Reticulons 1 and 3 are essential for axonal growth and synaptic maintenance associated with intellectual development.

Reticulon (RTN) proteins are a family of proteins biochemically identified for shaping tubular endoplasmic reticulum, a subcellular structure important for vesicular transport and cell-to-cell communication. In our recent study of mice with knockout of both reticulon 1 (Rtn1) and Rtn3, we discovered that Rtn1-/-;Rtn3-/- (brief as R1R3dKO) mice exhibited neonatal lethality, despite the fact that mice deficient in either RTN1 or RTN3 alone exhibit no discernible phenotypes. This has been the first case to find early lethality in animals with deletion of partial members of RTN proteins. The complete penetrance for neonatal lethality can be attributed to multiple defects including the impaired neuromuscular junction found in the diaphragm. We also observed significantly impaired axonal growth in a regional-specific manner, detected by immunohistochemical staining with antibodies to neurofilament light chain and neurofilament medium chain. Ultrastructural examination by electron microscopy revealed a significant reduction in synaptic active zone length in the hippocampus. Mechanistic exploration by unbiased proteomic assays revealed reduction of proteins such as FMR1, Staufen2, Cyfip1, Cullin-4B and PDE2a, which are known components in the fragile X mental retardation pathway. Together, our results reveal that RTN1 and RTN3 are required to orchestrate neurofilament organization and intact synaptic structure of the central nervous system.

Postnatal neuronal Bace1 deletion impairs neuroblast and oligodendrocyte maturation.

Beta amyloid cleaving enzyme 1 (BACE1) is largely expressed by neurons and is the sole ß-secretase for initiating the production of neuronal ß-amyloid peptides (Aß). To fully understand the physiological functions of neuronal BACE1, we used mouse genetic approach coupled with unbiased single nucleus RNA sequencing (snRNAseq) to investigate how targeted deletion of Bace1 in neurons, driven by Thy-1-Cre recombinase, would affect functions in the nervous system. Our transcriptome results revealed that BACE1 is essential for maturation of neural precursor cells and oligodendrocytes in mice. RNA velocity analysis confirmed deficit in the trajectory of neuroblasts in reaching the immature granule neuron state in young Bace1fl/fl; Thy1-cre mice. Further analysis of differential gene expression indicated changes in genes important for SNARE signaling, tight junction signaling, synaptogenesis and insulin secretion pathways. Morphological studies revealed a hypomyelination in Bace1fl/fl;Thy1-cre sciatic nerves, but no detectable myelination changes in the corpus callosum, despite clear reduction in myelination proteins in the brain. Functional studies showed reduction in long-term potential, defects in synaptogenesis and learning behavioral. Altogether, our results show that neuronal BACE1 is critical for optimal development of central and peripheral nervous system, and inhibition of neuronal BACE1 will result in deficits in synaptic functions and cognitive behaviors.

Bace1 Deletion in the Adult Reverses Epileptiform Activity and Sleep-wake Disturbances in AD Mice.

Alzheimer's disease (AD) increases the risk for seizures and sleep disorders. We show here that germline deletion of ß-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) in neurons, but not in astrocytes, increased epileptiform activity. However, Bace1 deletion at adult ages did not alter the normal EEG waveform, indicating less concern for BACE1 inhibition in patients. Moreover, we showed that deletion of Bace1 in the adult was able to reverse epileptiform activity in 5xFAD mice. Intriguingly, treating 5xFAD and APPNL-G-F/NL-G-F (APP KI) mice of either sex with one BACE1 inhibitor Lanabecestat (AZD3293) dramatically increased epileptiform spiking, likely resulting from an off-target effect. We also monitored sleep-wake pathologies in these mice and showed increased wakefulness, decreased non-rapid eye movement sleep, and rapid eye movement sleep in both 5xFAD and APP KI mice; BACE1 inhibition in the adult 5xFAD mice reversed plaque load and sleep disturbances, but this was not seen in APP KI mice. Further studies with and without BACE1 inhibitor treatment showed different levels of plaque-associated microgliosis and activated microglial proteins in 5xFAD mice compared with APP KI mice. Together, BACE1 inhibition should be developed to avoid off-target effect for achieving benefits in reducing epileptic activity and sleep disturbance in Alzheimer's patients.SIGNIFICANCE STATEMENT BACE1 is widely recognized as a therapeutic target for treating Alzheimer's disease patients. However, BACE1 inhibitors failed in clinical trials because of inability to show cognitive improvement in patients. Here we show that BACE1 inhibition actually reduces sleep disturbances and epileptic seizures; both are seen in AD patients. We further showed that one of clinically tested BACE1 inhibitors does have off-target effects, and development of safer BACE1 inhibitors will be beneficial to AD patients. Results from this study will provide useful guidance for additional drug development.

