The ufmylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER.

Ufmylation is implicated in multiple cellular processes, but little is known about its functions and regulation in protein trafficking. Here, we demonstrate that the genetic depletion of core components of the ufmylation cascade, including ubiquitin-fold modifier 1 (UFM1), UFM1 activation enzyme 5, UFM1-specific ligase 1 (UFL1), UFM1-specific protease 2, and UFM1-binding protein 1 (UFBP1) each markedly inhibits the endoplasmic reticulum (ER)-Golgi transport, surface delivery, and recruitment to COPII vesicles of a subset of G protein-coupled receptors (GPCRs) and UFBP1's function partially relies on UFM1 conjugation. We also show that UFBP1 and UFL1 interact with GPCRs and UFBP1 localizes at COPII vesicles coated with specific Sec24 isoforms. Furthermore, the UFBP1/UFL1-binding domain identified in the receptors effectively converts non-GPCR protein transport into the ufmylation-dependent pathway. Collectively, these data reveal important functions for the ufmylation system in GPCR recruitment to COPII vesicles, biosynthetic transport, and sorting at ER via UFBP1 ufmylation and interaction directly.

Small molecule induced STING degradation facilitated by the HECT ligase HERC4.

Stimulator of interferon genes (STING) is a central component of the cytosolic nucleic acids sensing pathway and as such master regulator of the type I interferon response. Due to its critical role in physiology and its' involvement in a variety of diseases, STING has been a focus for drug discovery. Targeted protein degradation (TPD) has emerged as a promising pharmacology for targeting previously considered undruggable proteins by hijacking the cellular ubiquitin proteasome system (UPS) with small molecules. Here, we identify AK59 as a STING degrader leveraging HERC4, a HECT-domain E3 ligase. Additionally, our data reveals that AK59 is effective on the common pathological STING mutations, suggesting a potential clinical application of this mechanism. Thus, these findings introduce HERC4 to the fields of TPD and of compound-induced degradation of STING, suggesting potential therapeutic applications.

Effectiveness of Probiotic Use in Alleviating Symptoms of Irritable Bowel Syndrome: A Systematic Review.

Irritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) condition, and changes in the gut microbiota's composition contribute to the development of symptoms. Although the precise mechanisms of probiotic use in the human body are not fully understood, probiotic supplements are believed to reduce symptoms, such as abdominal pain, by regulating neurotransmitters and receptors associated with pain modulation in IBS patients compared to placebo by altering the gut flora. This systematic review aimed to assess the most current randomized controlled trials (RCTs) on how probiotic supplementation affects the symptoms in people with IBS. The effects of probiotic supplements on IBS symptoms were studied in RCTs published between January 2018 and June 2023. After a search through PubMed and Google Scholar using the keywords probiotics, gut microbiota, irritable bowel syndrome, and IBS; eight articles matched the inclusion criteria and were reviewed. Four trials used a multistrain probiotic, whereas the remaining four trials examined the effects of a monostrain supplement. All eight trials came to the same conclusion: Probiotic treatment may significantly reduce symptoms.

Robenidine derivatives as potential antischistosomal drug candidates.

Schistosomiasis caused by Schistosoma spp. is a disease that causes a considerable health burden to millions of people worldwide. The limited availability of effective drugs on the market and the increased risk of resistance development due to extensive usage, highlight the urgent need for new antischistosomal drugs. Recent studies have shown that robenidine derivatives, containing an aminoguanidine core, exhibit promising activities against Plasmodium falciparum, motivating further investigation into their efficacy against Schistosoma mansoni, due to their similar habitat and the resulting related cellular mechanisms like the heme detoxification pathway. The conducted phenotypic screening of robenidine and 80 derivatives against newly transformed schistosomula and adult Schistosoma mansoni yielded 11 candidates with low EC50 values for newly transformed schistosomula (1.12-4.63 µM) and adults (2.78-9.47 µM). The structure-activity relationship revealed that electron-withdrawing groups at the phenyl moiety, as well as the presence of methyl groups adjacent to the guanidine moiety, enhanced the activity of derivatives against both stages of Schistosoma mansoni. The two compounds 2,2'-Bis[(3-cyano-4-fluorophenyl)methylene] carbonimidic Dihydrazide Hydrochloride (1) and 2,2'-Bis[(4-difluoromethoxyphenyl) ethylidene] carbonimidic Dihydrazide Hydrochloride (19), were selected for an in vivo study in Schistosoma mansoni-infected mice based on their potency, cytotoxicity, pharmacokinetic-, and physicochemical properties, but failed to reduce the worm burden significantly (worm burden reduction <20%). Thus, robenidine derivatives require further refinements to obtain higher antischistosomal specificity and in vivo activity.

