Nonlinear and abnormal relationship between turbidity and suspended solids concentration in mountainous rivers: A case study of the Lai Chi Wo river in Hong Kong, China.

Suspended solids concentration (SSC) in a river is closely relevant to river water turbidity. Investigation of their relationship in this study is accompanied by observed turbidity and SSC values, which were obtained from the testing results of water samples and monitored conditions in streamflow. The water samples were collected from two observation stations with a broad range of sediment concentrations in the Lai Chi Wo catchment in Hong Kong, China. We classified the target rainfall events into single-peak event type and dual-peak event type for a distinguished discussion of the relationship between SSC and turbidity in this study. At a finer classification, each event is separated into defined processes for the analysis, where two main processes refer to the periods that SSC rises from a normal state to a peak state first and the followed periods that SSC recesses to ordinary status gradually. It is advised by the analysis results that the estimation of SSC through turbidity values should be based on the same rainfall types for the upstream station. However, the results show that the classification of rainfall types does not need to take downstream areas into consideration. Furthermore, current research implies that the individual established connections between SSC and turbidity value at different stages (particularly referring to the rising period and recessing period) could be applied to estimate SSC at the same station via continuous turbidity values for both this and other ungauged stations with similar topographical features in the future. Meanwhile, this research approach provides new insight exploring various behaviors of sediments at different stages during an integral rainfall event. A comparison of distinguished performances of sediment during corresponding stages in a rainfall event makes contributions to diverse relationship between SSC and turbidity in the mountainous river.

Aquatic High Intensity Interval Deep Water Running Influence on Cardiometabolic Health and Cognitive Psychological Responses in Women.

ABSTRACT: Aquatic High Intensity Interval Training Deep water running (AHIIT-DWR) has the potential to improve cardiometabolic health and cognitive psychological responses, offering a reduced risk of injuries and greater affordability for inactive elderly women. Purpose: To investigate the effects of an 8-week AHIIT- DWR intervention compared to land-based HIT training (LHIIT) on cardiometabolic health, cognitive and psychological outcomes in inactive elderly women. Methods: Seventy inactive elderly women aged 60 or above were randomly assigned into two groups: AHIIT-DWR and LHIIT. The AHIIT-DWR group engaged in DWR sessions comprising 30-minutes of interval training, consisting of ten 2-minute exercise bouts at 80-90% of their maximal heart rate (HR max), with 1-minute active recovery at 70% HR max between bouts, for two sessions per week, for 8 weeks. The LHIIT group performed treadmill running at the same intensity. Results: Both groups showed similar cardiovascular fitness, maximal aerobic capacity (VO2max), maximal HR and respiratory exchange ratio (RER) improvement (p > 0.05), while AHIIT-DWR showed a significant improvement in aerobic capacity minute ventilation (VE), metabolic equivalents (METs) and O2 pulse (p < 0.05) over the 8- week intervention. Both AHIIT-DWR and LHIIT significantly decreased triglycerides, total cholesterol. HDL, LDL post intervention (p < 0.05). No significant group differences were observed for cognitive function assessed by MMSE and MOCA, (p > 0.05). Both groups showed similar enjoyment levels, self-efficacy scores and high adherence rates (>90%). Conclusions: Our study suggests that AHIIT-DWR can elicit a similar improvement in cardiorespiratory health, metabolic blood markers, cognitive function assessed by MMSE and MOCA and psychological responses as LHIIT in inactive elderly women.

Psychometric testing of the Chinese version of the International Classification of Functioning, Disability, and Health Measure of Participation and Activities Screener in people with stroke.

