A phase 2b, randomized, double-blind, placebo-controlled, clinical trial of atacicept for treatment of IgA nephropathy.

Atacicept is a first-in-class, dual anti-B-cell Activation Factor-A Proliferation-Inducing Ligand fusion protein in clinical evaluation for treatment of IgA nephropathy. To compare efficacy and safety of atacicept versus placebo in patients with IgAN, this randomized, double-blind, placebo-controlled phase 2b clinical trial ORIGIN enrolled 116 individuals with biopsy-proven IgA nephropathy. Participants were randomized to atacicept 150, 75, or 25 mg versus placebo once weekly for up to 36 weeks. Primary and key secondary endpoints were changes in urine protein creatinine ratio based on 24-hour urine collection at weeks 24 and 36, respectively, in the combined atacicept 150 mg and 75 mg group versus placebo. The primary endpoint was met at week 24 as the mean urine protein creatinine ratio was reduced from baseline by 31% in the combined atacicept group versus 8% with placebo, resulting in a significant 25% reduction with atacicept versus placebo. At week 36, the key secondary endpoint was met as the mean urine protein creatinine ratio reduced from baseline by 34% in the combined atacicept group versus a 2% increase with placebo, resulting in a significant 35% reduction with atacicept versus placebo. The reduction in proteinuria was accompanied by stabilization in endpoint eGFR with atacicept compared to a decline with placebo at week 36, resulting in significant between-group geometric mean difference of 11%, approximating an absolute difference of 5.7 mL/min/1.73m2. Endpoint galactose deficient IgA1 levels significantly decreased from baseline by 60% versus placebo. The safety profile of atacicept was like placebo. Thus, our results provide evidence to support a pivotal, phase 3 study of atacicept in IgA nephropathy.

Mechanics of two filaments in tight orthogonal contact.

Networks of flexible filaments often involve regions of tight contact. Predictively understanding the equilibrium configurations of these systems is challenging due to intricate couplings between topology, geometry, large nonlinear deformations, and friction. Here, we perform an in-depth study of a simple, yet canonical, problem that captures the essence of contact between filaments. In the orthogonal clasp, two filaments are brought into contact, with each centerline lying in one of a pair of orthogonal planes. Our data from X-ray tomography (µCT) and mechanical testing experiments are in excellent agreement with finite element method (FEM) simulations. Despite the apparent simplicity of the physical system, the data exhibit strikingly unintuitive behavior, even when the contact is frictionless. Specifically, we observe a curvilinear diamond-shaped ridge in the contact-pressure field between the two filaments, sometimes with an inner gap. When a relative displacement is imposed between the filaments, friction is activated, and a highly asymmetric pressure field develops. These findings contrast to the classic capstan analysis of a single filament wrapped around a rigid body. Both the µCT and FEM data indicate that the cross-sections of the filaments can deform significantly. Nonetheless, an idealized geometrical theory assuming undeformable tube cross-sections and neglecting elasticity rationalizes our observations qualitatively and highlights the central role of the small, but nonzero, tube radius of the filaments. We believe that our orthogonal clasp analysis provides a building block for future modeling efforts in frictional contact mechanics of more complex filamentary structures.

Formulation, Characterization and In Vitro Evaluation of Mesalamine and Bifidobacterium bifidum Loaded Hydrogel Beads in Capsule System for Colon Targeted Delivery.