Exploring the Impact of Personalized Nutritional Approaches on Metabolism and Immunity: A Systematic Review of Various Nutrients and Dietary Patterns.

The systematic review investigates the impact of different nutrients and dietary patterns on metabolism and immunity to answer the research question: "Can personalized nutritional approaches boost immunity?" The importance of diet in supporting the immune system has come to light in today's environment, where a strong immune system is crucial for protection against infectious illnesses, as highlighted by the COVID-19 pandemic. This systematic review adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. Four databases were screened for relevant data published in 2022-2023: PubMed, PubMed Central (PMC), MEDLINE, and Cochrane Library. Inclusion and exclusion criteria were utilized, and 13 papers were finalized after screening and employing the quality appraisal tool Cochrane Bias assessment for randomized controlled trials (RCT). Personalized nutrition can strengthen immunity and enhance overall health by adjusting dietary recommendations and following a person's genetic makeup, lifestyle, and health state. An adequate supply of vitamins, minerals, proteins, and fatty acids as well as an optimum caloric intake are essential for immune health, and individual requirements can vary significantly due to genetic factors, lifestyle choices, and underlying health conditions. Personalized nutrition considers these factors, enabling tailored dietary recommendations to address specific nutrient needs and optimize nutrient intake, leading to better health outcomes. The review concludes that personalized nutrition is more effective than a one-size-fits-all approach in boosting immunity, and its potential impact on health and immune function is highly important.

Levels of anti-insulin antibodies in diabetic retinopathy patients: an observational cross-sectional study.

Aim: This study evaluated the levels of anti-insulin antibodies (AIAs) and the influence of some antidiabetic medications on AIA in diabetes mellitus (DM) patients with retinopathy. Patient & methods: An observational cross-sectional study. Results: A lower titer of AIA IgG was observed in the diabetic retinopathy (DR) and DM-only study categories compared with the control group [DR = 86 (5-560), DM-only = 50 (5-500), versus control = 200 (7-565); p = 0.017]. Taking nifedipine and metformin were negatively correlated (r = -0.32, p = 0.04) with the levels of AIA IgE in the DR group. Conclusion: A decreased titer of circulating AIAs was observed in the DR study category, suggesting that AIA may not contribute to the pathogenesis of DR.

Diabetic retinopathy (DR) is the main reason people lose their sight in countries with few resources. Anti-insulin antibodies, or AIAs, help the body fight off infections and may play a role in the development of DR. The study looked at how much AIA was in DR patients and how some diabetes drugs affected AIA levels. There was a negative link between nifedipine and one AIA (IgE) in people with DR, but a positive link between metformin and another AIA (IgG). AIA levels were lower in the DR study group, which suggests that AIA may not cause DR.

Ensuring Throughput: Development and Validation of Charge Nurse Competencies for United States Emergency Care Settings.

