Taste dysfunctions may occur, for example, after viral infection, surgery, medications, or with age. In clinical practice, it is important to assess patients’ taste function with rapidity and reliability. This study aimed to develop a test that assesses human gustatory sensitivity together with somatosensory functions of astringency and spiciness. A total of 154 healthy subjects and 51 patients with chemosensory dysfunction rated their gustatory sensitivity. They underwent a whole-mouth identification test of 12 filter-paper strips impregnated with low and high concentrations of sweet, sour, salty, bitter (sucrose, citric acid, NaCl, quinine), astringency (tannin), and spiciness (capsaicin). The percentage of correct identifications for high-concentrated sweet and sour, and for low-concentrated salty, bitter and spicy was lower in patients as compared with healthy participants. Interestingly, a lower identification in patients for both astringent concentrations was found. Based on the results, we proposed the Seven-iTT to assess chemo/somatosensory function, with a cut-off of 6 out of 7. The test score discriminated patients from healthy controls and showed gender differences among healthy controls. This quantitative test seems to be suitable for routine clinical assessment of gustatory and trigeminal function. It also provides new evidence on the mutual interaction between the two sensory systems.

Nutrition plays an essential role in the regulation of optimal immunological response, by providing adequate nutrients in sufficient concentrations to immune cells. There are a large number of micronutrients, such as minerals, and vitamins, as well as some macronutrients such as some amino acids, cholesterol and fatty acids demonstrated to exert a very important and specific impact on appropriate immune activity. This review aims to summarize at some extent the large amount of data accrued to date related to the modulation of immune function by certain micro and macronutrients and to emphasize their importance in maintaining human health. Thus, among many, some relevant case in point examples are brought and discussed: (1) The role of vitamin A/all-trans-retinoic-acids (ATRA) in acute promyelocytic leukemia, being this vitamin utilized as a very efficient therapeutic agent via effective modulation of the immune function (2) The involvement of vitamin C in the fight against tumor cells via the increase of the number of active NK cells. (3) The stimulation of apoptosis, the suppression of cancer cell proliferation, and delayed tumor development mediated by calcitriol/vitamin D by means of immunity regulation (4) The use of selenium as a cofactor to reach more effective immune response to COVID vaccination (5). The crucial role of cholesterol to regulate the immune function, which is demonstrated to be very sensitive to the variations of this macronutrient concentration. Other important examples are reviewed as well.

We explored the structural features of recombinant ostreolysin A (rOlyA), a protein produced by Pleurotus ostreatus and responsible for binding to α/β-tubulin. We found that rOlyA cell internalization is essential for the induction of adipocyte-associated activity, which is mediated by the interaction of rOlyA and microtubule proteins. We created different point mutations at conserved tryptophan (W) sites in rOlyA and analyzed their biological activity in HIB-1B preadipocytes. We demonstrated that the protein’s cell-internalization ability and the differentiated phenotype induced, such as small lipid-droplet formation and gene expression of mitogenesis activity, were impaired in point-mutated proteins W96A and W28A, where W was converted to alanine (A). We also showed that an rOlyA homologue, OlyA6 complexed with mCherry, cannot bind to β-tubulin and does not induce mitochondrial biosynthesis-associated markers, suggesting that the OlyA6 region masked by mCherry is involved in β-tubulin binding. Protein–protein docking simulations were carried out to investigate the binding mode of rOlyA with β-tubulin. Taken together, we identified functional sites in rOlyA that are essential for its binding to β-tubulin and its adipocyte-associated biological activity.

{While there is an association between Western diets and the incidence of colorectal cancer (CRC), this dietary association has remained unexplored in Palestine. The aim of this study was to examine how fiber and fruit and vegetable (FV) intakes are associated with CRC risk among Palestinian adults. We recruited 528 Palestinians between 2014 and 2016. We identified 118 patients who received CRC treatment at Augusta Victoria Hospital, East Jerusalem. We additionally identified 410 controls who consisted of community-based Palestinians without cancer. All participants completed a survey on demographics and a validated dietary intake food screener. Multivariable logistic regression models tested associations between fiber and FV intakes (categorized into quartiles) with CRC risk. After adjusting for significant covariates (age, sex, education, physical activity, smoking status, BMI, IBD, and family history of CRC), as fibers increased across increasing quartiles, the CRC risk significantly decreased (OR = 0.36, 95% CI: 0.15–0.86

