Variability in humpback whale songs reveals how individuals can be distinctive when sharing a complex vocal display.

Individually distinctive acoustic signals in animal vocal communication are taxonomically widespread, however, the investigation of these signal types in marine mammals has focused only on a few species. Humpback whale songs are a stereotyped, hierarchically structured vocal display performed by males, and hence thought to be sexually selected. Within a population, whales conform to a common version of the song despite the song constantly evolving. While humpback songs have been studied extensively at the population level, individual level variation has been rarely described, with inconclusive results. Here, we quantified inter- and intra-individual variability at different levels in the song hierarchy using songs from 25 singers across two song types from the eastern Australian population song of 2002 (12 singers), and the revolutionary song introduced in 2003 (13 singers). Inter-individual variability was found heterogeneously across all hierarchical levels of the song structure. In addition, distinct and individually specific patterns of song production were consistently recorded across song levels, with clear structural differences between the two song types. These results suggest that within the constraints of song conformity, males can produce individually distinctive patterns that could function as an advertisement to females to convey individual qualities.

Community through Culture: From Insects to Whales: How Social Learning and Culture Manifest across Diverse Animal Communities.

It has become increasingly clear that social learning and culture occur much more broadly, and in a wider variety of animal communities, than initially believed. Recent research has expanded the list to include insects, fishes, elephants, and cetaceans. Such diversity allows scientists to expand the scope of potential research questions, which can help form a more complete understanding of animal culture than any single species can provide on its own. It is crucial to understand how culture and social learning present in different communities, as well as what influences community structure and culture may have on one another, so that the results across these different studies may most effectively inform one another. This review presents an overview of social learning in species across a spectrum of community structures, providing the necessary infrastructure to allow a comparison of studies that will help move the field of animal culture forward.

Network analysis reveals underlying syntactic features in a vocally learnt mammalian display, humpback whale song.

Vocal communication systems have a set of rules that govern the arrangement of acoustic signals, broadly defined as 'syntax'. However, there is a limited understanding of potentially shared or analogous rules across vocal displays in different taxa. Recent work on songbirds has investigated syntax using network-based modelling. This technique quantifies features such as connectivity (adjacent signals in a sequence) and recurring patterns. Here, we apply network-based modelling to the complex, hierarchically structured songs of humpback whales (Megaptera novaeangliae) from east Australia. Given the song's annual evolving pattern and the cultural conformity of males within a population, network modelling captured the patterns of multiple song types over 13 consecutive years. Song arrangements in each year displayed clear 'small-world' network structure, characterized by clusters of highly connected sounds. Transitions between these connected sounds further suggested a combination of both structural stability and variability. Small-world network structure within humpback songs may facilitate the characteristic and persistent vocal learning observed. Similar small-world structures and transition patterns are found in several birdsong displays, indicating common syntactic patterns among vocal learning in multiple taxa. Understanding the syntactic rules governing vocal displays in multiple, independently evolving lineages may indicate what rules or structural features are important to the evolution of complex communication, including human language.

Cultural revolutions reduce complexity in the songs of humpback whales.

Much evidence for non-human culture comes from vocally learned displays, such as the vocal dialects and song displays of birds and cetaceans. While many oscine birds use song complexity to assess male fitness, the role of complexity in humpback whale (Megaptera novaeangliae) song is uncertain owing to population-wide conformity to one song pattern. Although songs change gradually each year, the eastern Australian population also completely replaces their song every few years in cultural 'revolutions'. Revolutions involve learning large amounts of novel material introduced from the Western Australian population. We examined two measures of song structure, complexity and entropy, in the eastern Australian population over 13 consecutive years. These measures aimed to identify the role of complexity and information content in the vocal learning processes of humpback whales. Complexity was quantified at two hierarchical levels: the entire sequence of individual sound 'units' and the stereotyped arrangements of units which comprise a 'theme'. Complexity increased as songs evolved over time but decreased when revolutions occurred. No correlation between complexity and entropy estimates suggests that changes to complexity may represent embellishment to the song which could allow males to stand out amidst population-wide conformity. The consistent reduction in complexity during song revolutions suggests a potential limit to the social learning capacity of novel material in humpback whales.

Using self-organizing maps to classify humpback whale song units and quantify their similarity.

