Positive feedback in Ras activation by full-length SOS arises from autoinhibition release mechanism.

Signaling through the Ras-MAPK pathway can exhibit switch-like activation, which has been attributed to the underlying positive feedback and bimodality in the activation of RasGDP to RasGTP by SOS. SOS contains both catalytic and allosteric Ras binding sites, and a common assumption is that allosteric activation selectively by RasGTP provides the mechanism of positive feedback. However, recent single-molecule studies have revealed that SOS catalytic rates are independent of the nucleotide state of Ras in the allosteric binding site, raising doubt about this as a positive feedback mechanism. Here, we perform detailed kinetic analyses of receptor-mediated recruitment of full-length SOS to the membrane while simultaneously monitoring its catalytic activation of Ras. These results, along with kinetic modeling, expose the autoinhibition release step in SOS, rather than either recruitment or allosteric activation, as the underlying mechanism giving rise to positive feedback in Ras activation.

Bimodality in Ras signaling originates from processivity of the Ras activator SOS without deterministic bistability.

Ras is a small GTPase that is central to important functional decisions in diverse cell types. An important aspect of Ras signaling is its ability to exhibit bimodal or switch-like activity. We describe the total reconstitution of a receptor-mediated Ras activation-deactivation reaction catalyzed by SOS and p120-RasGAP on supported lipid membrane microarrays. The results reveal a bimodal Ras activation response, which is not a result of deterministic bistability but is rather driven by the distinct processivity of the Ras activator, SOS. Furthermore, the bimodal response is controlled by the condensation state of the scaffold protein, LAT, to which SOS is recruited. Processivity-driven bimodality leads to stochastic bursts of Ras activation even under strongly deactivating conditions. This behavior contrasts deterministic bistability and may be more resistant to pharmacological inhibition.

Vaccination with Mincle agonist UM-1098 and mycobacterial antigens induces protective Th1 and Th17 responses.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is one of the top infectious killers in the world. The only licensed vaccine against TB, Bacille Calmette-Guérin (BCG), provides variable protection against pulmonary TB, especially in adults. Hence, novel TB vaccine approaches are urgently needed. Both Th1 and Th17 responses are necessary for protection against TB, yet effective adjuvants and vaccine delivery systems for inducing robust Th1 and Th17 immunity are lacking. Herein we describe a synthetic Mincle agonist, UM-1098, and a silica nanoparticle delivery system that drives Th1/Th17 responses to Mtb antigens. Stimulation of human peripheral blood mononuclear cells (hPBMCs) with UM-1098 induced high levels of Th17 polarizing cytokines IL-6, IL-1ß, IL-23 as well as IL-12p70, IL-4 and TNF-α in vitro. PBMCs from both C57BL/6 and BALB/c mice responded with a similar cytokine pattern in vitro and in vivo. Importantly, intramuscular (I.M.) vaccination with UM-1098-adjuvanted TB antigen M72 resulted in significantly higher antigen-specific IFN-γ and IL-17A levels in C57BL/6 wt mice than Mincle KO mice. Vaccination of C57BL/6 wt mice with immunodominant Mtb antigens ESAT6/Ag85B or M72 resulted in predominantly Th1 and Th17 responses and induced antigen-specific serum antibodies. Notably, in a virulent Mtb challenge model, vaccination with UM-1098 adjuvanted ESAT6/Ag85B or M72 significantly reduced lung bacterial burden when compared with unvaccinated mice and protection occurred in the absence of pulmonary inflammation. These data demonstrate that the synthetic Mincle agonist UM-1098 induces strong Th1 and Th17 immunity after vaccination with Mtb antigens and provides protection against Mtb infection in mice.

Promotion of Th17 Polarized Immunity via Co-Delivery of Mincle Agonist and Tuberculosis Antigen Using Silica Nanoparticles.