INTRODUCTION: Charge nurses are shift leaders whose role includes managing nursing resources and facilitating appropriate patient care; in emergency departments, the charge nurse role requires both clinical and leadership skills to facilitate the flow of patients, while ensuring patient and staff safety. Literature on orientation and specific training is notably sparse. This study aimed to evaluate the content and process of core competency training and identify evaluation and implementation strategies necessary to improve charge nurse performance in United States emergency departments. METHODS: A modified Delphi technique was used in phase 1 and a qualitative content analysis method was used in phase 2 to address specific aims of the study. RESULTS: In total, 427 emergency nurse managers, directors, educators, and charge nurses responded to the initial survey to identify elements, teaching modalities, and evaluative processes; 22 participated in 1 of 2 focus groups to provide further information about the pedagogical approaches to teaching emergency charge nurse competencies. The top 5 competencies were identified as patient flow management, communication, situational awareness, clinical decision making, and nurse-patient assignment, with understanding that each competency overlapped significantly with the others. Low-fidelity simulation and gamification were identified as a preferred method of both training and evaluation. DISCUSSION: These findings have the potential to support a standardized approach to emergency charge nurse training and evaluation focusing on communication skills, clinical decision making, and situational awareness to facilitate safe and effective nurse-patient assignment and emergency department throughput.

Development and validation of the Gender Identity and Expression Microaggressions in Therapy Scale (GIEMTS).

Developing affirming interventions for transgender and nonbinary (TNB) therapy clients requires understanding their experiences with microaggressions in psychotherapy, yet no self-report measure of anti-TNB microaggressions in this context exists. Moreover, few studies have tested the associations between anti-TNB microaggressions and therapy processes. To better address the burden of unmet mental health care needs among TNB people, this three-study investigation designed and tested the psychometric properties of the Gender Identity and Expression Microaggressions in Therapy Scale (GIEMTS), a measure of TNB individuals' encounters with microaggressions in psychotherapy. Study 1 (N = 225) identified a four-factor model, comprising the themes of Educational Burdening, Lack of Affirmation, Inflation, and Invalidation. These subscales exhibited strong internal consistency reliabilities and demonstrated convergent and discriminant validity. The results of Study 2 (N = 435) replicated the four-factor structure through confirmatory factor analysis. However, bifactor analysis revealed that the Educational Burdening, Inflation, and Invalidation subscale scores were mostly accounted by a General Anti-TNB Microaggressions scale score-though Lack of Affirmation showed evidence of its independence. Also in Study 2, both scales were uniquely negatively associated with the working alliance. Study 3 (N = 151) found evidence for the test-retest reliability of GIEMTS scores over a 2-3-week period. Overall, the GIEMTS emerged as a robust and psychometrically sound instrument that captures the experiences of TNB individuals in therapy settings. The study concludes with valuable recommendations for training and clinical practice to bolster TNB mental health. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Comparison of Low-Dose Interleukin 2 Therapy in Conjunction With Standard Therapy in Patients With Systemic Lupus Erythematosus vs Rheumatoid Arthritis: A Systematic Review.

This systematic review aims to compare the efficacy and safety of a novel immunotherapy with low-dose interleukin 2 (IL2) across two of the most prevalent autoimmune diseases i.e. systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Contemporary therapeutic practices have not been able to achieve complete remission from these autoimmune disorders. In contrast, low-dose IL2 has shown promise in achieving this therapeutic goal via inducing self-tolerance in patients with autoimmune diseases; however, due to variable irregularities among autoimmune processes of variable diseases, the benefit of low-dose IL2 could not be determined among different autoimmune diseases. Therefore, we conducted a study to compare low-dose IL2 therapy effects on SLE and RA. We systematically screened four databases: PubMed, Medical Literature Analysis and Retrieval System Online (MEDLINE), PubMed Central (PMC), and Google Scholar. Inclusion and exclusion criteria were implemented. Quality appraisal of studies chosen for the review was done using the Cochrane Risk-of-Bias (RoB) assessment tool for randomized controlled trials, and the Newcastle-Ottawa Scale (NOS) and JBI critical appraisal tool for non-randomized clinical trials. Information was gathered from seven articles: three randomized controlled trials and four non-randomized clinical trials. Our review concluded that low-dose IL2 therapy in conjunction with respective standard therapies for SLE and RA has a higher efficacy and safety profile as compared to standard therapy alone and the therapeutic effects were comparable in both SLE and RA patients treated with low-dose IL2; however, this novel intervention does not seem to have a significant corrective effect on the biomarkers of RA as it does for SLE biomarkers.

