the intricate interplay between CNS and ANS rhythms in optimizing sensorimotor responses to environmental demands, suggesting a potential mechanism of embodied predictive processing.

Intake and digestibility of four rations with different fiber levels in alpacas (Vicugna pacos).

The aim of this study was to evaluated the impact of different fibre levels in alpaca diet on voluntary feed intake and apparent digestibility, and to estimate the digestibility of organic matter (OMD) from the content of crude protein (CP) in feces. The study was carried out with twelve alpacas (36.7 ± 6.4 kg body weight- BW), which were offered 4 treatments with different neutral detergent fiber content (NDF. T1: 40.3%; T2: 62%; T3: 68%; T4: 72%) under a switch back design. Absolute daily dry matter intake (DMI) was higher for T1 (678 g/d) than T4 (312 g/d) (p ≥ 005). NDF intake was similar between treatments when related to BW or MW (on average 1% BW and 22 g/kg MW. p ≥ 0.05). Water intake (L/kg DMI) was higher in T1 compared to the other treatments, with values ranging from 2.9 L/kg DMI(T1) to 2.8 L/kg DMI(T4), respectively (p ≤ 0.05). Digestibility of dry matter, organic matter and CP was higher in T1 than in the other treatments, with average values ranging from 72% for T1 to 32% for T4 (p ≤ 0.05). NDF digestibility was similar among treatments (p ≥ 0.05). The regression equation generated to predict OMD (y) was as follows: y = 0.360 + 0.08294*fecal CP (g/kg OM). Further studies will indicate whether faecal nitrogen can be used to estimate digestibility and hence diet quality in South American camelids.

Variation in Thickness of Embryo Covering Structures and Their Role in the Regulation of Seed Physiological Dormancy of Chenopodium hircinum (Amaranthaceae).

Chenopodium hircinum, the putative wild ancestor of quinoa, is a source of traits that could improve the tolerance of crop quinoa to high temperatures. However, seeds of C. hircinum have physiological dormancy (PD), which is an obstacle for plant propagation and use in breeding programs. We studied the intraspecific variability in morpho-anatomical traits of embryo covering structures and their association with PD. We also evaluated the effects of different dormancy-breaking treatments on PD alleviation and germination. Seeds were dispersed with a remnant perianth and a persistent pericarp that could be removed by scraping. The seed coat was formed by palisade cells impregnated with tannins, and the seed contained a thin layer of peripheral endosperm surrounding the embryo. In our investigation, the thickness of the pericarp (P) and/or seed coat (SC) varied among populations. Populations with higher P and/or SC thickness showed lower percentages of germination and water absorption. The combined dormancy-breaking treatment (bleach + perforated coverings + gibberellic acid) promoted dormancy release and increased germination. C. hircinum seeds showed non-deep physiological dormancy. Based on previous knowledge about quinoa, and our results, we conclude that embryo coverings, especially the seed coat, have an important role in dormancy control, imposing a mechanical restraint on radicle emergence.

Non-Ionic Fluorosurfactants for Droplet-Based in vivo Applications.

Fluorocarbon oils are uniquely suited for many biomedical applications due to their inert, bioorthogonal properties. In order to interface fluorocarbon oils with biological systems, non-ionic fluorosurfactants are necessary. However, there is a paucity of non-ionic fluorosurfactants with low interfacial tension to stabilize fluorocarbon phases in aqueous environments (such as oil-in-water emulsions). We developed non-ionic fluorosurfactants composed of a polyethylene glycol (PEG) segment covalently bonded to a flexible perfluoropolyether (PFPE) segment that confer lower interfacial tensions (IFTs) between a fluorocarbon oil, HFE-7700, and water. Synthesis of a panel of surfactants spanning a molecular weight range of 0.64-66 kDa with various hydrophilic-lipophilic balances allowed for identification of minimal IFTs, ranging from 1.4 to 17.8 mN m-1. The majority of these custom fluorosurfactants display poor solubility in water, allowing their co-introduction with fluorocarbon oils and minimal leaching. We applied the PEG5PFPE1 surfactant for mechanical force measurements in zebrafish, enabling exceptional sensitivity.

The southwesternmost record of late Silurian (Pridolian) early land plants of Gondwana.