Adjuvants and immunomodulators that effectively drive a Th17-skewed immune response are not part of the standard vaccine toolkit. Vaccine adjuvants and delivery technologies that can induce Th17 or Th1/17 immunity and protection against bacterial pathogens, such as tuberculosis (TB), are urgently needed. Th17-polarized immune response can be induced using agonists that bind and activate C-type lectin receptors (CLRs) such as macrophage inducible C-type lectin (Mincle). A simple but effective strategy was developed for codelivering Mincle agonists with the recombinant Mycobacterium tuberculosis fusion antigen, M72, using tunable silica nanoparticles (SNP). Anionic bare SNP, hydrophobic phenyl-functionalized SNP (P-SNP), and cationic amine-functionalized SNP (A-SNP) of different sizes were coated with three synthetic Mincle agonists, UM-1024, UM-1052, and UM-1098, and evaluated for adjuvant activity in vitro and in vivo. The antigen and adjuvant were coadsorbed onto SNP via electrostatic and hydrophobic interactions, facilitating multivalent display and delivery to antigen presenting cells. The cationic A-SNP showed the highest coloading efficiency for the antigen and adjuvant. In addition, the UM-1098-adsorbed A-SNP formulation demonstrated slow-release kinetics in vitro, excellent stability over 12 months of storage, and strong IL-6 induction from human peripheral blood mononuclear cells. Co-adsorption of UM-1098 and M72 on A-SNP significantly improved antigen-specific humoral and Th17-polarized immune responses in vivo in BALB/c mice relative to the controls. Taken together, A-SNP is a promising platform for codelivery and proper presentation of adjuvants and antigens and provides the basis for their further development as a vaccine delivery platform for immunization against TB or other diseases for which Th17 immunity contributes to protection.

Adaptations to nitrogen availability drive ecological divergence of chemosynthetic symbionts.

Bacterial symbionts, with their shorter generation times and capacity for horizontal gene transfer (HGT), play a critical role in allowing marine organisms to cope with environmental change. The closure of the Isthmus of Panama created distinct environmental conditions in the Tropical Eastern Pacific (TEP) and Caribbean, offering a "natural experiment" for studying how closely related animals evolve and adapt under environmental change. However, the role of bacterial symbionts in this process is often overlooked. We sequenced the genomes of endosymbiotic bacteria in two sets of sister species of chemosymbiotic bivalves from the genera Codakia and Ctena (family Lucinidae) collected on either side of the Isthmus, to investigate how differing environmental conditions have influenced the selection of symbionts and their metabolic capabilities. The lucinid sister species hosted different Candidatus Thiodiazotropha symbionts and only those from the Caribbean had the genetic potential for nitrogen fixation, while those from the TEP did not. Interestingly, this nitrogen-fixing ability did not correspond to symbiont phylogeny, suggesting convergent evolution of nitrogen fixation potential under nutrient-poor conditions. Reconstructing the evolutionary history of the nifHDKT operon by including other lucinid symbiont genomes from around the world further revealed that the last common ancestor (LCA) of Ca. Thiodiazotropha lacked nif genes, and populations in oligotrophic habitats later re-acquired the nif operon through HGT from the Sedimenticola symbiont lineage. Our study suggests that HGT of the nif operon has facilitated niche diversification of the globally distributed Ca. Thiodiazotropha endolucinida species clade. It highlights the importance of nitrogen availability in driving the ecological diversification of chemosynthetic symbiont species and the role that bacterial symbionts may play in the adaptation of marine organisms to changing environmental conditions.

Co-occurring nitrifying symbiont lineages are vertically inherited and widespread in marine sponges.

