Dans ce monde où les business model des entreprises et encore plus les technologies sont en rupture, le challenge est le même : rester en contact avec le consommateur hyper connecté d’aujourd’hui. Ce challenge peut être vu comme un véritable cauchemar ou à l’inverse, considéré comme la prochaine grande opportunité pour les entreprises. Elles sont obligées d’aller au-delà des prévisions, en identifiant et capitalisant sur des opportunités que d’autres entreprises ne voient pas.

L’entité sécurité d’IBM a annoncé aujourd'hui les résultats d'une étude mondiale sondant le niveau de préparation des organisations en matière de résistance à une cyberattaque et de récupération ensuite. L'étude, menée par le Ponemon Institute et sponsorisée par IBM Resilient, a révélé qu'une grande majorité des organisations interrogées ne sont toujours pas prêtes à répondre de façon adéquate aux incidents de cybersécurité, 77% des personne interrogées indiquant qu'ils n'ont pas de plan de réponse aux incidents de cybersécurité appliqué de manière cohérente dans l’ensemble de l'organisation.

New projects:

• anypool — General-purpose pooling library — BSD 2-Clause
• avl-tree — An implementation of the AVL tree data structure. — MIT
• cl-aubio — Aubio bindings for Common Lisp — GPLv3
• cl-interval — Intervals, interval trees — NewBSD, LLGPL
• cl-liballegro — Allegro 5 game programming library bindings for Common Lisp — Allegro 5 - http://alleg.sourceforge.net/license.html
• cl-mime-from-string — A one function library to return a mime-type based on the file extension found at the end of a string. ie abc.txt -> text/plain. The common types implemented are from https://developer.mozilla.org/en-US/docs/Web/HTTP/Basics_of_HTTP/MIME_types/Common_types — MIT
• cl-telegram-bot — Telegram Bot API, based on sovietspaceship's work but mostly rewritten. — MIT
• dns-client — A client for the DNS protocol. — zlib
• feeder — RSS, Atom and general feed parsing and generating — zlib
• perceptual-hashes — Perceptual hash algorithms for images — 2-clause BSD
• portable-condition-system — A portable condition system for Common Lisp — CC0
• ten — Template System for Common Lisp — MIT
• trivial-custom-debugger — Allows arbitrary functions to become the standard Lisp debugger — MIT
• trivial-with-current-source-form — Helps macro writers produce better errors for macro users — GPLv3
• vom-json — A json-formatted logger for vom — MIT
• vp-trees — Perceptual hash algorithms for images — 2-clause BSD

Updated projects: 3b-bmfont, 3bgl-shader, 3bmd, 3bz, a-cl-logger, alexandria, april, async-process, bdef, bp, ccldoc, chunga, cl+ssl, cl-ana, cl-capstone, cl-cffi-gtk, cl-collider, cl-containers, cl-environments, cl-gamepad, cl-gserver, cl-inotify, cl-markless, cl-pack, cl-patterns, cl-python, cl-rdkafka, cl-shlex, cl-sparql, cl-str, cl-tui, cl-utils, cl-webkit, clinenoise, clip, closer-mop, concrete-syntax-tree, croatoan, cserial-port, dartscltools, defenum, deploy, dexador, diff-match-patch, dissect, djula, doubly-linked-list, easy-routes, eclector, escalator, fast-generic-functions, fast-io, flexi-streams, flexichain, float-features, fset, fucc, functional-trees, fxml, gendl, graph, gtirb, hu.dwim.computed-class, hu.dwim.def, hu.dwim.perec, hu.dwim.presentation, hu.dwim.quasi-quote, hu.dwim.walker, hu.dwim.web-server, hunchentoot-multi-acceptor, ironclad, keystone, lispqr, literate-lisp, maiden, maxpc, mcclim, mmap, modularize, mutility, nodgui, numcl, numpy-file-format, origin, osicat, overlord, parachute, patchwork, petalisp, petri, phoe-toolbox, plump, policy-cond, polisher, postmodern, pzmq, qtools, quilc, qvm, roan, rpcq, s-graphviz, s-http-client, s-http-server, s-sysdeps, s-utils, sanity-clause, scalpl, sealable-metaobjects, sel, select-file, serapeum, sketch, skippy-renderer, snappy, softdrink, spinneret, staple, stumpwm, sucle, swank-client, swank-crew, tooter, trace-db, trivial-features, trivial-file-size, vgplot, woo.