Innovative stimuli-responsive membrane MSF brine rejection dilution by tertiary treated sewage effluent.

In this study, treated wastewater and Multi-Stage Flash (MSF) brine were integrated into the Forward Osmosis (FO) system using pressure stimuli-responsive Nanofiltration (PSRNF) membranes to dilute magnesium, calcium, and sulfate MSF plant brine reject. The deposition of magnesium sulfate and calcium sulfate in the heat exchanger is one of the main issues affecting the performance and efficiency of MSF thermal desalination plants. Reducing the concentration of the divalent ions can minimize scale formation and deposition to a level that allows the MSF plant to operate at high top brine temperature (TBT) and without scale problems. The PSRNF membranes were chosen in the FO process because of their high water permeability, rejection of divalent and monovalent ions, small structure parameter (S), and inexpensiveness compared to commercial FO membranes. Three PSRNF membranes were tested in the FO process with the feed solution facing the active membrane layer to avoid active layer delamination. Although the PSRNF membrane exhibited negligible water flux at 0 bar, it increased when a 2-4 bar was applied to the feed solution. The wastewater temperature was set at 25 °C while 40 °C was the brine operational temperature to mimic the field situation. A maximum average water flux of 39.5 L/m2h was recorded at 4 bar feed pressure when the PSRNF membrane was used for the brine dilution, achieving up to 42% divalent ions dilution at 0.02 kWh/m3 specific power consumption. The average water flux in the PRSNF membrane was 35% higher than that in the commercial TFC FO membrane. Notably, the PSRNF membrane is ten times cheaper than commercial FO membranes. Notably, the PSRNF membrane is ten times cheaper than commercial FO membranes, achieving substantial cost reductions and pioneering advancements in FO purification technology.

Synergistic control of urban heat island and urban pollution island effects using green infrastructure.

Urban heat island (UHI) and urban pollution island (UPI) effects are two major challenges that affect the liveability and sustainability of cities under the circumstance of climate change. However, existing studies mostly addressed them separately. Urban green infrastructure offers nature-based solutions to alleviate urban heat, enhance air quality and promote sustainability. This review paper provides a comprehensive synthesis of the roles of urban green spaces, street trees, street hedges, green roofs and vertical greenery in mitigating UHI and UPI effects. These types of green infrastructure can promote the thermal environment and air quality, but also potentially lead to conflicting impacts. Medium-sized urban green spaces are recommended for heat mitigation because they can provide a balance between cooling efficiency and magnitude. Conversely, street trees pose a complex challenge since they can provide cooling through shading and evapotranspiration while hindering pollutant dispersion due to reduced air ventilation. Integrated research that considers simultaneous UHI and UPI mitigation using green infrastructure, their interaction with building features, and the urban geographical environment is crucial to inform urban planning and maximize the benefits of green infrastructure installations.

1,6;2,3-Bis-BN Cyclohexane: Synthesis, Structure, and Hydrogen Release.

BN/CC isosterism has been widely investigated as a strategy to expand carbon-based compounds. The introduction of BN units in organic molecules always results in novel properties. In this work, we reported the first synthesis and characterization of 1,6;2,3-bis-BN cyclohexane, an isostere of cyclohexane with two adjacent BN pairs. Its ring flipping barrier is similar to that of cyclohexane. Protic hydrogens on N in 1,6;2,3-bis-BN cyclohexane show higher reactivity than its isomeric bis-BN cyclohexane. This compound exhibits an appealing hydrogen storage capability of >9.0 wt %, nearly twice as much as the 1,2;4,5-bis-BN cyclohexane.

Circular Nonuniform Electric Field Gel Electrophoresis for the Separation and Concentration of Nanoparticles.

