Parkinson's disease (PD) is characterized by α-synuclein aggregation and perturbation of the endolysosomal network (ELN), yet the molecular mechanisms linking α-synuclein pathology to neuronal dysfunction remain unclear. Here we report that treatment of mouse cortical neurons with α-synuclein preformed fibrils (PFFs) alters lysosomal composition and impairs lysosomal function, coupled with extensive chromatin remodeling and transcriptional reprogramming, including suppression of neuronal gene networks and activation of senescence-like programs. Mechanistically, these changes are associated with rapid recruitment and activation of the PD-associated kinase LRRK2 on early endosomes, where it phosphorylates Rab5, a key early endosomal GTPase, leading to remodeling of the Rab5 interactome, altered effector engagement, and endosomal dyshomeostasis. Pharmacological inhibition of LRRK2 with MLi-2 restores Rab5 activity, lysosomal function, chromatin accessibility, gene expression, and neuronal excitability. Knockdown of Rab5 partially rescues chromatin changes, supporting its role as a downstream effector. These findings identify LRRK2 hyperactivation and the LRRK2-Rab5 axis as key mediators of PFF-induced neuronal dysfunction, highlighting early endosomes as a central platform linking endolysosomal disruption to nuclear responses and offering potential targets for therapeutic intervention in PD.

Increased APP gene dosage is both necessary and sufficient to result in Down Syndrome Alzheimer’s Disease (DSAD) in humans and AD-related degenerative changes in mouse models of DS. We tested antisense oligonucleotides (ASOs) designed to suppress APP expression via RNAseH1-mediated degradation in the Dp(16)1Yey or Dp(16) model of Down Syndrome. Dp(16) is trisomic for human chromosome 21 syntenic regions on murine chromosome 16, containing 115 genes including APP. To evaluate efficacy of APP suppression, Dp16 and 2N euploid mice at 6-8 months of age were treated with a mouse App ASO, and endosomal pathology and downstream pathological processes were evaluated. APP suppression reverses not only Rab5 hyperactivation in this model, but also abnormal hyperactivation of other Rab GTPases such as Rab7 and Rab11. Furthermore, tau hyperphosphorylation was ameliorated, and neurotrophin signaling was restored following APP suppression. Taken together, these data support the hypothesis that APP suppression should restore normal endosomal function and neurotrophic signaling and benefit disease, and the potential of antisense-mediated APP suppression as a disease-modifying therapy for DSAD.

High-performance proof-of-concept 128x128 InGaAs/GaAs strained-layer superlattice (SLS) photodiode (PD) array, featuring 8 x 8 mu m2 pixels with 2 mu m interpixel gap, is demonstrated for efficient 1064 nm detection. The SLS photoabsorber design parameters are engineered using a calibrated 8-band k & sdot;p Schrodinger-Poisson solver, while Sentaurus-TCAD simulations guide device-level optimization for low dark-current, fast response, similar to 75% quantum efficiency, and low-bias operation. Initial design implementations with conventional vertical sidewall mesas exhibit similar to 60% surface leakage contribution in dense arrays. A quantum-well-intermixed tapered sidewall mesa (QWI-TSM) architecture, developed here using a low-thermal-budget Ar plasma-induced intermixing, and SU-8 passivation has helped devices reduce the surface current density contribution down to 14%. The fabricated arrays exhibit a dark current of 9 nA and QE similar to 60% at -1 V, approaching commercial 1064 nm PD performance, with further gains expected through improved epitaxy. These results validate the proposed scalable InGaAs/GaAs SLS PD arrays for next-generation high-performance 1064 nm near-infrared imaging and sensing.