Mesalamine is a first-line drug for the treatment of inflammatory bowel diseases. However, its premature release associated with marketed formulations leads to adverse effects like gastric trouble, vomiting, and diarrhoea. To minimize these side effects, colon-targeted drug delivery is essential. Besides conventional pharmacotherapy, bifidogenic probiotics with anti-inflammatory activity has been reported to elicit a significant impact on the remission of ulcerative colitis. Bifidogenic probiotics being acid-labile necessitate developing a gastro-resistant formulation for enhancing the delivery of viable cells to the colon. The present study was aimed at developing a fixed-dose unit dosage form of mucoadhesive hydrogel beads loaded with mesalamine and Bifidobacterium bifidum further encapsulated in Eudragit® capsules for the targeted drug delivery at colonic pH. The hydrogel beads were prepared by ionotropic gelation, with the effect of single and dual-crosslinking approaches on various formulation characteristics studied. Standard size 00 Eudragit® gastro-resistant capsules were prepared and the dried beads were filled inside the capsule shells. The formulation was then evaluated for various parameters, including physicochemical characterization, in vitro biocompatibility and anti-inflammatory activity. No interaction was observed between the drug and the polymers, as confirmed through FTIR, XRD, and DSC analysis. The mean particle size of the beads was ~ 457-485 µm. The optimized formulation showed a drug entrapment efficiency of 95.4 ± 2.58%. The Eudragit® capsule shells disintegrated in approximately 13 min at pH 7.4. The mucoadhesive hydrogel beads sustained the drug release above 18 h, with 50% of the drug released by the end of 12 h. The optimized formulation demonstrated significant (p < 0.05) gastro-resistance, biocompatibility, sustained drug release, cell viability, and anti-inflammatory activity.

Adhesion of a tape loop.

In this work, we revisit experimentally and theoretically the mechanics of a tape loop. Using primarily elastic materials (polydimethylsiloxane, PDMS, or polycarbonate, PC) and confocal microscopy, we monitor the shape as well as the applied forces during an entire cycle of compression and retraction of a half-loop compressed between parallel glass plates. We observe distinct differences in film shape during the cycle; points of equal applied force or equal plate separation differ in shape upon compression or retraction. To model the adhesion cycle in its entirety, we adapt the 'Sticky Elastica' of [T. J. W. Wagner et al., Soft Matter, 2013, 9, 1025-1030] to the tape loop geometry, which allows a complete analytical description of both the force balance and the film shape. We show that under compression the system is generally not sensitive to interfacial interactions, whereas in the limit of large separation of the confining parallel plates during retraction the system is well described by the peel model. Ultimately, we apply this understanding to the measurement of the energy release rate of a wide range of different cross-linker ratio PDMS elastomer half-loops in contact with glass. Finally, we show how the model illuminates an incredibly simple adhesion measurement technique, which only requires a ruler to perform.

Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia.

In preeclampsia, widespread maternal endothelial dysfunction is often secondary to excessive generation of placental-derived anti-angiogenic factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), along with proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) and activin A, understanding of which offers potential opportunities for the development of novel therapies. The antimalarial hydroxychloroquine is an anti-inflammatory drug improving endothelial homeostasis in lupus. It has not been explored as to whether it can improve placental and endothelial function in preeclampsia. In this in vitro study, term placental explants were used to assess the effects of hydroxychloroquine on placental production of sFlt-1, sEng, TNF-α, activin A, and 8-isoprostane after exposure to hypoxic injury or oxidative stress. Similarly, human umbilical vein endothelial cells (HUVECs) were used to assess the effects of hydroxychloroquine on in vitro markers of endothelial dysfunction. Hydroxychloroquine had no effect on the release of sFlt-1, sEng, TNF-α, activin A, or 8-isoprostane from placental explants exposed to hypoxic injury or oxidative stress. However, hydroxychloroquine mitigated TNF-α-induced HUVEC production of 8-isoprostane and Nicotinanamide adenine dinucleotide phosphate (NADPH) oxidase expression. Hydroxychloroquine also mitigated TNF-α and preeclamptic serum-induced HUVEC monolayer permeability and rescued the loss of zona occludens protein zona occludens 1 (ZO-1). Although hydroxychloroquine had no apparent effects on trophoblast function, it may be a useful endothelial protectant in women presenting with preeclampsia.

Effects of incorporation of groundnut oil and hydrogenated fat on pasting and dough rheological properties of flours from wheat varieties.