Ammonia-oxidising archaea and nitrite-oxidising bacteria are common members of marine sponge microbiomes. They derive energy for carbon fixation and growth from nitrification - the aerobic oxidation of ammonia to nitrite and further to nitrate - and are proposed to play essential roles in the carbon and nitrogen cycling of sponge holobionts. In this study, we characterise two novel nitrifying symbiont lineages, Candidatus Nitrosokoinonia and Candidatus Nitrosymbion in the marine sponge Coscinoderma matthewsi using a combination of molecular tools, in situ visualisation, and physiological rate measurements. Both represent a new genus in the ammonia-oxidising archaeal class Nitrososphaeria and the nitrite-oxidising bacterial order Nitrospirales, respectively. Furthermore, we show that larvae of this viviparous sponge are densely colonised by representatives of Ca. Nitrosokoinonia and Ca. Nitrosymbion indicating vertical transmission. In adults, the representatives of both symbiont genera are located extracellularly in the mesohyl. Comparative metagenome analyses and physiological data suggest that ammonia-oxidising archaeal symbionts of the genus Ca. Nitrosokoinonia strongly rely on endogenously produced nitrogenous compounds (i.e., ammonium, urea, nitriles/cyanides, and creatinine) rather than on exogenous ammonium sources taken up by the sponge. Additionally, the nitrite-oxidising bacterial symbionts of the genus Ca. Nitrosymbion may reciprocally support the ammonia-oxidisers with ammonia via the utilisation of sponge-derived urea and cyanate. Comparative analyses of published environmental 16S rRNA gene amplicon data revealed that Ca. Nitrosokoinonia and Ca. Nitrosymbion are widely distributed and predominantly associated with marine sponges and corals, suggesting a broad relevance of our findings.

Differential Roles of Kinetic On- and Off-Rates in T-Cell Receptor Signal Integration Revealed with a Modified Fab'-DNA Ligand.

Antibody-derived T-cell receptor (TCR) agonists are commonly used to activate T cells. While antibodies can trigger TCRs regardless of clonotype, they bypass native T cell signal integration mechanisms that rely on monovalent, membrane-associated, and relatively weakly-binding ligand in the context of cellular adhesion. Commonly used antibodies and their derivatives bind much more strongly than native peptide-MHC (pMHC) ligands bind their cognate TCRs. Because ligand dwell time is a critical parameter that tightly correlates with physiological function of the TCR signaling system, there is a general need, both in research and therapeutics, for universal TCR ligands with controlled kinetic binding parameters. To this end, we have introduced point mutations into recombinantly expressed α-TCRß H57 Fab to modulate the dwell time of monovalent Fab binding to TCR. When tethered to a supported lipid bilayer via DNA complementation, these monovalent Fab'-DNA ligands activate T cells with potencies well-correlated with their TCR binding dwell time. Single-molecule tracking studies in live T cells reveal that individual binding events between Fab'-DNA ligands and TCRs elicit local signaling responses closely resembling native pMHC. The unique combination of high on- and off-rate of the H57 R97L mutant enables direct observations of cooperative interplay between ligand binding and TCR-proximal condensation of the linker for activation of T cells (LAT), which is not readily visualized with pMHC. This work provides insights into how T cells integrate kinetic information from synthetic ligands and introduces a method to develop affinity panels for polyclonal T cells, such as cells from a human patient.

Morel-Lavallée lesion around the knee successfully treated with video-assisted endoscopic débridement: A case report.

We report a chronic Morel-Lavallée lesion around the knee in a competitive high schooler softball player, successfully treated with video-assisted endoscopic debridement. Endoscopic surgery is a viable option to treat Morel-Lavallée lesions in active patients who seek a rapid return to sport. The potential advantages of an endoscopic treatment would be a faster healing process and an earlier return to motion and function due to a less morbid and more cosmetic surgical approach.

Adjuvanted Vaccine Induces Functional Antibodies against Pseudomonas aeruginosa Filamentous Bacteriophages.

Pseudomonas aeruginosa (Pa), a WHO priority 1 pathogen, resulted in approximately 559,000 deaths globally in 2019. Pa has a multitude of host-immune evasion strategies that enhance Pa virulence. Most clinical isolates of Pa are infected by a phage called Pf that has the ability to misdirect the host-immune response and provide structural integrity to biofilms. Previous studies demonstrate that vaccination against the coat protein (CoaB) of Pf4 virions can assist in the clearance of Pa from the dorsal wound model in mice. Here, a consensus peptide was derived from CoaB and conjugated to cross-reacting material 197 (CRM197). This conjugate was adjuvanted with a novel synthetic Toll-like receptor agonist (TLR) 4 agonist, INI-2002, and used to vaccinate mice. Mice vaccinated with CoaB-CRM conjugate and INI-2002 developed high anti-CoaB peptide-specific IgG antibody titers. Direct binding of the peptide-specific antibodies to whole-phage virus particles was demonstrated by ELISA. Furthermore, a functional assay demonstrated that antibodies generated from vaccinated mice disrupted the replicative cycle of Pf phages. The use of an adjuvanted phage vaccine targeting Pa is an innovative vaccine strategy with the potential to become a new tool targeting multi-drug-resistant Pa infections in high-risk populations.

