Using AI/ML to predict blending performance and process sensitivity for Continuous Direct Compression (CDC).

Utilising three artificial intelligence (AI)/machine learning (ML) tools, this study explores the prediction of fill level in inclined linear blenders at steady state by mapping a wide range of bulk powder characteristics to processing parameters. Predicting fill levels enables the calculation of blade passes (strain), known from existing literature to enhance content uniformity. We present and train three AI/ML models, each demonstrating unique predictive capabilities for fill level. These models collectively identify the following rank order of feature importance: RPM, Mixing Blade Region (MB) size, Wall Friction Angle (WFA), and Feed Rate (FR). Random Forest Regression, a machine learning algorithm that constructs a multitude of decision trees at training time and outputs the mode of the classes (classification) or mean prediction (regression) of the individual trees, develops a series of individually useful decision trees. but also allows the extraction of logic and breakpoints within the data. A novel tool which utilises smart optimisation and symbolic regression to model complex systems into simple, closed-form equations, is used to build an accurate reduced-order model. Finally, an Artificial Neural Network (ANN), though less interrogable emerges as the most accurate fill level predictor, with an r2 value of 0.97. Following training on single-component mixtures, the models are tested with a four-component powdered paracetamol formulation, mimicking an existing commercial drug product. The ANN predicts the fill level of this formulation at three RPMs (250, 350 and 450) with a mean absolute error of 1.4%. Ultimately, the modelling tools showcase a framework to better understand the interaction between process and formulation. The result of this allows for a first-time-right approach for formulation development whilst gaining process understanding from fewer experiments. Resulting in the ability to approach risk during product development whilst gaining a greater holistic understanding of the processing environment of the desired formulation.

The association of multiple sclerosis, traumatic brain injury, and spinal cord injury to acute and long COVID-19 outcomes.

BACKGROUND: Although persons with disabilities are a high-risk group, little is known about the association between specific disabling conditions and acute or long COVID outcomes. OBJECTIVE: To examine the severity of acute SARS-CoV-2 infection and post-COVID outcomes among people with a preexisting diagnosis of multiple sclerosis (MS), spinal cord injury (SCI), or traumatic brain injury (TBI). METHODS: This was a retrospective cohort study using the TrinetX Research Database, a large representative database of medical records. COVID-19-positive persons with MS, SCI, or TBI (cases) were matched 1:1 on age, gender, race, ethnicity, and comorbidities to COVID-19-positive persons without these diagnoses (controls). The main outcomes assessed were hospitalization for acute COVID-19, length of stay (LOS), the total number of hospitalizations, mortality, and incidence of six prevalent post-COVID sequelae within 6 months following a COVID-19 diagnosis. RESULTS: There were 388,297 laboratory-confirmed COVID-19 cases identified. Of these cases, 2204 individuals had one of the following preexisting diagnoses: 51.3% TBI, 31.4% MS, and 17.3% SCI. People with TBI, MS, and SCI were significantly more likely to be hospitalized for COVID-19 (odds ratio [OR] = 1.22, 95% confidence interval [CI] = 1.03-1.46) than matched controls. There was no difference in LOS, total hospitalizations, or mortality during the 6 months following the initial COVID diagnosis. Multivariable analyses reveal that persons with TBI, MS, and SCI were more likely to experience new weakness (OR = 1.54, 95% CI = 1.19-2.00), mobility difficulties (OR = 1.66, 95% CI = 1.17-2.35), and cognitive dysfunction (OR = 1.79, 95% CI = 1.38-2.33) than controls, even after controlling for the presence of these symptoms prior to their COVID infection and other risk factors. There were no differences in fatigue, pain, or dyspnea. CONCLUSIONS: Having a history of MS, SCI or TBI was not associated with higher mortality risk from COVID-19. However, associations between these diagnoses and postacute COVID-19 symptoms raise concern about widening health outcome disparities for individuals with such potentially disabling conditions following COVID-19 infection.

Application of Positron Emission Particle Tracking (PEPT) for the evaluation of powder behaviour in an incline linear blender for Continuous Direct Compression (CDC).