Removed projects: cl-password-store, fomus, rfc3339-timestamp, rpc4cl.

All the removed projects are removed because they no longer build. For the first two (cl-password-store and fomus), I was unable to get a response from the authors. The other two (rfc3339-timestamp, rpc4cl) the author was responsive, but has abandoned the projects.

To get this update, use (ql:update-dist "quicklisp"). Enjoy!

A number of people support Quicklisp with a monthly contribution through PayPal. I recently set up a Quicklisp Patreon page as an alternative - if you are interested in supporting Quicklisp, feel free to check it out.

History of Lisp (The history of LISP according to McCarthy's memory in 1978, presented at the ACM SIGPLAN History of Programming Languages Conference.)

This is such a fun paper which I couldn't find on LtU. It's about the very early history of programming (1950s and '60s), back when things we take for granted today didn't exist yet.

On taking apart complex data structures with functions like CAR and CDR:

It was immediately apparent that arbitrary subexpressions of symbolic expressions could be obtained by composing the functions that extract immediate subexpressions, and this seemed reason enough to go to an algebraic language.

On creating new data, i.e. CONS:

At some point a cons(a,d,p,t) was defined, but it was regarded as a subroutine and not as a function with a value. ... Gelernter and Gerberich noticed that cons should be a function, not just a subroutine, and that its value should be the location of the word that had been taken from the free storage list. This permitted new expressions to be constructed out of subsubexpressions by composing occurrences of cons

On inventing IF:

This led to the invention of the true conditional expression which evaluates only one of N1 and N2 according to whether M is true or false and to a desire for a programming language that would allow its use.

On how supreme laziness led to the invention of garbage collection:

Once we decided on garbage collection, its actual implementation could be postponed, because only toy examples were being done.

You might have heard this before:

S.R. Russell noticed that eval could serve as an interpreter for LISP, promptly hand coded it, and we now had a programming language with an interpreter.

And the rest is history...

Late last month, CBS News in New York reported that 911 dispatchers in that beleaguered hub have received, on several occasions, more emergency calls than they took on September 11, 2001. Call volume in the most populated city in the US typically ranges

I’m a photographer and aspiring photo archivist. I was asked to digitize photos that were on display at a funeral/viewing. There were 65 photos.

Me: Sure, I could have this done pretty soon, no problem!

Client: Great! I didn’t have tape and didn’t want to use glue, so (with pride in their voice) guess what I used?

Me: (with pronounced fear in my voice) Uh… what?

Client: Toothpaste!

What was going to be an hour and a half project turned into two days of scraping and cleaning photos.

Two men were arrested in a fatal shooting in Flint, Mich.

The nation lurches toward November as a weakened giant. When Americans decide whether to end or extend the tenure of a reckless president, they will also be voting up or down on whether the rule of law and official accountability remain hallmarks of a great republic.

The bulk of students taking the test do so before starting Kindergarten—an aspect of the process critics say privileges parents with the money and savvy to prepare their young kids for the high-stakes exams.

Sligo's busy Quayside Shopping Centre promotes its shops and events on four display screens throughout the centre, keeping shoppers updated with dynamic content.

Two men were arrested in a fatal shooting in Flint, Mich.

The study, originally published in June, contained an error that its authors caught months later.

As COVID-19 spreads across the United States, only a few areas are breaking down the numbers of infections and deaths by racial and ethnic groups.

May we find the grace to discern hope and meaning in this season of faith and crisis.

Americans required to "shelter in place" should also be entitled to "shelter in job."

Two men were arrested in a fatal shooting in Flint, Mich.

