Autoreactive T cells target peripheral nerves in Guillain-Barré syndrome.

Guillain-Barré syndrome (GBS) is a rare heterogenous disorder of the peripheral nervous system, which is usually triggered by a preceding infection, and causes a potentially life-threatening progressive muscle weakness1. Although GBS is considered an autoimmune disease, the mechanisms that underlie its distinct clinical subtypes remain largely unknown. Here, by combining in vitro T cell screening, single-cell RNA sequencing and T cell receptor (TCR) sequencing, we identify autoreactive memory CD4+ cells, that show a cytotoxic T helper 1 (TH1)-like phenotype, and rare CD8+ T cells that target myelin antigens of the peripheral nerves in patients with the demyelinating disease variant. We characterized more than 1,000 autoreactive single T cell clones, which revealed a polyclonal TCR repertoire, short CDR3ß lengths, preferential HLA-DR restrictions and recognition of immunodominant epitopes. We found that autoreactive TCRß clonotypes were expanded in the blood of the same patient at distinct disease stages and, notably, that they were shared in the blood and the cerebrospinal fluid across different patients with GBS, but not in control individuals. Finally, we identified myelin-reactive T cells in the nerve biopsy from one patient, which indicates that these cells contribute directly to disease pathophysiology. Collectively, our data provide clear evidence of autoreactive T cell immunity in a subset of patients with GBS, and open new perspectives in the field of inflammatory peripheral neuropathies, with potential impact for biomedical applications.

Climate warming enhances snow avalanche risk in the Western Himalayas.

Ongoing climate warming has been demonstrated to impact the cryosphere in the Indian Himalayas, with substantial consequences for the risk of disasters, human well-being, and terrestrial ecosystems. Here, we present evidence that the warming observed in recent decades has been accompanied by increased snow avalanche frequency in the Western Indian Himalayas. Using dendrogeomorphic techniques, we reconstruct the longest time series (150 y) of the occurrence and runout distances of snow avalanches that is currently available for the Himalayas. We apply a generalized linear autoregressive moving average model to demonstrate linkages between climate warming and the observed increase in the incidence of snow avalanches. Warming air temperatures in winter and early spring have indeed favored the wetting of snow and the formation of wet snow avalanches, which are now able to reach down to subalpine slopes, where they have high potential to cause damage. These findings contradict the intuitive notion that warming results in less snow, and thus lower avalanche activity, and have major implications for the Western Himalayan region, an area where human pressure is constantly increasing. Specifically, increasing traffic on a steadily expanding road network is calling for an immediate design of risk mitigation strategies and disaster risk policies to enhance climate change adaption in the wider study region.

[Surgical treatment of adult spinal deformities]. / Operative Behandlung adulter spinaler Deformitäten.

BACKGROUND: Adult spinal deformity (ASD) is mostly a progressive disease which usually leads to chronic pain. Due to increased prevalence in older people many patients suffer from comorbidities, which make conservative and surgical treatment even more complex. OBJECTIVE: This article provides an overview on the current conservative and surgical treatment options. MATERIAL AND METHODS: An extensive literature search was carried out via Medline plus an additional evaluation of the authors' personal experiences was performed. RESULTS: The current conservative and surgical treatments are outlined and potential risk factors and predictors which may lead to inferior clinical outcome are discussed. CONCLUSION: Patients for whom even conservative treatment leads to success should be identified earlier and better. The surgical treatment ranges from minimally invasive decompression to multilevel fusions. Complications in large corrective interventions can be substantial but if the indications are correctly assessed, such complex surgical treatment has excellent clinical results in terms of pain and quality of life.

[Operative treatment of degenerative diseases of the lumbar spine]. / Operative Versorgung degenerativer Erkrankungen der Lendenwirbelsäule.