Positron Emission Particle Tracking (PEPT) is a non-invasive measurement technique which offers the ability to track the motion of individual particles with high temporal and spatial resolution, and thus build up an understanding of the bulk behaviour of a system from its microscopic (particle level) dynamics. Using this measurement technique, we have developed a series of novel metrics to better understand the behaviours of powders during the steady-state operation of a continuous blender system. Results are presented concerning the response of particle motion to processing parameters (mixing blade configuration and RPM), quantifying the motion in terms of predicted mixing performance. It was found that both increasing rpm and increasing hold-up mass (by selecting fewer transport blades and more mixing blades) provided improved mixing conditions. Interestingly, under specific conditions, there is evidence of convection-like mixing occurring at the interface of the transport and mixing region. This suggests the existence of a potential 'folding region' whereby powder is transported up the barrel (and away from the powder bulk bed) before being reconstituted back into the bulk mass. The results also provide valuable experimental data for the development, calibration and validation of future Discrete Element Method (DEM) simulations.

A synopsis of global frontiers in fertility preservation.

Since 2007, the Oncofertility Consortium Annual Conference has brought together a diverse network of individuals from a wide range of backgrounds and professional levels to disseminate emerging basic and clinical research findings in fertility preservation. This network also developed enduring educational materials to accelerate the pace and quality of field-wide scientific communication. Between 2007 and 2019, the Oncofertility Consortium Annual Conference was held as an in-person event in Chicago, IL. The conference attracted approximately 250 attendees each year representing 20 countries around the world. In 2020, however, the COVID-19 pandemic disrupted this paradigm and precluded an in-person meeting. Nevertheless, there remained an undeniable demand for the oncofertility community to convene. To maintain the momentum of the field, the Oncofertility Consortium hosted a day-long virtual meeting on March 5, 2021, with the theme of "Oncofertility Around the Globe" to highlight the diversity of clinical care and translational research that is ongoing around the world in this discipline. This virtual meeting was hosted using the vFairs ® conference platform and allowed over 700 people to participate, many of whom were first-time conference attendees. The agenda featured concurrent sessions from presenters in six continents which provided attendees a complete overview of the field and furthered our mission to create a global community of oncofertility practice. This paper provides a synopsis of talks delivered at this event and highlights the new advances and frontiers in the fields of oncofertility and fertility preservation around the globe from clinical practice and patient-centered efforts to translational research.

Positron Emission Particle Tracking of Granular Flows.

Positron emission particle tracking (PEPT) is a noninvasive technique capable of imaging the three-dimensional dynamics of a wide variety of powders, particles, grains, and/or fluids. The PEPT technique can track the motion of particles with high temporal and spatial resolution and can be used to study various phenomena in systems spanning a broad range of scales, geometries, and physical states. We provide an introduction to the PEPT technique, an overview of its fundamental principles and operation, and a brief review of its application to a diverse range of scientific and industrial systems.

Giant visible and infrared light attenuation effect in nanostructured narrow-bandgap glasses.

A unique effect of Bi on the optical and electrical properties of mixed Ga-containing Ge-Se and Ge-Te glasses is discovered. It is shown that glass with a low Bi content is completely transparent in a 3-16 µm spectral range, while the glass with a slightly higher Bi content possesses a large (>10 db/mm) attenuation coefficient, making a ∼millimeter thick glass sample fully opaque to VIS-IR radiation. Despite this contrast, both types of glass are found to retain their semiconducting properties, the DC conductivity at room temperature, σDC∼10-3 S/m, being comparable to that of silicon.

Free-Volume Nanostructurization in Ga-Modified As2Se3 Glass.

Different stages of intrinsic nanostructurization related to evolution of free-volume voids, including phase separation, crystalline nuclei precipitation, and growth, were studied in glassy As2Se3 doped with Ga up to 5 at. %, using complementary techniques of positron annihilation lifetime spectroscopy, X-ray powder diffraction, and scanning electron microscopy with energy-dispersive X-ray analysis. Positron lifetime spectra reconstructed in terms of a two-state trapping model testified in favor of a native void structure of g-As2Se3 modified by Ga additions. Under small Ga content (below 3 at. %), the positron trapping in glassy alloys was dominated by voids associated with bond-free solid angles of bridging As2Se4/2 units. This void agglomeration trend was changed on fragmentation with further Ga doping due to crystalline Ga2Se3 nuclei precipitation and growth, these changes being activated by employing free volume from just attached As-rich glassy matrix with higher content of As2Se4/2 clusters. Respectively, the positron trapping on free-volume voids related to pyramidal AsSe3/2 units (like in parent As2Se3 glass) was in obvious preference in such glassy crystalline alloys.