BACKGROUND: Clinicians need a validated measure to assess the activity and participation of Chinese people with stroke. OBJECTIVES: To culturally adapt and psychometrically test the Chinese (Cantonese) version of the International Classification of Functioning, Disability and Health Measure of Participation and Activities (C-IMPACT-S) in community-dwelling people with stroke. METHODS: We followed the standard translation procedures to culturally adapt the C-IMPACT-S. Then we administered the C-IMPACT-S to 100 people with stroke and 50 healthy counterparts for psychometric testing, including the ceiling and floor effects, internal consistency, test - retest, measurement error, minimal detectable change, correlations with other outcome measures, known-group validity and optimal cutoff scores. RESULTS: The C-IMPACT-S has no floor effects but ceiling effects in item 5. It has poor to excellent (Cronbach's α = 0.56-95) internal consistency and fair to excellent (Intraclass correlation coefficients = 0.58-1.00) test-retest reliability. The overall C-IMPACT-S mean score and activity and participation component mean scores had statistically significant no to weak correlations with the Fugl-Meyer Assessment, the Chinese versions of Geriatric Depression Scale, Fatigue Assessment Scale, Lawton Instrumental Activities of Daily Living Scale and Community Integration Measure. The stroke participants had lower C-IMPACT-S scores then their health counterparts. The optimal cutoff scores of the overall C-IMPACT-S and activity and participation domains were 88.02% (sensitivity 72%, specificity 80%), 80.56% (sensitivity 86%, specificity 68%) and 91.67% (sensitivity 68%, specificity 80%), respectively. CONCLUSIONS: C-IMPACT-S is a reliable and valid measure for assessing the levels of activity and participation of people with chronic stroke.

The paradox of tPA in ischemic stroke: tPA knockdown following recanalization improves functional and histological outcomes.

Previous studies have demonstrated that endogenous tissue-type plasminogen activator (tPA) is upregulated in the brain after an acute ischemic stroke (AIS). While mixed results were observed in genetic models, the pharmacological inhibition of endogenous tPA showed beneficial effects. Treatment with exogenous recombinant tPA exacerbated brain damage in rodent models of stroke. Despite the detrimental effects of tPA in ischemic stroke, recombinant tPA is administered to AIS patients to recanalize the occluded blood vessels because the benefits of its administration outweigh the risks associated with tPA upregulation and increased activity. We hypothesized that tPA knockdown following recanalization would ameliorate sensorimotor deficits and reduce brain injury. Young male and female rats (2-3 months old) were subjected to transient focal cerebral ischemia by occlusion of the right middle cerebral artery. Shortly after reperfusion, rats from appropriate cohorts were administered a nanoparticle formulation containing tPA shRNA or control shRNA plasmids (1 mg/kg) intravenously via the tail vein. Infarct volume during acute and chronic phases, expression of matrix metalloproteinases (MMPs) 1, 3, and 9, enlargement of cerebral ventricle volume, and white matter damage were all reduced by shRNA-mediated gene silencing of tPA following reperfusion. Additionally, recovery of somatosensory and motor functions was improved. In conclusion, our results provide evidence that reducing endogenous tPA following recanalization improves functional outcomes and reduces post-stroke brain damage.

Safety and tolerance of combination of monoamine oxidase inhibitors and direct dopamine agonists in adults and older adults with highly resistant depression.

INTRODUCTION: Dopamine (DA) is likely to be involved in some depressive dimensions, such as anhedonia and amotivation, which account for a part of treatment-resistant forms. Monoamine oxidase inhibitors (MAOI) and direct D2 and D3 receptors agonists (D2/3r-dAG) are known to help, but we lack safety data about their combined usage. We report on safety and tolerance of the MAOI+D2r-dAG combination in a clinical series. METHOD: All patients referred to our recourse center for depression between 2013 and 2021 were screened to select those who did receive the combo. Data were extracted from clinical files. RESULTS: Sixteen patients of 60±17 years of age (8 women, 7 with age>65years, all suffered from treatment resistant depression, 7 with bipolar disorder) received the combo. There were no life-threatening adverse effects (AE). However, AE were reported by 14 patients (88%) most of which were mild and consisted of insomnia, nausea, nervousness, confusion, impulse control disorder and/or "sleep attacks". One patient presented a serious AE requiring a short hospitalization for confusion. Intolerance led to failure to introduce treatment in two patients (13%). The retrospective non-interventional design, the variety of molecules, and the modest sample size limited the scope of these results. CONCLUSION: There was no life-threatening safety issue in combining MAOI and D2/3r-dAG, especially regarding cardiovascular side effects. The systematic screening of AE might account for their frequency, but these precluded the treatment in only two patients. Comparative studies are needed to assess the efficacy of this new combination.