BACKGROUND: Degenerative diseases of the lumbar spine and associated lower back pain represent a major epidemiological and health-related economic challenge. A distinction is made between specific and unspecific lower back pain. In specific lower back pain lumbar disc herniation and spinal canal stenosis with or without associated segment instability are among the most frequent pathologies. Diverse conservative and operative strategies for treatment of these diseases are available. OBJECTIVES: The aim of this article is to present an overview of current data and an evidence-based assessment of the possible forms of treatment. MATERIAL AND METHODS: An extensive literature search was carried out via Medline plus an additional evaluation of the authors' personal experiences. RESULTS: Conservative and surgical treatment represent efficient treatment options for degenerative diseases of the lumbar spine. Surgical treatment of lumbar disc herniation shows slight advantages compared to conservative treatment consisting of faster recovery of neurological deficits and a faster restitution of pain control. Surgical decompression is superior to conservative measures for the treatment of spinal canal stenosis and degenerative spondylolisthesis. In this scenario conservative treatment represents an important supporting measure for surgical treatment in order to improve the mobility of patients and the outcome of surgical treatment. CONCLUSION: The treatment of specific lower back pain due to degenerative lumbar pathologies represents an interdisciplinary challenge, requiring both conservative and surgical treatment strategies in a synergistic treatment concept in order to achieve the best results for patients.

[Operative treatment of the degenerative cervical spine]. / Operative Versorgung der degenerativen Halswirbelsäule.

BACKGROUND: Degenerative alterations of the cervical spine often entail disc herniations and stenoses of the spinal canal and/or neural foramen. Mediolateral or lateral compression of nerve roots causes cervical radiculopathy, which is an indication for surgery in cases of significant motor deficits or refractory pain. Median canal encroachment may result in compression of the spinal cord and cervical myelopathy. Its natural history is typically characterized by episodic deterioration, so that surgical decompression is indicated in cases of clear myelopathic signs. OBJECTIVE: The aim of the present article is to outline the operative options for patients with cervical radiculopathy and myelopathy. Furthermore, we describe the operative complications and the outcome in these patients. MATERIAL AND METHODS: For this manuscript a systematic PubMed search was carried out, the papers were systematically analyzed for the best evidence and this was combined with the authors' experience. RESULTS AND CONCLUSION: Depending on the cervical pathology, the most prevalent surgical options for radiculopathy include anterior cervical discectomy and fusion (ACDF), cervical arthroplasty or posterior cervical foraminotomy. Cervical myelopathy may be decompressed by ACDF, corpectomy or posterior approaches like laminectomy plus instrumented fusion or laminoplasty. The outcome depends on the cervical pathology and the type of operation. Overall, in long-term follow-up studies the results of all surgical techniques on the cervical spine are generally considered to be very good, although specific patient characteristics are more suited for a particular approach.

Ranid Herpesvirus 3 and Proliferative Dermatitis in Free-Ranging Wild Common Frogs (Rana Temporaria).

Amphibian pathogens are of current interest as contributors to the global decline of amphibians. However, compared with chytrid fungi and ranaviruses, herpesviruses have received relatively little attention. Two ranid herpesviruses have been described: namely, Ranid herpesvirus 1 (RHV1) and Ranid herpesvirus 2 (RHV2). This article describes the discovery and partial characterization of a novel virus tentatively named Ranid herpesvirus 3 (RHV3), a candidate member of the genus Batrachovirus in the family Alloherpesviridae. RHV3 infection in wild common frogs (Rana temporaria) was associated with severe multifocal epidermal hyperplasia, dermal edema, a minor inflammatory response, and variable mucous gland degeneration. Intranuclear inclusions were numerous in the affected epidermis together with unique extracellular aggregates of herpesvirus-like particles. The RHV3-associated skin disease has features similar to those of a condition recognized in European frogs for the last 20 years and whose cause has remained elusive. The genome of RHV3 shares most of the features of the Alloherpesviruses. The characterization of this presumptive pathogen may be of value for amphibian conservation and for a better understanding of the biology of Alloherpesviruses.

Pododermatitis in Captive and Free-Ranging Greater Flamingos (Phoenicopterus roseus).