Bacterium secretes chemical inhibitor that sensitizes competitor to bacteriophage infection.

To overtake competitors, microbes produce and secrete secondary metabolites that kill neighboring cells and sequester nutrients. This natural product-mediated competition likely evolved in complex microbial communities that included viral pathogens. From this ecological context, we hypothesized that microbes secrete metabolites that "weaponize" natural pathogens (i.e., bacteriophages) to lyse their competitors. Indeed, we discovered a bacterial secondary metabolite that sensitizes other bacteria to phage infection. We found that this metabolite provides the producer (a Streptomyces sp.) with a fitness advantage over its competitor (Bacillus subtilis) by promoting phage infection. The phage-promoting metabolite, coelichelin, sensitized B. subtilis to a wide panel of lytic phages, and it did so by preventing the early stages of sporulation through iron sequestration. Beyond coelichelin, other natural products may provide phage-mediated competitive advantages to their producers-either by inhibiting sporulation or through yet-unknown mechanisms.

Co-Delivery of a Novel Lipidated TLR7/8 Agonist and Hemagglutinin-Based Influenza Antigen Using Silica Nanoparticles Promotes Enhanced Immune Responses.

Co-delivery of antigens and adjuvants to the same antigen-presenting cells (APCs) can significantly improve the efficacy and safety profiles of vaccines. Here, we report amine-grafted silica nanoparticles (A-SNP) as a tunable vaccine co-delivery platform for TLR7/8 agonists along with the recombinant influenza antigen hemagglutinin H7 (H7) to APCs. A-SNP of two different sizes (50 and 200 nm) were prepared and coated with INI-4001 at different coating densities, followed by co-adsorption of H7. Both INI-4001 and H7 showed >90% adsorption to the tested A-SNP formulations. TNF-α and IFN-α cytokine release by human peripheral blood mononuclear cells as well as TNF-α, IL-6, and IL-12 release by mouse bone marrow-derived dendritic cells revealed that the potency of the INI-4001-adsorbed A-SNP (INI-4001/A-SNP) formulations was improved relative to aqueous formulation control. This improved potency was dependent on particle size and ligand coating density. In addition, slow-release profiles of INI-4001 were measured from INI-4001/A-SNP formulations in plasma with 30-50% INI-4001 released after 7 days. In vivo murine immunization studies demonstrated significantly improved H7-specific humoral and Th1/Th17-polarized T cell immune responses with no observed adverse reactions. Low-density 50 nm INI-4001/A-SNP elicited significantly higher IFN-γ and IL-17 induction over that of the H7 antigen-only group and INI-4001 aqueous formulation controls. In summary, this work introduces an effective and biocompatible SNP-based co-delivery platform that enhances the immunogenicity of TLR7/8 agonist-adjuvanted subunit influenza vaccines.

Thermal responses of dissolved organic matter under global change.

The diversity of intrinsic traits of different organic matter molecules makes it challenging to predict how they, and therefore the global carbon cycle, will respond to climate change. Here we develop an indicator of compositional-level environmental response for dissolved organic matter to quantify the aggregated response of individual molecules that positively and negatively associate with warming. We apply the indicator to assess the thermal response of sediment dissolved organic matter in 480 aquatic microcosms along nutrient gradients on three Eurasian mountainsides. Organic molecules consistently respond to temperature change within and across contrasting climate zones. At a compositional level, dissolved organic matter in warmer sites has a stronger thermal response and shows functional reorganization towards molecules with lower thermodynamic favorability for microbial decomposition. The thermal response is more sensitive to warming at higher nutrients, with increased sensitivity of up to 22% for each additional 1 mg L-1 of nitrogen loading. The utility of the thermal response indicator is further confirmed by laboratory experiments and reveals its positive links to greenhouse gas emissions.