Ice-binding proteins (IBPs) allow organisms to survive below the freezing point by modulating ice crystal growth. These proteins act by binding to ice surfaces, thus inhibiting ice growth. Until now, high-resolution imaging of ice growing in the presence of IBPs has not been possible. We developed a unique in-situ technique that enables atomic force microscopy (AFM) imaging of ice formation and growth in the ice-IBP system. The new technique enables controlling the growth of ice crystals under a strong and focused thermal gradient. We present images of ice crystals with sub-ten nanometer resolution. Ice was grown in the presence of two different IBPs that exhibit specific and unique structures. This development opens the path for fine elucidation of the interaction of IBPs with growing ice surfaces as well as with other frozen systems at unprecedented high resolution. Furthermore, with the exception of crystals growing in thin films, this is the first demonstration for imaging a growing crystal immersed in its own melt with AFM.

Bacterial ice nucleation proteins (INPs) can cause frost damage to plants by nucleating ice formation at high sub-zero temperatures. Modeling of Pseudomonas borealis INP by AlphaFold suggests that the central domain of 65 tandem sixteen-residue repeats forms a beta-solenoid with arrays of outward-pointing threonines and tyrosines, which may organize water molecules into an ice-like pattern. Here we report that mutating some of these residues in a central segment of P. borealis INP, expressed in Escherichia coli, decreases ice nucleation activity more than the section’s deletion. Insertion of a bulky domain has the same effect, indicating that the continuity of the water-organizing repeats is critical for optimal activity. The ~10 C-terminal coils differ from the other 55 coils in being more basic and lacking water-organizing motifs; deletion of this region eliminates INP activity. We show through sequence modifications how arrays of conserved motifs form the large ice-nucleating surface required for potency.

Half of the harvested food is lost due to rots caused by microorganisms. Plants emit various volatile organic compounds (VOCs) into their surrounding environment, and the VOC profiles of healthy crops are altered upon infection. In this study, a whole-cell bacterial biosensor was used for the early identification of potato tuber soft rot disease caused by the pectinolytic bacteria Pectobacterium in potato tubers. The detection is based on monitoring the luminescent responses of the bacteria panel to changes in the VOC profile following inoculation. First, gas chromatography-mass spectrometry (GC-MS) was used to specify the differences between the VOC patterns of the inoculated and non-inoculated potato tubers during early infection. Five VOCs were identified, 1-octanol, phenylethyl alcohol, 2-ethyl hexanol, nonanal, and 1-octen-3-ol. Then, the infection was detected by the bioreporter bacterial panel, firstly measured in a 96-well plate in solution, and then also tested in potato plugs and validated in whole tubers. Examination of the bacterial panel responses showed an extensive cytotoxic effect over the testing period, as seen by the elevated induction factor (IF) values in the bacterial strain TV1061 after exposure to both potato plugs and whole tubers. Moreover, quorum sensing influences were also observed by the elevated IF values in the bacterial strain K802NR. The developed whole-cell biosensor system based on bacterial detection will allow more efficient crop management during postharvest, storage, and transport of crops, to reduce food losses.

Taste GPCRs are expressed in taste buds on the tongue and play a key role in food choice and consumption. They are also expressed extra-orally, with various physiological roles that are currently under study. Unraveling the roles of these receptors relies on the knowledge of their ligands. Combining sensory, cell-based and computational approaches enabled the discovery of numerous agonists and several antagonists. Here we provide a short overview of taste receptor families, main recent methods for ligands discovery, and current sources of information about known ligands. The future directions that are likely to impact the taste GPCR field include focus on ligand interactions with naturally occurring polymorphisms, as well as harnessing the power of CryoEM and of multiple signaling readout techniques.

Sweet taste is innately appealing, ensuring that mammals are attracted to the sweetness of mother’s milk and other sources of carbohydrates and calories. In the modern world, the availability of sugars and sweeteners and the eagerness of the food industry to maximize palatability, result in an abundance of sweet food products, which poses a major health challenge. The aim of the current study is to analyze sweetness levels, liking, and ingredients of online reviews of food products, in order to obtain insights into sensory nutrition and to identify new opportunities for reconciling the palatability–healthiness tension. We collected over 200,000 reviews of  30,000 products on Amazon dated from 2002 to 2012 and  350,000 reviews of  2400 products on iHerb from 2006 to 2021. The reviews were classified and analyzed using manual curation, natural language processing, and machine learning. In total,  32,000 (Amazon) and  29,000 (iHerb) of these reviews mention sweetness, with 2200 and 4600 reviews referring to the purchased products as oversweet. Oversweet reviews were dispersed among consumers. Products that included sucralose had more oversweet reviews than average. 26 products had at least 50 reviews for which at least 10% were oversweet. For these products, the average liking by consumers reporting oversweetness was significantly lower (by 0.9 stars on average on a 1 to 5 stars scale) than by the rest of the consumers. In summary, oversweetness appears in 7–16% of the sweetness-related reviews and is less liked, which suggests an opportunity for customized products with reduced sweetness. These products will be simultaneously healthier and tastier for a substantial subgroup of customers and will benefit the manufacturer by expanding the products’ target audience. Analysis of consumers’ reviews of marketed food products offers new ways to obtain informative sensory data.