A circular nonuniform electric field strategy coupled with gel electrophoresis was proposed to control the precise separation and efficient concentration of nano- and microparticles. The circular nonuniform electric field has the feature of exponential increase in the electric field intensity along the radius, working with three functional zones of migration, acceleration, and concentration. The distribution form of electric field lines is regulated in functional zones to control the migration behaviors of particles for separation and concentration by altering the relative position of the ring electrode (outside) and rodlike electrode (inner). The circular nonuniform electric field promotes the target-type and high-precision separation of nanoparticles based on the difference in charge-to-size ratio. The concentration multiple of nanoparticles is also controlled randomly with the alternation of radius, taking advantage of vertical extrusion and concentric converging of the migration path. This work provides a brand new insight into the simultaneous separation and concentration of particles and is promising for developing a versatile tool for the separation and preparation of various samples instead of conventional methods.

BACE1 controls synaptic function through modulating release of synaptic vesicles.

BACE1 initiates production of ß-amyloid peptides (Aß), which is associated with cognitive dysfunction in Alzheimer's disease (AD) due to abnormal oligomerization and aggregation. While BACE1 inhibitors show strong reduction in Aß deposition, they fail to improve cognitive function in patients, largely due to its role in synaptic function. We show that BACE1 is required for optimal release of synaptic vesicles. BACE1 deficiency or inhibition decreases synaptic vesicle docking in the synaptic active zones. Consistently, BACE1-null mice or mice treated with clinically tested BACE1 inhibitors Verubecestat and Lanabecestat exhibit severe reduction in hippocampal LTP and learning behaviors. To counterbalance this synaptic deficit, we discovered that BACE1-null mice treated with positive allosteric modulators (PAMs) of metabotropic glutamate receptor 1 (mGluR1), whose levels were reduced in BACE1-null mice and significantly improved long-term potentiation and cognitive behaviors. Similarly, mice treated with mGluR1 PAM showed significantly mitigated synaptic deficits caused by BACE1 inhibitors. Together, our data suggest that a therapy combining BACE1 inhibitors for reducing amyloid deposition and an mGluR1 PAM for counteracting BACE1-mediated synaptic deficits appears to be an effective approach for treating AD patients.

Partitioning variability in animal behavioral videos using semi-supervised variational autoencoders.

Recent neuroscience studies demonstrate that a deeper understanding of brain function requires a deeper understanding of behavior. Detailed behavioral measurements are now often collected using video cameras, resulting in an increased need for computer vision algorithms that extract useful information from video data. Here we introduce a new video analysis tool that combines the output of supervised pose estimation algorithms (e.g. DeepLabCut) with unsupervised dimensionality reduction methods to produce interpretable, low-dimensional representations of behavioral videos that extract more information than pose estimates alone. We demonstrate this tool by extracting interpretable behavioral features from videos of three different head-fixed mouse preparations, as well as a freely moving mouse in an open field arena, and show how these interpretable features can facilitate downstream behavioral and neural analyses. We also show how the behavioral features produced by our model improve the precision and interpretation of these downstream analyses compared to using the outputs of either fully supervised or fully unsupervised methods alone.

Chirality-driven self-assembly: application toward renewable/exchangeable resin-immobilized catalysts.

Resin-immobilized catalysts were prepared through chirality-driven self-assembly. The method allows the resin-immobilized catalyst to be regenerated under mild conditions and in situ catalyst exchange to be carried out quantitatively. The uniqueness of the methodology was demonstrated by the preparation of a catalyst for TEMPO oxidation as well as a two-step sequential TEMPO oxidation/aldol condensation sequence enabled by facile catalyst exchange.

Recent advances in pre-clinical diagnosis of Alzheimer's disease.

Alzheimer's disease (AD) is the most common dementia with currently no known cures or disease modifying treatments (DMTs), despite much time and effort from the field. Diagnosis and intervention of AD during the early pre-symptomatic phase of the disease is thought to be a more effective strategy. Therefore, the detection of biomarkers has emerged as a critical tool for monitoring the effect of new AD therapies, as well as identifying patients most likely to respond to treatment. The establishment of the amyloid/tau/neurodegeneration (A/T/N) framework in 2018 has codified the contexts of use of AD biomarkers in neuroimaging and bodily fluids for research and diagnostic purposes. Furthermore, a renewed drive for novel AD biomarkers and innovative methods of detection has emerged with the goals of adding additional insight to disease progression and discovery of new therapeutic targets. The use of biomarkers has accelerated the development of AD drugs and will bring new therapies to patients in need. This review highlights recent methods utilized to diagnose antemortem AD.