Breaking It Down: A Systematic Review Unravelling the Impact of Attention Deficit Hyperactivity Disorder and Methylphenidate on Childhood Fractures.

Limb fractures are a common cause of pediatric hospital admissions and surgeries, with a significant prevalence in the United Kingdom across all injury categories. Among psychiatric conditions in children, attention deficit hyperactivity disorder (ADHD) stands out as frequently associated with fractures, particularly those involving extremities. ADHD, with diagnoses prevalent among a significant proportion of school-age children and adolescents, has witnessed a growing global incidence. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 checklist for our systematic literature search, using various databases and specific search terms related to ADHD and fractures. We considered articles from 2018 to 2023, focusing on English language papers with free full-text access. Our selection process used the PRISMA flowchart. We began with 1,890 articles and, after deduplication, title screening, abstract assessment, and quality evaluation included nine research papers in our review. Our primary focus was on examining fracture-related outcomes in individuals with ADHD compared to those without, considering medication status. These studies encompassed various designs, with a focus on the ADHD-fracture relationship and methylphenidate's (MPH) impact. Our study confirms that ADHD increases fracture risk and suggests that MPH may help mitigate this risk. Early ADHD detection is vital for nonpharmacological interventions. Orthopedic surgeons should proactively identify ADHD, while healthcare professionals should offer injury prevention guidance, particularly for at-risk groups.

An efficient mRNA display protocol yields potent bicyclic peptide inhibitors for FGFR3c: outperforming linear and monocyclic formats in affinity and stability.

Macrocyclization has positioned itself as a powerful method for engineering potent peptide drug candidates. Introducing one or multiple cyclizations is a common strategy to improve properties such as affinity, bioavailability and proteolytic stability. Consequently, methodologies to create large libraries of polycyclic peptides by phage or mRNA display have emerged, allowing the rapid identification of binders to virtually any target. Yet, within those libraries, the performance of linear vs. mono- or bicyclic peptides has rarely been studied. Indeed, a key parameter to perform such a comparison is to use a display protocol and cyclization chemistry that enables the formation of all 3 formats in equal quality and diversity. Here, we developed a simple, efficient and fast mRNA display protocol which meets these criteria and can be used to generate highly diverse libraries of thioether cyclized polycyclic peptides. As a proof of concept, we selected peptides against fibroblast growth factor receptor 3c (FGFR3c) and compared the different formats regarding affinity, specificity, and human plasma stability. The peptides with the best KD's and stability were identified among bicyclic peptide hits, further strengthening the body of evidence pointing at the superiority of this class of molecules and providing functional and selective inhibitors of FGFR3c.

NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo.

The YAP/Hippo pathway is an organ growth and size regulation rheostat safeguarding multiple tissue stem cell compartments. LATS kinases phosphorylate and thereby inactivate YAP, thus representing a potential direct drug target for promoting tissue regeneration. Here, we report the identification and characterization of the selective small-molecule LATS kinase inhibitor NIBR-LTSi. NIBR-LTSi activates YAP signaling, shows good oral bioavailability, and expands organoids derived from several mouse and human tissues. In tissue stem cells, NIBR-LTSi promotes proliferation, maintains stemness, and blocks differentiation in vitro and in vivo. NIBR-LTSi accelerates liver regeneration following extended hepatectomy in mice. However, increased proliferation and cell dedifferentiation in multiple organs prevent prolonged systemic LATS inhibition, thus limiting potential therapeutic benefit. Together, we report a selective LATS kinase inhibitor agonizing YAP signaling and promoting tissue regeneration in vitro and in vivo, enabling future research on the regenerative potential of the YAP/Hippo pathway.

The Role of Proton Pump Inhibitors in the Realm of Idiopathic Pulmonary Fibrosis and its Associated Comorbidities: A Systematic Review.