Positron annihilation lifetime study of polyvinylpyrrolidone for nanoparticle-stabilizing pharmaceuticals.

Positron annihilation lifetime spectroscopy was applied to characterize free-volume structure of polyvinylpyrrolidone used as nonionic stabilizer in the production of many nanocomposite pharmaceuticals. The polymer samples with an average molecular weight of 40,000 g mol(-1) were pelletized in a single-punch tableting machine under an applied pressure of 0.7 GPa. Strong mixing in channels of positron and positronium trapping were revealed in the polyvinylpyrrolidone pellets. The positron lifetime spectra accumulated under normal measuring statistics were analysed in terms of unconstrained three- and four-term decomposition, the latter being also realized under fixed 0.125 ns lifetime proper to para-positronium self-annihilation in a vacuum. It was shown that average positron lifetime extracted from each decomposition was primary defined by long-lived ortho-positronium component. The positron lifetime spectra treated within unconstrained three-term fitting were in obvious preference, giving third positron lifetime dominated by ortho-positronium pick-off annihilation in a polymer matrix. This fitting procedure was most meaningful, when analysing expected positron trapping sites in polyvinylpyrrolidone-stabilized nanocomposite pharmaceuticals.

Evaluating the impact of summer vacation on the visual acuity of AMD patients treated with ranibizumab.

PURPOSE: To evaluate the impact of traditional French summer vacation on visual acuity and spectral domain-optical coherence tomography (SD-OCT) of Wet AMD patients being treated with intravitreal Ranibizumab. METHODS: This was a consecutive, comparative, single-centre, prospective analysis. All patients who were being treated with intravitreal injection of 0.5 mg ranibizumab at Cergy Pontoise Hospital, Department of Ophthalmology between July 2013 and September 2014 were included. Patients were divided into two groups: (A) patients who skipped one ranibizumab intravitreal injection during holidays, and (B) patients who received injection during their holidays. Evaluations occurred prior to traditional holiday (baseline) and 2 months later, consisting of BCVA using ETDRS, and a complete ophthalmic examination that included slit-lamp biomicroscopy, fundus examination, fluorescein angiography (FA), indocyanine green angiography (ICGA), and spectral domain-optical coherence tomography (SD-OCT). All patients were being treated with PRN anti-VEGF regimen and criteria for reinjection included a visual acuity loss >5 ETDRS letters and/or an increase of central retinal thickness, presence of subretinal fluid, intraretinal fluid, or pigment epithelium detachment. If reinjection criteria were not met, patients were advised to return in 4 weeks. RESULTS: The mean visual acuity change was -0.071 ± 0.149 (LogMAR) in group A and + 0.003 ± 0.178 in group B (P = 0.041). At the second visit (2 months after preholidays visit), 61.8% of patients in group A had SRF and/or intraretinal cysts, and only 27.6% of patients in group B. There was a significant difference in the persistence of fluid between the two groups (P = 0.007, χ(2)-test). CONCLUSION: This cases series demonstrated the detrimental impact of holidays on visual acuity in patients treated with ranibizumab for AMD, which, in spite of their treatment regimen, still leave in vacation. Therefore, it is important to convey the message of treatment adherence to patients, despite their need of holidays.

Influence of phase separation on the devitrification of 45S5 bioglass.

The devitrification of the 45S5 variety of bioactive glasses (BGs) in relation to phase separation is studied with scanning electron microscopy, X-ray powder diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry and positron annihilation lifetime spectroscopy techniques. It is shown that the type of phase separation (such as spinodal vs. droplet-like) has a pronounced effect on the activation energy of viscous flow and crystallization, the onset temperature of crystallization and the void size distribution at the nanoscale. Generally, the Johnson-Mehl-Avrami (JMA) relation does not describe crystallization kinetics in bulk 45S5 BG. However, for powder samples (<300 µm) the difference in crystallization kinetics, which is surface-driven for the two kinds of glasses, becomes much smaller, and can be described with the JMA relation under some circumstances.

Caveolin-1 deficiency protects against mesangial matrix expansion in a mouse model of type 1 diabetic nephropathy.