Classification of vocal signals can be undertaken using a wide variety of qualitative and quantitative techniques. Using east Australian humpback whale song from 2002 to 2014, a subset of vocal signals was acoustically measured and then classified using a Self-Organizing Map (SOM). The SOM created (1) an acoustic dictionary of units representing the song's repertoire, and (2) Cartesian distance measurements among all unit types (SOM nodes). Utilizing the SOM dictionary as a guide, additional song recordings from east Australia were rapidly (manually) transcribed. To assess the similarity in song sequences, the Cartesian distance output from the SOM was applied in Levenshtein distance similarity analyses as a weighting factor to better incorporate unit similarity in the calculation (previously a qualitative process). SOMs provide a more robust and repeatable means of categorizing acoustic signals along with a clear quantitative measurement of sound type similarity based on acoustic features. This method can be utilized for a wide variety of acoustic databases especially those containing very large datasets and can be applied across the vocalization research community to help address concerns surrounding inconsistency in manual classification.

The devil is in the detail: Quantifying vocal variation in a complex, multi-levelled, and rapidly evolving display.

Identifying and quantifying variation in vocalizations is fundamental to advancing our understanding of processes such as speciation, sexual selection, and cultural evolution. The song of the humpback whale (Megaptera novaeangliae) presents an extreme example of complexity and cultural evolution. It is a long, hierarchically structured vocal display that undergoes constant evolutionary change. Obtaining robust metrics to quantify song variation at multiple scales (from a sound through to population variation across the seascape) is a substantial challenge. Here, the authors present a method to quantify song similarity at multiple levels within the hierarchy. To incorporate the complexity of these multiple levels, the calculation of similarity is weighted by measurements of sound units (lower levels within the display) to bridge the gap in information between upper and lower levels. Results demonstrate that the inclusion of weighting provides a more realistic and robust representation of song similarity at multiple levels within the display. This method permits robust quantification of cultural patterns and processes that will also contribute to the conservation management of endangered humpback whale populations, and is applicable to any hierarchically structured signal sequence.

Rapid molecular detection of tuberculosis and rifampin resistance.

BACKGROUND: Global control of tuberculosis is hampered by slow, insensitive diagnostic methods, particularly for the detection of drug-resistant forms and in patients with human immunodeficiency virus infection. Early detection is essential to reduce the death rate and interrupt transmission, but the complexity and infrastructure needs of sensitive methods limit their accessibility and effect. METHODS: We assessed the performance of Xpert MTB/RIF, an automated molecular test for Mycobacterium tuberculosis (MTB) and resistance to rifampin (RIF), with fully integrated sample processing in 1730 patients with suspected drug-sensitive or multidrug-resistant pulmonary tuberculosis. Eligible patients in Peru, Azerbaijan, South Africa, and India provided three sputum specimens each. Two specimens were processed with N-acetyl-L-cysteine and sodium hydroxide before microscopy, solid and liquid culture, and the MTB/RIF test, and one specimen was used for direct testing with microscopy and the MTB/RIF test. RESULTS: Among culture-positive patients, a single, direct MTB/RIF test identified 551 of 561 patients with smear-positive tuberculosis (98.2%) and 124 of 171 with smear-negative tuberculosis (72.5%). The test was specific in 604 of 609 patients without tuberculosis (99.2%). Among patients with smear-negative, culture-positive tuberculosis, the addition of a second MTB/RIF test increased sensitivity by 12.6 percentage points and a third by 5.1 percentage points, to a total of 90.2%. As compared with phenotypic drug-susceptibility testing, MTB/RIF testing correctly identified 200 of 205 patients (97.6%) with rifampin-resistant bacteria and 504 of 514 (98.1%) with rifampin-sensitive bacteria. Sequencing resolved all but two cases in favor of the MTB/RIF assay. CONCLUSIONS: The MTB/RIF test provided sensitive detection of tuberculosis and rifampin resistance directly from untreated sputum in less than 2 hours with minimal hands-on time. (Funded by the Foundation for Innovative New Diagnostics.)

The diarylquinoline TMC207 for multidrug-resistant tuberculosis.