Spectral Resolution and Speech Perception in Cochlear Implanted School-Aged Children.

OBJECTIVE: Cochlear implantation of prelingually deaf infants provides auditory input sufficient to develop spoken language; however, outcomes remain variable. Inability to participate in speech perception testing limits testing device efficacy in young listeners. In postlingually implanted adults (aCI), speech perception correlates with spectral resolution an ability that relies independently on frequency resolution (FR) and spectral modulation sensitivity (SMS). The correlation of spectral resolution to speech perception is unknown in prelingually implanted children (cCI). In this study, FR and SMS were measured using a spectral ripple discrimination (SRD) task and were correlated with vowel and consonant identification. It was hypothesized that prelingually deaf cCI would show immature SMS relative to postlingually deaf aCI and that FR would correlate with speech identification. STUDY DESIGN: Cross-sectional study. SETTING: In-person, booth testing. METHODS: SRD was used to determine the highest spectral ripple density perceived at various modulation depths. FR and SMS were derived from spectral modulation transfer functions. Vowel and consonant identification was measured; SRD performance and speech identification were analyzed for correlation. RESULTS: Fifteen prelingually implanted cCI and 13 postlingually implanted aCI were included. FR and SMS were similar between cCI and aCI. Better FR was associated with better speech identification for most measures. CONCLUSION: Prelingually implanted cCI demonstrated adult-like FR and SMS; additionally, FR correlated with speech identification. FR may be a measure of CI efficacy in young listeners.

Changes in Body Composition and Athletic Performance in National Collegiate Athletic Association Division I Female Field Hockey Athletes Throughout a Competitive Season.

ABSTRACT: Summer, LC, Cheng, R, Moran, JT, Lee, M, Belanger, AJ, TaylorIV, WL, and Gardner, EC. Changes in body composition and athletic performance in National Collegiate Athletic Association Division I female field hockey athletes throughout a competitive season. J Strength Cond Res 38(1): 146-152, 2024-The purposes of this study were (a) to analyze the changes in total and regional body composition measurements in a National Collegiate Athletic Association (NCAA) Division I female field hockey team throughout a 17-game competitive season using dual X-ray absorptiometry (DXA); (b) to examine improvements, if any, in athletic performance measures after a season; and (c) to report on the relationship between these body composition changes and changes in athletic performance. Preseason and postseason dual-energy DXA and performance data from the 2019-2020 season were retrospectively identified for 20 field players (forwards, midfielders, and defenders). Body composition data included total and regional fat mass, lean mass, and body fat percentage, whereas athletic performance measures included the vertical jump, 10-yard dash, and pro-agility (5-10-5) shuttle run. All variables were quantitative and analyzed using paired t -tests or its nonparametric equivalent and an alpha level of p < 0.05 was used to determine significance. After a competitive season, athletes had significant decreases in fat mass and increases in lean mass in their arms, legs, trunks, gynoids, and total body measurements. Android fat mass and body fat percentage also decreased. Athletes performed significantly better on the pro-agility shuttle run at the end of the season, but no significant differences were observed in other performance metrics. Moderate correlations were observed between changes in body composition (total fat mass and total lean mass) and changes in athletic performance. Our study provides a novel, longitudinal assessment of body composition and athletic performance for elite female field hockey athletes that will help trainers and coaches better understand how these variables change throughout a season and allow them to better prepare their players for competitive success.

Piezo1 facilitates optimal T cell activation during tumor challenge.