From a spirited Zoom session to binge-watching "Tiger King," there's a smoke-free option to pair with it.

Join the watch party for Ballet Hispánico's 'Con Brazos Abiertos' and catch a Q&A with choreographer Michelle Manzanales.

Firefighters are braced for a busy few days as Londoners celebrate Bonfire Night over the coming days

In one article, wealthy private schools get government aid. In another, desperate citizens beg for funds online.

IndyStar preps Insider Kyle Neddenriep identified the 64 "best" high school teams of all-time. That means the best team you can put together.

You can expect more abilities, a larger map, and more colors from 'Ori and the Will of the Wisps' than in the first., but the hope was to see a touch of subversion to its formula instead of straitlaced augmentation.

Tanzania says it has received its first shipment of Madagascar's self-proclaimed, plant-based "cure" for coronavirus, despite warnings from the World Health Organisation that its efficacy is unproven.

Luis Spencer Freitas, digital marketing director at Pernod Ricard USA, explains what will drive greater innovation in display advertising next year.

The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis.

The CRISPR/Cas9 nucleases have been widely applied for genome editing in various organisms. Cas9 nucleases complexed with a guide RNA (Cas9–gRNA) find their targets by scanning and interrogating the genomic DNA for sequences complementary to the gRNA. Recognition of the DNA target sequence requires a short protospacer adjacent motif (PAM) located outside this sequence. Given that the efficiency of target location may depend on the strength of interactions that promote target recognition, here we sought to compare affinities of different Cas9 nucleases for their cognate PAM sequences. To this end, we measured affinities of Cas9 nucleases from Streptococcus pyogenes, Staphylococcus aureus, and Francisella novicida complexed with guide RNAs (gRNAs) (SpCas9–gRNA, SaCas9–gRNA, and FnCas9–gRNA, respectively) and of three engineered SpCas9–gRNA variants with altered PAM specificities for short, PAM-containing DNA probes. We used a “beacon” assay that measures the relative affinities of DNA probes by determining their ability to competitively affect the rate of Cas9–gRNA binding to fluorescently labeled target DNA derivatives called “Cas9 beacons.” We observed significant differences in the affinities for cognate PAM sequences among the studied Cas9 enzymes. The relative affinities of SpCas9–gRNA and its engineered variants for canonical and suboptimal PAMs correlated with previous findings on the efficiency of these PAM sequences in genome editing. These findings suggest that high affinity of a Cas9 nuclease for its cognate PAM promotes higher genome-editing efficiency.

Members Event

Event participants

Oded Haklai, Associate Professor, Department of Political Studies, Queen's University, Ontario
Neophytos Loizides, Reader, University of Kent; Leverhulme Trust Research Fellow
Madurika Rasaratnam, Lecturer, International Conflict Analysis, University of Kent
Chair: Evangelos Liaras, IE University, Madrid; Academy Associate, Chatham House

7 October 2016

The void in governance in Syria caused by the conflict has enabled a previously oppressed civil society to rise. Now this new society is under threat. Sustained commitment from the international community is required.

The CRISPR/Cas9 nucleases have been widely applied for genome editing in various organisms. Cas9 nucleases complexed with a guide RNA (Cas9–gRNA) find their targets by scanning and interrogating the genomic DNA for sequences complementary to the gRNA. Recognition of the DNA target sequence requires a short protospacer adjacent motif (PAM) located outside this sequence. Given that the efficiency of target location may depend on the strength of interactions that promote target recognition, here we sought to compare affinities of different Cas9 nucleases for their cognate PAM sequences. To this end, we measured affinities of Cas9 nucleases from Streptococcus pyogenes, Staphylococcus aureus, and Francisella novicida complexed with guide RNAs (gRNAs) (SpCas9–gRNA, SaCas9–gRNA, and FnCas9–gRNA, respectively) and of three engineered SpCas9–gRNA variants with altered PAM specificities for short, PAM-containing DNA probes. We used a “beacon” assay that measures the relative affinities of DNA probes by determining their ability to competitively affect the rate of Cas9–gRNA binding to fluorescently labeled target DNA derivatives called “Cas9 beacons.” We observed significant differences in the affinities for cognate PAM sequences among the studied Cas9 enzymes. The relative affinities of SpCas9–gRNA and its engineered variants for canonical and suboptimal PAMs correlated with previous findings on the efficiency of these PAM sequences in genome editing. These findings suggest that high affinity of a Cas9 nuclease for its cognate PAM promotes higher genome-editing efficiency.

