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Proteomic studies utilizing postmortem human brain tissue samples have yielded robust assessments of the aging and neurodegenerative disease(s) proteomes. While these analyses provide lists of molecular alterations in human conditions, like Alzheimer’s disease (AD), identifying individual proteins that affect biological processes remains a challenge. To complicate matters, protein targets may be highly understudied and have limited information on their function. To address these hurdles, we sought to establish a blueprint to aid selection and functional validation of targets from proteomic datasets. A cross-platform pipeline was engineered to focus on synaptic processes in the entorhinal cortex of human patients, including controls, preclinical AD, and AD cases. Label-free quantification mass spectrometry data (n=2,260 proteins) was generated on synaptosome fractionated tissue from Brodmann area 28 (n=58 samples). In parallel, dendritic spine density and morphology was measured in the same individuals. Weighted gene co-expression network analysis was used to construct a network of protein co-expression modules that were correlated with dendritic spine metrics. Module-trait correlations were used to guide unbiased selection of Twinfilin-2 (TWF2), which was the top hub protein of a module that positively correlated with thin spine length. Using CRISPR-dCas9 activation strategies, we demonstrated that boosting endogenous TWF2 protein levels in primary hippocampal neurons increased thin spine length, thus providing experimental validation for the human network analysis. Collectively, this study describes alterations in dendritic spine density and morphology as well as synaptic proteins and phosphorylated tau from the entorhinal cortex of preclinical and advanced stage AD patients.Significance Statement:Proteomic studies can yield vast lists of molecules that are altered under various experimental or disease conditions. Here, we provide a blueprint to facilitate mechanistic validation of protein targets from human brain proteomic datasets. We conducted a proteomic analysis of human entorhinal cortex samples spanning cognitively normal and Alzheimer's disease cases with a comparison of dendritic spine morphology in the same samples. Network integration of proteomics with dendritic spine measurements allowed for unbiased discovery of Twinfilin-2 as a regulator of dendritic spine length. A proof-of-concept experiment in cultured neurons demonstrated that altering Twinfilin-2 protein level induced corresponding changes in dendritic spine length, thus providing experimental validation for the computational framework.

Dendritic spines are small protrusions on dendrites that serve as the postsynaptic site of the majority of excitatory synapses. These structures are important for normal synaptic transmission, and alterations in their density and morphology have been documented in various disease states. Over 130 years ago, Ramón y Cajal used Golgi-stained tissue sections to study dendritic morphology. Despite the array of technological advances, including iontophoretic microinjection of Lucifer yellow (LY) fluorescent dye, Golgi staining continues to be one of the most popular approaches to visualize dendritic spines. Here, we compared dendritic spine density and morphology among pyramidal neurons in layers 2/3 of the mouse medial prefrontal cortex (mPFC) and pyramidal neurons in hippocampal CA1 using three-dimensional digital reconstructions of (1) brightfield microscopy z-stacks of Golgi-impregnated dendrites and (2) confocal microscopy z-stacks of LY-filled dendrites. Analysis of spine density revealed that the LY microinjection approach enabled detection of approximately three times as many spines as the Golgi staining approach in both brain regions. Spine volume measurements were larger using Golgi staining compared to LY microinjection in both mPFC and CA1. Spine length was mostly comparable between techniques in both regions. In the mPFC, head diameter was similar for Golgi staining and LY microinjection. However, in CA1, head diameter was approximately 50% smaller on LY-filled dendrites compared to Golgi staining. These results indicate that Golgi staining and LY microinjection yield different spine density and morphology measurements, with Golgi staining failing to detect dendritic spines and overestimating spine size.

The challenge of the Chinese Church is to explore an innovative and effective operational model of its own. This essay studies the phenomenon of the Chinese Church in mainland China but does not include those in Taiwan, Hong Kong, and Macau. It discusses the complexity of Chinese churches as they have survived and thrived over the centuries and explores the compatibility of Chinese Christians’ religious experiences with the biblical tradition of the church. It surveys the rise, the struggle, the mission, and the hope of the following churches in China: Chinese Three-Self Patriotic Protestant (TSP), Protestant Family Churches, Catholic Churches, and Russian Orthodox Churches.