As the global incidence of idiopathic pulmonary fibrosis (IPF) is on the rise, there is a need for better diagnostic criteria, better treatment options, early and appropriate diagnosis, adequate care, and a multidisciplinary approach to the management of patients. This systematic review explores the role of proton pump inhibitors (PPIs) in IPF and answers the question, "Does proton pump inhibitor improve only the prognosis of gastroesophageal associated idiopathic pulmonary fibrosis or for other types of idiopathic pulmonary fibrosis too?" We used PubMed (PMC) and Google Scholar for data collection for this systematic review and followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for conducting this review. After in-depth literature screening and quality appraisal, 12 articles were selected for this systematic review. On the one hand, the efficacy of PPI therapy is supported by research such as the CAPACITY and ASCEND trials, a pilot randomized control trial (RCT) investigating the role of omeprazole in IPF and a bidirectional two-sample Mendelian randomization (MR) study, respectively. On the other hand, a systematic review and meta-analysis on antacid and antireflux surgery in IPF negate these results and show no statistical significance. Questions regarding the efficacy of PPI therapy must be dealt with in an adequately powered multicenter and double-blinded randomized control trial. The anti-inflammatory properties of antacids can serve as the cornerstone for future trials. In the following systematic review, antacid, antireflux therapy, omeprazole, and proton pump therapy are synonymous with stomach acid suppression therapy.

Statewide surveillance of Ixodes scapularis (Acari: Ixodidae) for the presence of the human pathogen Borrelia miyamotoi (Spirochaetales: Spirochaetaceae), a relapsing fever spirochete in Pennsylvania, USA, 2019-2020.

Borrelia miyamotoi disease is an emerging tick-borne human illness in the United States caused by Borrelia miyamotoi (Spirochaetales: Spirochaetaceae) bacterium. With Pennsylvania reporting thousands of tick-borne disease cases annually, determining the minimum infection rate (MIR) of B. miyamotoi in Ixodes scapularis (Say, Acari: Ixodidae) adults within Pennsylvania is of utmost importance. Active surveillance was performed from October 2019 to April 2020 to collect a minimum of 50 I. scapularis ticks from every county within Pennsylvania and then screened for B. miyamotoi via qPCR. Ticks were collected from all 67 counties with the majority of those being adult I. scapularis. Additional ticks collected were Dermacentor albipictus (Packard, Acari: Ixodidae), Haemaphysalis longicornis (Neumann, Acari: Ixodidae), and immature I. scapularis. Adult I. scapularis were pooled and tested for B. miyamotoi. MIR for positive B. miyamotoi pools and density of infected adult I. scapularis varied by county, with positive pools from 38 Pennsylvania counties. This is the first statewide evaluation of B. miyamotoi in Pennsylvania in questing adult I. scapularis. These prevalence and distribution data will aid health care practitioners within the state of Pennsylvania and the northeast United States to understand potential risk and bring awareness to the lesser known human Borrelia illness, Borrelia miyamotoi disease.

Ensuring fidelity: key elements to consider in disseminating a diabetes telemanagement program for underserved Hispanic/Latinos living with type 2 diabetes.