AIMS/HYPOTHESIS: Glomerular matrix protein accumulation, mediated largely by resident mesangial cells (MCs), is central to the pathogenesis of diabetic nephropathy. We previously showed that caveolin (CAV)-1/caveolae mediate matrix upregulation by MCs in response to high glucose and TGFß, two important pathogenic mediators of diabetic glomerular sclerosis. Here, we evaluated the in vivo role of CAV-1/caveolae in the development of diabetic nephropathy. METHODS: Diabetes was induced in Cav1-knockout (KO) mice and their wild-type (WT) counterparts by streptozotocin injection. After 10 months, kidneys were evaluated for the development of nephropathy, including glomerular sclerosis and upregulation of matrix proteins. Parallel experiments assessing glucose-induced matrix upregulation were carried out in MCs isolated from KO mice. RESULTS: KO diabetic mice developed hyperglycaemia and renal hypertrophy, but were protected from developing albuminuria and glomerular sclerosis compared with WT mice. KO mice were significantly protected from the upregulation of glomerular collagen I, fibronectin, connective tissue growth factor (CTGF) and TGFß. In vitro, glucose induced collagen I A1 promoter activation and collagen I, fibronectin and CTGF protein upregulation in WT but not KO MCs. Re-expression of Cav1 in KO cells restored this response. CONCLUSIONS/INTERPRETATION: Cav1 deletion rendered significant protection from glomerular matrix accumulation and albuminuria in a mouse model of type 1 diabetes. These studies provide a foundation for the development of renal-targeted interference with CAV-1/caveolae as a novel approach to the treatment of diabetic nephropathy.

Application of Positron Emission Particle Tracking (PEPT) to validate a Discrete Element Method (DEM) model of granular flow and mixing in the Turbula mixer.

The laboratory-scale Turbula mixer comprises a simple cylindrical vessel that moves with a complex, yet periodic 3D motion comprising of rotation, translation and inversion. Arising from this complexity, relatively few studies to obtain fundamental understanding of particle motion and mixing mechanisms have been reported. Particle motion within a cylindrical vessel of a Turbula mixer has been measured for 2mm glass spheres using Positron Emission Particle Tracking (PEPT) in a 2l blending mixing vessel at 50% fill level. These data are compared to results from Discrete Element Method (DEM) simulations previously published by the authors. PEPT mixing experiments, using a single particle tracer, gave qualitatively similar trends to the DEM predictions for axial and radial dispersion as well as for the axial displacement statistics at different operational speeds. Both experimental and simulation results indicate a minimum mixing efficiency at ca. 46 rpm. The occupancy plots also show a non-linear relationship with the operating speed. These results add further evidence to a transition between two flow and mixing regimes. Despite the similarity in overall flow and mixing behaviour measured and predicted, including the mixing speed at which the flow behaviour transition occurs, a systematic offset between measured and predicted result is observed.

Posterior to the ridge laser treatment for severe stage 3 retinopathy of prematurity.

BACKGROUND: Current methods of treating the avascular retina with laser photocoagulation for severe retinopathy of prematurity (ROP) are not completely effective in the reduction of visual morbidity. We report a case series in which additional laser treatment, called 'posterior laser', was delivered posterior to the neovascular ridge, for eyes with severe stage 3 ROP in zone II with avascular retina posterior to the ridge. DESIGN: Retrospective chart review. PARTICIPANTS: Infants who underwent laser treatment, posterior to the neovascular ridge for severe ROP at the Alberta Children's Hospital, between January 2005 and October 2008. METHODS: Charts were reviewed for 18 eyes of 11 patients and collected information included demographic data, clinical examination results, and digital retinal images. MAIN OUTCOME MEASURES: Structural and functional outcomes of treatment. RESULTS: Four (22%) of 18 eyes received 'posterior laser' as primary treatment and the remainder of eyes (78%) received 'posterior laser' following previous laser photocoagulation anterior to the neovascular ridge. Mean birthweight was 688 g (552-930) and mean gestational age was 24 weeks (23-28). There were no complications because of the posterior laser treatment. In all, 16 of 18 eyes experienced rapid regression of the ridge and subsequent decrease in vascular dilation and tortuosity within 1 week. Two eyes required vitrectomy for 4A retinal detachment; however, no eyes developed stage 4B ROP. CONCLUSION: Posterior to the ridge laser in the setting of the morphological criteria described had no increased safety concerns and resulted in rapid regression of ROP with good outcomes.

High glucose-induced RhoA activation requires caveolae and PKCß1-mediated ROS generation.

Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We previously showed that RhoA activation by high glucose in mesangial cells (MC) leads to matrix upregulation (Peng F, Wu D, Gao B, Ingram AJ, Zhang B, Chorneyko K, McKenzie R, Krepinsky JC. Diabetes 57: 1683-1692, 2008). Here, we study the mechanism whereby RhoA is activated. In primary rat MC, RhoA activation required glucose entry and metabolism. Broad PKC inhibitors (PMA, bisindolylmaleimide, Gö6976), as well as specific PKCß blockade with an inhibitor and small interfering RNA (siRNA), prevented RhoA activation by glucose. PKCß inhibition also abrogated reactive oxygen species (ROS) generation by glucose. The ROS scavenger N-acetylcysteine (NAC) or NADPH oxidase inhibitors apocynin and DPI prevented glucose-induced RhoA activation. RhoA and some PKC isoforms localize to caveolae. Chemical disruption of these microdomains prevented RhoA and PKCß1 activation by glucose. In caveolin-1 knockout cells, glucose did not induce RhoA and PKCß1 activation; these responses were rescued by caveolin-1 reexpression. Furthermore, glucose-induced ROS generation was significantly attenuated by chemical disruption of caveolae and in knockout cells. Downstream of RhoA signaling, activator protein-1 (AP-1) activation was also inhibited by disrupting caveolae, was absent in caveolin-1 knockout MC and rescued by caveolin-1 reexpression. Finally, transforming growth factor (TGF)-ß1 upregulation, mediated by AP-1, was prevented by RhoA signaling inhibition and by disruption or absence of caveolae. In conclusion, RhoA activation by glucose is dependent on PKCß1-induced ROS generation, most likely through NADPH oxidase. The activation of PKCß1 and its downstream effects, including upregulation of TGF-ß1, requires caveolae. These microdomains are thus important mediators of the profibrogenic process associated with diabetic nephropathy.

HB-EGF release mediates glucose-induced activation of the epidermal growth factor receptor in mesangial cells.

Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We showed that transactivation of the epidermal growth factor receptor (EGFR) is an important mediator of matrix upregulation in mesangial cells (MC) in response to high glucose (HG). Here, we study the mechanism of EGFR transactivation. In primary MC, EGFR transactivation by 1 h of HG (30 mM) was unaffected by inhibitors of protein kinase C, reactive oxygen species, or the angiotensin II AT1 receptor. However, general metalloprotease inhibition, as well as specific inhibitors of heparin-binding EGF-like growth factor (HB-EGF), prevented both EGFR and downstream Akt activation. HB-EGF was released into the medium by 30 min of HG, and this depended on metalloprotease activity. One of the metalloproteases shown to cleave proHB-EGF is ADAM17 (TACE). HG, but not an osmotic control, activated ADAM17, and its inhibition prevented EGFR and Akt activation and HB-EGF release into the medium. siRNA to either ADAM17 or HB-EGF prevented HG-induced EGFR transactivation. We previously showed that EGFR/Akt signaling increases transforming growth factor (TGF)-ß1 transcription through the transcription factor activator protein (AP)-1. HG-induced AP-1 activation, as assessed by EMSA, was abrogated by inhibitors of metalloproteases, HB-EGF and ADAM17. HB-EGF and ADAM17 siRNA also prevented AP-1 activation. Finally, these inhibitors and siRNA prevented TGF-ß1 upregulation by HG. Thus, HG-induced EGFR transactivation in MC is mediated by the release of HB-EGF, which requires activity of the metalloprotease ADAM17. The mechanism of ADAM17 activation awaits identification. Targeting upstream mediators of EGFR transactivation including HB-EGF or ADAM17 provides novel therapeutic targets for the treatment of diabetic nephropathy.

Structural origin of the green iridescence on the chelicerae of the red-backed jumping spider, Phidippus johnsoni (Salticidae: Araneae).

The structurally coloured chelicerae of jumping spiders (Salticidae) display some of the most striking of all colours in this family, in which they predominantly occur. Remarkably, however, the source of this iridescence has not been studied. For this reason, we chose to investigate the green iridescent chelicerae of the red-backed jumping spider, Phidippus johnsoni. The colour is restricted to the dorsal region of the basal chelicera segment--the paturon. This was confirmed by reflectance measurements taken at normal incidence and in backscatter, which gave a peak reflectance in the green (520 nm), arising from the first harmonic of a Bragg resonance in the near infrared. Transmission electron microscope analysis of the paturon cuticle revealed a stack of 86 layers of alternating low and high density materials, identified as air and chitin respectively. Simulations based on a periodic multilayer model of the ten outermost layers of this structure gave theoretical reflectance spectra, closely matching those observed, suggesting that the stack functions as a multilayer reflector for green. The colour is thought to function as a conspecific signal, since studies of vision in a closely related species, also displaying green chelicerae, have shown that the eyes have a peak spectral sensitivity, matching that of the chelicerae.