Tumid lupus erythematosus (TLE) is a rare form of chronic cutaneous lupus that has triggered much debate regarding its clinical and histopathological features. It has been classically defined as annular erythematous, succulent, plaques involving the face and trunk that typically are devoid of any papulosquamous features such as scale and follicular plugging. These lesions are a clinical mimicker of other urticarial lesions such as urticarial vasculitis and lymphocytic infiltrate of Jessner. We report a case of TLE presenting in a 49-year-old Caucasian female whose initial clinical presentation was concerning for urticarial vasculitis due to presence of urticarial-like lesions present for approximately three months. Laboratory studies and histopathological correlations confirmed the diagnosis of TLE and the patient was successfully treated with topical corticosteroids.

Immune checkpoints have been the subject of a wave of new studies. Among these checkpoints are tytotoxic T-lymphocyte-associated antigen 4, checkpoints programmed death-1 and programmed death-ligand 1; their blockades have been approved by the Food and Drug Administration for therapy of melanoma and other types of cancers. Immunogenomics, which combines the latest nucleic acid sequencing strategy with immunotherapy, provides precise information about genomic alterations (e.g. mutations) and enables a paradigm shift of immune checkpoint therapy from tumor types to molecular signatures. Studying these critical checkpoints in relation to genomic mutations and neoantigens has produced groundbreaking results. This article examines these studies and delves into the relationships between immune checkpoint blockade and tumors harboring certain genomic mutations. Moreover, this article reviews recent studies on resistance to immune checkpoint therapy.

In this research, we employed distributed systems to explore the similarities in parking ticket records using unsupervised machine learning algorithms on a large dataset. Using 37 million ticket records (9 GB) collected by the New York City Department of Finance, we applied an algorithm to cluster existing tickets and dive deeper to find the distribution of precincts within different clusters. Amazon Web Services including S3, EC2 and EMR, and tools like MongoDB and Apache Spark were used in this endeavor. In this study, computational time and cost for different EMR settings were evaluated. We conclude that there are significant computational advantages to using distributed systems when implementing unsupervised learning on a large dataset as well as storing and managing data. We also observed that it is time efficient for a cluster with more workers instead of fewer workers with large memory space for the utilized data set. However we observed a trade-off between the execution time and the total cost for the cluster configuration.

Influenza is a contagious respiratory virus that infects epithelial cells throughout the respiratory tract. The viral infection is facilitated by the attachment of the viral hemagglutinin to the si...

Due to low cost and good electrical performance, wafer-level chip scale packaging (WLCSP) has gained more attention in both industry and academia. However, because the coefficient of thermal expansion (CTE) mismatches between silicon and organic printed circuit board (PCB), WLCSP technology still faces reliability challenges, such as the solder joint fragile life issue. In this paper, a new WLCSP design (WLCSP-PN) is proposed, based on the structure of WLCSP with Cu posts (WLCSP-P), to release the stress on the solder joints. In the new design, there is a space between the Cu post and the polymer which permits NiSn coating on the post sidewall. The overcoating enhances the solder–post interface where cracks were initiated and enlarges the intermetallic compounds (IMC) joint area to enhance the adhesion strength. Design of experiment (DOE) with the Taguchi method is adopted to obtain the sensitivity information of design parameters of the new design by the three-dimensional (3D) finite element model (FEM), leading to the optimized configuration. The finite element analysis results demonstrate that compared to WLCSP-P, the proposed WLCSP-PN reduces the package displacement, equivalent stress, and plastic strain energy density and thus improves the fatigue life of solder joints.