Background: The Hispanic/Latino population has greater risk (estimated >50%) of developing type 2 diabetes (T2D) and developing it at a younger age. The American Diabetes Association estimates costs of diagnosed diabetes in 2017 was $327 billion; with medical costs 2.3x higher than patients without diabetes. The purpose of this manuscript is to describe the methodology utilized in a randomized controlled trial aimed at evaluating the efficacy of a diabetes telemanagement (DTM) program for Hispanic/Latino patients with T2D. The intent is to provide information for future investigators to ensure that this study can be accurately replicated. Methods: This study was a randomized controlled trial with 240 participants. Eligible patients (Hispanic/Latino, aged 18+, living with T2D) were randomized to Comprehensive Outpatient Management (COM) or DTM. DTM was comprised of usual care, including routine clinic visits every three months, as well as: Biometrics (a tablet, blood glucose meter, blood pressure monitor, and scale); Weekly Video Visits (facilitated in the patient's preferred language); and Educational Videos (including culturally congruent diabetes self-management education and quizzes). COM consisted of usual care including routine clinic visits every three months. For this study, COM patients received a glucometer, glucose test strips, and lancets. Establishing a therapeutic nurse-patient relationship was a fundamental component of our study for both groups. First contact (post-enrollment) centered on ensuring that patients and caregivers understood the program, building trust and rapport, creating a non-judgmental environment, determining language preference, and establishing scheduling availability (including evenings and weekends). DTM were provided with a tablet which allowed for self-paced education through videos and weekly video visits. The research team and Community Advisory Board identified appropriate educational video content, which was incorporated in diabetes educational topics. Video visits allowed us to assess patient involvement, motivation, and nonverbal communication. Communicating in Spanish, and awareness of diverse Hispanic/Latino backgrounds was critical, as using relevant and commonly-used terms can increase adherence and improve outcomes. Shared decision-making was encouraged to make realistic health care choices. Conclusion: Key elements discussed above provide a framework for future dissemination of an evidence-based DTM intervention to meet the needs of underserved Hispanic/Latino people living with T2D.

Leaching of unexpected cyazofamid degradation products into groundwater demonstrates gaps in current pesticide risk assessment.

To investigate the formation and leaching potential of degradation products N,N-dimethylsulfamide (DMS) and dimethylsulfamic acid (DMSA) from cyazofamid under real-world agricultural conditions, the fungicide cyazofamid was applied in a potato crop as part of the Danish Pesticide Leaching Assessment Programme (PLAP). Leaching of DMS, DMSA, 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carbonitrile (CCIM), and 4-chloro-5-(4-methylphenyl)-1H-imidazole-2-carboxylicacid (CTCA) was monitored in water from the variably saturated zone (suction cups) and groundwater for more than two years following the applications. In total, 424 samples were analyzed for the content of the four degradation products. An additional laboratory study was executed in parallel with the field monitoring study. Here, cyazofamid was applied to soil columns and leaching of the four degradation products was studied under controlled conditions. In the EFSA conclusion on cyazofamid, CCIM and CTCA are mentioned as major relevant metabolites; DMS is not mentioned in the risk assessment and DMSA is only included in acute oral toxicity studies and an in vitro bacterial mutation assay. In contrast to the EFSA conclusion on cyazofamid, our studies showed no leaching of the two major metabolites, CTCA and CCIM, but instead, major leaching of DMS and DMSA in both the field and laboratory studies was observed. That is, both DMS and DMSA leached to the groundwater in concentrations >0.1 µg/L for more than half a year. Based on this, we suggest improvements to the current pesticide risk assessment.

Mirizzi syndrome: The Trojan horse of gallbladder disease.

Background: The incidence of Mirizzi Syndrome ranges from 0.05 to 5.7 % of patients who undergo cholecystectomy. The purpose of this study is to examine the preoperative workup and postoperative outcomes for patients diagnosed with Mirizzi Syndrome. Methods: Retrospective chart review was conducted between January 2018 and January 2022 at a single institution. All adult patients who underwent cholecystectomy were included. Results: 1628 patients underwent cholecystectomy of which 47 were diagnosed with Mirizzi Syndrome. The majority of patients had type 1 Mirizzi Syndrome. Preoperative studies were often nondiagnostic and 81 % of cases were diagnosed intraoperatively. 66 % of cases were performed laparoscopically, an open approach was required for type V Mirizzi Syndrome. The complication rate was 25 %; most commonly a bile leak requiring ERCP. Conclusion: Mirizzi syndrome is more common than previously expected and related to patient's ability to seek timely medical care. Most cases can be completed laparoscopically however there is a high rate of complications. Key message: This study presents an additional cohort of patients found to have Mirizzi syndrome and supports the hypothesis that it is difficult to diagnose preoperatively. Cases should be attempted laparoscopically but there remains a high complication rate.

