Voltage mapping in subcellular nanodomains using electro-diffusion modeling.

Voltage distribution in sub-cellular micro-domains such as neuronal synapses, small protrusions, or dendritic spines regulates the opening and closing of ionic channels, energy production, and thus, cellular homeostasis and excitability. Yet how voltage changes at such a small scale in vivo remains challenging due to the experimental diffraction limit, large signal fluctuations, and the still limited resolution of fast voltage indicators. Here, we study the voltage distribution in nano-compartments using a computational approach based on the Poisson-Nernst-Planck equations for the electro-diffusion motion of ions, where inward and outward fluxes are generated between channels. We report a current-voltage (I-V) logarithmic relationship generalizing Nernst law that reveals how the local membrane curvature modulates the voltage. We further find that an influx current penetrating a cellular electrolyte can lead to perturbations from tens to hundreds of nanometers deep, depending on the local channel organization. Finally, we show that the neck resistance of dendritic spines can be completely shunted by the transporters located on the head boundary, facilitating ionic flow. To conclude, we propose that voltage is regulated at a subcellular level by channel organization, membrane curvature, and narrow passages.

Analyzing Photoactivation with Diffusion Models to Study Transport in the Endoplasmic Reticulum Network.

Photoactivation is a paradigm consisting in local molecular fluorescent activation by laser illumination in a chosen region (source) while measuring the concentration at a target region. Data-driven modeling is concerned with the following questions: how from the measurement in these two regions is it possible to infer the properties of molecular propagation? How is it possible to use such responses to infer motions occurring in networks such as the endoplasmic reticulum? In this book chapter, we shall review the data-driven analysis based on diffusion-transport models and numerical simulations to interpret the photoactivation dynamics and extract biophysical parameters. We will discuss modeling approaches to reconstruct local network properties from photoactivation transients.

Aneurysmal Disease in Patients With Takayasu Arteritis.

OBJECTIVE: Takayasu arteritis (TA) leads to stenotic disease. Aneurysmal lesions are rarer. This study assessed the main characteristics of aneurysmal disease in a Canadian cohort of patients with TA. METHODS: This monocentric retrospective study included patients with TA followed at the Mount Sinai Hospital Vasculitis Clinic in Toronto. Diagnosis of TA was based on clinical findings and/or satisfied the 1990 American College of Rheumatology classification criteria. RESULTS: Seventy-four patients were included. At any time, aneurysmal disease was found in 23 (31%) patients. Median disease duration was 9.0 (IQR 7.0-19.0) years. Prior hypertension (P = 0.02), fever (P = 0.04), and seizure disorders (P = 0.03) were more common. Limb claudication was less frequent (P = 0.01). Persistent and/or new aneurysms were demonstrated in 22/23 patients at follow-up. Thoracic aorta aneurysm (13/22) was most common, followed by abdominal aorta (8/22), subclavian (7/22), and carotid (6/22) artery disease. Aortic valve regurgitation was more frequent (9/23 vs 3/48; P = 0.001). Twenty-one patients had been treated with glucocorticoids (median 6.1 years [IQR 3.7-8.1]). Methotrexate, azathioprine, and leflunomide were repeatedly used. Infliximab (7/23) was used more often (P = 0.04), whereas tocilizumab was received by only 4 patients with aneurysmal disease (P = 0.01). Patients with aneurysms suffered more frequent relapses (2.0 [IQR 0.0-4.0] vs 1.0 [IQR 0.0-2.0], P = 0.04). CONCLUSION: Aneurysmal disease was found in a significant proportion of patients with TA. Given that aneurysms may carry a risk of rupture, and are associated with a higher rate of relapse, this finding should be reported systematically in TA studies.

CanVasc consensus recommendations for the use of avacopan in antineutrophil cytoplasm antibody-associated vasculitis: 2022 addendum.

OBJECTIVE: In 2020, the Canadian Vasculitis Research Network (CanVasc) published their updated recommendations for the management of ANCA-associated vasculitides (AAV). The current addendum provides further recommendations regarding the use of avacopan in AAV based on a review of newly available evidence. METHODS: An updated systematic literature review on avacopan (formerly, CCX168) using Medline, Embase, and the Cochrane Library was performed for publications up to September 2022. New recommendations were developed and categorized according to the EULAR grading levels, as done for previous CanVasc recommendations. A modified Delphi procedure and videoconferences were used to reach ≥80% consensus on the inclusion, wording and grading of each recommendation. RESULTS: Three new recommendations were developed. They focus on avacopan therapy indication and duration, as well as timely glucocorticoid tapering. CONCLUSION: These 2022 addended recommendations provide rheumatologists, nephrologists and other specialists caring for patients with AAV with guidance for the use of avacopan, based on current evidence and consensus from Canadian experts.

