The Midfoot Joint Complex (Foot Arch) Contributes to the Upper Body Position in Bipedal Walking and Coordinates With the Lower Limb Joints.

This study estimated the contribution of the midfoot joint complex (MJC) kinematics to the pelvis anterior-posterior positions during the stance phase of walking and investigated whether the MJC is functionally coordinated with the lower limb joints to maintain similar pelvic positions across steps. Hip, knee, ankle, and MJC sagittal angles were measured in 11 nondisabled participants during walking. The joints' contributions to pelvic positions were computed through equations derived from a link-segment model. Functional coordination across steps was identified when the MJC contribution to pelvic position varied and the summed contributions of other joints varied in the opposite direction (strong negative covariations [r ≤ -.7] in stance phase instants). We observed that the MJC plantarflexion (arch raising) during the midstance and late stance leads the pelvis backward, avoiding excessive forward displacement. The MJC was the second joint that contributed most to the pelvis positions (around 18% of all joints' contributions), after the ankle joint. The MJC and ankle were the joints that were most frequently coordinated with the other joints (≅70% of the stance phase duration). The findings suggest that the MJC is part of the kinematic chain that determines pelvis positions during walking and is functionally coordinated with the lower limb joints.

Unveiling metabolic changes in marsupialized odontogenic keratocyst: A pilot study.

OBJECTIVE: We aimed to assess which metabolic pathways would be implicated in the phenotypic changes of the epithelial lining of odontogenic keratocyst after marsupialization, comparing pre- and post-marsupialized lesions with adjacent oral mucosa. MATERIALS AND METHODS: Eighteen formalin-fixed and paraffin-embedded tissues from six subjects were divided into three paired groups: odontogenic keratocyst pre- (n = 6) and post-marsupialization (n = 6), and adjacent oral mucosa (n = 6). The metabolic pathways found in these groups were obtained by high-performance liquid chromatography-mass spectrometry-based untargeted metabolomics performed. RESULTS: Through putative metabolite annotation followed by pathway enrichment and predictive analysis with automated algorithms (Mummichog and Gene Set Enrichment Analysis), we found differences in many cellular processes that may be involved in inflammation, oxidative stress response, keratinocyte-basal membrane attachment, differentiation, and proliferation functions, all relevant to odontogenic keratocyst pathobiology and the phenotype acquired after marsupialization. CONCLUSION: Our study was able to identify several metabolic pathways potentially involved in the metaplastic changes induced by marsupialization of odontogenic keratocysts. An improved comprehension of this process could pave the way for the development of targeted therapies.

Total Testosterone and Cortisol During Wheelchair Rugby Training in Athletes With Cervical Spinal Cord Injury.

CONTEXT: Hormonal assessment in the sport context is important to monitor the physiological adaptations of athletes. However, Paralympic athletes, especially with cervical spinal cord injury (CSCI), may have different hormonal responses than nondisabled athletes. Therefore, the aim of this study was to evaluate the blood concentrations of total testosterone (TT) and cortisol (C) during acute (one training session) and chronic (1 and 2 month) training of athletes with CSCI in wheelchair rugby (WCR). DESIGN: Longitudinal and observational study. METHODS: Eight high-performance athletes with CSCI (31 [3.9] y; 75.6 [15.8] kg; 22.9 [4.2] kg/m2 body mass index; 6.2 [2] y of experience in sport) were evaluated at 3 different intervals (evaluations 1, 2, and 3 [E1, E2, and E3]) over 2 months of training. TT and C blood were evaluated before (pre) and after (post) the training sessions at each training moment, as well as the training load through the ratings of perceived exertion. RESULTS: Athletes with CSCI had low TT concentrations. In acute training sessions, at E3, C decreases after the training session, unlike the TT/C ratio, which increased after the session. Regarding hormonal changes during chronic training at the end of the training period, unlike C, which increased. The training load (arbitrary units) decreased in E3 when compared with the other evaluation moments. CONCLUSION: It was concluded that in chronic training, TT concentrations decreased, while C increased at the end of the 2 months of training. These results may indicate that training volume was high throughout training and that a reduction in training volume could benefit athletes. On the other hand, in the acute training session with reduced training load, a decrease in C was observed after the training session. This indicates that athletes may be well recovered in this training session. Therefore, we suggest acute and long-term hormonal assessment for athletes with CSCI as a strategy to monitor anabolic/catabolic hormonal status during WCR training.