The Silurian-Devonian transition played a crucial role in the development of early terrestrial ecosystems due to the rapid diversification of early vascular plants. However, records of Pridolian plants in western Gondwana are scarce, limited to outcrops located in southern Bolivia. In this contribution, an association of fossil plants housed in the Rinconada Formation is presented. This association corresponds to primitive fossil flora with reproductive structures and sterile axes linked to basal tracheophytes. The fossil assemblage is composed of Aberlemnia caledonica, Caia langii Cooksonia cf. cambrensis, C. paranensis, C. cf. pertoni, Hostinella sp, Cf. Isidrophyton sp, Salopella marcensis, Steganoteca striata, two morphotypes of doubtful taxonomy, and graptolites colonies. The association between flora remains and graptolites, represents a parautochthonous assemblage in an inner marine platform, dominated by gravity flows. This record has paleophytogeographic importance indicating the extension of the northwest Gondwana-southern Laurusia unit to more southern areas of Gondwana. This expansion would have been favored by the post-glacial climatic improvement of the Late Silurian, together with a great radiation capacity and environmental flexibility of the flora. Furthermore, the biochron is extended of three taxa (A. caledonica, C. paranensis and Cf. Isidrophyton sp) first known from the Lochkovian, to the Pridoli.

Effect on the Antioxidant Properties of Native Chilean Endemic Honeys Treated with Ionizing Radiation to Remove American Foulbrood Spores.

In Chile, honey is produced from several native species with interesting biological properties. Accordingly, those attributes are present in Chilean honeys owing to the presence of phenolic compounds inherited from specific floral sources. In recent years, the exported volume of Chilean honeys has been increased, reaching new markets with demanding regulations directed toward the fulfilment of consumers' expectations. Accordingly, there are countries with special requirements referring to Paenibacillus larvae spore-free honeys. This microorganism is the pathogen responsible for American foulbrood disease in beehives; however, antibiotics are not allowed when an apiary tests positive for P. larvae. On the other hand, it is mandatory to have an accurate method to remove the potential presence of spores in bee products intended for export. Exposure to ionizing radiation can be an efficient way to achieve this goal. In this work, 54 honey samples harvested from northern, central and southern Chile were analyzed for physicochemical patterns, total phenols, antioxidant activity and antiradical activity. Honeys with and without spores were exposed to ionizing radiation at three levels of intensity. Afterwards, the presence of spores and the effect on phenol bioavailability, antiradical activity and antioxidant activity were measured again. This research presents results showing a positive correlation between the percentage of prevalence of native endemic species in the set of honeys analyzed and the capacity to resist this process, without altering their natural attributes determined before irradiation treatments.

Ehrlichiosis and anaplasmosis in solid organ transplantation: A case series and review of the literature.

Ehrlichiosis and anaplasmosis are rising tickborne infections posing significant risks to solid-organ transplant (SOT) patients. We present three cases highlighting clinical presentations, diagnostic challenges, and the benefits of microbial cell-free DNA (mcfDNA) sequencing. Emphasizing early diagnosis and preventive measures, we advocate for advanced diagnostic modalities to improve outcomes in this vulnerable population.

Integrative workflows for the characterization of hydrophobin and cerato-platanin in the marine fungus Paradendryphiella salina.

Hydrophobins (HFBs) and cerato-platanins (CPs) are surface-active extracellular proteins produced by filamentous fungi. This study identified two HFB genes (pshyd1 and pshyd2) and one CP gene (pscp) in the marine fungus Paradendryphiella salina. The proteins PsCP, PsHYD2, and PsHYD1 had molecular weights of 12.70, 6.62, and 5.98 kDa, respectively, with isoelectric points below 7. PsHYD1 and PsHYD2 showed hydrophobicity (GRAVY score 0.462), while PsCP was hydrophilic (GRAVY score - 0.202). Stability indices indicated in-solution stability. Mass spectrometry identified 2,922 proteins, including CP but not HFB proteins. qPCR revealed differential gene expression influenced by developmental stage and substrate, with pshyd1 consistently expressed. These findings suggest P. salina's adaptation to marine ecosystems with fewer hydrophobin genes than other fungi but capable of producing surface-active proteins from seaweed carbohydrates. These proteins have potential applications in medical biocoatings, food industry foam stabilizers, and environmental bioremediation.