The Impact of Social Isolation and Environmental Deprivation on Blood Pressure and Depression-Like Behavior in Young Male and Female Mice.

Background: Social isolation (SI) and loneliness are major adult and adolescent health concerns, particularly in the coronavirus disease 2019 (COVID-19) era. Recent prospective cohort studies indicate that older women who experienced both SI and loneliness had a significantly higher risk of cardiovascular disease (CVD). Hypertension, a well-established risk factor for CVD, is more prevalent in elderly women than men. Furthermore, a lack of social relationships is strongly associated with an increased risk of hypertension in middle-aged and elderly women compared to men. Although this has not been extensively studied, adolescents and young adults who experience loneliness or SI may also be at risk for CVD and depression. The purpose of this study was to examine the effect of SI on blood pressure and depression-like behavior in young male and female mice. Methods: Weaned C57BL/6 mice were randomly assigned (n = 6/group/sex) to either group housing (GH) or SI. Animals in the SI group were housed in individual cages for 8 weeks with no view of other animals. The cages were kept in ventilated racks to prevent pheromone exposure and socially isolated animals had no cage enrichment. Results: SI increased systolic, diastolic, and mean arterial blood pressure in females and elevated heart rate in both sexes. Body weight gain was dramatically increased in socially isolated females but tended to decrease in socially isolated males. In the forced swim test, which detects depression-like behavior, there was no difference between groups in total immobility time. The latency to immobility, however, was significantly decreased in socially isolated females. Serum concentrations of corticosterone and metanephrine did not differ between socially isolated and group-housed females, but corticosterone levels were significantly reduced in socially isolated males. Conclusions: Our results indicate that 8 weeks of SI leads to significant changes in blood pressure and heart rate and mild changes in depression-like behavior in young mice, with females affected more than males.

High fat diet allows food-predictive stimuli to energize action performance in the absence of hunger, without distorting insulin signaling on accumbal cholinergic interneurons.

Obesity can disrupt how food-predictive stimuli control action performance and selection. These two forms of control recruit cholinergic interneurons (CIN) located in the nucleus accumbens core (NAcC) and shell (NAcS), respectively. Given that obesity is associated with insulin resistance in this region, we examined whether interfering with CIN insulin signaling disrupts how food-predictive stimuli control actions. To interfere with insulin signaling we used a high-fat diet (HFD) or genetic excision of the insulin receptor (InsR) from cholinergic cells. HFD left intact the capacity of food-predictive stimuli to energize performance of an action earning food when mice were tested hungry. However, it allowed this energizing effect to persist when the mice were tested sated. This persistence was linked to NAcC CIN activity but was not associated with distorted CIN insulin signaling. Accordingly, InsR excision had no effect on how food-predicting stimuli control action performance. Next, we found that neither HFD nor InsR excision altered the capacity of food-predictive stimuli to guide action selection. Yet, this capacity was associated with changes in NAcS CIN activity. These results indicate that insulin signaling on accumbal CINs does not modulate how food-predictive stimuli control action performance and selection. However, they show that HFD allows food-predictive stimuli to energize performance of an action earning food in the absence of hunger.

The Potential Role of PET in the Management of Peripheral Artery Disease.

PURPOSE OF REVIEW: Current non-invasive tests for evaluating patients with peripheral artery disease (PAD) have significant limitations for early detection and management of patients with PAD and are generally focused on the evaluation of large vessel disease. PAD often involves disease of microcirculation and altered metabolism. Therefore, there is a critical need for reliable quantitative non-invasive tools that can assess limb microvascular perfusion and function in the setting of PAD. RECENT FINDINGS: Recent developments in positron emission tomography (PET) imaging have enabled the quantification of blood flow to the lower extremities, the assessment of the viability of skeletal muscles, and the evaluation of vascular inflammation and microcalcification and angiogenesis in the lower extremities. These unique capabilities differentiate PET imaging from current routine screening and imaging methods. The purpose of this review is to highlight the promising role of PET in the early detection and management of PAD providing a summary of the current preclinical and clinical research related to PET imaging in patients with PAD and related advancement of PET scanner technology.