Pododermatitis is frequent in captive flamingos worldwide, but little is known about the associated histopathologic lesions. Involvement of a papillomavirus or herpesvirus has been suspected. Histopathologic evaluation and viral assessment of biopsies from 19 live and 10 dead captive greater flamingos were performed. Selected samples were further examined by transmission electron microscopy and immunohistochemistry. Feet from 10 dead free-ranging greater flamingos were also evaluated. The histologic appearance of lesions of flamingos of increasing age was interpreted as the progression of pododermatitis. Mild histologic lesions were seen in a 3-week-old flamingo chick with no macroscopic lesions, and these were characterized by Micrococcus-like bacteria in the stratum corneum associated with exocytosis of heterophils. The inflammation associated with these bacteria may lead to further histologic changes: irregular columnar proliferations, papillary squirting, and dyskeratosis. In more chronic lesions, hydropic degeneration of keratinocytes, epidermal hyperplasia, and dyskeratosis were seen at the epidermis, as well as proliferation of new blood vessels and increased intercellular matrix in the dermis. Papillomavirus DNA was not identified in any of the samples, while herpesvirus DNA was seen only in a few cases; therefore, these viruses were not thought to be the cause of the lesions. Poor skin health through suboptimal husbandry may weaken the epidermal barrier and predispose the skin to invasion of Micrococcus-like bacteria. Histologic lesions were identified in very young flamingos with no macroscopic lesions; this is likely to be an early stage lesion that may progress to macroscopic lesions.

Histo-morphological effects on equine synovium after arthroscopic synovectomy using two different motorized synovial resectors and two different intensities.

The purpose of the study was to determine the histo-morphological effects on villous synovium after synovectomy using two different motorized synovial resectors and two different intensities ex-vivo. Thirty-three (n = 33) equine metacarpophalangeal/metatarsophalangeal joints were used. Synovectomy was performed along the dorsomedial/dorsolateral synovium (n = 66) using two motorized synovial resectors (aggressive full radius resector, AFRR, used at two intensities: single treatment, n = 24 vs. triple treatment, n = 21 vs. aggressive meniscus side cutter, AMSC, n = 21). Arthroscopic images were evaluated blindly for resector type and intensity. Histological images were evaluated descriptive for synovial morphology and the extent of tissue loss using a microscopic scale. Scanning electron microscopy described the synovial morphology. The synovectomized areas were specific for each resector used and distinguishable from arthroscopic images. The AFRR demonstrated a clear demarcation between treated and non-treated areas and removed the stratum synoviale completely including parts of the underlying stratum fibrosum. In contrast, the AMSC showed less clear demarcation, villous scaffolds and no involvement of the stratum fibrosum. Triple intense treated AFFR samples resulted in significantly deeper lesions compared to single treatments (p = 0.037) but could not be distinguished on arthroscopic images. The morphological effects on villous synovium differ according to the resector type used. The extent of synovial tissue loss cannot be estimated from arthroscopic images but histologically. The type and use of motorized synovial resector determines the morphological alterations of the treated synovium. Arthroscopic control is considered unsuitable to control synovectomy depth.

A glacial lake outburst floods hazard assessment in the Patagonian Andes combining inventory data and case-studies.

We present a glacial-related lake inventory for a region spanning 41.5° - 47° S in Patagonian Andes, where information on past glacier lake outburst floods (GLOF's) has hitherto remained significantly underreported. Analyzing remotely sensed images, we obtained data on 702 glacial-related lakes. Through detailed geomorphic assessments and manual supervision, we revised current inventories and added 35 GLOFs triggered from moraine/bedrock dammed lakes failures. The regional GLOF inventory presented contains information on 71 historical failures of moraine/bedrock dammed glacial lakes. From this database we analyzed outburst timing and managed to constrain 37 events occurrences within a period of 1 year. Around 40 % of them have occurred since the early 2000's, most of them originating from lakes probably formed as a delayed response to the glacial retreat imposed by the end of the Little Ice Age. On the other hand, we analyzed meteorological conditions for a sub-set of 10 events constrained within a 10-days period, finding a strong link between atmospheric rivers, cut-off lows impacting the southern Andes, and GLOFs. Only one case is likely to have been triggered by a Mw 4.9 earthquake. Based on topographic potential for avalanching, we estimated GLOF hazard potential, recognizing at least 3 subregions with high hazard, which moreover can be highly susceptible to climate conditions that regionally affect GLOF occurrence.

Nature of tunable hole g factors in quantum dots.

We report an electric-field-induced giant modulation of the hole g factor in SiGe nanocrystals. The observed effect is ascribed to a so-far overlooked contribution to the g factor that stems from the mixing between heavy- and light-hole wave functions. We show that the relative displacement between the confined heavy- and light-hole states, occurring upon application of the electric field, alters their mixing strength leading to a strong nonmonotonic modulation of the g factor.