A new suture fixation technique for the Akin osteotomy of the proximal phalanx: You don't need any implant.

BACKGROUND: Various fixation methods have been described for Akin osteotomy, based on using metal implants or transosseous sutures. The aim of this study was to evaluate radiological outcomes and complications of closing wedge Akin osteotomy based on a crossed suture configuration of the joint capsule rather than using implants. The null hypothesis is that a crossed suture has comparable radiological results to other techniques, with no additional complications. METHODS: It's a retrospective study. Patients who underwent Akin osteotomy fixed either with implant or joint capsule suture between 2015 and 2018 were included. Distal articular set angle corrections in pre- and postoperative anteroposterior foot x-rays were calculated by 2 observers. Complications, such as pain, infection, non-union and need of surgery revision, was compared at 1 year follow-up. RESULTS: 89 patients, 30 in the implant group and 59 in the suture group. Mean distal articular set angle corrections were 6.43 (SD 5.54) and 7.36 (SD 5.48) degrees in the implant and suture groups, respectively, without statistically significant differences (p 0454). Complications were 2 local pain and 1 wound infection cases in the suture and implant groups, respectively (p 0138, p 0197). CONCLUSION: Akin osteotomy with suture fixation yields comparable radiological results to metal implant fixation methods without increasing the associated complications.

Effects of Plyometric Training on Running Biomechanics and Jumping Ability of U14 Athletes.

ABSTRACT: Cardiel-Sánchez, S, Rubio-Peirotén, A, Molina-Molina, A, García-Cebadera Gómez, C, Almenar-Arasanz, A, Ráfales-Perucha, A, Roche-Seruendo, LE, and Cartón-Llorente, A. Effects of plyometric training on running biomechanics and jumping ability of U14 athletes. J Strength Cond Res XX(X): 000-000, 2024-Children under the age of 14 years (U14) are particularly susceptible to musculoskeletal disorders because of growth spurts. Plyometric training has been shown to be beneficial for both injury reduction and performance enhancement. The aim of this study was to evaluate the effects of plyometric training on the jumping ability and running biomechanics of U14 track-and-field athletes. A single-blind randomized controlled trial was conducted. Thirty-five (18 female and 17 male) U14 athletes (age: 12.5 ± 1.2 years; height: 152.3 ± 7.7 cm; body mass: 47.3 ± 6.9 kg) were randomized into experimental and control groups. All subjects completed their usual training for 4 weeks, and those in the intervention group added a low-volume plyometric program twice a week. Preintervention and postintervention assessments included a countermovement jump (CMJ) to determine maximum jump height, 10-second repeated jumps to assess reactive strength index (RSI), and a 3-minute run at 12 km·h-1 to analyze running kinematics contact time, flight time, step length (SL), step frequency (SF), mean power output, vertical spring stiffness, and leg spring stiffness (LSS). The results revealed no main effect of time for any of the variables. A group-by-time interaction was found for RSI (p = 0.045) in the intervention group, whereas a significant increase in LSS was also found after the intervention (p = 0.031). However, no changes in CMJ height or other running parameters were observed. The significance level for the study was set at ρ ≤ 0.05. Plyometric-jump training may improve the stretch-shortening cycle in U14 athletes by increasing RSI and LSS. Athletes and coaches in running-related sports should be aware of these short-term effects when aiming to optimize the energy storage and release mechanism.

Tracking EEG network dynamics through transitions between eyes-closed, eyes-open, and task states.

Our study aimed to verify the possibilities of effectively applying chronnectomics methods to reconstruct the dynamic processes of network transition between three types of brain states, namely, eyes-closed rest, eyes-open rest, and a task state. The study involved dense EEG recordings and reconstruction of the source-level time-courses of the signals. Functional connectivity was measured using the phase lag index, and dynamic analyses concerned coupling strength and variability in alpha and beta frequencies. The results showed significant and dynamically specific transitions regarding processes of eyes opening and closing and during the eyes-closed-to-task transition in the alpha band. These observations considered a global dimension, default mode network, and central executive network. The decrease of connectivity strength and variability that accompanied eye-opening was a faster process than the synchronization increase during eye-opening, suggesting that these two transitions exhibit different reorganization times. While referring the obtained results to network studies, it was indicated that the scope of potential similarities and differences between rest and task-related networks depends on whether the resting state was recorded in eyes closed or open condition.

