The mammalian cochlea contains two types of mechanosensory hair cell that have different and critical functions in hearing. Inner hair cells (IHCs), which have an elaborate presynaptic apparatus, signal to cochlear neurons and communicate sound information to the brain. Outer hair cells (OHCs) mechanically amplify sound-induced vibrations, providing enhanced sensitivity to sound and sharp tuning. Cochlear hair cells are solely generated during development, and hair cell death-most often of OHCs-is the most common cause of deafness. OHCs and IHCs, together with supporting cells, originate in embryos from the prosensory region of the otocyst, but how hair cells differentiate into two different types is unknown1-3. Here we show that Insm1, which encodes a zinc finger protein that is transiently expressed in nascent OHCs, consolidates their fate by preventing trans-differentiation into IHCs. In the absence of INSM1, many hair cells that are born as OHCs switch fates to become mature IHCs. To identify the genetic mechanisms by which Insm1 operates, we compared the transcriptomes of immature IHCs and OHCs, and of OHCs with and without INSM1. In OHCs that lack INSM1, a set of genes is upregulated, most of which are normally preferentially expressed by IHCs. The homeotic cell transformation of OHCs without INSM1 into IHCs reveals a mechanism by which these neighbouring mechanosensory cells begin to differ: INSM1 represses a core set of early IHC-enriched genes in embryonic OHCs and makes them unresponsive to an IHC-inducing gradient, so that they proceed to mature as OHCs. Without INSM1, some of the OHCs in which these few IHC-enriched transcripts are upregulated trans-differentiate into IHCs, identifying candidate genes for IHC-specific differentiation.

The genetic architecture of brain structure and function is largely unknown. To investigate this, we carried out genome-wide association studies of 3,144 functional and structural brain imaging phenotypes from UK Biobank (discovery dataset 8,428 subjects). Here we show that many of these phenotypes are heritable. We identify 148 clusters of associations between single nucleotide polymorphisms and imaging phenotypes that replicate at P < 0.05, when we would expect 21 to replicate by chance. Notable significant, interpretable associations include: iron transport and storage genes, related to magnetic susceptibility of subcortical brain tissue; extracellular matrix and epidermal growth factor genes, associated with white matter micro-structure and lesions; genes that regulate mid-line axon development, associated with organization of the pontine crossing tract; and overall 17 genes involved in development, pathway signalling and plasticity. Our results provide insights into the genetic architecture of the brain that are relevant to neurological and psychiatric disorders, brain development and ageing.

Three-dimensional (3D) treatment planning of patient undergoing radiotherapy uses complex and meticulous computational algorithms. These algorithms use 3D voxel data of the patient to calculate the radiation dose distribution and display it over the CT image dataset for treatment plan evaluation.

We aimed to identify new predictive biomarkers for cetuximab in first-line treatment for patients with RAS wild-type metastatic colorectal cancer (mCRC).

Tissue ischemia can arise in response to numerous physiologic and pathologic conditions. The cellular response to decreased perfusion, most notably a decrease in glucose and oxygen, is important for cellular survival. In response to oxygen deprivation or hypoxia, one of the key response elements is hypoxia inducible factor (HIF) and a key protein induced by hypoxia is vascular endothelial growth factor (VEGF). Under hypoxia, we and others have reported an increase in the half-life of VEGF and other hypoxia related mRNAs including MYC and CYR61; however, the mediator of this response has yet to be identified. For this study, we sought to determine if HIF-mediated transcriptional activity is involved in the mRNA stabilization induced by hypoxia.

The potentially harmful nature of electromagnetic fields (EMF) and static magnetic fields (SMF) has become a major problem in recent years. All these elements could be combined to produce cellular responses. For example, the orientation of molecules of water or other complex molecules, growth and cell viability, cell morphology, and intracellular metabolic pathways have demonstrated binding to magnetic fields. The effect of EMF and SMF on humans is a topic of great importance, especially because modern technology has introduced artificial magnetic fields such as those generated by power lines, mobile communications, and medical imaging equipment. A relevant problem is certainly that of professional exposure. The aim of this study was the evaluation of the effectiveness of a commercially available device, Skudo® patches (Edil Natura S.r.l., Novara, Italy), in protecting magnetic resonance operators from the influence of magnetic fields such as those present in the workplace. Skudo® patches are designed to protect microareas of the body from external electromagnetic disturbances. In this study, 10 male Italian volunteers aged between 50 and 60 were enrolled in the hospital. All participants were subjected to measurements at 4 specific time points to evaluate the effectiveness of Skudo® to counteract both EMF and SMF magnetic fields by evaluating the level of bioenergetic reactivity. To perform the measurements, a variant of the Ryodoraku method has been used, based upon the assessment of electropermeability. In particular, 12 acupoints were measured, one for each of the main meridians. This study shows that both SMF and EMF cause an alteration of the body's water system. The application of Skudo® patches determines a regularization of bioenergetic levels related to the water system. The application of Skudo® on the EMF source has suppressed the imbalance effect of the water system found in the subject without any protection.