BACKGROUND: The diarylquinoline TMC207 offers a new mechanism of antituberculosis action by inhibiting mycobacterial ATP synthase. TMC207 potently inhibits drug-sensitive and drug-resistant Mycobacterium tuberculosis in vitro and shows bactericidal activity in patients who have drug-susceptible pulmonary tuberculosis. METHODS: In the first stage of a two-stage, phase 2, randomized, controlled trial, we randomly assigned 47 patients who had newly diagnosed multidrug-resistant pulmonary tuberculosis to receive either TMC207 (400 mg daily for 2 weeks, followed by 200 mg three times a week for 6 weeks) (23 patients) or placebo (24 patients) in combination with a standard five-drug, second-line antituberculosis regimen. The primary efficacy end point was the conversion of sputum cultures, in liquid broth, from positive to negative. RESULTS: The addition of TMC207 to standard therapy for multidrug-resistant tuberculosis reduced the time to conversion to a negative sputum culture, as compared with placebo (hazard ratio, 11.8; 95% confidence interval, 2.3 to 61.3; P=0.003 by Cox regression analysis) and increased the proportion of patients with conversion of sputum culture (48% vs. 9%). The mean log(10) count of colony-forming units in the sputum declined more rapidly in the TMC207 group than in the placebo group. No significant differences in average plasma TMC207 concentrations were noted between patients with and those without culture conversion. Most adverse events were mild to moderate, and only nausea occurred significantly more frequently among patients in the TMC207 group than among patients in the placebo group (26% vs. 4%, P=0.04). CONCLUSIONS: The clinical activity of TMC207 validates ATP synthase as a viable target for the treatment of tuberculosis. (ClinicalTrials.gov number, NCT00449644.)

Optimizing outpatient serial sputum colony counting for studies of tuberculosis treatment in resource-poor settings.

Serial Sputum Colony Counting (SSCC) is an important technique in clinical trials of new treatments for tuberculosis (TB). Quantitative cultures on selective Middlebrook agar are used to calculate the rate of bacillary elimination from sputum collected from patients at different time points during the first 2 months of therapy. However, the procedure can be complicated by high sample contamination rates. This study, conducted in a resource-poor setting in Malawi, assessed the ability of different antifungal drugs in selective agar to reduce contamination. Overall, 229 samples were studied and 15% to 27% were contaminated. Fungal organisms were particularly implicated, and samples collected later in treatment were at particular risk (P < 0.001). Amphotericin B (AmB) is the standard antifungal drug used on SSCC plates at a concentration of 10 mg/ml. On selective Middlebrook 7H10 plates, AmB at 30 mg/ml reduced sample contamination by 17% compared with AmB at 10 mg/ml. The relative risk of contamination using AmB at 10 mg/ml was 1.79 (95% confidence interval [CI], 1.25 to 3.55). On Middlebrook 7H11 plates, a combination of AmB at 10 mg/ml and carbendazim at 50 mg/ml was associated with 10% less contamination than AmB at 30 mg/ml. The relative risk of contamination with AmB at 30 mg/ml was 1.79 (95% CI, 1.01 to 3.17). Improved antifungal activity was accompanied by a small reduction in bacillary counts, but this did not affect modeling of bacillary elimination. In conclusion, a combination of AmB and carbendazim optimized the antifungal activity of selective media for growth of TB. We recommend this method to reduce contamination rates and improve SSCC studies in African countries where the burden of TB is highest.

Expression and purification of two Family GH31 α-glucosidases from Bacteroides thetaiotaomicron.

Microorganisms in the human gut outnumber human cells by a factor of 10. These microbes have been shown to have relevance to the human immune, nutrition and metabolic systems. A dominant symbiont of this environment is Bacteroides thetaiotaomicron which is characterized as being involved in degrading non-digestible plant polysaccharides. This organism's genome is highly enriched in genes predicted to be involved in the hydrolysis of various glycans. Presented here is a comparative functional analysis of two α-glucosidases (designated BT_0339 and BT_3299), Family 31 Glycoside Hydrolases from B. thetaiotaomicron. The purpose of this research is to explore the contributions these enzymes may have to human nutrition and specifically starch digestion. Expression of both α-glucosidases in pET-29a expression vector resulted in high levels of expressed protein in the soluble fraction. Two-step purification allowed for the isolation of the enzymes of interest in significant yield and fractions were observed to be homogenous. Both enzymes demonstrated activity on maltose, isomaltose and malto-oligosaccharide substrates and low level of activity on lactose and sucrose. Enzymatic kinetics revealed these enzymes both preferentially cleave the α1-6 linkage in comparison to the expected α1-4 and specifically favor maltose-derived substrates of longer length. The flexible hydrolytic capabilities of BT_0339 and BT_3299 reveal the ability of this bacterium to maintain its dominant position in its environment by utilizing an array of substrates. Specifically, these enzymes demonstrate an important aspect of this organism's contribution to starch digestion in the distal gut and the overall energy intake of humans.