The upcoming 6G communication network requires unprecedented data rates. However, RF systems with restricted bandwidth are insufficient for supporting services like multimedia applications, autonomous vehicles, online gaming etc. Inter-satellite Optical Wireless Communication (IsOWC) is a special category of optical wireless communication (OWC) system that enables high speed data transmission between satellites in the absence of any physical medium. Conversely, IsOWC face challenges such as satellite vibration, pointing error, background noise, and Doppler shift. These issues require sophisticated methods to improve the quality of data transmission. The construction and simulation of a novel IsOWC system utilizing multiple transmitters and receivers (TX/RX) antennas are explored in this study. In this work, the Dual Polarization Quadrature Amplitude Modulation (DP-QAM) with diversity scheme is employed. The proposed model enables the transmission of 100 Gbps data over a 6,000 km link distance. The system performance is conducted for both with and without diversity. The outcome illustrates that a system using hybrid diversity optimizes received power, link distance, bit error rate (BER), and quality factor (Q-factor). The study also emphasizes that the combined effect of polarization and spatial diversity is more effective in minimizing channel non-linearities. Therefore, hybrid diversity techniques effectively address challenges in inter-satellite optical communication enabling resilient, high-speed, and secure satellite network.

A three-parameter probability distribution is derived from a composed cumulative distribution function, which is itself a family of bounded support transformations. The transformed model called the doubly bounded exponential distribution, which exhibits decreasing shaped density while the hazard rate has increasing shape. Some statistical properties are obtained in closed form, such as the moments and various entropy functions. The parameter estimation is carried out by the methods of maximum likelihood estimate, least squares estimate, weighted least squares estimate, Anderson-Darling estimate, and Cramer-von Mises estimate. The performance of these estimators is assessed through a Monte Carlo simulation study. The identifiability of the DB-Exp model's parameters is also investigated. The proposed distribution can produce a higher performance than several well-known bounded distributions in the literature, as shown by an application to rainfall data.

An efficient tapered coupling mechanism for monolithic integration of active and passive devices on InGaAsP/InP quantum well (QW) structures is theoretically analyzed and experimentally demonstrated. An easier fabrication technique using ZrO_2 impurity-free QW-intermixing is used to achieve vertical tapering, while photolithography is used to optimize horizontal tapering. The importance of designing the epitaxial layer specifically for this fabrication technique and the device combination to be used is demonstrated. First, on a regular InGaAsP/InP waveguide photodiode structure and then redesigning the same for optimization and experimental verification. The improvement is achieved by introducing an InGaAs/InP superlattice (SL)—graded index (GRIN) with a single QW absorption layer in the waveguide core. Asymmetrical InGaAs/InP SL cladding layers are used for lower optical losses and higher index contrast. While the regular structure shows a reduction in coupling and insertion loss of 1 and 3 dB, respectively, a redesign of the epitaxial structure brought down the same by 7.5 and 9.0 dB, respectively.

Amyloid β (Aβ) peptides accumulating in the brain are proposed to trigger Alzheimer's disease (AD). However, molecular cascades underlying their toxicity are poorly defined. Here, we explored a novel hypothesis for Aβ42 toxicity that arises from its proven affinity for γ-secretases. We hypothesized that the reported increases in Aβ42, particularly in the endolysosomal compartment, promote the establishment of a product feedback inhibitory mechanism on γ-secretases, and thereby impair downstream signaling events. We show that human Aβ42 peptides, but neither murine Aβ42 nor human Aβ17-42 (p3), inhibit γ-secretases and trigger accumulation of unprocessed substrates in neurons, including C-terminal fragments (CTFs) of APP, p75 and pan-cadherin. Moreover, Aβ42 treatment dysregulated cellular -homeostasis, as shown by the induction of p75-dependent neuronal death in two distinct cellular systems. Our findings raise the possibility that pathological elevations in Aβ42 contribute to cellular toxicity via the γ-secretase inhibition, and provide a novel conceptual framework to address Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling.