The effects of incorporation of groundnut oil (GO) and hydrogenated fat (HF) at different levels (1%, 3% and 5%) on pasting, dough rheology and mixing properties of strong wheat flour (SWF) and weak wheat flour (WWF) were evaluated. SWF showed higher paste viscosities as compared to WWF. However, higher setback viscosity for SWF than WWF was observed. Paste viscosity and mixograph peak time of both flours decreased with an increase in level of GO and HF. Pasting temperature of both flours decreased with an increase in GO. Storage modulus (G') was higher than loss modulus (G″) for dough from both SWF and WWF. G' increased while G″ decreased with an increase in levels of GO and HF. Dough prepared from SWF needed longer time for mixing and showed wider peak width, indicating strong and stable dough as compared to WWF. Addition of GO up to 3% level progressively decreased dough consistency and mixing tolerance and further addition led to an increase in both properties. Contrarily, addition of HF showed opposite effect in WWF. Both GO and HF showed variables effects towards mixing in both flour types. Dough tolerance and breakdown during mixing improved with increase in GO while adversely affected with increase in HF.

Formyl peptide receptor-2 is decreased in foetal growth restriction and contributes to placental dysfunction.

STUDY QUESTION: What is the association between placental formyl peptide receptor 2 (FPR2) and trophoblast and endothelial functions in pregnancies affected by foetal growth restriction (FGR)? SUMMARY ANSWER: Reduced FPR2 placental expression in idiopathic FGR results in significantly altered trophoblast differentiation and endothelial function in vitro. WHAT IS KNOWN ALREADY: FGR is associated with placental insufficiency, where defective trophoblast and endothelial functions contribute to reduced feto-placental growth. STUDY DESIGN, SIZE, DURATION: The expression of FPR2 in placental tissues from human pregnancies complicated with FGR was compared to that in gestation-matched uncomplicated control pregnancies (n = 25 from each group). Fpr2 expression was also determined in placental tissues obtained from a murine model of FGR (n = 4). The functional role of FPR2 in primary trophoblasts and endothelial cells in vitro was assessed in diverse assays in a time-dependent manner. PARTICIPANTS/MATERIALS, SETTING, METHODS: Placentae from third-trimester pregnancies complicated by idiopathic FGR (n = 25) and those from gestation-matched pregnancies with appropriately grown infants as controls (n = 25) were collected at gestation 27-40 weeks. Placental tissues were also collected from a spontaneous CBA/CaH × DBA/2 J murine model of FGR. Placental FPR2/Fpr2 mRNA expression was determined by real-time PCR, while protein expression was examined by immunoblotting and immunohistochemistry. siRNA transfection was used to silence FPR2 expression in primary trophoblasts and in human umbilical vein endothelial cells (HUVEC), and the quantitation of cytokines, chemokines and apoptosis was performed following a cDNA array analyses. Functional effects of trophoblast differentiation were measured using HCGB/ß-hCG and syncytin-2 expression as well as markers of apoptosis, tumour protein 53 (TP53), caspase 8, B cell lymphoma 2 (BCL2) and BCL associated X (BAX). Endothelial function was assessed by proliferation, network formation and permeability assays. MAIN RESULTS AND THE ROLE OF CHANCE: Placental FPR2/Fpr2 expression was significantly decreased in FGR placentae (n = 25, P < 0.05) as well as in murine FGR placentae compared to controls (n = 4, P < 0.05). FPR2 siRNA (siFPR2) in term trophoblasts significantly increased differentiation markers, HCGB and syncytin-2; cytokines, interleukin (IL)-6, CXCL8; and apoptotic markers, TP53, caspase 8 and BAX, but significantly reduced the expression of the chemokines CXCL12 and its receptors CXCR4 and CXCR7; CXCL16 and its receptor, CXCR6; and cytokine, IL-10, compared with control siRNA (siCONT). Treatment of HUVECs with siFPR2 significantly reduced proliferation and endothelial tube formation, but significantly increased permeability of HUVECs. LARGE SCALE DATA: N/A. LIMITATIONS, REASONS FOR CAUTION: Reduced expression of placental FPR2/Fpr2 was observed in the third trimester at delivery after development of FGR, suggesting that FPR2 is associated with FGR pregnancies. However, there is a possibility that the decreased placental FPR2 observed in FGR may be a consequence rather than a cause of FGR, although our in vitro functional analyses using primary trophoblasts and endothelial cells suggest that FPR2 may have a direct or indirect regulatory role on trophoblast differentiation and endothelial function in FGR. WIDER IMPLICATIONS OF THE FINDINGS: This is the first study linking placental FPR2 expression with changes in the trophoblast and endothelial functions that may explain the placental insufficiency observed in FGR. STUDY FUNDING/COMPETING INTERESTS: P.M. and P.R.E. received funding from the Australian Institute of Musculoskeletal Science, Western Health, St. Albans, Victoria 3021, Australia. M.L. is supported by a Career Development Fellowship from the National Health and Medical Research Council (NHMRC; Grant no. 1047025). Monash Health is supported by the Victorian Government's Operational Infrastructure Support Programme. The authors declare that there is no conflict of interest in publishing this work.

