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The olfactory system must recognize and discriminate amongst an enormous variety of chemicals in the environment. To contend with such diversity, insects have evolved a family of odorant-gated ion channels comprised of a highly conserved co-receptor (Orco) and a divergent odorant receptor (OR) that confers chemical specificity. Here, we present the single-particle cryo-electron microscopy structure of an Orco homomer from the parasitic fig wasp Apocrypta bakeri at 3.5 Å resolution, providing structural insight into this receptor family. Orco possesses a novel channel architecture, with four subunits symmetrically arranged around a central pore that diverges into four lateral conduits that open to the cytosol. The Orco tetramer has few inter-subunit interactions within the membrane and is bound together by a small cytoplasmic anchor domain. The minimal sequence conservation among ORs maps largely to the pore and anchor domain, shedding light on how the architecture of this receptor family accommodates its remarkable sequence diversity and facilitates the evolution of odour tuning. A cryo-electron microscopy structure of the insect Orco subunit, which forms ion channels with diverse olfactory receptors, reveals a tetrameric cation channel and sheds light on insect olfaction.

Early eukaryotic ribosome biogenesis involves large multi-protein complexes, which co-transcriptionally associate with pre-ribosomal RNA to form the small subunit processome. The precise mechanisms by which two of the largest multi-protein complexes—UtpA and UtpB—interact with nascent pre-ribosomal RNA are poorly understood. Here, we combined biochemical and structural biology approaches with ensembles of RNA–protein cross-linking data to elucidate the essential functions of both complexes. We show that UtpA contains a large composite RNA-binding site and captures the 5′ end of pre-ribosomal RNA. UtpB forms an extended structure that binds early pre-ribosomal intermediates in close proximity to architectural sites such as an RNA duplex formed by the 5′ ETS and U3 snoRNA as well as the 3′ boundary of the 18S rRNA. Both complexes therefore act as vital RNA chaperones to initiate eukaryotic ribosome assembly. Eukaryotic ribosome biogenesis involves a large number of maturations factors which are responsible for the stepwise assembly of the ribosomal subunits. Here the authors use an array of biochemical and structural biology methods to investigate the function of the UtpA and UtpB complexes as part of the small subunit processome.

Well before Trump ascended to office in 2016, media pundits on both sides of the mainstream political aisle struggled to understand the politics and culture of the elusive “working-class” voter. They have often leaned heavily on outdated stereotypes and classist profiling, and whether it is Fox News or CNN, their use of the term “working class” paints a very specific picture: white, male, blue collar, conservative, or politically disaffected. However, theirs is an image that does not accurately reflect the real face of America’s working people. Those in search of more accurate representation can occasionally find it on the scripted side of things, and more specifically in family-oriented sitcoms. These irreverent, heart-warming programs offer a potent, and in some ways unparalleled, platform for satirizing the conditions of American working-class life. Since the high water mark of All in the Family, many sitcoms starring working-class characters and families have failed in this regard, while only a handful have managed to examine and critique the impact of increasingly precarious work lives on increasingly diverse workers and their families. Despite efforts over the past several years by major television networks to skew toward more conservative characters and storylines in an effort to appeal to an imagined ideal working-class viewer, these more diverse offerings have done the most compelling job of showing the American working class as it actually is now. Those who have focused on the struggles facing immigrant workers, single-parent families, and low-wage workers in particular have painted an accurate portrait of modern working life in this country, challenging the status quo while keeping the laugh track rolling.Television has been the premiere American pop culture delivery system since it first supplanted the wireless radio as both the pinnacle of home entertainment and a cherished staple of working-class life. And, if we are to understand the category of “working class” to describe those workers who exercise little to no control over the content and pace of their work1 and thus comprise the majority of those employed, then this is an extremely diverse group. As such, the U.S. working class is now predominantly made up of women and people of color and exerts much of its labor in industries such as health care, agriculture, education, retail, and food service. Only a third are engaged in traditional manufacturing jobs, and the online publication CityLab estimates that the working class will be majority people of color by 2032.