Metabolic Engineering Design Strategies for Increasing Carbon Fluxes Relevant for Biosynthesis in Cyanobacteria.

Cyanobacteria are promising microbial cell factories for the direct production of biochemicals and biofuels from CO2. Through genetic and metabolic engineering, they can be modified to produce a variety of both natural and non-natural compounds. To enhance the yield of these products, various design strategies have been developed. In this chapter, strategies used to enhance metabolic fluxes towards common precursors used in biosynthesis, including pyruvate, acetyl-CoA, malonyl-CoA, TCA cycle intermediates, and aromatics, are discussed. Additionally, strategies related to cofactor availability and mixotrophic conditions for bioproduction are also summarize.

Association between time spent on smartphones and digital eye strain: A 1-year prospective observational study among Hong Kong children and adolescents.

Prolonged electronic screen use can cause digital eye strain. It can be difficult to rectify due to increasing smartphone reliance, potentially leading to serious public health problems. To investigate the association between time spent on smartphones and digital eye strain (DES) among Hong Kong Chinese school-aged children. Of a total of 1,508 students (748 males, 49.6%) from 8 to 14 years old (mean age = 10.91 years, SD = 2.01) who provided valid data on DES, the 1,298 (86%) who completed the DES questionnaire at 1-year follow-up were included in the analysis. DES was measured using a 10-item scale, and the sum of the 10 dichotomised scores was used as the DES total score. The most commonly reported symptoms were eye fatigue (n = 804, 53.3%), blurred vision (changing from reading to distance viewing) (n = 586, 38.9%), and irritated or burning eyes (n = 516, 34.2%). The DES total scores at baseline and 1-year follow-up were 2.91 (SD = 2.90) and 3.20 (SD = 3.19), respectively. Linear regression controlling for demographic and socio-economic confounders showed that participants with baseline smartphone usage of 241 + min/d had a significantly higher baseline total DES score than those with baseline smartphone usage of 0-60 min/d (2.44 vs 3.21, P < 0.001), and participants with baseline smartphone usage of 181-240 min/d had a significantly higher 1-year follow-up total DES score than those with baseline smartphone usage of 0-60 min/d (2.80 vs 3.50, P = 0.003).

Assessing the Turning Ability during Walking in People with Stroke Using L Test.

BACKGROUND: The L Test of Functional Mobility (L Test) was developed to assess the advanced mobility, which includes both turning and walking ability. This study aimed to evaluate (1) the intra-rater reliability of the L Test in four turning conditions, (2) the correlation with other stroke-specific impairment for community-dwelling older adults with stroke, and (3) the optimal cut-off completion time of the L Test to distinguish the difference of performance between healthy older adults and people with stroke. METHODS: This is a cross-sectional design. Thirty older adults with stroke and healthy older adults were included. The subjects were assessed by L Test along with other stroke-specific outcomes. RESULTS: The L Test showed excellent intra-rater reliability (ICC = 0.945-0.978) for the four turning conditions. There were significant correlations between L Test completion times and Fugl-Meyer Assessment-Lower Extremity (FMA-LE) scores, Fugl-Meyer Assessment-Upper Extremity (FMA-UE) scores, Berg Balance Scale (BBS) score, and Timed Up and Go (TUG) Test scores. The cut-off of the L Test was established as 23.41-24.13 s. CONCLUSION: The L Test is an easy-to-administer clinical test for assessing the turning ability of people with stroke.

Relationship of Post-Transplant Lymphoproliferative Disorders (PTLD) Subtypes and Clinical Outcome in Pediatric Heart Transplant Recipients: A Retrospective Single Institutional Analysis/Experience of 558 Patients.

Post-transplant lymphoproliferative disorders (PTLD) are heterogenous lymphoproliferative disorders that develop as a consequence of immunosuppression in transplant recipients. We sought to determine if subtypes of PTLD correlated with different outcomes. We performed a retrospective review of PTLD occurring in pediatric heart transplant recipients. A total of 558 children and infants underwent cardiac transplantation at our institution between 1985 and 2019 and were followed until March 2021. Forty-nine of 558 patients developed PTLD (8.8%). As compared to older children (>one year of age), infant recipients (

Lower Limb Muscles' Activation during Ascending and Descending a Single Step-Up Movement: Comparison between In water and On land Exercise at Different Step Cadences in Young Injury-Free Adults.