Abstract Subjectively perceived impairment of taste is a common and distinct symptom of coronavirus disease 2019 (COVID-19). Large meta-analyses identified this symptom in approximately 50% of cases. However, this high prevalence is not supported by blinded and validated psychophysical gustatory testing, which showed a much lower prevalence in up to 26% of patients. This discrepancy may be due to misinterpretation of impaired retronasal olfaction as gustatory dysfunction. In addition, we hypothesized that COVID-19?associated hyposmia is involved in the decrease of gustatory function, as found for hyposmia of different origin. This indirect mechanism would be based on the central-nervous mutual amplification between the chemical senses, which fails in COVID-19?associated olfactory loss. However, further research is necessary on how severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) may directly impair the gustatory pathway as well as its subjective perception.

During fasting, hepatocytes produce glucose in response to hormonal signals. Glucagon and glucocorticoids are principal fasting hormones that cooperate in regulating glucose production via gluconeogenesis. However, how these hormone signals are integrated and interpreted to a biological output is unknown. Here, we use genome-wide profiling of gene expression, enhancer dynamics and transcription factor (TF) binding in primary mouse hepatocytes to uncover the mode of cooperation between glucagon and glucocorticoids. We found that compared to a single treatment with each hormone, a dual treatment directs hepatocytes to a pro-gluconeogenic gene program by synergistically inducing gluconeogenic genes. The cooperative mechanism driving synergistic gene expression is based on ‘assisted loading’ whereby a glucagon-activated TF (cAMP responsive element binding protein; CREB) leads to enhancer activation which facilitates binding of the glucocorticoid receptor (GR) upon glucocorticoid stimulation. Glucagon does not only activate single enhancers but also activates enhancer clusters, thereby assisting the loading of GR also across enhancer units within the cluster. In summary, we show that cells integrate extracellular signals by an enhancer-specific mechanism: one hormone-activated TF activates enhancers, thereby assisting the loading of a TF stimulated by a second hormone, leading to synergistic gene induction and a tailored transcriptional response to fasting.

Mice lacking the functional cystinosin gene (Ctns(-/-)), a model of infantile nephropathic cystinosis (INC), exhibit the cachexia phenotype with adipose tissue browning and muscle wasting. Elevated leptin signaling is an important cause of chronic kidney disease-associated cachexia. The pegylated leptin receptor antagonist (PLA) binds to but does not activate the leptin receptor. We tested the efficacy of this PLA in Ctns(-/-) mice. We treated 12-month-old Ctns(-/-) mice and control mice with PLA (7 mg/kg/day, IP) or saline as a vehicle for 28 days. PLA normalized food intake and weight gain, increased fat and lean mass, decreased metabolic rate and improved muscle function. It also attenuated perturbations of energy homeostasis in adipose tissue and muscle in Ctns(-/-) mice. PLA attenuated adipose tissue browning in Ctns(-/-) mice. PLA increased gastrocnemius weight and fiber size as well as attenuated muscle fat infiltration in Ctns(-/-) mice. This was accompanied by correcting the increased expression of muscle wasting signaling while promoting the decreased expression of myogenesis in gastrocnemius of Ctns(-/-) mice. PLA attenuated aberrant expressed muscle genes that have been associated with muscle atrophy, increased energy expenditure and lipolysis in Ctns(-/-) mice. Leptin antagonism may represent a viable therapeutic strategy for adipose tissue browning and muscle wasting in INC.