Acute diarrhea in the hospitalized immunocompromised patient: what is new on diagnostic and treatment?

PURPOSE OF REVIEW: This article aims to provide an intuitive framework for diagnosing and managing healthcare-associated diarrhea (HCAD) in the immunocompromised (IC) host. RECENT FINDINGS: Our understanding of diarrhea in hospitalized IC patients has significantly evolved. However, the challenge lies in distinguishing between these patients' numerous causes of diarrhea. The incorporation of gastrointestinal (GI) multiplex polymerase chain reaction (PCR) panels has led to a paradigm shift in our approach to diarrhea. However, using these panels judiciously is of utmost importance, as their misuse can lead to over-testing, overtreatment, and increased hospital costs. We propose a stepwise diagnostic algorithm that ensures diagnostic stewardship, optimal patient care, and resource utilization. SUMMARY: Diarrhea is a common complication in hospitalized IC patients and is associated with significant morbidity and rare mortality. The advent of new diagnostics, such as GI multiplex PCR panels, holds promise in facilitating the detection of recognized pathogens and may allow for improved outcomes using pathogen-targeted therapy.

Continuous measurements of respiratory muscle blood flow and oxygen consumption using noninvasive frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy.

Prior studies of muscle blood flow and muscle-specific oxygen consumption have required invasive injection of dye and magnetic resonance imaging, respectively. Such measures have limited utility for continuous monitoring of the respiratory muscles. Frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy (FD-NIRS & DCS) can provide continuous surrogate measures of blood flow index (BFi) and metabolic rate of oxygen consumption (MRO2). This study aimed to validate sternocleidomastoid FD-NIRS & DCS outcomes against electromyography (EMG) and mouth pressure (Pm) during incremental inspiratory threshold loading (ITL). Six female and six male healthy adults (means ± SD; 30 ± 7 yr, maximum inspiratory pressure 118 ± 61 cmH2O) performed incremental ITL starting at low loads (8 ± 2 cmH2O) followed by 50-g increments every 2 min until task failure. FD-NIRS & DCS continuously measured sternocleidomastoid oxygenated and deoxygenated hemoglobin + myoglobin (oxy/deoxy[Hb + Mb]), tissue saturation of oxygen (StO2), BFi, and MRO2. Ventilatory parameters including inspiratory Pm were also evaluated. Pm increased during incremental ITL (P < 0.05), reaching -47[-74 to -34] cmH2O (median [IQR: 25%-75%]) at task failure. Ventilatory parameters were constant throughout ITL (all P > 0.05). Sternocleidomastoid BFi and MRO2 increased from the start of the ITL (both P < 0.05). Deoxy[Hb + Mb] increased close to task failure, concomitantly with a constant increase in MRO2, and decreased StO2. Sternocleidomastoid deoxy[Hb + Mb], BFi, StO2, and MRO2 obtained during ITL via FD-NIRS & DCS correlated with sternocleidomastoid EMG (all P < 0.05). In healthy adults, FD-NIRS & DCS can provide continuous surrogate measures of respiratory BFi and MRO2. Increasing sternocleidomastoid oxygen consumption near task failure was associated with increased oxygen extraction and reduced tissue saturation.NEW & NOTEWORTHY This study introduces a novel approach, frequency-domain near-infrared spectroscopy and diffuse correlation spectroscopy (FD-NIRS & DCS), for noninvasive continuous monitoring of respiratory muscle blood flow and metabolic rate of oxygen consumption. Unlike prior methods involving invasive dye injection and magnetic resonance imaging, FD-NIRS & DCS offers the advantage of continuous measurement without the need for invasive procedures. It holds promise for advancing muscle physiology understanding and opens avenues for real-time monitoring of respiratory muscles.

Age-related changes in brain oscillatory patterns during an n-back task in children and adolescents.