The effects of using hearing aids and a frequency modulated system on listening effort among adolescents with hearing loss.

Objective: To develop a web-based application for a colour pattern memory recognition task as the secondary task of a dual-task paradigm and to compare the listening effort required by adolescents with hearing loss (HL) under two conditions (HA and HA + FM system), to adolescents with normal hearing (NH).Design: Cohort study. The participants underwent a dual-task paradigm, including the Hearing in Noise Test as the primary task and a colour memory task as the secondary task. A platform, PALETA, was developed to assess the secondary task.Study sample: In total, 31 adolescents were enrolled, of which 13 adolescents had HL and 18 adolescents had NH (mean age, 14 years).Results: Adolescents with NH scored significantly better on the secondary task compared to participants with HL using a HA. However, on analysing response time, no significant differences were observed among the groups.Conclusion: PALETA is proposed as a test procedure for the secondary task. The results revealed that the use of an FM system reduces the listening effort that adolescents with HL deploy to recognise speech in noise, and that listening effort data by number of correct responses is a way of investigating the benefits of using FM system.

Dental Implants in Patients with Oral Lichen Planus: A Systematic Review.

Background and Objectives: To integrate the available published data on patients with oral lichen planus (OLP) rehabilitated with dental implants, as well as to review the recommendations for OLP patients receiving implants. Materials and Methods: An electronic search was undertaken in February 2019 using five databases. Publications reporting cases of patients with OLP and rehabilitated with implant-supported oral prosthesis were included. Results: Twenty-two publications were included (230 patients, 615 implants). The overall implant failure rate was 13.9% (85/610). In patients with oral squamous cell carcinoma (OSCC) the failure rate was 90.6% (29/32), but none of these implants lost osseointegration; instead, the implants were removed together with the tumor. One study presented a very high implant failure rate, 76.4% (42/55), in patients with "active lichen planus", with all implants failing between 7-16 weeks after implant placement, and its conflicting and incongruent results are discussed in detail. There was a statistically significant difference between the failure rates in implants installed in different jaws (maxilla/mandible) and when implants of different surfaces were used (turned/moderately rough), but not between patients with reticular or erosive OLP types, or between male and female patients. If OSCC patients and the cases of the latter study are not considered, then the failure rate becomes very low (2.7%, 14/523). The time between implant placement and failure was 25.4 ± 32.6 months (range 1-112). The mean ± SD follow-up was 58.9 ± 26.7 months (1-180). Conclusions: When the results of the one study with a very high failure rate and of the cases that developed OSCC are not considered, the dental implant failure rate in OLP patients was 2.7% after a follow-up of approximately five years. Recommendations are given when treating OLP patients with dental implants.

PHYTOCHROME-INTERACTING FACTOR 3 mediates light-dependent induction of tocopherol biosynthesis during tomato fruit ripening.

Tocopherols are important antioxidants exclusively produced in plastids that protect the photosynthetic apparatus from oxidative stress. These compounds with vitamin E activity are also essential dietary nutrients for humans. Although the tocopherol biosynthetic pathway has been elucidated, the mechanisms that regulate tocopherol production and accumulation remain elusive. Here, we investigated the regulatory mechanism underlying tocopherol biosynthesis during ripening in tomato fruits, which are an important source of vitamin E. Our results show that ripening under light conditions increases tocopherol fruit content in a phytochrome-dependent manner by the transcriptional regulation of biosynthetic genes. Moreover, we show that light-controlled expression of the GERANYLGERANYL DIPHOSPHATE REDUCTASE (SlGGDR) gene, responsible for the synthesis of the central tocopherol precursor phytyl diphosphate, is mediated by PHYTOCHROME-INTERACTING FACTOR 3 (SlPIF3). In the absence of light, SlPIF3 physically interacts with the promoter of SlGGDR, down-regulating its expression. By contrast, light activation of phytochromes prevents the interaction between SlPIF3 and the SlGGDR promoter, leading to transcriptional derepression and higher availability of the PDP precursor for tocopherol biosynthesis. The unraveled mechanism provides a new strategy to manipulate fruit metabolism towards improving tomato nutritional quality.