Ultra-processed foods (UPFs) are negatively perceived by part of the scientific community, the public, and policymakers alike, to the extent they are sometimes referred to as not ``real food ``. Many observational surveys have linked consumption of UPFs to adverse health outcomes. This narrative synthesis and scientific reappraisal of available evidence aims to: (i) critically evaluate UPF-related scientific literature on diet and disease and identify possible research gaps or biases in the interpretation of data; (ii) emphasize the innovative potential of various processing technologies that can lead to modifications of the food matrix with beneficial health effects; (iii) highlight the possible links between processing, sustainability and circular economy through the valorisation of by-products; and (iv) delineate the conceptual parameters of new paradigms in food evaluation and classification systems. Although greater consumption of UPFs has been associated with obesity, unfavorable cardiometabolic risk factor profiles, and increased risk for non-communicable diseases, whether specific food processing techniques leading to ultra-processed formulations are responsible for the observed links between UPFs and various health outcomes remains elusive and far from being understood. Evolving technologies can be used in the context of sustainable valorisation of food processing by-products to create novel, low-cost UPFs with improved nutritional value and health potential. New paradigms of food evaluation and assessment should be funded and developed on several novel pillars-enginomics, signalling, and precision nutrition-taking advantage of available digital technologies and artificial intelligence. Research is needed to generate required scientific knowledge to either expand the current or create new food evaluation and classification systems, incorporating processing aspects that may have a significant impact on health and wellness, together with factors related to the personalization of foods and diets, while not neglecting recycling and sustainability aspects. The complexity and the predicted immense size of these tasks calls for open innovation mentality and a new mindset promoting multidisciplinary collaborations and partnerships between academia and industry.

Neoantigens are now recognized drivers of the antitumor immune response. Recurrent neoantigens, shared among groups of patients, have thus become increasingly coveted therapeutic targets. Here, we report on the data-driven identification of a robustly presented, immunogenic neoantigen that is derived from the combination of HLA-A*01:01 and RAS.Q61K. Analysis of large patient cohorts indicated that this combination applies to 3% of patients with melanoma. Using HLA peptidomics, we were able to demonstrate robust endogenous presentation of the neoantigen in 10 tumor samples. We detected specific reactivity to the mutated peptide within tumor-infiltrating lymphocytes (TILs) from 2 unrelated patients, thus confirming its natural immunogenicity. We further investigated the neoantigen-specific clones and their T cell receptors (TCRs) via a combination of TCR sequencing, TCR overexpression, functional assays, and single-cell transcriptomics. Our analysis revealed a diverse repertoire of neoantigen-specific clones with both intra-and interpatient TCR similarities. Moreover, 1 dominant clone proved to cross-react with the highly prevalent RAS.Q61R variant. Transcriptome analysis revealed a high association of TCR clones with specific T cell phenotypes in response to cognate melanoma, with neoantigen-specific cells showing an activated and dysfunctional phenotype. Identification of recurrent neoantigens and their reactive TCRs can promote ``off-the shelf'' precision immunotherapies, alleviating limitations of personalized treatments.

Obesity is one of the foremost risk factors in coronavirus infection resulting in severe illness and mortality as the pandemic progresses. Obesity is a well-known predisposed chronic inflammatory condition. The dynamics of obesity and its impacts on immunity may change the disease severity of pneumonia, especially in acute respiratory distress syndrome, a primary cause of death from SARS-CoV-2 infection. The adipocytes of adipose tissue secret leptin in proportion to individuals' body fat mass. An increase in circulating plasma leptin is a typical characteristic of obesity and correlates with a leptin-resistant state. Leptin is considered a pleiotropic molecule regulating appetite and immunity. In immunity, leptin functions as a cytokine and coordinates the host's innate and adaptive responses by promoting the Th1 type of immune response. Leptin induced the proliferation and functions of antigen-presenting cells, monocytes, and T helper cells, subsequently influencing the pro-inflammatory cytokine secretion by these cells, such as TNF-alpha, IL-2, or IL-6. Leptin scarcity or resistance is linked with dysregulation of cytokine secretion leading to autoimmune disorders, inflammatory responses, and increased susceptibility towards infectious diseases. Therefore, leptin activity by leptin long-lasting super active antagonist's dysregulation in patients with obesity might contribute to high mortality rates in these patients during SARS-CoV-2 infection. This review systematically discusses the interplay mechanism between leptin and inflammatory cytokines and their contribution to the fatal outcomes in COVID-19 patients with obesity.