Humans adjust their grip force when passing an object according to the observed speed of the partner's reaching out movement.

The way an object is released by the passer to a partner is fundamental for the success of the handover and for the experienced fluency and quality of the interaction. Nonetheless, although its apparent simplicity, object handover involves a complex combination of predictive and reactive control mechanisms that were not fully investigated so far. Here, we show that passers use visual-feedback based anticipatory control to trigger the beginning of the release, to launch the appropriate motor program, and adapt such predictions to different speeds of the receiver's reaching out movements. In particular, the passer starts releasing the object in synchrony with the collision with the receiver, regardless of the receiver's speed, but the passer's speed of grip force release is correlated with receiver speed. When visual feedback is removed, the beginning of the passer's release is delayed proportionally with the receiver's reaching out speed; however, the correlation between the passer's peak rate of change of grip force is maintained. In a second study with 11 participants receiving an object from a robotic hand programmed to release following stereotypical biomimetic profiles, we found that handovers are experienced as more fluent when they exhibit more reactive release behaviours, shorter release durations, and shorter handover durations. The outcomes from the two studies contribute understanding of the roles of sensory input in the strategy that empower humans to perform smooth and safe handovers, and they suggest methods for programming controllers that would enable artificial hands to hand over objects with humans in an easy, natural and efficient way.

Maternal 25-hydroxyvitamin D is inversely correlated with foetal serotonin.

OBJECTIVE: Maternal vitamin D deficiency during pregnancy has been linked to impaired neurocognitive development in childhood. The mechanism by which vitamin D affects childhood neurocognition is unclear but may be via interactions with serotonin, a neurotransmitter involved in foetal brain development. In this study, we aimed to explore associations between maternal and foetal vitamin D concentrations, and foetal serotonin concentrations at term. STUDY DESIGN AND MEASUREMENTS: Serum 25-hydroxyvitamin D (25(OH)D, nmol/l) and serotonin (5-HT, nmol/l) concentrations were measured in maternal and umbilical cord blood from mother-infant pairs (n = 64). Association between maternal 25(OH)D, cord 25(OH)D and cord serotonin was explored using linear regression, before and after adjusting for maternal serotonin levels. We also assessed the effects of siRNA knockdown of the vitamin D receptor (VDR) and administration of 10 nm 1,25-dihydroxyvitamin D3 on serotonin secretion in human umbilical vein endothelial cells (HUVECs) in vitro. RESULTS: We observed an inverse relationship between both maternal and cord 25(OH)D concentrations with cord serotonin concentrations. The treatment of HUVECs with 1,25-dihydroxyvitamin D3 in vitro decreased the release of serotonin (193·9 ±14·8 nmol/l vs 458·9 ± 317·5 nmol/l, control, P < 0·05). Conversely, inactivation of VDR increased serotonin release in cultured HUVECs. CONCLUSIONS: These observations provide the first evidence of an inverse relationship between maternal 25(OH)D and foetal serotonin concentrations. We propose that maternal vitamin D deficiency increases foetal serotonin concentrations and thereby contributes to longer-term neurocognitive impairment in infants and children.

Multidimensional impact on families of children with steroid-sensitive nephrotic syndrome.