Reticular and erosive oral lichen planus have a distinct metabolomic profile: A preliminary study using gas chromatography-mass spectrometry.

BACKGROUND: Oral Lichen Planus is a chronic inflammatory disorder that affects the oral mucosa, with the reticular and erosive forms representing the primary clinical variants of the disease. Previous studies have shown that metabolic alterations may well be involved in the pathogenesis of the disease; however, the molecular mechanisms related to the clinicopathological differences between erosive and reticular forms remain unknown. METHODS: A comparative metabolomic analysis was performed on formalin-fixed and paraffin-embedded tissue samples of erosive (n = 6) and reticular (n = 10) oral lichen planus using gas chromatography-mass spectrometry. RESULTS: The metabolomic analysis showed a distinct profile between the two clinical variants. Five metabolites (cyclohexanamine, glycine, mannitol/sorbitol, methyl palmitate and trehalose) were significantly diminished in erosive oral lichen planus as compared to the reticular form. CONCLUSIONS: Reticular and erosive forms of oral lichen planus have a distinct metabolic profile. However, further studies using a large number of fresh tissue samples are necessary to confirm this data.

New insights about the effect of the synthesis method on the CuOCeO2 redox properties and catalytic performance towards CO-PROX reaction for fuel cell applications.

The preferential oxidation of CO (CO-PROX) is promoted at the interface between CuO and CeO2. For this reason, different synthesis methods of CuO/CeO2 catalysts have been investigated in order to maximize this interface. However, the understanding of the effect of CuO/CeO2 catalysts preparation method on the redox properties and CO-PROX reaction performance is still unclear. In the present work, 2 wt% CuO/CeO2 catalysts were prepared by four synthesis methods, namely co-precipitation with ammonium hydroxide (CP), deposition-precipitation with ammonium hydroxide (DA) or urea (DU), and impregnation (IM). The materials were characterized by XRD, SEM-EDS, H2-TPR, REDOX cycles, N2O passivation and applied to the CO-PROX reaction. The catalytic performance of the investigated materials was evaluated by the TOF values of CO oxidation. CuCe (CP) and CuCe (DU) catalysts were the most stable in terms of redox properties and the most active in the CO-PROX reaction. On the other hand, the CuCe (DA) catalyst presented the least stable behaviour during the redox cycles and the worst performance in CO-PROX reaction. These results clearly show that the stability of the CuO/CeO2 interface, submitted to successive redox cycles, plays a significant role towards the CO-PROX reaction and that this stability depends on the employed synthesis method.

Inclusion of licuri meal in the diet of pasture dairy cows.

The objective of this study was to evaluate the inclusion of increasing levels of licuri meal as a substitute for soybean bran in the diet of pasture-based dairy cows and its effects on the intake, nutrient digestibility, and milk production and composition. Eight crossbred Holstein/Zebu cows were used in two 4 × 4 Latin square plots. The diets contained increasing percentage of licuri meal (0.0, 4.16, 7.09, and 9.45%) in the total diet, replacing soybean bran. The inclusion of licuri meal in the diet affected total dry matter intake and dry matter intake in relation to body weight, which presented a quadratic effect. The same behavior was observed for the consumption of EE, CP, TDN, and NDFap. The NFC consumption showed a linear decrease with the addition of the by-product in the diet. There was no influence of the inclusion of the licuri meal on the digestibility of the DM, CP, NFC, and TDN, while the digestibility of the NDFap and EE presented increasing linear effect. There was a reduction of milk production and food efficiency with the inclusion of increasing levels of the meal. The fat content in milk showed a linear increasing effect. Ditto for cholesterol. It is recommended to include not more than 7.00% of licuri meal for lactating cows with an average production of 20 kg day-1.

DNA methylation patterns of genes related to immune response in the different clinical forms of oral lichen planus.