Physical exercise (PE), virtual reality-based exercise (VRE), and brain exercise (BE) can influence physical and cognitive conditions in older persons. However, it is not known which of the three types of exercises provide the best effects on physical and cognitive status, and which exercise is preferred by older persons. This study compared the effects of PE, VRE, and BE on balance, muscle strength, cognition, and fall concern. In addition, exercise effort perception and contentment in older persons was evaluated.

The expression of programmed death 1 (PD1) and programmed death ligand 1 (PDL1) can be induced by the interferon (IFN)/signal transducer and activator of transcription (STAT) pathway. The PD1/PDL1 reverse signaling can activate the eukaryotic translation initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4) pathway which in turn regulates the expression of IFN regulatory factor (IRF) 7 and IFNα. The eIF2α/ATF4 pathway is responsible for the integrated stress response (ISR) of unfolded protein response (UPR) which can affect immune cell function in tumor microenvironment.

The outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies for these patients. Human cancers, including MCL, present recurrent alterations in genes that encode transcription machinery proteins and of proteins involved in regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain and Extra Terminal domain (BET) family proteins act as transcriptional regulators of key signalling pathways including those sustaining cell viability. Birabresib (MK-8628/OTX015) has shown antitumour activity in different preclinical models and has been the first BET inhibitor to successfully undergo early clinical trials.

We sought to determine the association of echocardiographically derived epicardial adipose tissue (EAT) thickness, which is a component of visceral adipose tissue, with the metabolic syndrome (MetS) in a cohort of randomly selected community participants.

CD48 is a costimulatory receptor associated with human asthma. We aimed to assess the significance of the soluble form of CD48 (sCD48) in allergic and nonallergic asthma. Volunteer patients completed an asthma and allergy questionnaire, spirometry, methacholine challenge test, a common allergen skin prick test, and a complete blood count. sCD48, IgE, IL5, IL17A, IL33, and IFNγ were quantitated in serum by ELISA. Asthma was defined as positive methacholine challenge test or a 15% increase in FEV1 post bronchodilator in symptomatic individuals. Allergy was defined as positive skin test or IgE levels > 200 IU/l in symptomatic individuals. 137 individuals participated in the study: 82 (60%) were diagnosed with asthma of which 53 (64%) was allergic asthma. sCD48 levels were significantly elevated in patients with nonallergic asthma compared to control and to the allergic asthma cohort (median (IQR) pg/ml, 1487 (1338-1758) vs. 1308 (1070-1581), p < 0.01, and 1336 (1129-1591), p = 0.02, respectively). IL17A, IL33, and IFNγ levels were significantly elevated in allergic and nonallergic asthmatics when compared to control. No correlation was found between sCD48 level and other disease markers. sCD48 is elevated in nonallergic asthma. Additional studies are required for understanding the role of sCD48 in airway disease.

Stress fractures of the elbow are rare in throwing athletes and present a challenge from both a management and rehabilitation perspective. Although the incidence of stress fractures of the elbow is increasing, there is a lack of data in the literature focused on throwers.

Rehabilitation techniques have been used to facilitate reading acquisition in dyslexia. However, many individuals continue to present academic impairment throughout life. New intervention strategies are necessary to further help this population.

The tremendous diversity of floral and fruit traits is, to a large extent, a set of adaptations that promote plant reproduction through animal pollinators and seed dispersers. Yet, it is still unknown whether fruit scent is a by-product of fruit maturation or an evolved communication channel with animal mutualists. We show that in species that specialize on seed dispersal by lemurs-an olfactorily oriented primate-fruits increase scent production and change their chemical composition significantly more than sympatric species whose seeds are largely dispersed by birds. We further show that lemurs use these shifts in fruit scent to identify ripe fruits. These results show that fruit scent is an evolved communication system that facilitates animal-plant mutualism.

Participation in youth soccer carries a significant risk of injury, most commonly non-contact injuries of the lower extremity. A growing body of research supports the use of neuromuscular interventions by teams to prevent such injuries, yet the uptake of these recommendations by soccer teams remains largely unexplored. The purposes of the study were to determine (1) the level of awareness by youth coaches of injury prevention programs and their efficacy; (2) the number of youth coaches that use these interventions; and (3) barriers and potential facilitators to implementing a sustainable injury prevention program.

Nonosmotic sodium storage has been reported in animals, healthy individuals and patients with hypertension, hyperaldosteronism and end-stage kidney disease. Sodium storage has not been studied in ICU patients, who frequently receive large amounts of sodium chloride-containing fluids. The objective of our study was to estimate sodium that cannot be accounted for by balance studies in critically ill patients. Chloride was also studied. We used multiple scenarios and assumptions for estimating sodium and chloride balances.