Variations in Takayasu arteritis characteristics in a cohort of patients with different racial backgrounds.

OBJECTIVES: We aimed to describe differences in disease characteristics and outcomes in Takayasu arteritis (TA) patients with different racial backgrounds. METHODS: This was a retrospective cohort study consisting of TA patients seen at specialty vasculitis clinics from five academic hospitals across Canada. Disease features, treatments and outcomes were compared between White and non-White patients. RESULTS: The cohort included 113 patients, of which 51 were White. Over 50% of the non-White patients were Asian. Compared to non-White patients, White patients had higher CRP and ESR at diagnosis (33.6 mg/l versus 9.4 mg/l, p = 0.033; and 51 mm/h versus 24 mm/h, p = 0.047; respectively), and were less likely to have baseline cardiovascular comorbidities including dyslipidemia (11.8% versus 29%, p = 0.037). There were no significant differences between racial groups for other disease characteristics or outcomes. CONCLUSION: Patient race did not appear to play a significant role in determining disease characteristics and outcomes when comparing TA patients from various racial backgrounds living in the same country.

Cessation of immunosuppressive therapies in patients with Takayasu arteritis with sustained inactive disease.

OBJECTIVE: Takayasu arteritis (TA) is a chronic and relapsing vasculitis. The objectives of this study were to describe the characteristics and identify predictive factors associated with successful treatment discontinuation in a cohort of patients with TA. METHODS: We conducted a retrospective monocentric analysis of patients with TA, followed at the tertiary Vasculitis Clinic in Toronto, from inception to January 2021, and for at least 2 years after diagnosis. The objectives were to determine the frequency of patients whose immunosuppressive medications had been stopped for at least 6 months before their last follow-up visit and whose disease remained inactive, and analyze their characteristics, in comparison with the remaining of the cohort still on medications for TA. RESULTS: The cohort included 65 patients (95.4% women; 46.7% white). Twenty-five (38.5%) patients had successfully discontinued their treatment for more than 6 months at their last visit. Median disease duration was 18 years (IQR, 10-23 years) in the group off treatment, compared to 9 years (IQR, 5.3-16.0 years) in the group still on treatment (P = 0.004). Renal artery involvement was less frequent in patients who had stopped their immunosuppressants, especially left renal artery (P = 0.035). Median CRP level at diagnosis was 16.4 mg/L (IQR, 5.4-32.2 mg/L) in the group off treatment, and 45 mg/L (IQR, 15.0-75.5 mg/L) in the group on treatment (P = 0.023). No other difference was found when comparing disease characteristics of the two groups, on or off medications. CONCLUSION: One third of TA patients were able to discontinue their treatment. They had lower CRP levels at diagnosis, less frequent renal artery involvement and longer disease duration. No other specific disease features seem to help identify patients with greater chances to be weaned off treatment successfully.

Scleromyositis: A distinct novel entity within the systemic sclerosis and autoimmune myositis spectrum. Implications for care and pathogenesis.

Systemic sclerosis and autoimmune myositis are both associated with decreased quality of life and increased mortality. Their prognosis and management largely depend on the disease subgroups. Indeed, systemic sclerosis is a heterogeneous disease, the two predominant forms of the disease being limited and diffuse scleroderma. Autoimmune myositis is also a heterogeneous group of myopathies that classically encompass necrotizing myopathy, antisynthetase syndrome, dermatomyositis and inclusion body myositis. Recent data revealed that an additional disease subset, denominated "scleromyositis", should be recognized within both the systemic sclerosis and the autoimmune myositis spectrum. We performed an in-depth review of the literature with the aim of better delineating scleromyositis. Our review highlights that this concept is supported by recent clinical, serological and histopathological findings that have important implications for patient management and understanding of the disease pathophysiology. As compared with other subsets of systemic sclerosis and autoimmune myositis, scleromyositis patients can present with a characteristic pattern of muscle involvement (i.e. distribution of muscle weakness) along with multisystemic involvement, and some of these extra-muscular complications are associated with poor prognosis. Several autoantibodies have been specifically associated with scleromyositis, but they are not currently integrated in diagnostic and classification criteria for systemic sclerosis and autoimmune myositis. Finally, striking vasculopathic lesions at muscle biopsy have been shown to be hallmarks of scleromyositis, providing a strong anatomopathological substratum for the concept of scleromyositis. These findings bring new insights into the pathogenesis of scleromyositis and help to diagnose this condition, in patients with subtle SSc features and/or no autoantibodies (i.e. "seronegative" scleromyositis). No guidelines are available for the management of these patients, but recent data are showing the way towards a new therapeutic approach dedicated to these patients.