AIM: Children with nephrotic syndrome (NS) have prolonged disease course with relapses requiring frequent visits and prolonged steroid therapy with their long-term concerns. All these factors affect the child and their families in many domains of functioning. The objective of this study was to assess multidimensional impact on families of children with nephrotic syndrome using (PedsQL) Family Impact Module (FIM). METHODS: This cross-sectional study was conducted in a paediatric nephrology clinic of a tertiary care hospital. Fifty cases of steroid-sensitive nephrotic syndrome between age group of 2-18 years were included, and equal age-sex matched healthy children were taken as controls. Baseline demographic factors including age, gender and education status, modified Kuppuswamy's socio-economic status were collected and clinical variables of NS cases were recorded. FIM is a parent-reported instrument that measures the impact of paediatric chronic health conditions on care giver's HRQOL and their family function. Mean FIM scores were compared among the cases and controls, and different predictive factors affecting family impact (FI) were analysed. RESULTS: The FI total score showed significantly lower scores in cases (mean score: 60.76 ± 15.66) as compared to controls (mean 100). Among the individual groups, lowest scores were found in two domains, namely 'worry' and 'emotional function' with mean scores of 46.20 ± 20.66 and 46.80 ± 24.61, respectively, although other domains were also significantly affected. CONCLUSION: FI score should be evaluated in all cases of NS as parenting such children may significantly affect all domains of family functioning.

Effect of NSAIDs on Na⁺/H⁺ exchanger activity in rat colonic crypts.

Nonsteroidal anti-inflammatory drugs (NSAIDs; 1) are widely recommended for several acute and chronic conditions. For example, both indomethacin and aspirin are taken for pain relief. Aspirin is also used for prevention of myocardial infarction, and indomethacin can be administered orally or as a suppository for patients with rheumatoid disease and other chronic inflammatory states. However, use of NSAIDs can cause damage to the mucosal barrier surrounding the gastrointestinal (GI) tract, increasing the risk of ulcer formation. While microencapsulation of NSAIDs has been shown to reduce upper GI injury, sustained release in the lower GI tract and colon may cause epithelial erosion due to increased acidification. The use of suppositories has also been linked to rectal and lower GI bleeding. In this study, we investigated the role of NSAIDs aspirin and indomethacin on Na⁺/H⁺ exchanger (NHE) activity in rat colonic crypts. By comparing average rates of pH recovery between control and NSAID perfusion runs, we were able to determine that both aspirin and indomethacin increase hydrogen extrusion into the colonic lumen. Through treatment with 5-ethylisopropyl amiloride (EIPA), amiloride, and zoniporide dihydrochloride, we further demonstrated that indomethacin specifically enhances proton excretion through regulation of apical NHE-3 and NHE-2 and to a lesser extent on basolateral NHE-1 and NHE-4. Our results suggest that clinical exposure to NSAIDs may affect colonic tissue at the site of selected NHE isoforms, resulting in modulation of transport and barrier function.

A Ribbon Model for Nematic Polymer Networks.

We present a theory of deformation of ribbons made of nematic polymer networks (NPNs). These materials exhibit properties of rubber and nematic liquid crystals, and can be activated by external stimuli of heat and light. A two-dimensional energy for a sheet of such a material has already been derived from the celebrated neo-classical energy of nematic elastomers in three space dimensions. Here, we use a dimension reduction method to obtain the appropriate energy for a ribbon from the aforementioned sheet energy. We also present an illustrative example of a rectangular NPN ribbon that undergoes in-plane serpentine deformations upon activation under an appropriate set of boundary conditions.

Are we moving from symptomatic to asymptomatic syphilis: A retrospective analysis.