Diacetyl contributes to the flavor profile of many fermented products. Its typical buttery flavor is considered as an off flavor in lager-style beers, and its removal has a major impact on time and energy expenditure in breweries. Here, we investigated the possibility of lowering beer diacetyl levels through evolutionary engineering of lager yeast for altered synthesis of α-acetolactate, the precursor of diacetyl. Cells were exposed repeatedly to a sub-lethal level of chlorsulfuron, which inhibits the acetohydroxy acid synthase responsible for α-acetolactate production. Initial screening of 7 adapted isolates showed a lower level of diacetyl during wort fermentation and no apparent negative influence on fermentation rate or alcohol yield. Pilot-scale fermentation was carried out with one isolate and results confirmed the positive effect of chlorsulfuron adaptation. Diacetyl levels were over 60% lower at the end of primary fermentation relative to the non-adapted lager yeast and no significant change in fermentation performance or volatile flavor profile was observed due to the adaptation. Whole-genome sequencing revealed a non-synonymous SNP in the ILV2 gene of the adapted isolate. This mutation is known to confer general tolerance to sulfonylurea compounds, and is the most likely cause of the improved tolerance. Adaptive laboratory evolution appears to be a natural, simple and cost-effective strategy for diacetyl control in brewing.

Group 2 innate lymphoid cells (ILC2s) have been implicated in the pathogenesis of allergic disease. However, the effect of allergen-specific immunotherapy (AIT) on ILCs remains to be clarified. The aim of this study was to evaluate the levels of ILC subsets in allergic rhinitis (AR) patients in response to house dust mite (HDM)-specific immunotherapy.

Equine chorionic girdle trophoblast cells play important endocrine and immune functions critical in supporting pregnancy. Very little is known about the genes and pathways that regulate chorionic girdle trophoblast development. Our aim was to identify genes and signalling pathways active in vivo in equine chorionic girdle trophoblast within a critical 7-days window. We exploited the late implantation of the equine conceptus to obtain trophoblast tissue. An Agilent equine 44K microarray was performed using RNA extracted from chorionic girdle and chorion (control) from equine pregnancy days 27, 30, 31 and 34 (n = 5), corresponding to the initiation of chorionic girdle trophoblast proliferation, differentiation and migration. Data were analysed using R packages limma and maSigPro, Ingenuity Pathway Analysis and DAVID and verified using qRT-PCR, promoter analysis, western blotting and migration assays. Microarray analysis showed gene expression (absolute log FC >2, FDR-adjusted P < 0.05) was rapidly and specifically induced in the chorionic girdle between days 27 and 34 (compared to day 27, day 30 = 116, day 31 = 317, day 34 = 781 genes). Pathway analysis identified 35 pathways modulated during chorionic girdle development (e.g. FGF, integrin, Rho GTPases, MAPK) including pathways that have limited description in mammalian trophoblast (e.g. IL-9, CD40 and CD28 signalling). Rho A and ERK/MAPK activity was confirmed as was a role for transcription factor ELF5 in regulation of the CGB promoter. The purity and accessibility of chorionic girdle trophoblast proved to be a powerful resource to identify candidate genes and pathways involved in early equine placental development.

Although low pressure baroreflex (LPB) has been shown to elicit various cardiovascular responses, its impact on sympathetic nerve activity (SNA) and arterial baroreflex (ABR) function has not been fully elucidated. The aim of this study was to clarify how volume loading-induced acute LPB activation impacts on SNA and ABR function in normal rats. In 20 anesthetized Sprague-Dawley rats, we isolated bilateral carotid sinuses, controlled carotid sinus pressure (CSP), and measured central venous pressure (CVP), splanchnic SNA, and arterial pressure (AP). We infused blood stepwise (3 mL/kg/step) to activate volume loading-induced LPB. Under the ABR open-loop condition, stepwise volume loading markedly increased SNA by 76.8 ± 21.6% at CVP of 3.6 ± 0.2 mmHg. In contrast, further volume loading suppressed SNA toward the baseline condition. Bilateral vagotomy totally abolished the changes in SNA by volume loading. To assess the impact of LPB on ABR function, we changed CSP stepwise. Low volume loading (CVP = 3.6 ± 0.4 mmHg) significantly shifted the sigmoidal CSP-SNA relationship (central arc) upward from baseline, whereas high volume loading (CVP = 5.4 ± 0.4 mmHg) returned it to the baseline level. Volume loading shifted the linear SNA-AP relationship (peripheral arc) upward without significant changes in slope. In conclusions, volume loading-induced acute LPB activation evoked two-phase changes, an initial increase followed by decline from baseline value, in SNA via resetting of the ABR central arc. LPB may contribute greatly to stabilize AP in response to volume status.