Site-specific arrest of RNA polymerases (RNAPs) is fundamental to several technologies that assess RNA structure and function. Current in vitro transcription “roadblocking” approaches inhibit transcription elongation by blocking RNAP with a protein bound to the DNA template. One limitation of protein-mediated transcription roadblocking is that it requires inclusion of a protein factor extrinsic to the minimal in vitro transcription reaction. In this work, we developed a chemical approach for halting transcription by Escherichia coli RNAP. We first established a sequence-independent method for site-specific incorporation of chemical lesions into dsDNA templates by sequential PCR and translesion synthesis. We then show that interrupting the transcribed DNA strand with an internal desthiobiotin-triethylene glycol modification or 1,N6-etheno-2'-deoxyadenosine base efficiently and stably halts Escherichia coli RNAP transcription. By encoding an intrinsic stall site within the template DNA, our chemical transcription roadblocking approach enables display of nascent RNA molecules from RNAP in a minimal in vitro transcription reaction.

K. D. Cherednichenko, Yu. Yu. Ershova, A. V. Kiselev and S. N. Naboko
Trans. Moscow Math. Soc. 80 (2020), 251-294.
Abstract, references and article information

David S. Lipham
Proc. Amer. Math. Soc. 148 (2020), 2671-2682.
Abstract, references and article information

In view of the severe economic repercussions caused by the COVID-19 pandemic globally and locally, the Government announced another package of measures to support the affected individuals and businesses last Wednesday. Two of which are particularly relevant to the legal and dispute resolution sector - the LawTech Fund and the COVID-19 Online Dispute Resolution (ODR) Scheme. The LawTech Fund was briefly introduced in this blog a few days ago. Today, I would like to give an online explanation of the COVID-19 ODR.

 

In anticipation of an upsurge of disputes arising from or relating to COVID-19, the scheme aims to provide speedy and cost-effective means to resolve such disputes, especially for those involving micro, small and medium-sized enterprises (MSMEs) that may be adversely affected or hard hit by the pandemic. The scheme will engage eBRAM (electronic Business Related Arbitration & Mediation system) to provide ODR services to the general public and businesses, in particular MSMEs, involved in low value disputes.

 

The scheme plans to cover COVID-19 related disputes with the claim amount for each case to be capped at $500,000. Either one of the parties (claimant or respondent) must be a Hong Kong resident or company and they will only be required to each pay $200 registration fees. Under the scheme, the parties are required to enter into a dispute resolution agreement to record their consent.

 

The process to be adopted is a multi-tiered dispute resolution mechanism where the parties will first attempt to negotiate their disputes, followed by mediation and if that does not result in settlement, then subsequently to arbitration for a final and binding award. This is in line with the "Mediate First" policy that we have been advocating under our "Mediate First" Pledge Programmes.

 

The scheme aims to offer a fast and effective means to resolve disputes among parties. Each tier of dispute resolution will be conducted within a limited time. The tiers are devised with a view to avoiding disputes and differences from being entrenched. If the disputes can be resolved successfully and amicably through negotiation or mediation, we hope it will help build and reinforce a harmonious society and enable the parties to preserve their long term business relationship.

 

We also hope the scheme will have the benefit of job creation and job advancement for mediators and arbitrators (including their pupils). Parties are at liberty to appoint the third party neutral of their choice and if no agreement is reached, there will be a mechanism for appointment. The third party neutrals and the parties or their representatives can still handle cases under the social distancing measures online and indeed to practice on the handling of cases online. We would like the scheme to be launched in June if funding is provided in April.