BACKGROUND: The oral lichen planus is a chronic inflammatory disease. Although its aetiology is not well understood, the role of T lymphocytes in its inflammatory events is recognised. Identifying the epigenetic mechanisms involved in the pathogenesis of this immune-mediated condition is fundamental for understanding the inflammatory reaction that occurs in the disease. The purpose of this work was to evaluate the methylation pattern of 21 immune response-related genes in the different clinical forms of oral lichen planus. METHODS: A cross-sectional study was performed to analyse the DNA methylation patterns in three distinct groups of oral lichen planus: (i) reticular/plaque lesions; (ii) erosive lesions; (iii) normal oral mucosa (control group). After DNA extraction from biopsies, the samples were submitted to digestions by methylation-sensitive and methylation-dependent enzymes and double digestion. The relative percentage of methylated DNA for each gene was provided using real-time polymerase chain reaction arrays. RESULTS: Hypermethylation of the STAT5A gene was observed only in the control group (59.0%). A higher hypermethylation of the ELANE gene was found in reticular/plaque lesions (72.1%) compared to the erosive lesions (50.0%). CONCLUSION: Our results show variations in the methylation profile of immune response-related genes, according to the clinical type of oral lichen planus after comparing with the normal oral mucosa. Further studies are necessary to validate these findings using gene expression analysis.

Graduated Compression Stockings Does Not Decrease Walking Capacity and Muscle Oxygen Saturation during 6-Minute Walk Test in Intermittent Claudication Patients.

BACKGROUND: We analyze the effects of graduated compression stoking (GCS) on walking capacity and oxygen saturation in intermittent claudication (IC) patients. METHODS: Eighteen patients with IC performed the 6-minute walking test in 2 conditions in random order: GCS or placebo sock. Onset claudication distance and total walking distance were obtained. The calf muscle oxygen saturation was continuously monitored before, during, and after 6-minute walk test. Comparisons of the walking capacity and StO2 parameters between GCS and placebo conditions were analyzed by Wilcoxon rank-sum test. RESULTS: The onset claudication distance (GCS: 120 ± 99 meters vs. placebo: 150 ± 126 meters; P = 0.798) and total walking distance (GCS: 330 ± 108 meters vs. placebo: 324 ± 60 meters; P = 0.130) were similar between conditions. There were no differences in StO2 parameters between conditions (P > 0.05). CONCLUSIONS: GCS does not decrease walking performance and calf muscle oxygenation saturation during 6-minute walk test in patients with IC.

Analysis of information received during treatment and adherence to tamoxifen in breast cancer patients.

This study examines whether women with breast cancer, who are adherent and non-adherent to tamoxifen, differ in their perceptions of information received during treatment. This cross-sectional study included women receiving tamoxifen as adjuvant treatment for breast cancer recruited from a teaching hospital specialised in women's health in the state of São Paulo (Brazil). Women were interviewed and their records were reviewed for socio demographic data and clinical characteristics. We assessed tamoxifen adherence using the Morisky-Green Test, and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire - Information module (EORTC QLQ-INFO25) was used to evaluate the information received by the women. The sample contained 31 women (mean age = 55.4; SD = 11.6 years). According to the Morisky-Green Test, 74.2% of the women had suboptimal tamoxifen adherence. The global score for women's perceptions of information they received about the treatment and disease was 57.0 ±19.1 on a scale of 0 to 100, and no significant differences in scores were observed between adherents and non-adherents. A high prevalence of suboptimal tamoxifen adherence was observed. We found no significant differences between women with breast cancer who were adherent and non-adherent to tamoxifen.

Evaluating effectiveness of dynamic soundfield system in the classroom.

Research has reported on the use of soundfield amplification devices in the classroom. However, no study has used standardized tests to determine the potential advantages of the dynamic soundfield system for normally hearing students and for the teacher's voice. Our aim was to evaluate the impact of using dynamic soundfield system on the noise of the classroom, teacher's voice and students' academic performance. This was a prospective cohort study in which 20 student participants enrolled in the third year of basic education were divided into two groups (i.e., control and experimental); their teacher participated. The experimental group was exposed to the dynamic soundfield system for 3 consecutive months. The groups were assessed using standardized tests to evaluate their academic performance. Further, questionnaires and statements were collected on the participants' experience of using the soundfield system. We statistically analyzed the results to compare the academic performance of the control group with that of the experimental group. In all cases, a significance level of P < .05 was adopted. Use of the dynamic soundfield system was effective for improving the students' academic performance on standardized tests for reading, improving the teacher's speech intelligibility, and reducing the teacher's vocal strain. The dynamic soundfield system minimizes the impact of noise in the classroom as demonstrated by the mensuration of the signal-to-noise ratio (SNR) and pupil performance on standardized tests for reading and student and teacher ratings of amplification system effectiveness.