Song complexity is maintained during inter-population cultural transmission of humpback whale songs.

Among animal species, the songs of male humpback whales (Megaptera novaeangliae) are a rare example of social learning between entire populations. Understanding fine-scale similarity in song patterns and structural features will better clarify how accurately songs are learned during inter-population transmission. Here, six distinct song types (2009-2015) transmitted from the east Australian to New Caledonian populations were quantitatively analysed using fine-scale song features. Results found that New Caledonian whales learned each song type with high accuracy regardless of the pattern's complexity. However, there were rare instances of themes (stereotyped patterns of sound units) only sung by a single population. These occurred more often in progressively changing 'evolutionary' songs compared to rapidly changing 'revolutionary' songs. Our results suggest that populations do not need to reduce complexity to accurately learn song patterns. Populations may also incorporate changes and embellishments into songs in the form of themes which are suggested to be learnt as distinct segments. Maintaining complex song patterns with such accuracy suggests significant acoustic contact, supporting the hypothesis that song learning may occur on shared feeding grounds or migration routes. This study improves the understanding of inter-population mechanisms for large-scale cultural transmission in animals.

Health promotion in an Australian Aboriginal community: the Growing Strong Brains® toolkit.

AIM: The aim of this paper is to describe the implementation and evaluation of the Growing Strong Brains® (GSB) toolkit in a remote Aboriginal community in Western Australia (WA) over a 2-year period, 2018-2019. BACKGROUND: Ngala, a community service organisation in WA, developed the GSB toolkit in 2014, a culturally appropriate and interactive resource to build knowledge of early childhood development within Aboriginal communities. This was in response to evidence that a higher percentage of children in Aboriginal communities were developmentally vulnerable compared to the rest of the population. The GSB toolkit promotes awareness and understanding of early brain development pre-birth and in the early years of a child's life. METHODS: The project was underpinned by participatory action research (PAR). Reflective PAR review cycles (n = 5) monitored local community engagement, navigated challenges and utilised community strengths. Fifty-nine local service providers attended a 2-day formal training. Data were collected by using various methods throughout the project, including feedback following training, focus groups, surveys, one-on-one interviews using yarning techniques and reflective feedback from the Project Lead. FINDINGS: Establishing local Aboriginal project staff was pivotal to the success of the project. When delivering services for and with Aboriginal people, it is essential that cultural competence, safety and decision-making is carried through from planning to implementation and evaluation, and involves genuine, respectful and authentic relationships. Sufficient time allocation directed towards building relationships with other service providers and local community members needs to be considered and built into future projects.The Growing Strong Brains® project is embedded within the local community, and anticipated implementation outcomes were achieved. The support of the local people and service providers was beyond expectation, enabling the building of local capacity, and the development of a common understanding of the key messages from the GSB toolkit to allow integration throughout all levels of the community. This project has been important to build on the strategies necessary to introduce, implement and evaluate the GSB toolkit in other remote Aboriginal communities.

Intensive tuberculosis screening for HIV-infected patients starting antiretroviral therapy in Durban, South Africa.