 

It is a global trend to develop and use ODR to provide reliable and efficient platform to facilitate alternative dispute resolution. The scheme is in line with the development under Asia-Pacific Economic Cooperation's Collaborative Framework on ODR (APEC Framework), with MSMEs as the major beneficiary. The mechanism of adopting negotiation and mediation in the first stage under the APEC Framework is also to prevent entrenched views on the conflicts, thereby helping to create harmony in society.

 

Some forms of alternative dispute resolution, such as mediation, are a more cost-effective way to resolve disputes. The costs of mediation are almost always lower than the disputed amounts, making it an economical way to resolve disputes. Mediation can save time too. Some cases may be resolved following just one day of mediation.

 

LawTech has greatly helped the development of dispute resolution services. The establishment of a safe, reliable and credible platform to provide enterprises with convenient and cost-effective online dispute resolution will become a new trend.

 

It is one of the major long-term policy objectives of the Department of Justice (DoJ) in recent years to enhance and promote Hong Kong's status as an international legal hub for deal-making and dispute resolution. A further promotion of the use of ODR will help consolidate Hong Kong's position as an international business and financial centre.

 

The social media accounts of the DoJ's IDAR Office have been introducing the procedure, characteristics and benefits of mediation and arbitration. You may wish to visit the dedicated pages of the IDAR Office to keep abreast of the dispute resolution services.

 

In addition to the relief measures announced by the Government, the DoJ has also taken the initiative to speed up payment of fees to counsel. Counsel engaged by the DoJ could submit their interim fee notes together with the interim case reports after certain work has been completed. Each case will be considered individually on a case-by-case basis and interim payments could be made. I have enquired and am also glad to learn from the Legal Aid Department and the Duty Lawyer Service that they made similar arrangements.

 

We are confident that Hong Kong can weather the storm with our fundamental strengths and resilience. We also trust that we would overcome this unprecedented challenge by standing in solidarity.

 

Secretary for Justice Teresa Cheng wrote this article and posted it on her blog on April 13.

(University of Southampton) Scientists have published highly detailed images of lab-grown neurons using Extreme Ultraviolet radiation that could aid the analysis of neurodegenerative diseases.

Cas12a (Cpf1) is an RNA-guided endonuclease in the bacterial type V-A CRISPR-Cas anti-phage immune system that can be repurposed for genome editing. Cas12a can bind and cut dsDNA targets with high specificity in vivo, making it an ideal candidate for expanding the arsenal of enzymes used in precise genome editing. However, this reported high specificity contradicts Cas12a's natural role as an immune effector against rapidly evolving phages. Here, we employed high-throughput in vitro cleavage assays to determine and compare the native cleavage specificities and activities of three different natural Cas12a orthologs (FnCas12a, LbCas12a, and AsCas12a). Surprisingly, we observed pervasive sequence-specific nicking of randomized target libraries, with strong nicking of DNA sequences containing up to four mismatches in the Cas12a-targeted DNA-RNA hybrid sequences. We also found that these nicking and cleavage activities depend on mismatch type and position and vary with Cas12a ortholog and CRISPR RNA sequence. Our analysis further revealed robust nonspecific nicking of dsDNA when Cas12a is activated by binding to a target DNA. Together, our findings reveal that Cas12a has multiple nicking activities against dsDNA substrates and that these activities vary among different Cas12a orthologs.