(1) Background: Forward step-up (FSU) simulates the stance phase in stair ascension. With the benefits of physical properties of water, aquatic FSU exercise may be more suitable for patients with lower limb weakness or pain. The purpose of this study is to investigate the effect of progressive steps per min on the surface electromyography (sEMG) of gluteus maximus (GM), biceps femoris (BF), rectus femoris (RF), and gastrocnemius (GA), when performing FSU exercise with different steps per min in water and on land. (2) Methods: Participants (N = 20) were instructed to perform FSU exercises at different steps per min (35, 60, and 95 bpm) in water and on land. The sEMG of the tested muscles were collected. The percentage maximum voluntary isometric contraction (%MVIC) of GM, RF, GA and BF at different environments and steps per min was compared. (3) Result: There was a statistically significant difference of %MVIC of RF at all steps per min comparisons regardless of the movement phases and environments (p < 0.01, except for descending phases of 35 bpm vs. 60 bpm). All tested muscles showed a statistically significant lower muscle activation in water (p < 0.05) (4) Conclusion: This study found that the %MVIC of the tested muscle in both investigated environments increase as steps per minute increases. It is also found that the movement pattern of FSU exercise activates RF the most among all the tested muscles. Muscle activation of all tested muscles is also found to be smaller in water due to buoyancy property of water. Aquatic FSU exercise might be applicable to patients with lower limb weakness or knee osteoarthritis to improve their lower limb strength.

Spatiotemporal variations of river water turbidity in responding to rainstorm-streamflow processes and farming activities in a mountainous catchment, Lai Chi Wo, Hong Kong, China.

River turbidity is an important factor in evaluating environmental water quality, and turbidity dynamics can reflect water sediment changes. During rainfall periods, specifically in mountainous areas, river turbidity varies dramatically, and knowledge of spatiotemporal turbidity variations in association with rainfall features and farming activities is valuable for soil erosion prevention and catchment management. However, due to the difficulties in collecting reliable field turbidity data during rainstorms at a fine temporal scale, our understanding of the features of turbidity variations in mountainous rivers is still vague. This study conducted field measurements of hydrological and environmental variables in a mountainous river, the Lai Chi Wo river, in Hong Kong, China. The study results revealed that variations of turbidity graphs during rainstorms closely match variations of streamflow hydrographs, and the occurrence of the turbidity peaks and water level peaks are almost at the same time. Moreover, the study disclosed that the increasing rates of the turbidity values are closely related to the rainfall intensity at temporal scales of 15 and 20 min, and the impact of farming activities on river turbidity changes is largely dependent on rainfall intensity. In the study area, when the rainfall intensity is larger than 35 mm/hr at a time interval of 15 min, the surface runoff over the farmland would result in higher river water turbidity downstream than that upstream. The study results would enrich our understanding of river water turbidity dynamics at minute scales and be valuable for further exploration of the river water environment in association with turbidity.

Basal forebrain cholinergic signaling in the basolateral amygdala promotes strength and durability of fear memories.

The basolateral amygdala (BLA) complex receives dense cholinergic projections from the nucleus basalis of Meynert (NBM) and the horizontal limb of the diagonal band of Broca (HDB). The present experiments examined whether these projections regulate the formation, extinction, and renewal of fear memories. This was achieved by employing a Pavlovian fear conditioning protocol and optogenetics in transgenic rats. Silencing NBM projections during fear conditioning weakened the fear memory produced by that conditioning and abolished its renewal after extinction. By contrast, silencing HDB projections during fear conditioning had no effect. Silencing NBM or HDB projections during extinction enhanced the loss of fear produced by extinction, but only HDB silencing prevented renewal. Next, we found that systemic blockade of nicotinic acetylcholine receptors during fear conditioning mimicked the effects produced by silencing NBM projections during fear conditioning. However, this blockade had no effect when given during extinction. These findings indicate that basal forebrain cholinergic signaling in the BLA plays a critical role in fear regulation by promoting strength and durability of fear memories. We concluded that cholinergic compounds may improve treatments for post-traumatic stress disorder by durably stripping fear memories from their fear-eliciting capacity.