Functional effector T cells in the tumor microenvironment (TME) are critical for successful anti-tumor responses. T cell anti-tumor function is dependent on their ability to differentiate from a naïve state, infiltrate into the tumor site, and exert cytotoxic functions. The factors dictating whether a particular T cell can successfully undergo these processes during tumor challenge are not yet completely understood. Piezo1 is a mechanosensitive cation channel with high expression on both CD4+ and CD8+ T cells. Previous studies have demonstrated that Piezo1 optimizes T cell activation and restrains the CD4+ regulatory T cell (Treg) pool in vitro and under inflammatory conditions in vivo. However, little is known about the role Piezo1 plays on CD4+ and CD8+ T cells in cancer. We hypothesized that disruption of Piezo1 on T cells impairs anti-tumor immunity in vivo by hindering inflammatory T cell responses. We challenged mice with T cell Piezo1 deletion (P1KO) with tumor models dependent on T cells for immune rejection. P1KO mice had the more aggressive tumors, higher tumor growth rates and were unresponsive to immune-mediated therapeutic interventions. We observed a decreased CD4:CD8 ratio in both the secondary lymphoid organs and TME of P1KO mice that correlated inversely with tumor size. Poor CD4+ helper T cell responses underpinned the immunodeficient phenotype of P1KO mice. Wild type CD8+ T cells are sub-optimally activated in vivo with P1KO CD4+ T cells, taking on a CD25loPD-1hi phenotype. Together, our results suggest that Piezo1 optimizes T cell activation in the context of a tumor response.

A Compact Monitor for Ethylene and Other Plant-Produced Volatile Organic Compounds for NASA Space Missions.

In this work, we discuss the development of a compact analytical instrument for monitoring ethylene in compact greenhouses utilized by NASA to grow fresh vegetables in space. Traditionally, ethylene measurements are conducted by GC-MS systems. However, in space, they are not applicable due to their bulky size, heavy weight, special carrier gas requirement and high maintenance. Our group developed a compact and robust battery-powered ethylene monitor based on the principles of analytical gas chromatography. The device utilizes purified ambient air as a carrier gas and a metal oxide sensor as a GC detector. Implementation of a CarboWax 20 M packed column from Restek together with a Tenax TA pre-concentrator allowed us to achieve a 20 ppb limit of detection for ethylene. Full automation of measurements and reporting of concentrations was accomplished via the implementation of a Raspberry Pi 4 computer and a 7″ 720P LED capacitive touchscreen utilized for data output. Based on a feasibility study, a fully automated, industrial-grade ethylene monitoring and removal system for greenhouses was developed.

Allosteric inhibition of the T cell receptor by a designed membrane ligand.

The T cell receptor (TCR) is a complex molecular machine that directs the activation of T cells, allowing the immune system to fight pathogens and cancer cells. Despite decades of investigation, the molecular mechanism of TCR activation is still controversial. One of the leading activation hypotheses is the allosteric model. This model posits that binding of pMHC at the extracellular domain triggers a dynamic change in the transmembrane (TM) domain of the TCR subunits, which leads to signaling at the cytoplasmic side. We sought to test this hypothesis by creating a TM ligand for TCR. Previously we described a method to create a soluble peptide capable of inserting into membranes and binding to the TM domain of the receptor tyrosine kinase EphA2 (Alves et al., eLife, 2018). Here, we show that the approach is generalizable to complex membrane receptors, by designing a TM ligand for TCR. We observed that the designed peptide caused a reduction of Lck phosphorylation of TCR at the CD3ζ subunit in T cells. As a result, in the presence of this peptide inhibitor of TCR (PITCR), the proximal signaling cascade downstream of TCR activation was significantly dampened. Co-localization and co-immunoprecipitation in diisobutylene maleic acid (DIBMA) native nanodiscs confirmed that PITCR was able to bind to the TCR. AlphaFold-Multimer predicted that PITCR binds to the TM region of TCR, where it interacts with the two CD3ζ subunits. Our results additionally indicate that PITCR disrupts the allosteric changes in the compactness of the TM bundle that occur upon TCR activation, lending support to the allosteric TCR activation model. The TCR inhibition achieved by PITCR might be useful to treat inflammatory and autoimmune diseases and to prevent organ transplant rejection, as in these conditions aberrant activation of TCR contributes to disease.