The transfer of a phosphate from ATP to a protein substrate, a modification known as protein phosphorylation, is catalyzed by protein kinases. Protein kinases play a crucial role in virtually every cellular activity. Recent studies of atypical protein kinases have highlighted the structural similarity of the kinase superfamily despite notable differences in primary amino acid sequence. Here, using a bioinformatics screen, we searched for putative protein kinases in the intracellular bacterial pathogen Legionella pneumophila and identified the type 4 secretion system effector Lpg2603 as a remote member of the protein kinase superfamily. Employing an array of biochemical and structural biology approaches, including in vitro kinase assays and isothermal titration calorimetry, we show that Lpg2603 is an active protein kinase with several atypical structural features. Importantly, we found that the eukaryote-specific host signaling molecule inositol hexakisphosphate (IP6) is required for Lpg2603 kinase activity. Crystal structures of Lpg2603 in the apo-form and when bound to IP6 revealed an active-site rearrangement that allows for ATP binding and catalysis. Our results on the structure and activity of Lpg2603 reveal a unique mode of regulation of a protein kinase, provide the first example of a bacterial kinase that requires IP6 for its activation, and may aid future work on the function of this effector during Legionella pathogenesis.

Disposable masks can be used more than once, but it's important to make sure the mask isn't carrying coronavirus.

The currently available therapeutic radiopharmaceutical for high-risk neuroblastoma, ¹³¹I-MIBG, is ineffective at targeting micrometastases due to the low linear energy transfer (LET) properties of high-energy beta particles. In contrast, Auger radiation has high-LET properties with nanometer ranges in tissue, efficiently causing DNA damage when emitted in close proximity to DNA. The aim of this study was to evaluate the cytotoxicity of targeted Auger therapy in pre-clinical models of high-risk neuroblastoma. Methods: Using a radiolabeled poly(ADP-ribose) polymerase (PARP) inhibitor, ¹²⁵I-KX1, we delivered an Auger emitter iodine-125 to PARP-1: a chromatin-binding enzyme overexpressed in neuroblastoma. In vitro cytotoxicity of ¹²⁵I-KX1 was assessed in nineteen neuroblastoma cell lines, followed by in-depth pharmacological analysis in a sensitive and resistant pair of cell lines. Immunofluorescence microscopy was used to characterize ¹²⁵I-KX1-induced DNA damage. Finally, in vitro/in vivo microdosimetry was modeled from experimentally derived pharmacological variables. Results: ¹²⁵I-KX1 was highly cytotoxic in vitro across a panel of neuroblastoma cell lines, directly causing double strand DNA breaks. Based on subcellular dosimetry, ¹²⁵I-KX1 was approximately twice as effective compared to ¹³¹I-KX1, whereas cytoplasmic ¹²⁵I-MIBG demonstrated low biological effectiveness. Despite the ability to deliver focused radiation dose to the cell nuclei, ¹²⁵I-KX1 remained less effective than its alpha-emitting analog ²¹¹At-MM4, and required significantly higher activity for equivalent in vivo efficacy based on tumor microdosimetry. Conclusion: Chromatin-targeted Auger therapy is lethal to high-risk neuroblastoma cells with potential use in micrometastatic disease. This study provides the first evidence for cellular lethality from a PARP-1 targeted Auger emitter, calling for further investigation into targeted Auger therapy.

BiTE® (Bispecific T-cell engager) molecules are designed to engage and activate cytotoxic T-cells to kill tumor cells. Little is known about their biodistribution in immunocompetent settings. To explore their pharmacokinetics and the role of the immune cells, BiTE molecules were radiolabeled with positron emission tomography (PET) isotope zirconium-89 (89Zr) and studied in immunocompetent and immunodeficient mouse models. PET images and ex-vivo biodistribution in immunocompetent mice with 89Zr-muS110, targeting mouse CD3 (Kd = 2.9 nM) and mouse EpCAM (Kd = 21 nM), and 89Zr-hyS110, targeting only mouse CD3 (Kd = 2.9 nM), showed uptake in tumor, spleen and other lymphoid organs, while the human-specific control BiTE 89Zr-AMG 110 showed similar tumor uptake but lacked spleen uptake. 89Zr-muS110 spleen uptake was lower in immunodeficient than in immunocompetent mice. After repeated administration of non-radiolabeled muS110 to immunocompetent mice 89Zr-muS110 uptake in spleen, and other lymphoid tissues, decreased and was comparable to uptake in immunodeficient mice, indicating saturation of CD3 binding sites. Autoradiography and immunohistochemistry demonstrated colocalization of 89Zr-muS110 and 89Zr-hyS110 with CD3-positive T-cells in the tumor and spleen but not with EpCAM expression. Also, uptake in the duodenum correlated with a high incidence of T-cells. This study shows that in immunocompetent mice the BiTE 89Zr-muS110 distribution is predominantly based on its high affinity CD3 binding arm. Significance: 89Zr-muS110 biodistribution is mainly dependent on the T-cell targeting arm with limited contribution of its second arm, targeting EpCAM. These findings highlight the need for extensive biodistribution studies of novel bispecific constructs as results might have implications for their respective drug development and clinical translation.