BACKGROUND: The World Health Organization (WHO) recommends cough as the trigger for tuberculosis screening in human immunodeficiency virus (HIV)-infected patients, with acid-fast bacillus (AFB) smear as the initial diagnostic test. Our objective was to assess the yield and cost of a more intensive tuberculosis screening in HIV-infected patients starting antiretroviral therapy (ART) in Durban, South Africa. METHODS: We prospectively enrolled adults, regardless of tuberculosis signs/symptoms, who were undergoing ART training from May 2007 to May 2008. After the symptom screen, patients expectorated sputum for AFB smear, tuberculosis polymerase chain reaction (PCR), and mycobacterial culture. Sensitivity and specificity of different symptoms and tests, alone and in combination, were compared with the reference standard of 6-week tuberculosis culture results. Program costs included personnel, materials, and cultures. RESULTS: Of 1035 subjects, 487 (59%) were female; median CD4 cell count was 100 cells/microL. A total of 210 subjects (20%) were receiving tuberculosis treatment and were excluded. Of the remaining 825 subjects, 158 (19%) had positive sputum cultures, of whom 14 (9%) had a positive AFB smear and 82 (52%) reported cough. The combination of cough, other symptoms, AFB smear, and chest radiograph had 93% sensitivity (95% confidence interval, 88%-97%) and 15% specificity (95% confidence interval, 13%-18%). The incremental cost of intensive screening including culture was $360 per additional tuberculosis case identified. CONCLUSIONS: Nearly 20% of patients starting ART in Durban, South Africa, had undiagnosed, culture-positive pulmonary tuberculosis. Despite WHO recommendations, neither cough nor AFB smear were adequately sensitive for screening. Tuberculosis sputum cultures should be performed before ART initiation, regardless of symptoms, in areas with a high prevalence of HIV and tuberculosis.

Urine lipoarabinomannan (LAM) and antimicrobial usage in seriously-ill HIV-infected patients with sputum smear-negative pulmonary tuberculosis.

BACKGROUND: Based on current WHO guidelines, hospitalized tuberculosis (TB) and HIV co-infected patients with CD4 count <100 cells/mm3 who are urine lipoarabinomannan (LAM) positive should be initiated on TB treatment. This recommendation is conditional, and data are limited in sputum smear-negative patients from TB endemic countries where the LAM test is largely inaccessible. Other potential benefits of LAM, including reduction in antibiotic usage have, hitherto, not been explored. METHODS: We consecutively enrolled newly-admitted seriously-ill HIV-infected patients (n=187) with suspected TB from three hospitals in KwaZulu-Natal, South Africa. All patients were empirically treated for TB as per the WHO 2007 smear-negative TB algorithm (patients untreated for TB were not recruited). Bio-banked urine, donated prior to anti-TB treatment, was tested for TB-infection using a commercially available LAM-ELISA test. TB sputum and blood cultures were performed. RESULTS: Data from 156 patients containing CD4 count, urine-LAM, sputum and blood culture results were analysed. Mean age was 37 years, median CD4-count was 75 cells/mm3 [interquartile range (IQR), 34-169 cells/mm3], 54/156 (34.6%) were sputum culture-positive, 12/54 (22.2%) blood-culture positive, and 53/156 (34.0%) LAM-positive. Thus, LAM sensitivity was 55.6% (30/54). The study design did not allow for calculation of specificity. Urine-LAM positivity was associated with low CD4 count (P=0.002). Ninety-point-six percent (48/53) of LAM-positive patients received antibiotics [15/48 (31.3%), 23/48 (47.9%) and 10/48 (20.8%) received one, two or three different antibiotics respectively], while the duration of antibiotic therapy was more than 5 days in 26 of 46 (56.5%) patients. CONCLUSIONS: Urine LAM testing in sputum smear-negative severely-ill hospitalized patients with TB-HIV co-infection and advanced immunosuppression, offered an immediate rule-in diagnosis in one-third of empirically treated patients. Moreover, LAM, by providing a rapid alternative diagnosis, could potentially reduce antibiotic overusage in such patients thereby reducing health-care costs and facilitating antibiotic stewardship.

Migratory convergence facilitates cultural transmission of humpback whale song.

Cultural transmission of behaviour is important in a wide variety of vertebrate taxa from birds to humans. Vocal traditions and vocal learning provide a strong foundation for studying culture and its transmission in both humans and cetaceans. Male humpback whales (Megaptera novaeangliae) perform complex, culturally transmitted song displays that can change both evolutionarily (through accumulations of small changes) or revolutionarily (where a population rapidly adopts a novel song). The degree of coordination and conformity underlying song revolutions makes their study of particular interest. Acoustic contact on migratory routes may provide a mechanism for cultural revolutions of song, yet these areas of contact remain uncertain. Here, we compared songs recorded from the Kermadec Islands, a recently discovered migratory stopover, to multiple South Pacific wintering grounds. Similarities in song themes from the Kermadec Islands and multiple wintering locations (from New Caledonia across to the Cook Islands) suggest a location allowing cultural transmission of song eastward across the South Pacific, active song learning (hybrid songs) and the potential for cultural convergence after acoustic isolation at the wintering grounds. As with the correlations in humans between genes, communication and migration, the migration patterns of humpback whales are written into their songs.