Background: Syphilis remains a global health problem with recent reports of resurgence from various parts of the world. We undertook this study to analyze the current epidemiological and clinical trends of syphilis in our part of the country. Aim and Objectives: To analyze the changing trends in clinical presentation of syphilis and the current status of HIV/AIDS-syphilis co-infection in our area. Materials and Methods: This is a hospital-based retrospective analysis of records of sexually transmitted disease (STD) patients enrolled in "Suraksha clinic" in the department of Skin and VD at a Tertiary Care Hospital in North India. Patient records were analyzed from January 2018 to December 2021. The demographic, clinical, and serological profiles of patients were assessed to study the percentage of syphilis patients attending the STD clinic and their clinical presentations. Results: A total of 7153 patients were enrolled in the"Suraksha clinic" from January 2018 to December 2021, these included the venereal disease patients (3137) and nonvenereal disease patients (4016) who were registered for HIV and venereal disease research laboratory (VDRL) screening from the dermatology outpatient department. Out of 3137 sexually transmitted infection (STI) patients, 139 patients tested positive for VDRL. Treponema pallidum hemagglutination was found positive in 137 patients and negative in two patients. Hence, 137 patients were confirmed syphilis cases, constituting 4.36% of total STD cases in our STI clinic in 4 years. Out of 137 patients, 2 (1.45%) presented with primary chancre, 6 (4.37%) with lesions of secondary syphilis and 129 (94.16%) were found serologically reactive without any symptoms or clinical signs, i.e., in latent syphilis. Our records also showed 14 (10.21%) cases of HIV and syphilis co-infection. Conclusion: In our study, a remarkable rise in the number of patients in the latent syphilis stage is observed over primary and secondary syphilis stage. This signifies the persistence of syphilis in subclinical phase in the community and unfortunately, it goes unnoticed. These could be "warning signs" for changing disease pattern of syphilis in India and points toward hidden resurgence of syphilis as being reported in various parts of the world. To actively look for these "hidden cases," there is a need to strengthen "Suraksha clinics." VDRL testing should be mandatory along with routine testing in all patients visiting the hospital irrespective of their disease. We also propose for the central registration of syphilis patients on lines of HIV-infected patients' registry.

Effect of Root Canal Taper on the Ability of Endodontically Treated Teeth using the TruNatomy and Protaper Next File Systems to Resist Fracture.

Objectives: This research was done to evaluate how the root canal taper affects the Endodontically Treated Teeth (ETT) prepared with the TruNatomy and Protaper Next file systems in terms of fracture resistance. Materials and Method: Forty recently extracted mandibular premolar teeth were used in this research, which was classified into four groups at random. Groups 1a and 1b used TruNatomy 4% and 6%, respectively, while groups 2a and 2b used the Protaper Next 4% and 6% file systems, respectively. The root canals were cleaned, shaped, and sealed using cold lateral compaction. The root canals were then fixed in standardized autopolymerizing acrylic resin blocks and tested for vertical root fracture using a universal testing machine. Newtons were used to measure the forces needed to cause fractures. Data were statistically analyzed. Results: In comparison with other groups, group 1a (TruNatomy 4%) displayed greater fracture resistance (423.322.43 Newtons), and group 2b (Protaper Next 6%) displayed the least fracture resistance (264.512.76 Newtons). Conclusion: Protaper Next file system had lower fracture resistance than TruNatomy file system. With the use of greater taper instruments, a notable decrease in the fracture resistance of ETT was observed.

Assessment of the Apical Transportation and Quantity of Root Canal Dentin Removed Using Different New Rotary File Systems: An Original Study.

Introduction: The rotary systems have found a common application in the clinical practice for the endodontic therapies. Hence, we compared three recent endodontic systems for the comparison of the dentine removal and the apical transportation particularly in the curved canals. Methods: Oneshape, Pro Taper Next, and Edgefile X3 were the three systems that were compared. Thirty maxillary mesio buccal canals of the human permanent teeth were compared due to its curved nature. The volume of dentin removed and apical transportation (mm) were measured using micro-computed tomographic imaging (mm). Both the coronal section and the entire canal length had their dentin removed in accordance with measurements. Total dentine removed, coronal dentine removed, and the canal transportations were compared for the three rotary file systems. The values were compared with appropriate statistical tests for evaluating the significance. Results: There was no statistically significant difference between the three file systems for the dentin removed. The mean canal transportation was 0.33 ± 0.12, 0.21 ± 0.25, and 0.23 ± 0.21 mm, respectively, for Oneshape, Pro Taper Next, and Typhoon CM. In terms of statistics, there were no appreciable variations among the three rotary tools for apical transfer. Conclusions: The three rotary systems were comparable for the apical transportation and the dentine removal. Despite variations in the magnitude of apical enlargements, none of the instrumentation methods detected apical transportation.