Björn Morén
Apr 15, 2020; 0:jlr.ILR120000808v1-jlr.ILR120000808
Images in Lipid Research

Ankylosing Spondylitis (AS) is a common, inflammatory rheumatic disease, which primarily affects the axial skeleton and is associated with sacroiliitis, uveitis and enthesitis. Unlike other autoimmune rheumatic diseases, such as rheumatoid arthritis or systemic lupus erythematosus, autoantibodies have not yet been reported to be a feature of AS. We therefore wished to determine if plasma from patients with AS contained autoantibodies and if so, characterize and quantify this response in comparison to patients with Rheumatoid Arthritis (RA) and healthy controls. Two high-density nucleic acid programmable protein arrays expressing a total of 3498 proteins were screened with plasma from 25 patients with AS, 17 with RA and 25 healthy controls. Autoantigens identified were subjected to Ingenuity Pathway Analysis in order to determine patterns of signalling cascades or tissue origin. 44% of patients with Ankylosing Spondylitis demonstrated a broad autoantibody response, as compared to 33% of patients with RA and only 8% of healthy controls. Individuals with AS demonstrated autoantibody responses to shared autoantigens, and 60% of autoantigens identified in the AS cohort were restricted to that group. The AS patients autoantibody responses were targeted towards connective, skeletal and muscular tissue, unlike those of RA patients or healthy controls. Thus, patients with AS show evidence of systemic humoral autoimmunity and multispecific autoantibody production. Nucleic Acid Programmable Protein Arrays constitute a powerful tool to study autoimmune diseases.

Clinical studies have shown a link between hyperuricemia (HU) and diabetes, while the exact effect of soluble serum urate on glucose metabolism remains elusive. This study aims to characterize the glucose metabolic phenotypes and investigate the underlying molecular mechanisms using a novel spontaneous HU mouse model in which the Uricase (Uox) gene is absent. In an attempt to study the role of HU in glycometabolism, we implemented external stimulation on Uox-knockout (KO) and wild-type (WT) males with a high-fat diet (HFD) and/or injections of multiple low-dose streptozotocin (MLD-STZ) to provoke the potential role of urate. Notably, while Uox-KO mice developed glucose intolerance in the basal condition, no mice spontaneously developed diabetes, even with aging. HFD-fed Uox-KO mice manifested similar insulin sensitivity compared with WT controls. HU augmented the existing glycometabolism abnormality induced by MLD-STZ and eventually led to diabetes, as evidenced by the increased random glucose. Reduced β-cell masses and increased terminal deoxynucleotidyl TUNEL-positive β-cells suggested that HU-mediated diabetes was cell death dependent. However, urate-lowering treatment (ULT) cannot ameliorate the diabetes incidence or reverse β-cell apoptosis with significance. ULT displayed a significant therapeutic effect of HU-crystal– associated kidney injury and tubulointerstitial damage in diabetes. Moreover, we present transcriptomic analysis of isolated islets, using Uox-KO versus WT mice and streptozotocin-induced diabetic WT (STZ-WT) versus diabetic Uox-KO (STZ-KO) mice. Shared differentially expressed genes of HU primacy revealed Stk17β is a possible target gene in HU-related β-cell death. Together, this study suggests that HU accelerates but does not cause diabetes by inhibiting islet β-cell survival.