Histopathological features of systemic sclerosis-associated myopathy: A scoping review.

BACKGROUND: Scleromyositis (SM) is an emerging subset of myositis associated with features of systemic sclerosis (SSc) but it is currently not recognized as a distinct histopathological subset by the European NeuroMuscular Center (ENMC). Our aim was to review studies reporting muscle biopsies from SSc patients with myositis and to identify unique histopathological features of SM. METHODS: A scoping review was conducted and included all studies reporting histopathological findings in SSc patients with myositis searching the following databases: PubMed, MEDLINE, EMBASE, CINAHL and EBM-Reviews. Clinical, serological, and histopathological data were extracted using a standardized protocol. RESULTS: Out of 371 citations, 77 studies that included 559 muscle biopsies were extracted. Fifty-seven percent (n = 227/400) had inflammatory infiltrates, predominantly T cells, which were endomysial (49%), perimysial (42%) and perivascular (41%). Few studies (18%, n = 8/44) evaluated the presence of B-cells. Myofiber atrophy was present in 48% (n = 104/218) of biopsies, and was predominantly perifascicular in 19% (n = 6/31), with necrosis reported in 56% (n = 162/290) of cases. Sarcolemmal MHC-I upregulation was found in 72% (n = 64/89) of biopsies. Non-specified C5b-9 deposition was described in 39% of muscle biopsies (n = 28/72). Neurogenic features were present in 23% (n = 44/191); endomysial fibrosis was reported in 35% (n = 120/340); and rimmed vacuoles were observed in 32% (n = 11/34) of biopsies. Capillaropathy, such as capillary dropout and/or ultrastructural endothelial abnormalities, was reported in 33% (n = 43/129) of cases. Reported ENMC categories were mainly polymyositis (21%), non-specific myositis (19%), immune-mediated necrotizing myopathy (16%), and dermatomyositis (8%). Histopathological features were analyzed according to serological subtypes in 28 studies, including anti-PM-Scl (n = 48), -Ku (n = 23) and -U1RNP (n = 90). Most of these biopsies demonstrated inflammatory infiltrates (range 49-85%) as well as MHC-I expression (range 63-81%). Necrosis was associated with anti-Ku (85%) and anti-U1RNP (73%), while anti-Ku was also associated with neurogenic features and rimmed vacuoles in 57% and 25% of cases, respectively. CONCLUSION: Our review suggests that SM is characterized by heterogeneous pathological features using definitions included in current histopathological criteria. Whether a distinct histopathological signature exists in SM remains to be determined. SSc-specific and SSc-associated autoantibodies may help define more homogeneous histopathological subsets.

Mortality and morbidity in scleroderma renal crisis: A systematic literature review.

Objectives: The objective of this study was to systematically review the mortality and morbidity associated with scleroderma renal crisis and to determine temporal trends. Methods: We searched MEDLINE, Embase and the Cochrane Database of Systematic Reviews from database inception to 10 February 2020. Bibliographies of selected articles were hand-searched for additional references. Data were extracted using a standardized extraction form. Study quality was assessed using the Newcastle-Ottawa scale. Results were analysed qualitatively. Results: Twenty studies with 14,059 systemic sclerosis subjects, of which 854 had scleroderma renal crisis and 4095 had systemic sclerosis-associated end-stage renal disease, met inclusion criteria. Study quality was generally moderate. Cumulative mortality in the post-angiotensin-converting enzyme inhibitor era was approximately 20% at 6 months, 30%-36% at 1 year, 19%-40% at 3 years and almost 50% at 10 years from scleroderma renal crisis onset. Although the introduction of angiotensin-converting enzyme inhibitors in the early 1970s resulted in a 50% improvement in scleroderma renal crisis mortality, there was no further improvement thereafter. Scleroderma renal crisis mortality rates were proportionally higher than mortality rates associated with other systemic sclerosis organ involvement. The rate of permanent dialysis after scleroderma renal crisis in the post-angiotensin-converting enzyme inhibitor era ranged from 19%-40%. Three to 17% of systemic sclerosis patients underwent renal transplant. Survival was better in patients post-renal transplant (54%-91%) compared to those on dialysis (31%-56%). Graft survival improved over time and appeared similar to that of patients with other types of end-stage renal disease. Conclusion: While there has been considerable improvement in scleroderma renal crisis-related outcomes since the introduction of angiotensin-converting enzyme inhibitors, morbidity and mortality remain high for affected patients without convincing evidence of further improvement in the post-angiotensin-converting enzyme inhibitor era. Novel treatments are required to improve outcomes of scleroderma renal crisis.