Many polyubiquitinated proteins are extracted from membranes or complexes by the conserved ATPase Cdc48 (in yeast; p97 or VCP in mammals) before proteasomal degradation. Each Cdc48 hexamer contains two stacked ATPase rings (D1 and D2) and six N-terminal (N) domains. Cdc48 binds various cofactors, including the Ufd1–Npl4 heterodimer. Here, we report structures of the Cdc48–Ufd1–Npl4 complex from Chaetomium thermophilum. Npl4 interacts through its UBX-like domain with a Cdc48 N domain, and it uses two Zn2+-finger domains to anchor the enzymatically inactive Mpr1–Pad1 N-terminal (MPN) domain, homologous to domains found in several isopeptidases, to the top of the D1 ATPase ring. The MPN domain of Npl4 is located above Cdc48’s central pore, a position similar to the MPN domain from deubiquitinase Rpn11 in the proteasome. Our results indicate that Npl4 is unique among Cdc48 cofactors and suggest a mechanism for binding and translocation of polyubiquitinated substrates into the ATPase.

ObjectivesTo examine the internal consistency reliability and measurement invariance of a questionnaire battery designed to identify college student athletes at risk for mental health symptoms and disorders.MethodsCollege student athletes (N=993) completed questionnaires assessing 13 mental health domains: strain, anxiety, depression, suicide and self-harm ideation, sleep, alcohol use, drug use, eating disorders, attention deficit hyperactivity disorder (ADHD), bipolar disorder, post-traumatic stress disorder (PTSD), gambling and psychosis. Internal consistency reliability of each measure was assessed and compared between sexes as well as to previous results in elite athletes. Discriminative ability analyses were used to examine how well the cut-off score on the strain measure (Athlete Psychological Strain Questionnaire) predicted cut-offs on other screening questionnaires.ResultsStrain, anxiety, depression, suicide and self-harm ideation, ADHD, PTSD and bipolar questionnaires all had acceptable or better internal consistency reliability. Sleep, gambling and psychosis questionnaires had questionable internal consistency reliability, although approaching acceptable for certain sex by measure values. The athlete disordered eating measure (Brief Eating Disorder in Athletes Questionnaire) had poor internal consistency reliability in males and questionable internal consistency reliability in females.ConclusionsThe recommended mental health questionnaires were generally reliable for use with college student athletes. To truly determine the validity of the cut-off scores on these self-report questionnaires, future studies need to compare the questionnaires to a structured clinical interview to determine the discriminative abilities.

Oral microbiome dysbiosis has been associated with various local and systemic human diseases such as dental caries, periodontal disease, obesity, and cardiovascular disease. Bacterial composition may be affected by age, oral health, diet, and geography, although information about the natural variation found in the general public is still lacking. In this study, citizen-scientists used a crowdsourcing model to obtain oral bacterial composition data from guests at the Denver Museum of Nature & Science to determine if previously suspected oral microbiome associations with an individual’s demographics, lifestyle, and/or genetics are robust and generalizable enough to be detected within a general population. Consistent with past research, we found bacterial composition to be more diverse in youth microbiomes when compared to adults. Adult oral microbiomes were predominantly impacted by oral health habits, while youth microbiomes were impacted by biological sex and weight status. The oral pathogen Treponema was detected more commonly in adults without recent dentist visits and in obese youth. Additionally, oral microbiomes from participants of the same family were more similar to each other than to oral microbiomes from non-related individuals. These results suggest that previously reported oral microbiome associations are observable in a human population containing the natural variation commonly found in the general public. Furthermore, these results support the use of crowdsourced data as a valid methodology to obtain community-based microbiome data.