Apolipoprotein M can discriminate HNF1A-MODY from Type 1 diabetes.

AIMS: Missed diagnosis of maturity-onset diabetes of the young (MODY) has led to an interest in biomarkers that enable efficient prioritization of patients for definitive molecular testing. Apolipoprotein M (apoM) was suggested as a biomarker for hepatocyte nuclear factor 1 alpha (HNF1A)-MODY because of its reduced expression in Hnf1a(-/-) mice. However, subsequent human studies examining apoM as a biomarker have yielded conflicting results. We aimed to evaluate apoM as a biomarker for HNF1A-MODY using a highly specific and sensitive ELISA. METHODS: ApoM concentration was measured in subjects with HNF1A-MODY (n = 69), Type 1 diabetes (n = 50), Type 2 diabetes (n = 120) and healthy control subjects (n = 100). The discriminative accuracy of apoM and of the apoM/HDL ratio for diabetes aetiology was evaluated. RESULTS: Mean (standard deviation) serum apoM concentration (µmol/l) was significantly lower for subjects with HNF1A-MODY [0.86 (0.29)], than for those with Type 1 diabetes [1.37 (0.26), P = 3.1 × 10(-18) ) and control subjects [1.34 (0.22), P = 7.2 × 10(-19) ). There was no significant difference in apoM concentration between subjects with HNF1A-MODY and Type 2 diabetes [0.89 (0.28), P = 0.13]. The C-statistic measure of discriminative accuracy for apoM was 0.91 for HNF1A-MODY vs. Type 1 diabetes, indicating high discriminative accuracy. The apoM/HDL ratio was significantly lower in HNF1A-MODY than other study groups. However, this ratio did not perform well in discriminating HNF1A-MODY from either Type 1 diabetes (C-statistic = 0.79) or Type 2 diabetes (C-statistic = 0.68). CONCLUSIONS: We confirm an earlier report that serum apoM levels are lower in HNF1A-MODY than in controls. Serum apoM provides good discrimination between HNF1A-MODY and Type 1 diabetes and warrants further investigation for clinical utility in diabetes diagnostics.

Ciliary beating plane and wave propagation in the bovine oviduct.

The uterine tube is an essential conduit for the gametes and zygote during reproduction. The necessary bidirectional conveyance occurs through peristalsis and ciliary activity, but unlike in respiratory tract, little is known about mucociliary transport in the uterine tube, and the direction of transport and the alignment of oviductal cilia have not been conclusively characterized. This study aimed to determine the uniformity in the axonemal orientation of motile cilia in the bovine uterine tube, to identify the direction of mucociliary transport and to relate the presumptive beating plane and the mucociliary transport direction to the long axis of the uterine tube. The angular spread of oviductal motile cilia was determined by electron microscopy, and by maintaining the accurate alignment of the samples throughout the processing steps, axonemal orientation was determined relative to the long axis of the oviduct. The direction of the effective mucociliary transport was determined by the analysis of video microscopic data recorded on explants. Vector-based analysis of electron micrographs yielded the mean angle of deviation between the 'effective ciliary stroke', as derived from axonemal orientation, and the tubal longitudinal axis pointing towards the uterus to be 0.8°, with a standard deviation of 35.2°. The corresponding angular deviation of the short-wave propagation was -6.8° (SD 34.6°). These results show that oviductal motile cilia are rigorously aligned, that the beating plane of the cilia is parallel to the long axis of the uterine tube and that the 'effective stroke' and mucociliary transport are directed towards the uterus.

Leptin activation of Stat3 in the hypothalamus of wild-type and ob/ob mice but not db/db mice.