Hypertensive Disorders in Pregnancy at the John F. Kennedy Maternity Center (JFKMC), Liberia: Burden, Sub-Types, and Maternofetal Outcome.

Background: Hypertensive disorders in pregnancy (HDP) are a leading cause of maternal and fetal death, especially in a resource-constrained setting. There is no study from Liberia on the disorder. This pilot study aimed to determine the burden, sub-types, and maternal-fetal outcomes of hypertensive disorders in pregnancy at the John F. Kennedy Maternity Center (JFKMC), Liberia. Methods: From January 1 to December 31, 2020, the medical records of 130 pregnant and post-partum patients admitted with Hypertensive disorders in pregnancy (HDP) in a census method of sampling were retrieved, while 83.1% (108) were suitable for analysis in an institutional cross-sectional retrospective study in the department of obstetrics and gynecology at the John F. Kennedy Maternity Center, Liberia. The extracted information was analyzed using SPSS version 26. Results were presented in frequencies and percentages. The statistical association between categorical variables was subjected to the Chi-square test. The level of significance was set at a P-value of < 0.05. Results: There was an institutional prevalence of 3.0% of HDP. The maternal fatality rate was 12.3%, while the perinatal fatality rate was 14.3%. There was a significant association between HELLP syndrome and Severe pre-eclampsia with maternal death, P< 0.001. Prematurity, first minutes Apgar score <5, NICU admission, and low birth weight were associated with perinatal deaths (P <0.001). Conclusion: HDP was an important contributor to maternal and perinatal deaths at the JFKMC, Liberia. Continuous support by the government and development partners for the provision of critical life-saving medical equipment at the JFKMC is recommended.

Effects of Aquatic versus Land High-Intensity Interval Training on Acute Cardiometabolic and Perceptive Responses in Healthy Young Women.

The effects of aquatic high-intensity interval training (AHIIT) on cardiometabolic and perceptive responses when compared to similar land-based exercise (LHIIT) remain unknown. Here, we aimed to (1) establish a matched intensity between mediums and (2) compare the acute cardiometabolic and perceptive responses to the two interventions in healthy young women. Twenty healthy young women performed a stationary running exercise at a matched exercise intensity. The incremental stages, in terms of percentage of heart rate (HR), maximal oxygen uptake (%VO2max), percentage of oxygen uptake reserve (%VO2R), percentage of heart rate reserve (%HRR), and rate of perceived exertion (RPE), were examined and acute cardiometabolic and perceptive responses were evaluated. The results showed that HR was significantly reduced (AHIIT: W 150 ± 19, R 140 ± 18, LHIIT: W 167 ± 16, R 158 ± 16 p < 0.01) and oxygen pulse (AHIIT: W 12 ± 2, R 10 ± 2, LHIIT: W 11 ± 2, R 9 ± 2 p < 0.05) was significantly increased with AHIIT compared to LHIIT. No significant group differences were observed for the perceptive responses. The comparable results demonstrated by the aquatic and land incremental tests allow precise AHIIT and LHIIT prescriptions. AHIIT had distinct differences in HR and oxygen pulse, despite having no distinct difference from LHIIT for some cardiometabolic and affective responses.

Abnormal proximal-distal interactions in upper-limb of stroke survivors during object manipulation: A pilot study.