In the present scenario, ultra-high bit rate communication systems are highly indispensable for 5G and 6G wireless communication applications such as: live video streaming, autonomous driving, online gaming, drone-based delivery etc. For smooth operations, spectrally efficient and low bit error communication system are highly essential. But the conventional RF based systems cannot support this demand. So, to meet these ever-growing requirements, optical systems are the viable option. It enables ultra-high data rate (~ 40Gbps), ultra-low latency (<1ms), ultra reliable, wide range of coverage, integrating with air/space and under water networks. The optical wireless communication (OWC) system and inter-satellite optical wireless communication (IsOWC) technology look promising for meeting all these high demand applications. IsOWC system is a type of OWC setup that ensures faster data transfer between satellites in space. The key drawbacks of IsOWC system includes attenuation, pointing error, channel impairments, background noise etc. In this work, an IsOWC system is proposed with Dual Polarization Quadrature Phase Shift Keying (DP-QPSK) modulation and artificial neural network (ANN) based equalizer, which overcomes these challenges. Performance parameters like bit error rate (BER), time domain visualizers, link distance, OSNR are used here. The proposed model will be highly useful for upcoming ultra-high speed communication applications.

A physical model-based simulation is conducted to investigate the design of an efficient high-speed quantum-well waveguide-photodetector (WGPD). The WGPD structure is optimized in terms of photoabsorber thickness, i-region thickness, cladding doping and thickness. The carrier transit-time and device capacitance effect are reduced for a WGPD by employing a ≤ 50 nm thin-photoabsorber in a 0.66 μ m thick i-region design. A three-fold improvement in responsivity up to 0.82 A/W is obtained by using two graded-index layers. The accurately positioned TPA layer in a thick i-region can provide up to 50 μ m long WGPD. The optimized WGPD design can achieve 3-dB bandwidth over 80 and 50 GHz for 25 and 50 μ m long WGPD, respectively. The device satisfies the requirements of high-speed, low dark current, high responsivity, and integration capabilities, which is an essential prerequisite for high-performance detectors in future optical communication systems.

Here, a study of steady, magnetohydrodynamic flow of incompressible, cold fluid around a moving plate with a non‐Darcian porous medium in existence of heat source and n th‐order chemical reaction incorporating Soret and Dufour effects is considered. MATLAB bvp4c technique is used to solve the prevailing equations. Variations in velocity, temperature and concentration are analysed. It is observed that the applicable parameters such as non‐Darcy, Soret, Dufour, chemical reaction play a significant role in controlling the flow. Chemical reaction parameter reduces skin friction, heat transfer, and mass transfer while Eckert number enhances the mass transfer and skin friction.

In this study an attempt has been made to propose a way to develop new distribution. For this purpose, we need only idea about distribution function. Some important statistical properties of the new distribution like moments, cumulants, hazard and survival function has been derived. The renyi entropy, shannon entropy has been obtained. Also ML estimate of parameter of the distribution is obtained, that is not closed form. Therefore, numerical technique is used to estimate the parameter. Some real data sets are used to check the suitability of this distribution over some other existing distributions such as Lindley, Garima, Shanker and many more. AIC, BIC, -2loglikihood, K-S test suggest the proposed distribution works better than others distributions considered in this study.

Inter-satellite optical wireless communication (IsOWC) is a promising technology that can be used for high-speed data transfer between satellites in space. In this paper, using decision feedback equalizer (DFE) and Dual Polarization Quadrature Phase Shift Keying (DP-QPSK) modulation techniques an IsOWC system is proposed. It is a 16-channel multiplexed system. Optical systems perform better in terms of bandwidth, power and light weight comparing to radio frequency (RF) systems. For satellite systems, weight is also an important factor. Thus, IsOWC is becoming more popular in recent days. The proposed system uses 30 dBm input power at 1550 nm wavelength. The major limitations of the IsOWC systems are pointing error, bean divergence, back ground light etc. These limitations can be minimized by using advanced modulation, equalization, diversity, coding techniques etc. As the communication channel behavior is non-linear in nature, here DFE equalizer is used. The system performance is compared with equalization and without equalization techniques. It has been designed and analyzed using OptiSystem and MATLAB environment. The date rate used is 40 Gbps for high-speed communication applications. Bit error rate (BER), link distance, optical spectra, optical time domain reflectometer (OTDR) diagrams, and Q-factor are all used to analyze the system performance. Future 5G wireless communication applications will greatly benefit from the suggested approach.