Leptin, a hormone secreted by adipocytes, regulates the size of the adipose tissue mass through effects on satiety and energy metabolism. Leptin's precise sites of action are not known. The leptin receptor (Ob-R) is found in many tissues in several alternatively spliced forms raising the possibility that leptin exerts effects on many tissues including the hypothalamus. Ob-R is a member of the gp130 family of cytokine receptors which are known to stimulate gene transcription via activation of cytosolic STAT proteins. In order to identify the sites of leptin action in vivo, we assayed for activation of STAT proteins in mice treated with leptin. The STAT proteins bind to phosphotyrosine residues in the cytoplasmic domain of the ligand-activated receptor where they are phosphorylated. The activated STAT proteins dimerize and translocate to the nucleus where they bind DNA and activate transcription. The activation of STAT proteins in response to leptin was assayed in a variety of mouse tissues known to express Ob-R. Leptin injection activated Stat3 but no other STAT protein in the hypothalamus of ob/ob and wild-type mice but not db/db mice, mutants that lack an isoform of the leptin receptor. Leptin did not induce STAT activation in any of the other tissues tested. Activation of Stat3 by leptin was dose dependent and first observed after 15 minutes and maximal at 30 minutes. Our data indicate the hypothalamus is a direct target of leptin action and that this activation is critically dependent on the gp-130-like leptin receptor isoform missing in C57BLKS/J db/db mice. This is the first in vivo demonstration of leptin signal transduction.

beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass.

Regulation of glucose homeostasis by insulin depends on the maintenance of normal beta-cell mass and function. Insulin-like growth factor 1 (Igf1) has been implicated in islet development and differentiated function, but the factors controlling this process are poorly understood. Pancreatic islets produce Igf1 and Igf2, which bind to specific receptors on beta-cells. Igf1 has been shown to influence beta-cell apoptosis, and both Igf1 and Igf2 increase islet growth; Igf2 does so in a manner additive with fibroblast growth factor 2 (ref. 10). When mice deficient for the Igf1 receptor (Igf1r(+/-)) are bred with mice lacking insulin receptor substrate 2 (Irs2(-/-)), the resulting compound knockout mice show a reduction in mass of beta-cells similar to that observed in pancreas of Igf1r(-/-) mice (ref. 11), suggesting a role for Igf1r in growth of beta-cells. It is possible, however, that the effects in these mice occur secondary to changes in vascular endothelium or in the pancreatic ductal cells, or because of a decrease in the effects of other hormones implicated in islet growth. To directly define the role of Igf1, we have created a mouse with a beta-cell-specific knockout of Igf1r (betaIgf1r(-/-)). These mice show normal growth and development of beta-cells, but have reduced expression of Slc2a2 (also known as Glut2) and Gck (encoding glucokinase) in beta-cells, which results in defective glucose-stimulated insulin secretion and impaired glucose tolerance. Thus, Igf1r is not crucial for islet beta-cell development, but participates in control of differentiated function.

Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes.

We describe a codon 299 mutation in the glucokinase gene in a British pedigree with maturity-onset diabetes of the young (MODY) resulting in a substitution of glycine to arginine. One out of fifty patients diagnosed with classical late-onset type 2 diabetes mellitus was also found to have this mutation. All nine relatives of this patient who have inherited the mutation have type 2 diabetes, although six others without the mutation are also present with diabetes. The discovery that glucokinase mutations can cause MODY and was also found in ten affected members of a pedigree with type 2 diabetes in which MODY had not previously been considered indicates that diagnosis based on molecular pathology will be helpful in understanding the aetiology of type 2 diabetes.

Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism.

Maturity-onset diabetes of the young type 3 (MODY3) is caused by haploinsufficiency of hepatocyte nuclear factor-1alpha (encoded by TCF1). Tcf1-/- mice have type 2 diabetes, dwarfism, renal Fanconi syndrome, hepatic dysfunction and hypercholestrolemia. Here we explore the molecular basis for the hypercholesterolemia using oligonucleotide microchip expression analysis. We demonstrate that Tcf1-/- mice have a defect in bile acid transport, increased bile acid and liver cholesterol synthesis, and impaired HDL metabolism. Tcf1-/- liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations. In intestine and kidneys, Tcf1-/- mice lack expression of the ileal bile acid transporter (Slc10a2), resulting in increased fecal and urinary bile acid excretion. The Tcf1 protein (also known as HNF-1alpha) also regulates transcription of the gene (Nr1h4) encoding the farnesoid X receptor-1 (Fxr-1), thereby leading to reduced expression of small heterodimer partner-1 (Shp-1) and repression of Cyp7a1, the rate-limiting enzyme in the classic bile acid biosynthesis pathway. In addition, hepatocyte bile acid storage protein is absent from Tcf1-/- mice. Increased plasma cholesterol of Tcf1-/- mice resides predominantly in large, buoyant, high-density lipoprotein (HDL) particles. This is most likely due to reduced activity of the HDL-catabolic enzyme hepatic lipase (Lipc) and increased expression of HDL-cholesterol esterifying enzyme lecithin:cholesterol acyl transferase (Lcat). Our studies demonstrate that Tcf1, in addition to being an important regulator of insulin secretion, is an essential transcriptional regulator of bile acid and HDL-cholesterol metabolism.