Clinical and cost effectiveness evaluation of low friction and shear garments.

OBJECTIVE: To determine the effectiveness of Parafricta low-friction garments in reducing the incidence and prevalence of pressure ulceration and to evaluate the curative aspects of these products on pre-existing skin breakdown within a hospital setting. METHOD: Patients with a Waterlow score of >15 and who were unable to reposition independently were offered the low-friction undergarments and bootees. A total of 650 patient cases were initially reviewed. Of these, 204 met the criteria for use of the products in the 3 months prior to the start of the evaluation (cohort 1) and 165 patients met the criteria during the period when the garments were used (cohort 2). Data collected included pressure ulcer incidence, location, grading, and outcome of ulcer on discharge. Locally derived costs for length of stay, wound dressings, pressure-redistributing mattresses and additional cost of the low-friction garments were applied to build a cost-effectiveness model. RESULTS: In patients at risk of skin breakdown there was a statistically significant reduction in the number of patients who developed pressure ulcers following use of the low-friction garments in cohort 2 when compared with cohort 1 (16% reduction; p = 0.0286). In addition, the number of patients who were ulcer free on admission but who developed ulcers and then improved or completely healed before discharge was also statistically significant (41% increase; p = 0.0065) when cohort 2 was compared with cohort 1. Fewer patients admitted with ulcers deteriorated when using the low-friction garments (21% reduction; p = 0.0012). The costs, which were calculated by comparing patient throughput for these patients, suggest that the savings associated with preventing skin breakdown outweighed the cost of the products used (base case model indicated a saving of over £63,000 per 100 at risk patients). CONCLUSION: The results support the conclusion that low-friction garment products have a role to play in the prevention of skin breakdown, and appear to be both clinically effective and cost effective. DECLARATION OF INTEREST: The authors have no conflicts of interest to declare. APA Parafricta provided the products, as well as financial support for training of the ward staff who participated in the evaluation and for the data collection and analysis (which was performed by Xcelerate Health Outcomes Unit, NHS Innovations London).

EGFR-PLCgamma1 signaling mediates high glucose-induced PKCbeta1-Akt activation and collagen I upregulation in mesangial cells.

Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We have recently shown that epidermal growth factor receptor (EGFR) transactivation mediates high glucose (HG)-induced collagen I upregulation through PI3K-PKCbeta1-Akt signaling in mesangial cells (MC). Phospholipase Cgamma1 (PLCgamma1) interacts with activated growth factor receptors and activates classic PKC isoforms. We thus studied its role in HG-induced collagen I upregulation in MC. Primary rat MC were treated with HG (30 mM) or mannitol as osmotic control. Protein kinase activation was assessed by Western blotting and collagen I upregulation by Northern blotting. Diabetes was induced in rats by streptozotocin. HG treatment for 1 h led to PLCgamma1 membrane translocation and Y783 phosphorylation, both indicative of its activation. Mannitol was without effect. PLCgamma1 Y783 phosphorylation was also seen in cortex and glomeruli of diabetic rats. HG induced a physical association between EGFR and PLCgamma1 as identified by coimmunoprecipitation. PLCgamma1 activation required EGFR kinase activity since it was prevented by the EGFR inhibitor AG1478 or overexpression of kinase-inactive EGFR (K721A). Phosphoinositide-3-OH kinase inhibition also prevented PLCgamma1 activation. HG-induced Akt S473 phosphorylation, effected by PKCbeta1, was inhibited by the PLCgamma inhibitor U73122. PLCgamma1 inhibition or downregulation by small interference RNA also prevented HG-induced collagen I upregulation. Our results indicate that EGFR-PLCgamma1 signaling mediates HG-induced PKCbeta1-Akt activation and subsequent collagen I upregulation in MC. Inhibition of EGFR or PLCgamma1 may provide attractive therapeutic targets for the treatment of diabetic nephropathy.