Γ-secretases are proteolytic switches at the membrane regulating multiple signaling cascades. Their dysfunction, resulting in enhanced generation of longer amyloid β (Aβ) peptides from the amyloid precursor protein (APP), leads to neurodegeneration in the context of Alzheimer’s disease (AD), while their inhibition causes neurodegenerative phenotypes in mice and cognitive worsening in AD patients treated with γ-secretase inhibitors. The accumulation of Aβ in the brain is the earliest pathological hallmark of AD. Based on the proven affinity of Aβ peptides for γ-secretases, we hypothesized that elevations in Aβ levels would promote an inhibitory-feedback mechanism on γ-secretases and impair downstream cell signaling events. We conducted rigorous kinetic analyses of γ-secretase activity in the presence of a series of Aβ and p3 peptides, by quantifying the levels of intracellular domains generated from different γ-secretase substrates in cell-free assays. In addition, we determined the effects of these peptides on endogenous γ-secretase activity in living neurons, using a ratiometric FRET-based reporter and western blot analysis of the levels of immediate γ-secretase substrates. Furthermore, we assessed the impact of Aβ and p3 peptides on γ-secretase-mediated, p75- and TrkA-dependent downstream signaling via immunostaining for an apoptotic marker: cleaved caspase 3. Finally, we evaluated the impact of Aβ peptides on APP processing in synaptosome fractions derived from mouse brains. Our analyses showed that human Aβ42 inhibited γ-secretase activity and accordingly caused accumulation of unprocessed γ-secretase substrates in neuronal cells, i.e. CTFs of APP, p75 and pan-cadherin. Remarkably, neither murine Aβ42 nor human p3 (17-42) peptides exerted the inhibition. In TrkA signaling deficient PC12 cells and basal forebrain cholinergic neurons, Aβ1-42-mediated inhibition of γ-secretase led to the accumulation of unprocessed p75-CTFs and potentiated p75-dependent cell death, mimicking the effects of γ-secretase inhibitors. We demonstrate that the pathologically relevant human Aβ1-42 exerts product feedback inhibition on γ-secretases, leading to dysregulation of downstream cellular signaling. These findings provide a novel conceptual framework for investigations of Aβ toxicity in the context of γ-secretase-dependent homeostatic signaling and raise the possibility that Aβ42-mediated inactivation of these enzymes contributes to AD development.

This work represents a particular application of waveguide fabricated by femtosecond laser micromachining technology. More specifically, we report the development of an optical modulator based on the fabrication of single-mode optical waveguide structures buried in X-cut lithium niobate crystal with the femtosecond laser direct writing method. Here, change in refractive index profile is measured using near field intensity profile measurement method at optimized writing conditions. It has been observed that the change refractive index ({\Delta}n) is in the range of 10-4. Finally, the behavior of femtosecond written waveguides as an intensity modulator at 632.8 nm and 1550 nm under the influence of an external electric field is analyzed by pattering electrode structures on the substrate respectively.

Analysis of a time‐independent magnetohydrodynamic viscoelastic fluid flow in a deformable inclined porous layer with first‐order chemical reaction has been investigated. Walters' fluid model has been used to study viscoelastic fluid. The walls are suctioned/injected at a constant rate. The expression representing the solution for solid displacement, fluid velocity, temperature, and concentration distribution is obtained. The effect of applicable parameters on solid displacement, fluid velocity, temperature, and concentration are discussed graphically, while skin friction, heat transfer, and mass transfer are revealed in a tabular structure. It is noticed that solid displacement, fluid velocity, and temperature profiles decrease when the viscoelastic parameter increase. Solid displacement enhances and the velocity of the fluid reduces owing to the influence of increasing drag parameter, whereas the reverse effect is seen for the volume fraction parameter. Nusselt number at the walls shows the opposite behavior for the viscoelastic parameter and Eckert number. Sherwood number at the walls shows opposite behavior for Reynolds number, Schmidt number, and radiation parameter. Also, the entropy generation number rises as a result of the influence of viscoelasticity and Eckert number.