CDH1 mutations in gastric cancer patients from northern Brazil identified by Next- Generation Sequencing (NGS).

Gastric cancer is considered to be the fifth highest incident tumor worldwide and the third leading cause of cancer deaths. Developing regions report a higher number of sporadic cases, but there are only a few local studies related to hereditary cases of gastric cancer in Brazil to confirm this fact. CDH1 germline mutations have been described both in familial and sporadic cases, but there is only one recent molecular description of individuals from Brazil. In this study we performed Next Generation Sequencing (NGS) to assess CDH1 germline mutations in individuals who match the clinical criteria for Hereditary Diffuse Gastric Cancer (HDGC), or who exhibit very early diagnosis of gastric cancer. Among five probands we detected CDH1 germline mutations in two cases (40%). The mutation c.1023T > G was found in a HDGC family and the mutation c.1849G > A, which is nearly exclusive to African populations, was found in an early-onset case of gastric adenocarcinoma. The mutations described highlight the existence of gastric cancer cases caused by CDH1 germline mutations in northern Brazil, although such information is frequently ignored due to the existence of a large number of environmental factors locally. Our report represent the first CDH1 mutations in HDGC described from Brazil by an NGS platform.

Mast cells are crucial in the resistance against Toxoplasma gondii oral infection.

During oral infection, mucosal immunity assumes a predominant role. Here, we addressed the role of mast cells (MCs), which are mainly located in mucosa during oral infection with Toxoplasma gondii, using MC-deficient (W/W(v) ) mice. We show that in the absence of MCs the resistance of W/W(v) mice to oral infection was considerably reduced. W/W(v) mice uniformly succumbed within 15 days of infection after administration of cysts of the ME49 strain of T. gondii. The rapid lethality of T. gondii in W/W(v) mice correlated with a delayed Th1-cell response, since IFN-γ and IL-12 levels peaked in the later phase of the infection. In vitro, BM-derived MCs were able to recognize parasite lysate in a MyD88-dependent way, reaffirming the role of this TLR adapter in immune responses to T. gondii. The importance of MCs in vivo was confirmed when W/W(v) mice reconstituted with BM-derived MCs from control mice retrieved an early strong Th1-cell response and specially a significant IL-12 production. In conclusion, MCs play an important role for the development of a protective immune response during oral infection with T. gondii.

Carotenoids and Tocopherol Profiling in Fleshy Fruits.

Carotenoids and tocopherols are among the most powerful lipophilic antioxidants accumulated in fruit and vegetable crops. This chapter describes a method for the separation and quantification of carotenoids/chlorophylls and tocopherols based on microextraction followed by reverse- and normal-phase HPLC, respectively. Using this method, high-throughput, accurate analysis of these compounds can be performed in leaf and fruit samples.

Ultrasound biomicroscopy in the quantification of brain perfusion parameters of a rat stroke model: Analysis of contrast agent bolus kinetic dynamics.

BACKGROUND: Ischemic stroke represents a significant global health concern, necessitating thorough investigations and the utilization of stroke animal models to explore novel treatment modalities and diagnostic imaging techniques. NEW METHOD: Ultrasound biomicroscopy (BMU), operating at a center frequency of 21 MHz, along with ultrasound contrast agents (UCAs), was used to quantify microcirculation cerebral blood flow in a rat model of ischemic stroke. The microcirculation parameters were derived from time intensity curve (TIC) plots obtained based on UCA-bolus kinetics. RESULTS: Semiquantitative perfusion-related parameters were assessed. The TIC curves showed differences in amplitude when compared intra-animal between the left and right sides, and three situations were observed: normal perfusion, hypoperfusion, and nonperfusion. ROC analysis of delays between the left and right time intensity peak (TIP) for regions of interest (ROIs) in the control and stroke-hypoperfusion groups revealed an optimal cutpoint of 0.39 s to indicate when hypoperfusion is occurring in rats, with a sensitivity of 93.33 % and a specificity of 80 %. COMPARISON WITH EXISTING METHOD(S): Ultrasound perfusion imaging through the temporal bone window has been clinically applied to stroke patients using a UCA bolus for TIC analysis. TIC parameters were correlated with MRI- and CT-based measurements. CONCLUSIONS: This investigation quantified cerebral blood flow in a rat model of ischemic stroke by measuring microcirculation parameters. The study demonstrated the efficacy of this approach as a valuable tool for conducting preclinical studies.