Despite its importance, abnormal interactions between the proximal and distal upper extremity muscles of stroke survivors and their impact on functional task performance has not been well described, due in part to the complexity of upper extremity tasks. In this pilot study, we elucidated proximal-distal interactions and their functional impact on stroke survivors by quantitatively delineating how hand and arm movements affect each other across different phases of functional task performance, and how these interactions are influenced by stroke. Fourteen subjects, including nine chronic stroke survivors and five neurologically-intact subjects participated in an experiment involving transport and release of cylindrical objects between locations requiring distinct proximal kinematics. Distal kinematics of stroke survivors, particularly hand opening, were significantly affected by the proximal kinematics, as the hand aperture decreased and the duration of hand opening increased at the locations that requires shoulder abduction and elbow extension. Cocontraction of the extrinsic hand muscles of stroke survivors significantly increased at these locations, where an increase in the intermuscular coherence between distal and proximal muscles was observed. Proximal kinematics of stroke survivors was also affected by the finger extension, but the cocontraction of their proximal muscles did not significantly increase, suggesting the changes in the proximal kinematics were made voluntarily. Our results showed significant proximal-to-distal interactions between finger extension and elbow extension/shoulder abduction of stroke survivors exist during their functional movements. Increased cocontraction of the hand muscles due to increased neural couplings between the distal and proximal muscles appears to be the underlying mechanism.

Therapeutic efficacy of matrix metalloproteinase-12 suppression on neurological recovery after ischemic stroke: Optimal treatment timing and duration.

We recently showed that the post-ischemic induction of matrix metalloproteinase-12 (MMP-12) in the brain degrades tight junction proteins, increases MMP-9 and TNFα expression, and contributes to the blood-brain barrier (BBB) disruption, apoptosis, demyelination, and infarct volume development. The objectives of this study were to (1) determine the effect of MMP-12 suppression by shRNA-mediated gene silencing on neurological/functional recovery, (2) establish the optimal timing of MMP-12shRNA treatment that provides maximum therapeutic benefit, (3) compare the effectiveness of acute versus chronic MMP-12 suppression, and (4) evaluate potential sex-related differences in treatment outcomes. Young male and female Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion and reperfusion. Cohorts of rats were administered either MMP-12shRNA or scrambled shRNA sequence (control) expressing plasmids (1 mg/kg; i.v.) formulated as nanoparticles. At designated time points after reperfusion, rats from various groups were subjected to a battery of neurological tests to assess their reflex, balance, sensory, and motor functions. Suppression of MMP-12 promoted the neurological recovery of stroke-induced male and female rats, although the effect was less apparent in females. Immediate treatment after reperfusion resulted in a better recovery of sensory and motor function than delayed treatments. Chronic MMP-12 suppression neither enhanced nor diminished the therapeutic effects of acute MMP-12 suppression, indicating that a single dose of plasmid may be sufficient. We conclude that suppressing MMP-12 after an ischemic stroke is a promising therapeutic strategy for promoting the recovery of neurological function.

The interplay between MMP-12 and t-PA in the brain after ischemic stroke.

Tissue-type plasminogen activator (t-PA) expression is known to increase following transient focal cerebral ischemia and reperfusion. Previously, we reported downregulation of t-PA upon suppression of matrix metalloproteinase-12 (MMP-12), following transient focal cerebral ischemia and reperfusion. We now present data on the temporal expression of t-PA in the brain after transient ischemia, as well as the interaction between MMP-12 and t-PA, two proteases associated with the breakdown of the blood-brain barrier (BBB) and ischemic brain damage. We hypothesized that there might be reciprocal interactions between MMP-12 and t-PA in the brain after ischemic stroke. This hypothesis was tested using shRNA-mediated gene silencing and computational modeling. Suppression of t-PA following transient ischemia and reperfusion in rats attenuated MMP-12 expression in the brain. The overall effect of t-PA shRNA administration was to attenuate the degradation of BBB tight junction protein claudin-5, diminish BBB disruption, and reduce neuroinflammation by decreasing the expression of the microglia/macrophage pro-inflammatory M1 phenotype (CD68, iNOS, IL-1ß, and TNFα). Reduced BBB disruption and subsequent lack of infiltration of macrophages (the main source of MMP-12 in the ischemic brain) could account for the decrease in MMP-12 expression after t-PA suppression. Computational modeling of in silico protein-protein interactions indicated that MMP-12 and t-PA may interact physically. Overall, our findings demonstrate that MMP-12 and t-PA interact directly or indirectly at multiple levels in the brain following an ischemic stroke. The present findings could be useful in the development of new pharmacotherapies for the treatment of stroke.