Background: Dietary advanced glycation end-products (AGEs) are linked to cognitive decline. However, clinical trials have not tested the effect of AGEs on cognition in older adults. Objective: The aim of the current pilot trial was to examine the feasibility of an intervention to reduce dietary AGEs on cognition and on cerebral blood flow (CBF). Methods: The design is a pilot randomized controlled trial of dietary AGEs reduction in older adults with type 2 diabetes. Seventy-five participants were randomized to two arms. The control arm received standard of care (SOC) guidelines for good glycemic control; the intervention arm, in addition to SOC guidelines, were instructed to reduce their dietary AGEs intake. Global cognition and CBF were assessed at baseline and after 6 months of intervention. Results: At baseline, we found a reverse association between AGEs and cognitive functioning, possibly reflecting the long-term toxicity of AGEs on the brain. There was a significant improvement in global cognition at 6 months in both the intervention and SOC groups which was more prominent in participants with mild cognitive impairment. We also found that at baseline, higher AGEs were associated with increased CBF in the left inferior parietal cortex; however, 6 months of the AGEs lowering intervention did not affect CBF levels, despite lowering AGEs exposure in blood. Conclusion: The current pilot trial focused on the feasibility and methodology of intervening through diet to reduce AGEs in older adults with type 2 diabetes. Our results suggest that participants with mild cognitive impairment may benefit from an intensive dietary intervention.

{{Introduction: Advanced glycation end products (AGEs) in diet and serum are positively correlated with chronic conditions such as type 2 diabetes and cognitive decline. Dietary reduction of AGEs was shown to reduce their level in serum and to have a beneficial effect on metabolic biomarkers. However, in part due to limitations of feasibility, clinical trials have not tested its effect on cognition in elderly. The current pilot study examines the feasibility of AGE reduction in elderly with diabetes in terms of recruitment and retention. Methods: The design is a randomized controlled pilot trial of dietary AGEs in elderly with type 2 diabetes (clinicaltrials.gov NCT02739971). Recruitment followed two stages: we first recruited participants with mild cognitive impairment (MCI), and after expanding inclusion criteria, we later recruited cognitively normal participants with subjective memory complaints (SMCs). Participants were randomized to two arms. Participants in the control arm received standard of care (SOC) guidelines for good glycemic control; those in the experimental arm, in addition to SOC guidelines, were instructed to lower their dietary AGE intake, primarily by changing their cooking methods. Participants were closely followed for dietary adherence over 6 months and evaluated before and after the intervention for adherence to the assigned diet, blood tests, cognitive performance, and brain MRI. Results: Seventy-five participants (52 with MCI and 23 cognitively normal with SMCs) were recruited primarily through mass mailing and advertising in social media websites. Seventy participants finished the study, and dropout was similar in both groups (7.5% in control vs. 5.7% in intervention

Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-Gs signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that calcium (Ca2+) is required for agonist, but not antagonist, efficacy. These results fill a gap in the understanding of MC4R activation and could guide the design of future weight-management drugs.

Background. Clinical diagnosis of coronavirus disease 2019 (COVID-19) is essential to the detection and prevention of COVID-19. Sudden onset of loss of taste and smell is a hallmark of COVID-19, and optimal ways for including these symptoms in the screening of patients and distinguishing COVID-19 from other acute viral diseases should be established. Methods. We performed a case-control study of patients who were polymerase chain reaction-tested for COVID-19 (112 positive and 112 negative participants), recruited during the first wave (March 2020-May 2020) of the COVID-19 pandemic in Israel. Patients reported their symptoms and medical history by phone and rated their olfactory and gustatory abilities before and during their illness on a 1-10 scale. Results. Changes in smell and taste occurred in 68% (95% CI, 60%-76%) and 72% (95% CI, 64%-80%) of positive patients, with odds ratios of 24 (range, 11-53) and 12 (range, 6-23), respectively. The ability to smell was decreased by 0.5 +/- 1.5 in negatives and by 4.5 +/- 3.6 in positives. A penalized logistic regression classifier based on 5 symptoms had 66% sensitivity, 97% specificity, and an area under the receiver operating characteristics curve (AUC) of 0.83 on a holdout set. A classifier based on degree of smell change was almost as good, with 66% sensitivity, 97% specificity, and 0.81 AUC. The predictive positive value of this classifier was 0.68, and the negative predictive value was 0.97. Conclusions. Self-reported quantitative olfactory changes, either alone or combined with other symptoms, provide a specific tool for clinical diagnosis of COVID-19. A simple calculator for prioritizing COVID-19 laboratory testing is presented here. [GRAPHICS] .