Synthesis, structural elucidation, characterization and theoretical DFT study of 1-(o-tolyl)biguanidium chloride.

The structure of the new salt 1-(o-tolyl)biguanidium chloride, C9H14N5+·Cl-, has been determined by single-crystal X-ray diffraction. The salt crystallizes in the monoclinic space group C2/c. In this structure, the chloride and biguanidium hydrophilic ions are mostly connected to each other via N-H...N and N-H...Cl hydrogen bonds to form layers parallel to the ab plane around y = 1/3 and y = 2/3. The 2-methylbenzyl groups form layers between these layers around y = 0 and y = 1/2, with the methyl group forming C-H...π interactions with the aromatic ring. Intermolecular interactions on the Hirshfeld surface were investigated in terms of contact enrichment and electrostatic energy, and confirm the role of strong hydrogen bonds along with hydrophobic interactions. A correlation between electrostatic energy and contact enrichment is found only for the strongly attractive (N-H...Cl-) and repulsive contacts. Electrostatic energies between ions reveal that the interacting biguanidium cation pairs are repulsive and that the crystal is maintained by attractive cation...Cl- dimers. The vibrational absorption bands were identified by IR spectroscopy.

Pattern formation in a coupled membrane-bulk reaction-diffusion model for intracellular polarization and oscillations.

Reaction-diffusion systems have been widely used to study spatio-temporal phenomena in cell biology, such as cell polarization. Coupled bulk-surface models naturally include compartmentalization of cytosolic and membrane-bound polarity molecules. Here we study the distribution of the polarity protein Cdc42 in a mass-conserved membrane-bulk model, and explore the effects of diffusion and spatial dimensionality on spatio-temporal pattern formation. We first analyze a one-dimensional (1-D) model for Cdc42 oscillations in fission yeast, consisting of two diffusion equations in the bulk domain coupled to nonlinear ODEs for binding kinetics at each end of the cell. In 1-D, our analysis reveals the existence of symmetric and asymmetric steady states, as well as anti-phase relaxation oscillations typical of slow-fast systems. We then extend our analysis to a two-dimensional (2-D) model with circular bulk geometry, for which species can either diffuse inside the cell or become bound to the membrane and undergo a nonlinear reaction-diffusion process. We also consider a nonlocal system of PDEs approximating the dynamics of the 2-D membrane-bulk model in the limit of fast bulk diffusion. In all three model variants we find that mass conservation selects perturbations of spatial modes that simply redistribute mass. In 1-D, only anti-phase oscillations between the two ends of the cell can occur, and in-phase oscillations are excluded. In higher dimensions, no radially symmetric oscillations are observed. Instead, the only instabilities are symmetry-breaking, either corresponding to stationary Turing instabilities, leading to the formation of stationary patterns, or to oscillatory Turing instabilities, leading to traveling and standing waves. Codimension-two Bogdanov-Takens bifurcations occur when the two distinct instabilities coincide, causing traveling waves to slow down and to eventually become stationary patterns. Our work clarifies the effect of geometry and dimensionality on behaviors observed in mass-conserved cell polarity models.

On the Effect of Age-Dependent Mortality on the Stability of a System of Delay-Differential Equations Modeling Erythropoiesis.

We present an age-structured model for erythropoiesis in which the mortality of mature cells is described empirically by a physiologically realistic probability distribution of survival times. Under some assumptions, the model can be transformed into a system of delay differential equations with both constant and distributed delays. The stability of the equilibrium of this system and possible Hopf bifurcations are described for a number of probability distributions. Physiological motivation and interpretation of our results are provided.

Formation of a covalent bond between a polyoxometalate and silica covered by SiH moieties.

Dehydroxylated silica was modified by grafting reaction of SiHMe2 groups. The resulting material was fully characterized by various methods including infrared and one- and two-dimensional solid-state NMR. This material can further react with dehydrated polyoxometalates (POMs), leading to the formation of a covalent POM-silica bond. In the case of H4PVMo11O40, hydrogen released during the grafting reaction reduces the POM. This leads to the formation of two surface species, which can be reoxidized in presence of oxygen. In the case of H3PW12O40, no reduction is observed. In both cases, (29)Si solid-state NMR shows that the POM-silica bond is covalent, contrary to what was observed in homogeneous conditions.