[Applications of numerical simulation in musculoskeletal research and its impact on orthopedic surgery]. / Einsatzgebiete der numerischen Simulation in der muskuloskelettalen Forschung und ihre Bedeutung für die Orthopädische Chirurgie.

Finite element analyses (FEA) as well as multibody system dynamics (MSD) are the main tools used for numerical simulation in the field of musculoskeletal research. While FEA is utilized for field problems, such as calculation of stress and strain distribution, MSD is applied for solving kinematic analyses, such as calculation of muscle and joint forces. Depending on the focus of investigation, modelling of biological tissue may vary from simple homogeneous behavior to modelling biochemical processes on the microscale and nanoscale. An important milestone in biomechanical research was the analysis of stress shielding, which led to further research on bone remodelling. Various models of implant-bone fixation used for the prediction of micromotion have been published. New possibilities for biomechanical analyses are achieved by consideration of complex muscle forces which are generated by MSD simulation and imported into FEA models as limiting conditions. A numerical model always requires experimental validation. If the results are confirmed experimentally, various advantages of numerical simulation apply and problems can be analysed isolated from many influencing factors. Therefore, straightforward parameter variation is possible, enabling studies which would be impossible in an experimental or clinical setup.

Combining conventional tree-ring measurements with wood anatomy and strontium isotope analyses enables dendroprovenancing at the local scale.

Dendroprovenancing provides critical information regarding the origin of wood, allowing further insights into economic exploitation strategies and source regions of timber products. Traditionally, dendroprovenancing relies on pattern-matching of tree rings, but its spatial resolution is limited by the geographical coverage of species-specific chronologies available for crossdating and, in the case of short-distance trades, by scarce environmental variability. Here, we present an approach to provenance timber with high spatial resolution from forested areas that have been exploited intensively throughout history, with the aim to understand the sustainability of the various woodland management practices used to supply timber products. To this end, we combined tree-ring width (TRW), wood anatomical and geochemical analyses in addition to multivariate statistical validation procedures to trace the origin of living oak trees (Quercus robur) sampled in four stands located within a 30-km radius around the city of Limoges (Haute-Vienne, France). We demonstrate that TRW and wood anatomical variables (and in particular cell density) robustly discriminate the eastern from the western site, while failing to trace the origin of trees from the northern and southern sites. Here, strontium isotopic ratios (87Sr/86Sr) and Ca concentrations identify clusters of trees which could not be identified with TRW or wood anatomy. Ultimately, our study demonstrates that the coupling of wood anatomy with geochemical signatures allows to correctly pinpoint the origin of trees. Given the small geographic scale of our study and the limited differences in elevation and climate between study sites, our results are particularly promising for future dendroprovenancing studies. We thus conclude that the combination of multiple approaches will not only increase the accuracy of dendroprovenancing studies at local scales, but could also be implemented at much larger scales to identify trends in historic timber supply throughout Europe.

The pancreatic beta cell surface proteome.

The pancreatic beta cell is responsible for maintaining normoglycaemia by secreting an appropriate amount of insulin according to blood glucose levels. The accurate sensing of the beta cell extracellular environment is therefore crucial to this endocrine function and is transmitted via its cell surface proteome. Various surface proteins that mediate or affect beta cell endocrine function have been identified, including growth factor and cytokine receptors, transporters, ion channels and proteases, attributing important roles to surface proteins in the adaptive behaviour of beta cells in response to acute and chronic environmental changes. However, the largely unknown composition of the beta cell surface proteome is likely to harbour yet more information about these mechanisms and provide novel points of therapeutic intervention and diagnostic tools. This article will provide an overview of the functional complexity of the beta cell surface proteome and selected surface proteins, outline the mechanisms by which their activity may be modulated, discuss the methods and challenges of comprehensively mapping and studying the beta cell surface proteome, and address the potential of this interesting subproteome for diagnostic and therapeutic applications in human disease.