The development of brain oscillatory responses and their possible role in the working memory (WM) performance of children, adolescents and young adults was investigated. A set of 0- and 1-back tasks with letter stimuli were administered to a final sample of 131 subjects (between 6 and 20 years of age). A decrease in response times (RTs) and an increase of the sensitivity index d-prime (d') were seen with increased age. RTs increased and d' decreased with load, indicating higher difficulty for higher loads. Event-related synchronization (ERS) and event-related desynchronization (ERD) were obtained by the convolution of Morlet wavelets on the recorded EEG. Statistical analyses were performed of the absolute and relative power of brain oscillations defined by topography, frequency and latency. Posterior alpha and beta ERD, and frontocentral theta ERS, were induced by the stimuli presented during the n-back task. While relative theta ERS increased with age, absolute theta ERS, absolute and relative alpha and, absolute beta ERD, decreased with age. Age-related improvement in behavioral performance was mediated by relative theta. Alpha and beta ERD were more pronounced for the most difficult task (1-back) and for the target condition. Globally, there was high consistency of the effects of target type and task load across development. Theta ERS maturation is a crucial step for improving WM performance during development, while alpha and beta ERD maturation seem to be less critical for behavioral performance improvement with age, possibly due to a sufficient level of alpha-beta ERD for good performance in young children.

Dengue NS1 antibodies are associated with clearance of viral NS1.

BACKGROUND: Dengue vascular permeability syndrome is the primary cause of death in severe dengue infections. The protective versus potentially pathogenic role of dengue NS1 antibodies are not well understood. The main goal of this analysis was to characterize the relationship between free NS1 concentration and NS1 antibody titers in primary and secondary dengue infection in order to better understand the presence and duration of NS1 antibody complexes in clinical dengue infections. METHODS: Hospitalized participants with acute dengue infection were recruited from Northern Colombia between 2018 to 2020. Symptom assessment including dengue signs and symptoms, chart review and blood collection was performed. Primary versus secondary Dengue was assessed serologically. NS1 titers and anti-NS1 antibodies were measured daily. RESULTS: Patients with secondary infection have higher antibody titers than those in primary infection, and we find a negative correlation between anti-NS1 antibody titer and NS1 protein. We demonstrate that in a subset of secondary infection, there are indeed NS1 antibody-antigen complexes at the admission day during the febrile phase that are not detectable by the recovery phase. Furthermore, dengue infection status is associated with higher circulating sialidases. DISCUSSION: The negative correlation between antibody and protein suggests that antibodies may play a role in clearing this viral protein.

Molecular epidemiology and antimicrobial resistance in Clostridioides difficile strains isolated from children and adolescents in a tertiary referral pediatric hospital in Fortaleza, Brazil.

BACKGROUND: C. difficile has been increasingly reported as a cause of gastrointestinal disease in children, ranging from mild self-limiting diarrhea to severe conditions such as pseudomembranous colitis and toxic megacolon. Only two pediatric research groups reported the presence of C. difficile infection in Brazilian children, but no previous research has examined C. difficile infection among children in northeastern Brazil. This prospective cross-sectional study investigated the molecular epidemiology and antimicrobial resistance of C. difficile strains isolated from children and adolescents with diarrhea referred to a tertiary pediatric hospital in Brazil while exploring the associated risk factors. RESULTS: Toxin positivity or C. difficile isolation was found in 30.4 % (17/56) samples. C. difficile was isolated from 35 % (6/17) samples. Four toxigenic strains were identified (tpi+, tcdA+, tcdB+, cdtB-, without tcdC deletions) belonging to PCR ribotypes and PFGE-pulsotypes: 046 (new pulsotype 1174), 106 (NAP11), 002 (new pulsotype 1274), 012 (new pulsotype NML-1235). Two of the six isolates belonging to ribotypes 143 and 133 were non-toxigenic. All toxigenic strains were sensitive to metronidazole and vancomycin. Regarding the clinical manifestation, diarrhea lasted an average of 11 days, ranging from 3 to 50 days and was often associated with mucus and/or blood. All six patients from whom the C. difficile was isolated had a chronic disease diagnosis, with these comorbidities as the main risk factors. CONCLUSION: Our study enhances our understanding of the present epidemiological landscape of C. difficile-associated diarrhea (CDI) among children in northeastern Brazil, reveling a substantial CDI frequency of 30.4 %, with toxigenic strains detected in 76.4 % of cases, highlighting a higher prevalence compared to earlier Brazilian studies. In the globalized world, an understanding of disease-generating strains, the associated risk factors, clinical manifestation, and antimicrobial sensitivity has fundamental epidemiological importance and draws attention to preventive measures, allowing for more decisive action.