Membrane Permeability in a Large Macrocyclic Peptide Driven by a Saddle-Shaped Conformation.

The effort to modulate challenging protein targets has stimulated interest in ligands that are larger and more complex than typical small-molecule drugs. While combinatorial techniques such as mRNA display routinely produce high-affinity macrocyclic peptides against classically undruggable targets, poor membrane permeability has limited their use toward primarily extracellular targets. Understanding the passive membrane permeability of macrocyclic peptides would, in principle, improve our ability to design libraries whose leads can be more readily optimized against intracellular targets. Here, we investigate the permeabilities of over 200 macrocyclic 10-mers using the thioether cyclization motif commonly found in mRNA display macrocycle libraries. We identified the optimal lipophilicity range for achieving permeability in thioether-cyclized 10-mer cyclic peptide-peptoid hybrid scaffolds and showed that permeability could be maintained upon extensive permutation in the backbone. In one case, changing a single amino acid from d-Pro to d-NMe-Ala, representing the loss of a single methylene group in the side chain, resulted in a highly permeable scaffold in which the low-dielectric conformation shifted from the canonical cross-beta geometry of the parent compounds into a novel saddle-shaped fold in which all four backbone NH groups were sequestered from the solvent. This work provides an example by which pre-existing physicochemical knowledge of a scaffold can benefit the design of macrocyclic peptide mRNA display libraries, pointing toward an approach for biasing libraries toward permeability by design. Moreover, the compounds described herein are a further demonstration that geometrically diverse, highly permeable scaffolds exist well beyond conventional drug-like chemical space.

Retinal eccentricity modulates saliency-driven but not relevance-driven visual selection.

Where we move our eyes during visual search is controlled by the relative saliency and relevance of stimuli in the visual field. However, the visual field is not homogeneous, as both sensory representations and attention change with eccentricity. Here we present an experiment investigating how eccentricity differences between competing stimuli affect saliency- and relevance-driven selection. Participants made a single eye movement to a predefined orientation singleton target that was simultaneously presented with an orientation singleton distractor in a background of multiple homogenously oriented other items. The target was either more or less salient than the distractor. Moreover, each of the two singletons could be presented at one of three different retinal eccentricities, such that both were presented at the same eccentricity, one eccentricity value apart, or two eccentricity values apart. The results showed that selection was initially determined by saliency, followed after about 300 ms by relevance. In addition, observers preferred to select the closer over the more distant singleton, and this central selection bias increased with increasing eccentricity difference. Importantly, it largely emerged within the same time window as the saliency effect, thereby resulting in a net reduction of the influence of saliency on the selection outcome. In contrast, the relevance effect remained unaffected by eccentricity. Together, these findings demonstrate that eccentricity is a major determinant of selection behavior, even to the extent that it modifies the relative contribution of saliency in determining where people move their eyes.

Does crowding predict conjunction search? An individual differences approach.

Searching for objects in the visual environment is an integral part of human behavior. Most of the information used during such visual search comes from the periphery of our vision, and understanding the basic mechanisms of search therefore requires taking into account the inherent limitations of peripheral vision. Our previous work using an individual differences approach has shown that one of the major factors limiting peripheral vision (crowding) is predictive of single feature search, as reflected in response time and eye movement measures. Here we extended this work, by testing the relationship between crowding and visual search in a conjunction-search paradigm. Given that conjunction search involves more fine-grained discrimination and more serial behavior, we predicted it would be strongly affected by crowding. We tested sixty participants with regard to their sensitivity to both orientation and color-based crowding (as measured by critical spacing) and their efficiency in searching for a color/orientation conjunction (as indicated by manual response times and eye movements). While the correlations between the different crowding tasks were high, the correlations between the different crowding measures and search performance were relatively modest, and no higher than those previously observed for single-feature search. Instead, observers showed very strong color selectivity during search. The results suggest that conjunction search behavior relies more on top-down guidance (here by color) and is therefore relatively less determined by individual differences in sensory limitations as caused by crowding.