Water treatment sludge conversion to biochar as cementitious material in cement composite.

Water treatment sludge was successfully thermally converted to obtain biochar as a stable material with resource potential. This research explored the application of sludge biochar as a supplementary cementitious material. The cement paste samples incorporating different amounts of sludge biochar were prepared, hardened, and analyzed for performance. The results show an improvement in hydration kinetics and mechanical properties of cement paste incorporating biochar, compared to raw sewage sludge. The mineralogical, thermal and microscopic analyses show evidence of pozzolanic activity of the biochar. The samples with 2% and 5% biochar showed higher heat release than the reference material. Specimens with 1%, 2% and 5% biochar showed a slightly higher compressive strength at 28 days compared to the reference material. Sludge conversion to biochar will incur an estimated cost of US$398.23/ton, which is likely to be offset by the substantial benefits from avoiding landfill and saving valuable cementitious materials. Therefore, this research has demonstrated that through conversion to biochar, water treatment sludge can be promoted as a sustainable and alternative cementitious material for cement with minimum environmental impacts, hence contributing to circular economy.

Adsorption and desorption behavior of arsenite and arsenate at river sediment-water interface.

The adsorption of inorganic arsenic (As) plays an important role in the mobility and transport of As in the river environment. In this work, the adsorption and desorption of arsenite [As(III)] and arsenate [As(V)] on river sediment were conducted under different pH, initial As concentrations, river water and sediment composition to assess As adsorption behavior and mechanism. Both adsorption kinetics and equilibrium results showed higher adsorption capacity of sediment for As(V) than As(III). Adsorption of As(III) and As(V) on river sediment was favored in acidic to neutral conditions and on finer sediment particles, while sediment organic matter marginally reduced adsorption capacity. In addition, higher adsorption affinity of As(III) and As(V) in river sediment was observed in deionised water than in river water. For the release process, the desorption of both As(III) and As(V) followed nonlinear kinetic models well, showing higher amount of As(III) release from sediment than As(V). Adsorption isotherm was well described by both Langmuir and Freundlich models, demonstrating higher maximum adsorption capacity of As(V) at 298.7 mg/kg than As(III) at 263.3 mg/kg in deionised water, and higher maximum adsorption capacity of As(III) of 234.3 mg/kg than As(V) of 206.2 mg/kg in river water. The XRD showed the changes in the peaks of mineral groups of sediment whilst FTIR results revealed the changes related to surface functional groups before and after adsorption, indicating that Fe-O/Fe-OH, Si(Al)-O, hydroxyl and carboxyl functional groups were predominantly involved in As(III) and As(V) adsorption on sediment surface. XPS analysis evidenced the transformation between these As species in river sediment after adsorption, whilst SEM-EDS revealed higher amount of As(V) in river sediment than As(III) due to the lower signal of Al.

Advances in As contamination and adsorption in soil for effective management.

Arsenic (As) is a heavy metal that causes widespread contamination and toxicity in the soil environment. This article reviewed the levels of As contamination in soils worldwide, and evaluated how soil properties (pH, clay mineral, organic matter, texture) and environmental conditions (ionic strength, anions, bacteria) affected the adsorption of As species on soils. The application of the adsorption isotherm models for estimating the adsorption capacities of As(III) and As(V) on soils was assessed. The results indicated that As concentrations in contaminated soil varying significantly from 1 mg/kg to 116,000 mg/kg, with the highest concentrations being reported in Mexico with mining being the dominating source. Regarding the controlling factors of As adsorption, soil pH, clay mineral and texture had demonstrated the most significant impacts. Both Langmuir and Freundlich isotherm models can be well fitted with As(III) and As(V) adsorption on soils. The Langmuir adsorption capacity varied in the range of 22-42400 mg/kg for As(V), which is greater than 45-8901 mg/kg for As(III). The research findings have enhanced our knowledge of As contamination in soil and its underlying controls, which are critical for the effective management and remediation of As-contaminated soil.

Feasibility of H2O2 cleaning for forward osmosis membrane treating landfill leachate.