Focal adhesion kinase-YAP signaling axis drives drug-tolerant persister cells and residual disease in lung cancer.

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

Intermediate-risk endometrial cancer treated with adjuvant brachytherapy using single dosimetric planning: long-term outcome and toxicity assessment.

OBJECTIVE: Brachytherapy of the vaginal dome is the recommended adjuvant treatment for intermediate-risk endometrial cancer. This study assessed the results of dosimetric planning of high-dose-rate brachytherapy exclusively in the first treatment session. STUDY DESIGN: This retrospective study included all patients who underwent hysterectomy for endometrial cancer followed by adjuvant brachytherapy of the vaginal dome between 2012 and 2015. Local recurrence rates, overall survival (OS) rates, recurrence-free survival (RFS) rates, and related acute and late toxicity rates were evaluated. RESULTS: This analysis included 250 patients, of whom 208 were considered to be at high-intermediate risk of disease recurrence. After a median follow-up of 56 months, the cumulative incidence of local recurrence was 4.8% at 3 years [95% confidence interval (CI) 2.8-8.3] and 7.8% at 5 years (95% CI 4.8-12.6). The 5-year OS rate was 86.2% (95% CI 80.6-90.3), and the 5-year RFS rate was 77.5% (95% CI 71.1-82.7). Acute toxicity occurred in 20 (8%) patients, of which two patients had grade ≥3 toxicity. Only one patient (0.4%) presented with late grade ≥3 toxicity. CONCLUSION: These findings confirm the tolerability of this brachytherapy approach, indicating minimal cases of late grade ≥3 toxicity, associated with a good 5-year OS rate. With the advent of molecular prognostic factors, the current focus revolves around discerning those individuals who gain the greatest benefit from adjuvant therapy, and tailoring treatment more effectively.

Robust genetic codes enhance protein evolvability.

The standard genetic code defines the rules of translation for nearly every life form on Earth. It also determines the amino acid changes accessible via single-nucleotide mutations, thus influencing protein evolvability-the ability of mutation to bring forth adaptive variation in protein function. One of the most striking features of the standard genetic code is its robustness to mutation, yet it remains an open question whether such robustness facilitates or frustrates protein evolvability. To answer this question, we use data from massively parallel sequence-to-function assays to construct and analyze 6 empirical adaptive landscapes under hundreds of thousands of rewired genetic codes, including those of codon compression schemes relevant to protein engineering and synthetic biology. We find that robust genetic codes tend to enhance protein evolvability by rendering smooth adaptive landscapes with few peaks, which are readily accessible from throughout sequence space. However, the standard genetic code is rarely exceptional in this regard, because many alternative codes render smoother landscapes than the standard code. By constructing low-dimensional visualizations of these landscapes, which each comprise more than 16 million mRNA sequences, we show that such alternative codes radically alter the topological features of the network of high-fitness genotypes. Whereas the genetic codes that optimize evolvability depend to some extent on the detailed relationship between amino acid sequence and protein function, we also uncover general design principles for engineering nonstandard genetic codes for enhanced and diminished evolvability, which may facilitate directed protein evolution experiments and the bio-containment of synthetic organisms, respectively.

Proliferation-driven mechanical compression induces signalling centre formation during mammalian organ development.

Localized sources of morphogens, called signalling centres, play a fundamental role in coordinating tissue growth and cell fate specification during organogenesis. However, how these signalling centres are established in tissues during embryonic development is still unclear. Here we show that the main signalling centre orchestrating development of rodent incisors, the enamel knot (EK), is specified by a cell proliferation-driven buildup in compressive stresses (mechanical pressure) in the tissue. Direct mechanical measurements indicate that the stresses generated by cell proliferation are resisted by the surrounding tissue, creating a circular pattern of mechanical anisotropy with a region of high compressive stress at its centre that becomes the EK. Pharmacological inhibition of proliferation reduces stresses and suppresses EK formation, and application of external pressure in proliferation-inhibited conditions rescues the formation of the EK. Mechanical information is relayed intracellularly through YAP protein localization, which is cytoplasmic in the region of compressive stress that establishes the EK and nuclear in the stretched anisotropic cells that resist the pressure buildup around the EK. Together, our data identify a new role for proliferation-driven mechanical compression in the specification of a model signalling centre during mammalian organ development.