Phosphorylation of a-synuclein at the Serine-129 site (a-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In physiologic states, only a small fraction of a-syn is phosphorylated at this site, and most studies have focused on the pathologic roles of this post-translational modification. We found that unlike wild-type (WT) a-syn which is widely expressed throughout the brain, the overall pattern of a-syn Ser129P is restricted, suggesting intrinsic regulation. Surprisingly, preventing Ser129P blocked activity-dependent synaptic attenuation by a-syn – thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments Ser129P, which is a trigger for protein-protein interactions that are necessary for mediating a-syn function at the synapse. AlphaFold2-driven modeling and membrane-binding simulations suggest a scenario where Ser129P induces conformational changes that facilitate interactions with binding partners. Our experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for drug-development.

Antibiotics, the primary drugs used to cure bacterial diseases, are increasingly becoming ineffective due to the emergence of multiple drug resistance (MDR) leading to recurrence of previously sensitive pathogens. Human gut microbiome (GM), known to play an important role in various physiological processes, consists of pool of diverse microbes. Indiscriminate use of antibiotics during the life span of an individual may lead to development of resistant microbes e.g. Vibrio, Acinetobacter, Escherichia, Klebsiella, Clostridia, etc. in the human GM. Transmission of antibiotic resistant genes (ARGs) between pathogenic and commensal bacteria occurs more frequently in microbiome communities wherein bacteria communicate and exchange cellular constituents both among themselves and with the host. Additionally, co-factors like 'early vs. late' exposure, type of antibiotics and duration of treatment modulate the adverse effects of antibiotics on GM maturation. Furthermore, factors like mode of birth, ethnicity, malnutrition, demography, diet, lifestyle, etc., which influence GM composition, can also indirectly alter the host response to antibiotics. Currently, advanced 'omics' and culturomics approaches are revealing novel avenues to study the interplay between antibiotics and the microbiome and to identify resistant genes in these bacterial communities. Here, we discuss the recent developments that have given insights into the effects of antibiotics on the homeostatic balance of the gut microbiome and thus on human health.

Here, an investigation of MHD Couette flow of a chemically reacting viscoelastic fluid past a deformable porous layer with entropy generation using Walters liquid model has been considered. A binary, homogeneous, and isotropic mixture of fluid and solid phases in the porous medium is considered. The impact of heat source parameter and Soret effect are taken into account. The governing equations are solved analytically to obtain the expressions for solid displacement, fluid velocity, temperature, and concentration. The impact of relevant parameters on the flow system, temperature, concentration, mass transfer flux, entropy generation number, and Bejan number are discussed graphically. It is observed that solid displacement enhances due to the growth of drag and viscoelastic parameter, while it reduces due to rising volume fraction parameter. Fluid velocity rises when the volume fraction parameter increases. Rising Brinkmann number enhances the temperature, while Brinkmann number and Soret number reduces the species concentration. The irreversibility of heat transfer dominates the flow near the channel plates, while the effect of fluid friction irreversibility can be observed within the channel centerline region.

The present experiment was conducted to estimate the physico-chemical diversity of twelve Indian jujube cultivars. A sum of fifteen quantitative characters were explored and subjected to multivariate analyses. Significant variability was observed across the ber cultivars under study. Pearson's correlation analysis identified days to first flower initiation, a higher number of flowers per cluster and a higher number of retained fruits per cluster which could be used as the basis of selection for identification of high yielding ber cultivars. The principal component analysis (PCA) estimates 60.2% of the total variability in ber cultivars is contributed by PC1 and PC2. The scatter plot of the first two components highlights the number of retained fruits per cluster, yield per tree, pulp weight, fruit width, stone weight and number of flowers per cluster as principal characters that played a significant role in the total variability. Further, PCA also helped to identify Mehrun, Manuki and Chhuhara as superior ber cultivars which performed well with respect to the PC1 and PC2. The Mahalanobis D-2 statistics grouped all the twelve ber cultivars into five clusters indicating the existence of ample genetic diversity among the cultivars. Considering the inter-cluster distance along with cluster mean it could be concluded that the cultivars of cluster II and Cluster III may be utilized to estimate the combining ability for effective exploitation of heterosis or to isolate desirable transgressive segregants.