This study reports landfill leachate treatment by the forward osmosis (FO) process using hydrogen peroxide (H2O2) for membrane cleaning. Although chemical cleaning is an effective method for fouling control, it could compromise membrane integrity. Thus, understanding the impact of chemical cleaning on the forward osmosis membrane is essential to improving the membrane performance and lifespan. Preliminary results revealed a flux recovery of 98% in the AL-FS mode (active layer facing feed solution) and 90% in the AL-DS (draw solution faces active layer) using 30% H2O2 solution diluted to 3% by pure water. The experimental work investigated the effects of chemical cleaning on the polyamide active and polysulfone support layers since the FO membrane could operate in both orientations. Results revealed that polysulfone support layer was more sensitive to H2O2 damage than the polyamide active at a neutral pH. The extended exposure of thin-film composite (TFC) FO membrane to H2O2 was investigated, and the active layer tolerated H2O2 for 72 h, and the support layer for only 40 h. Extended operation of the TFC FO membrane in the AL-FS based on a combination of physical (hydraulic flushing with DI water) and H2O2 was reported, and chemical cleaning with H2O2 could still recover 92% of the flux.

A remote sensing emissions monitoring programme reduces emissions of gasoline and LPG vehicles.

Vehicle emissions are a major source of air pollution in Hong Kong affecting human health. A 'strengthened emissions control of gasoline and liquefied petroleum gas (LPG) vehicles' programme has been operating in Hong Kong since September 2014 utilising remote sensing (RS) technology. RS has provided measurement data to successfully identify high emitting gasoline and LPG vehicles which then need to be repaired or removed from the on-road vehicle fleet. This paper aims to evaluate the effectiveness of this globally unique RS monitoring programme. A large RS dataset of 2,144,422 records was obtained covering the period from 6th January 2012 to 30th December 2016, of which 1,206,762 records were valid and suitable for further investigation. The results show that there have been significant reductions of emissions factors (EF) for 40.5% HC, 45.3% CO and 29.6% NO for gasoline vehicles. Additionally, EF reductions of 48.4% HC, 41.1% CO and 58.7% NO were achieved for LPG vehicles. For the combined vehicle fleet, the reductions for HC, CO and NO were 55.9%, 50.5% and 60.9% respectively during this survey period. The findings demonstrate that the strengthened emissions control programme utilising RS has been very effective in identifying high emitting vehicles for repair so as to reduce the emissions from gasoline and LPG vehicles under real driving.

Chemical and microbiological risk assessment of urban river water quality in Vietnam.

The contamination and risk by nutrients (NH4+, NO2-, NO3- and PO43-), COD, BOD5, coliform and potentially toxic elements (PTEs) of As, Cd, Ni, Hg, Cu, Pb, Zn and Cr were investigated in urban river (Nhue River), Vietnam during 2010-2017. The extensive results demonstrated that concentrations of these contaminants showed significant spatial and temporal variations. The Nhue River was seriously polluted by NH4+ (0.025-11.28 mg/L), PO43- (0.17-1.72 mg/L), BOD5 (5.8-179.6 mg/L), COD (1.4-239.8 mg/L) and coliform (1540-326,470 CFU/100 mL); moderately polluted by As (0.2-131.15 µg/L) and Hg (0.11-4.1 µg/L); and slightly polluted by NO2- (0.003-0.33 mg/L) and Cd (2.1-18.2 µg/L). The concentrations of NH4+, PO43-, COD, BOD5 and coliform frequently exceeded both drinking water guidelines and irrigation water standards. Regarding PTEs, As, Cd and Hg concentrations were frequently higher than the regulatory limits. Human health risks of PTEs were evaluated by estimating hazard index (HI) and cancer risk through ingestion and dermal contacts for adults and children. The findings indicated that As was the most important pollutant causing both non-carcinogenic and carcinogenic concerns. The non-carcinogenic risks of As were higher than 1.0 at all sites for both adults (HI = 1.83-7.4) and children (HI = 2.6-10.5), while As posed significant carcinogenic risks for adults (1 × 10-4-4.96 × 10-4). A management strategy for controlling wastewater discharge and protecting human health is urgently needed.

Industrial metal pollution in water and probabilistic assessment of human health risk.