Identification and functional characterization of two novel mutations in the α-helical loop (residues 484-503) of CYBB/gp91(phox) resulting in the rare X91(+) variant of chronic granulomatous disease.

Chronic granulomatous disease (CGD) is mainly caused by mutations in X-linked CYBB that encodes gp91. We have identified two novel mutations in CYBB resulting in the rare X91(+)-CGD variant, c.1500T>G (p.Asp500Glu) in two male siblings and c.1463C>A (p.Ala488Asp) in an unrelated male. Zymosan and/or PMA (Phorbol 12-myristate 13-acetate)-induced recruitment of p47(phox) and p67(phox) to the membrane fraction was normal for both mutants. Cell-free assays using recombinant wild-type and the mutant proteins revealed that these mutants were not activated by NADPH (nicotinamide adenine dinucleotide phosphate). Interestingly, the Ala488Asp mutant was activated by NADPH in the presence of glutathione. These data suggest that the mutations prevented NADPH from binding to gp91(phox) and the requirement of a negative charge at residue 500 in gp91(phox) for NADPH oxidase assembly, in contrast to a previously described Asp500Gly change. These mutations and the effect of glutathione provide a unique insight into disease pathogenesis and potential therapy in variant X91(+)-CGD.

Proprotein convertases in post-menopausal endometrial cancer: distinctive regulation and non-invasive diagnosis.

Proprotein convertases (PCs) play critical roles in cleaving precursor proteins (growth factors, hormones, receptors and adhesion molecules) for activation. PCs are implicated in a number of cellular functions, including oncogenesis. Endometrial cancer is the most common gynecological cancer in the developed world, but the involvement of PCs is unclear. To characterize the role of PCs in endometrial cancer, we assessed expression of seven PCs (PC1/3, PC2, PACE4, PC4, furin, PC5/6 and PC7) by RT-PCR in six well characterized endometrial cancer cell lines. Expression was variable in all lines, with furin being most consistently expressed in all cell lines tested. We next determined the cellular localization and expression levels of four ubiquitously expressed PCs (furin, PACE4, PC5/6 and PC7) in post-menopausal endometrial biopsies from control (n=7) and endometrial cancer patients (n=30) by immunohistochemistry. Furin increased in tumors, whereas PC5/6, PACE4 and PC7 expression was reduced with increasing cancer grades. Uterine lavage is a non-invasive source material for evaluating the endometrium. We thus assessed whether total PC activity was altered in uterine lavage of endometrial cancer patients (n=36) compared to controls (n=10). PC activity was detected in all uterine lavage samples, and significantly elevated in all grades of endometrial cancer. This study demonstrates a complex association between individual PCs and endometrial cancer. Importantly, we show that monitoring the total PC activity in uterine lavage may provide a rapid and non-invasive method for the diagnosis of endometrial cancer in postmenopausal women.

Planar Equilibria of an Elastic Rod Wrapped Around a Circular Capstan.

We present a study on planar equilibria of a terminally loaded elastic rod wrapped around a rigid circular capstan. Both frictionless and frictional contact between the rod and the capstan are considered. We identify three cases of frictionless contact - namely where the rod touches the capstan at one point, along a continuous arc, and at two points. We show that, in contrast to a fully flexible filament, an elastic rod of finite length wrapped around a capstan does not require friction to support unequal loads at its two ends. Furthermore, we classify rod equilibria corresponding to the three aforementioned cases in a limit where the length of the rod is much larger than the radius of the capstan. In the same limit, we incorporate frictional interaction between the rod and the capstan, and compute limiting equilibria of the rod. Our solution to the frictional case fully generalizes the classic capstan problem to include the effects of finite thickness and bending elasticity of a flexible filament wrapped around a circular capstan. Supplementary Information: The online version contains supplementary material available at 10.1007/s10659-022-09939-8.