Reductions in rearfoot eversion posture due to proximal muscle strengthening are dependent on foot-ankle varus alignment.

BACKGROUND: Strengthening the hip and trunk muscles may decrease foot pronation in upright standing due to expected increases in hip passive torque and lower-limb external rotation. However, considering the increased pronation caused by a more varus foot-ankle alignment, subjects with more varus may experience smaller or no postural changes after strengthening. OBJECTIVE: To investigate the effects of hip and trunk muscle strengthening on lower-limb posture during upright standing and hip passive torque of women with more and less varus alignment. METHODS: This nonrandomized controlled experimental study included 50 young, able-bodied women. The intervention group (n = 25) performed hip and trunk muscle strengthening exercises, and the control group (n = 25) maintained their usual activities. Each group was split into two subgroups: those with more and less varus alignment. Hip, shank, and rearfoot-ankle posture and hip passive external rotation torque were evaluated. Mixed analyses of variance and preplanned contrasts were used to assess prepost changes and between-group differences (α = 0.05). RESULTS: The less-varus subgroup of the intervention group had a reduced rearfoot eversion posture (P = 0.02). No significant changes were observed in the less-varus subgroup of the control group (P = 0.31). There were no significant differences in posture between the control and intervention groups when varus was not considered (P ≥ 0.06). The intervention group had increased hip passive torque (P = 0.001) compared to the control group, independent of varus alignment. CONCLUSION: Despite the increases in hip passive torque, the rearfoot eversion posture was reduced only in women with a less-varus alignment. Having more foot-ankle varus may prevent eversion reductions.

Cardiac autonomic nervous activity during different sleep stages in individuals with spinal cord injury: The influence of physical training.

OBJECTIVE: The present study assessed the influence of physical training on cardiac autonomic activity in individuals with spinal cord injury (SCI) during different sleep stages. METHODS: Twenty-six volunteers were allocated into three groups: 9 sedentary individuals without SCI (control, CON); 8 sedentary tetraplegic individuals with chronic SCI (SED-SCI); 9 physically trained tetraplegic individuals with chronic SCI (TR-SCI). All participants underwent nocturnal polysomnography to monitor sleep stages: wakefulness, non-rapid eye movement (NREM) sleep (N1, N2, and N3 stages), and REM sleep. The electrocardiography data obtained during this exam were extracted to analyze the heart rate variability (HRV). RESULTS: Sleep stages influenced HRV in the time [RR interval and root mean square of successive RR interval differences (RMSSD)] and frequency [low-frequency (LF) and high-frequency (HF) powers and LF-to-HF ratio] domains (P < 0.05). SED-SCI individuals showed unchanged HRV compared to CON (P > 0.05). When comparing the TR-SCI and SED-SCI groups, no significant differences in HRV were reported in the time domain (P > 0.05). However, in the frequency domain, more accentuated HF power was observed in TR-SCI than in SED-SCI individuals during the N2 and N3 stages and REM sleep (P < 0.05). Moreover, TR-SCI had higher HF power than CON during the N3 stage (P < 0.05). CONCLUSIONS: TR-SCI individuals have greater HF power, indicative of parasympathetic modulation, than sedentary (injured or not injured) individuals during different sleep stages. Therefore, enhanced parasympathetic activity induced by physical training may improve cardiac autonomic modulation during sleep in individuals with chronic SCI.

Ambient pH sensing in filamentous fungi: pitfalls in elucidating regulatory hierarchical signaling networks.

In this article, the experiments used to construct the ambient pH-signaling network involved in the secretion of enzymes by filamentous fungi have been reviewed, focusing on the phosphate-repressible phosphatases in Aspergillus nidulans. Classic and molecular genetics have been used to demonstrate that proteolysis of the transcription factor PacC at alkaline ambient pH is imperative for its action, implying that the full-length version is not an active molecular form of PacC. It has been hypothesized that the transcriptional regulator PacC may be functional at both acidic and alkaline ambient pH, in either the full-length or the proteolyzed form, if it carries a pal-dependent molecular tag. The products of the pal genes are involved in a metabolic pathway that led to the synthesis of effector molecules that tag the pacC product, perhaps facilitating its proteolysis.