Concentration of eight heavy metals in surface and groundwater around Dhaka Export Processing Zone (DEPZ) industrial area were investigated, and the health risk posed to local children and adult residents via ingestion and dermal contact was evaluated using deterministic and probabilistic approaches. Metal concentrations (except Cu, Mn, Ni, and Zn) in Bangshi River water were above the drinking water quality guidelines, while in groundwater were less than the recommended limits. Concentration of metals in surface water decreased as a function of distance. Estimations of non-carcinogenic health risk for surface water revealed that mean hazard index (HI) values of As, Cr, Cu, and Pb for combined pathways (i.e., ingestion and dermal contact) were >1.0 for both age groups. The estimated risk mainly came from the ingestion pathway. However, the HI values for all the examined metals in groundwater were <1.0, indicating no possible human health hazard. Deterministically estimated total cancer risk (TCR) via Bangshi River water exceeded the acceptable limit of 1 × 10-4 for adult and children. Although, probabilistically estimated 95th percentile values of TCR exceeded the benchmark, mean TCR values were less than 1 × 10-4. Simulated results showed that 20.13% and 5.43% values of TCR for surface water were >1 × 10-4 for adult and children, respectively. Deterministic and probabilistic estimations of cancer risk through exposure to groundwater were well below the safety limit. Overall, the population exposed to Bangshi River water remained at carcinogenic and non-carcinogenic health threat and the risk was higher for adults. Sensitivity analysis identified exposure duration (ED) and ingestion rate (IR) of water as the most relevant variables affecting the probabilistic risk estimation model outcome.

Estrogenic compounds in Tunisian urban sewage treatment plant: occurrence, removal and ecotoxicological impact of sewage discharge and sludge disposal.

The occurrence, fate and ecotoxicological assessment of selected estrogenic compounds were investigated at Tunisian urban sewage treatment plant. The influents, effluents, as well as primary, secondary and dehydrated sludge, were sampled and analyzed for the target estrogens to evaluate their fate. All target compounds were detected in both sewage and sludge with mean concentrations from 0.062 to 0.993 µg L-1 and from 11.8 to 792.9 µg kg-1dry weight, respectively. A wide range of removal efficiencies during the treatment processes were observed, from 6.3 % for estrone to 76.8 % for estriol. Ecotoxicological risk assessment revealed that the highest ecotoxicological risk in sewage effluent and dehydrated sludge was due to 17ß-estradiol with a risk quotient (RQ) of 4.6 and 181.9, respectively, and 17α-ethinylestradiol with RQ of 9.8 and 14.85, respectively. Ecotoxicological risk after sewage discharge and sludge disposal was limited to the presence of 17ß-estradiol in dehydrated-sludge amended soil with RQ of 1.38. Further control of estrogenic hormones in sewage effluent and sludge is essential before their discharge and application in order to prevent their introduction into the natural environment.

Photocatalytic Degradation of Pharmaceutical Residues from Water and Sewage Effluent Using Different TiO2 Nanomaterials.

Pharmaceuticals are widely used and often discharged without metabolism into the aquatic systems. The photocatalytic degradation of pharmaceutical compounds propranolol, mebeverine, and carbamazepine was studied using different titanium dioxide nanostructures suspended in water under UV and UV-visible irradiation. Among three different photocatalysts, the degradation was most effective by using Degussa P25 TiO2, followed by Hombikat UV100 and Aldrich TiO2. The photocatalytic performance was dependent on photocatalyst dosage, with an optimum concentration of 150 mg L-1. The natural aquatic colloids were shown to enhance the extent of photocatalysis, and the effect was correlated with their aromatic carbon content. In addition, the photocatalysis of pharmaceuticals was enhanced by the presence of nitrate, but inhibited by the presence of 2-propanol, indicating the importance of hydroxyl radicals. Under optimum conditions, the pharmaceuticals were rapidly degraded, with a half-life of 1.9 min, 2.1 min, and 3.2 min for propranolol, mebeverine, and carbamazepine, respectively. In treating sewage effluent samples, the photocatalytic rate constants for propranolol (0.28 min-1), mebeverine (0.21 min-1), and carbamazepine (0.15 min-1) were similar to those in water samples, demonstrating the potential of photocatalysis as a clean technology for the effective removal of pharmaceuticals from sewage effluent.