Network-based diffusion analysis reveals cultural transmission of lobtail feeding in humpback whales.

We used network-based diffusion analysis to reveal the cultural spread of a naturally occurring foraging innovation, lobtail feeding, through a population of humpback whales (Megaptera novaeangliae) over a period of 27 years. Support for models with a social transmission component was 6 to 23 orders of magnitude greater than for models without. The spatial and temporal distribution of sand lance, a prey species, was also important in predicting the rate of acquisition. Our results, coupled with existing knowledge about song traditions, show that this species can maintain multiple independently evolving traditions in its populations. These insights strengthen the case that cetaceans represent a peak in the evolution of nonhuman culture, independent of the primate lineage.

Drug-resistant tuberculosis among HIV-infected patients starting antiretroviral therapy in Durban, South Africa.

OBJECTIVE: To estimate the prevalence of drug-resistant tuberculosis (TB) and describe the resistance patterns in patients commencing antiretroviral therapy (ART) in an HIV clinic in Durban, South Africa. DESIGN: Cross-sectional cohort study. METHODS: Consecutive HIV-infected adults (≥ 18y/o) initiating HIV care were enrolled from May 2007-May 2008, regardless of signs or symptoms of active TB. Prior TB history and current TB treatment status were self-reported. Subjects expectorated sputum for culture (MGIT liquid and 7H11 solid medium). Positive cultures were tested for susceptibility to first- and second-line anti-tuberculous drugs. The prevalence of drug-resistant TB, stratified by prior TB history and current TB treatment status, was assessed. RESULTS: 1,035 subjects had complete culture results. Median CD4 count was 92/µl (IQR 42-150/µl). 267 subjects (26%) reported a prior history of TB and 210 (20%) were receiving TB treatment at enrollment; 191 (18%) subjects had positive sputum cultures, among whom the estimated prevalence of resistance to any antituberculous drug was 7.4% (95% CI 4.0-12.4). Among those with prior TB, the prevalence of resistance was 15.4% (95% CI 5.9-30.5) compared to 5.2% (95% CI 2.1-8.9) among those with no prior TB. 5.1% (95% CI 2.4-9.5) had rifampin or rifampin plus INH resistance. CONCLUSIONS: The prevalence of TB resistance to at least one drug was 7.4% among adults with positive TB cultures initiating ART in Durban, South Africa, with 5.1% having rifampin or rifampin plus INH resistance. Improved tools for diagnosing TB and drug resistance are urgently needed in areas of high HIV/TB prevalence.

WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells.

In Wolfram syndrome, a rare form of juvenile diabetes, pancreatic beta-cell death is not accompanied by an autoimmune response. Although it has been reported that mutations in the WFS1 gene are responsible for the development of this syndrome, the precise molecular mechanisms underlying beta-cell death caused by the WFS1 mutations remain unknown. Here we report that WFS1 is a novel component of the unfolded protein response and has an important function in maintaining homeostasis of the endoplasmic reticulum (ER) in pancreatic beta-cells. WFS1 encodes a transmembrane glyco-protein in the ER. WFS1 mRNA and protein are induced by ER stress. The expression of WFS1 is regulated by inositol requiring 1 and PKR-like ER kinase, central regulators of the unfolded protein response. WFS1 is normally up-regulated during insulin secretion, whereas inactivation of WFS1 in beta-cells causes ER stress and beta-cell dysfunction. These results indicate that the pathogenesis of Wolfram syndrome involves chronic ER stress in pancreatic beta-cells caused by the loss of function of WFS1.

High ER stress in beta-cells stimulates intracellular degradation of misfolded insulin.

Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins in the ER, elicits an adaptive response, the unfolded protein response (UPR). One component of the UPR, the endoplasmic reticulum-associated protein degradation (ERAD) system, has an important function in the survival of ER stressed cells. Here, we show that HRD1, a component of the ERAD system, is upregulated in pancreatic islets of the Akita diabetes mouse model and enhances intracellular degradation of misfolded insulin. High ER stress in beta-cells stimulated mutant insulin degradation through HRD1 to protect beta-cells from ER stress and ensuing death. If HRD1 serves the same function in humans, it may serve as a target for therapeutic intervention in diabetes.