Behavioral characterization of the cochlear amplifier lesion due to loss of function of stereocilin (STRC) in human subjects.

Loss of function of stereocilin (STRC) is the second most common cause of inherited hearing loss. The loss of the stereocilin protein, encoded by the STRC gene, induces the loss of connection between outer hair cells and tectorial membrane. This only affects the outer hair cells (OHCs) function, involving deficits of active cochlear frequency selectivity and amplifier functions despite preservation of normal inner hair cells. Better understanding of cochlear features associated with mutation of STRC will improve our knowledge of normal cochlear function, the pathophysiology of hearing impairment, and potentially enhance hearing aid and cochlear implant signal processing. Nine subjects with homozygous or compound heterozygous loss of function mutations in STRC were included, age 7-24 years. Temporal and spectral modulation perception were measured, characterized by spectral and temporal modulation transfer functions. Speech-in-noise perception was studied with spondee identification in adaptive steady-state noise and AzBio sentences with 0 and -5 dB SNR multitalker babble. Results were compared with normal hearing (NH) and cochlear implant (CI) listeners to place STRC-/- listeners' hearing capacity in context. Spectral ripple discrimination thresholds in the STRC-/- subjects were poorer than in NH listeners (p < 0.0001) but remained better than for CI listeners (p < 0.0001). Frequency resolution appeared impaired in the STRC-/- group compared to NH listeners but did not reach statistical significance (p = 0.06). Compared to NH listeners, amplitude modulation detection thresholds in the STRC-/- group did not reach significance (p=  0.06) but were better than in CI subjects (p < 0.0001). Temporal resolution in STRC-/- subjects was similar to NH (p = 0.98) but better than in CI listeners (p = 0.04). The spondee reception threshold in the STRC-/- group was worse than NH listeners (p = 0.0008) but better than CI listeners (p = 0.0001). For AzBio sentences, performance at 0 dB SNR was similar between the STRC-/- group and the NH group, 88 % and 97 % respectively. For -5 dB SNR, the STRC-/- performance was significantly poorer than NH, 40 % and 85 % respectively, yet much better than with CI who performed at 54 % at +5 dB SNR in children and 53 % at + 10 dB SNR in adults. To our knowledge, this is the first study of the psychoacoustic performance of human subjects lacking cochlear amplification but with normal inner hair cell function. Our data demonstrate preservation of temporal resolution and a trend to impaired frequency resolution in this group without reaching statistical significance. Speech-in-noise perception compared to NH listeners was impaired as well. All measures were better than those in CI listeners. It remains to be seen if hearing aid modifications, customized for the spectral deficits in STRC-/- listeners can improve speech understanding in noise. Since cochlear implants are also limited by deficient spectral selectivity, STRC-/- hearing may provide an upper bound on what could be obtained with better temporal coding in electrical stimulation.

Morphological and evolutionary insights into the keystone element of the human foot's medial longitudinal arch.

The evolution of the medial longitudinal arch (MLA) is one of the most impactful adaptations in the hominin foot that emerged with bipedalism. When and how it evolved in the human lineage is still unresolved. Complicating the issue, clinical definitions of flatfoot in living Homo sapiens have not reached a consensus. Here we digitally investigate the navicular morphology of H. sapiens (living, archaeological, and fossil), great apes, and fossil hominins and its correlation with the MLA. A distinctive navicular shape characterises living H. sapiens with adult acquired flexible flatfoot, while the congenital flexible flatfoot exhibits a 'normal' navicular shape. All H. sapiens groups differentiate from great apes independently from variations in the MLA, likely because of bipedalism. Most australopith, H. naledi, and H. floresiensis navicular shapes are closer to those of great apes, which is inconsistent with a human-like MLA and instead might suggest a certain degree of arboreality. Navicular shape of OH 8 and fossil H. sapiens falls within the normal living H. sapiens spectrum of variation of the MLA (including congenital flexible flatfoot and individuals with a well-developed MLA). At the same time, H. neanderthalensis seem to be characterised by a different expression of the MLA.