3-Amino-5,6-dimethyl-1,2,4-triazin-2-ium nitrate.

In the title compound, C5H9N4 (+)·NO3 (-), the organic cations and the nitrate anions have both crystallographically imposed mirror symmetry and are linked via N-H⋯O hydrogen bonds, forming infinite chains running along the c-axis direction. The values of the N-O bond lengths [1.2256 (19)-1.2642 (18) Å] and O-N-O angles [118.39 (16)-121.64 (15)°] indicate that the nitrate anion exhibits a slightly distorted C3h geometry. The N atom of the NH2 group has sp (2) character.

4-Acetamido-anilinium nitrate monohydrate.

In the title hydrated salt, C(8)H(11)N(2)O(+)·NO(3) (-)·H(2)O, the N-C bond distances [1.349 (2) and 1.413 (2) Å] along with the sum of the angles (359.88°) around the acetamide N atom clearly indicate that the heteroatom has an sp(2) character. The ammonium group is involved in a total of three N-H⋯O hydrogen bonds, two of these are with a water mol-ecule, which forms two O-H⋯O hydrogen bonds. All these hydrogen bonds link the ionic units and the water mol-ecule into infinite planar layers parallel to (100). The remaining two N-H⋯O inter-actions in which the ammoniun group is involved link these layers into an infinite three-dimensional network.

Polyoxometalate grafting onto silica: stability diagrams of H3PMo12O40 on {001}, {101}, and {111} ß-cristobalite surfaces analyzed by DFT.

The process of grafting H(3)PMo(12)O(40) onto silica surfaces is studied using periodic density functional theory methods. For surfaces with a high hydroxyl coverage, the hydroxyl groups are consumed by the polyoxometalate protons, resulting in water formation and the creation of a covalent bond between the polyoxometalate and the surface, and mostly no remaining acidic proton on the polyoxometalate. When the surfaces are partially dehydroxylated and more hydrophobic, after temperature pretreatment, less covalent and hydrogen bonds are formed and the polyoxometalate tends to retain surface hydroxyl groups, while at least one acidic proton remains. Hence the hydroxylation of the surface has a great impact on the chemical properties of the grafted polyoxometalate. In return, the polyoxometalate species affects the compared stability of the partially hydroxylated silica surfaces in comparison with the bare silica case.

1-(2,5-Dimethyl-phen-yl)piperazine-1,4-diium tetra-chloridozincate monohydrate.

In the title compound, (C(12)H(20)N(2))[ZnCl(4)]·H(2)O, the two piperazine N atoms are protonated and the [ZnCl(4)](2-) anions adopt a slightly distorted tetra-hedral configuration. In the crystal, O-H⋯Cl hydrogen bonds link the tetra-chloridozincate anions and the water mol-ecules into corrugated inorganic chains parallel to [010]. The crystal structure is stabilized by N-H⋯Cl, N-H⋯O and O-H⋯Cl hydrogen bonds, with the N-H hydrogen bond originating from one of the two N atoms being trifurcated.

Bis(2-amino-1,3-benzothia-zol-3-ium) tetra-chloridozincate(II).

The asymmetric unit of the title compound, (C(7)H(7)N(2)S)(2)[ZnCl(4)], contains a network of 2-amino-benzothia-zolium cations and tetra-hedral [ZnCl(4)](2-) anions. The crystal packing is influenced by cation-to-anion N-H⋯Cl and C-H⋯Cl hydrogen bonds. The [ZnCl(4)](2-) anions have a distorded tetra-hedral geometry. Inter-molecular π-π stacking inter-actions are present between neighboring benzene rings, thia-zole and benzene rings and neighboring thia-zole rings [centroid-centroid distances = 3.711 (2), 3.554 (1), 3.536 (2) and 3.572 (1) Å].

Bis(4-methylbenzylammonium) tetrachloridozincate: a new noncentrosymmetric structure characterized by 13C CP-MAS NMR spectroscopy.

A new noncentrosymmetric organic-inorganic hybrid material, (C(8)H(12)N)(2)[ZnCl(4)], has been synthesized as single crystals at room temperature and characterized by X-ray diffraction and solid-state NMR spectroscopy. Its novel structure consists of two 4-methylbenzylammonium cations and one [ZnCl(4)](2-) anion connected by N-H···Cl and C-H···Cl hydrogen bonds, two of which are three-centre interactions. The Zn(II) metal centre has a slightly distorted tetrahedral coordination geometry. Results from (13)C CP-MAS NMR spectroscopy are in good agreement with the X-ray structure. Density functional theory calculations allow the assignment of the carbon peaks to the independent crystallographic sites.