While a variety of human papillomavirus (HPV) tests and surrogate markers are available, currently there is no consensus on the best detection method(s) that should be used to identify HPV‐related oropharyngeal squamous cell carcinomas and serve as a standard test (or tests) for routine diagnostic use. As we begin to consider using the results of HPV testing for clinical purposes beyond simple prognostication, such as making decisions on treatment dose or duration or for targeted therapies that may be highly dependent on viral‐mediated pathways, we need to be more rigorous in assessing and ensuring the performance of the test (or tests) used. Here we provide an overview of the platforms and technologies, including the strengths and limitations of each test, and discuss what steps are needed to generate confidence in their performance for use in clinical practice.

A checklist of criteria to determine the readiness of high-throughput ‘omics’-based tests for guiding patient therapy in clinical trials is discussed; the checklist, developed by the US National Cancer Institute in collaboration with additional scientists with relevant expertise, provides a framework to evaluate the strength of evidence for a test and outlines practical issues to consider before using the test in a clinical setting, with an aim to avoid premature advancement of omics-based tests in clinical trials. Guidelines for clinical use of omics data The potential of high-throughput 'omics' in clinical medicine is immense, with oncology leading the way in adopting these technologies. Working with researchers and clinicians from across the spectrum of these disciplines, the US National Cancer Institute (NCI) has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. Published in this Perspective feature, the checklist focuses on best practice in specimen preparation, assays, mathematical modelling, clinical trial design, ethics and more. It will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests guide therapy. The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to ‘omics’-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy.

Defining the denatured state ensemble (DSE) and disordered proteins is essential to understanding folding, chaperone action, degradation, and translocation. As compared with water-soluble proteins, the DSE of membrane proteins is much less characterized. Here, we measure the DSE of the helical membrane protein GlpG of Escherichia coli (E. coli) in native-like lipid bilayers. The DSE was obtained using our steric trapping method, which couples denaturation of doubly biotinylated GlpG to binding of two streptavidin molecules. The helices and loops are probed using limited proteolysis and mass spectrometry, while the dimensions are determined using our paramagnetic biotin derivative and double electron–electron resonance spectroscopy. These data, along with our Upside simulations, identify the DSE as being highly dynamic, involving the topology changes and unfolding of some of the transmembrane (TM) helices. The DSE is expanded relative to the native state but only to 15 to 75% of the fully expanded condition. The degree of expansion depends on the local protein packing and the lipid composition. E. coli’s lipid bilayer promotes the association of TM helices in the DSE and, probably in general, facilitates interhelical interactions. This tendency may be the outcome of a general lipophobic effect of proteins within the cell membranes.

Abstract Background Crohn’s disease (CD) is a type of inflammatory bowel disease that can occur at any age, though is most common between ages 15–35 years. CD symptoms can have a significant impact on health-related quality of life (HRQL). Although key symptoms and impacts of CD in adults are well-known, exploration of these in children and the level of agreement between child reported symptoms and impacts and those observed by parents/caregiver have not been well documented. Objectives Understand patients’ experiences of CD, including CD symptoms and the burden of living with CD, from the perspective of CD child and adolescent participants and parents/caregivers of children with CD. Methods Children (ages 5–11 years) and adolescents (ages 12–17 years) with CD and parents/caregivers of children with CD (ages 2–11 years) were recruited from US clinical sites. Qualitative semi-structured interview guides were developed, informed by published literature. Face-to-face and telephone concept elicitation interviews were conducted, audio-recorded and transcribed. Transcripts were analyzed using thematic methods facilitated by Nvivo. Results A total of 43 participants participated in this study. Preliminary results showed that pain, frequent bowel movements, diarrhea, and tiredness were spontaneously discussed by ≥60% of the participants, while blood in stool, cramping in abdomen, urgent bowel movement, nausea, and low appetite were spontaneously discussed by ≥30% of the participants. More than 15 other symptoms such as joint issues, abscess/fissures, and hives/rashes were each mentioned by at least one participant. In addition, ≥50% of the participants discussed impacts related to CD including school attendance, exercise/sports, eating and drinking limitations, and play and leisure. Conclusions The results from CE interviews demonstrate the clear burden of CD on children and adolescents.