Deploying shunt capacitor banks in distribution systems can effectively reduce the power loss and provide additional benefits for system operation. In practice, the power loss on distribution transformers can account for a considerable portion of the overall loss. This paper proposes a method for optimal placement of capacitor banks to the distribution transformers to reduce power loss. The capacitor bank locations are considered at the low-side of transformers. The net present value (NPV) criterion is adopted to evaluate the cost benefit of the capacitor installation project. First, an explicit formula for directly calculating the power loss of radial distribution systems is derived. Then, the optimal capacitor bank placement is formulated as a mixed-integer programming (MIP) model maximizing the NPV of the project subject to certain constraints. The model is suitable for being solved by commercial MIP packages, and the operational control of the capacitor banks to maximize the power loss reduction can be simply achieved by local automatic switching according to VAR measurements. The proposed method has been practically applied in the Macau distribution system, and the simulation results show that the proposed method is computationally efficient, and a considerable positive NPV can be obtained from the optimal capacitor bank placement.

Typical controlled collapse chip connection (C4) bump structurally composed of solder bump, Ni UBM and Cu/Ti sputtered film on the top side of Si wafer in which polyimide film patterned and coated onto wafer as a buffer layer between substrate and UBM for stress relief. C4 bump structure is widely used in high-performance device of semiconductor package industries for many years and has achieved good reliability performance. In the past experience, stress-induced polyimide crack would happen on low-k IC package and be associated with inter-layer dielectric (ILD) cracking during thermal process and resulting in reliability problem. In order to resolve polyimide cracking problem, this preliminary study is attempted to optimize the bumping process based on the experimental of C4 bump structure with Copper pad as polyimide underneath to simulate the key condition of bumping process. Three key parameters in process, curing temperature, reflow peak temperature and reflow cooling rate, were considered to differentiate the influence degree related to the thermal stress from coefficient of thermal expansion (CTE) mismatch. Focus ion beam (FIB) and finite element methods were separately employed for cranny observation and stress modeling. The result exhibits the cured polyimide cranny formed under the condition of higher curing temperature, higher reflow cooling rate. The dominant factor is polyimide curing temperature (PCT), and followed by reflow peak temperature (RPT) and reflow cooling rate (RCR), sequentially. The cranny on polyimide propagated to and around the round-shaped Ni undercut spot after reflow due to the thermal stress arising from CTE mismatch between the polyimide and contained metals. Low curing temperature (350°C) with lower modulus of elasticity, low reflow temperature (240°C) and slow cooling rate (2.9°C/s) allow polyimide to absorb more strain energy and flexibly adjust internal stress far from fracture stress.

A previous surveillance study of human pathogens within ticks collected in the country of Georgia showed a relatively high infection rate for Rickettsia raoultii, R. slovaca, and R. aeschlimannii. These 3 spotted fever group rickettsiae are human pathogens: R. raoultii and R. slovaca cause tick-borne lymphadenopathy (TIBOLA), and R. aeschlimannii causes an infection characterized by fever and maculopapular rash. Three quantitative real-time polymerase chain reaction (qPCR) assays, Rraoul, Rslov, and Raesch were developed and optimized to detect R. raoultii, R. slovaca, and R. aeschlimannii, respectively, by targeting fragments of the outer membrane protein B gene (ompB) using species-specific molecular beacon or TaqMan probes. The 3 qPCR assays showed 100% specificity when tested against a rickettsiae DNA panel (n=20) and a bacteria DNA panel (n=12). The limit of detection was found to be at least 3 copies per reaction for all assays. Validation of the assays using previously investigated tick nucleic acid preparations, which included Rickettsia-free tick samples, tick samples that contain R. raoultii, R. slovaca, R. aeschlimannii, and other Rickettsia spp., gave 100% sensitivity for all 3 qPCR assays. In addition, a total of 65 tick nucleic acid preparations (representing 259 individual ticks) collected from the country of Georgia and the Republic of Azerbaijan in 2009 was tested using the 3 qPCR assays. R. raoultii, R. slovaca, and R. aeschlimannii were not detected in any ticks (n=31) from the Republic of Azerbaijan, but in the ticks from the country of Georgia (n=228) the minimal infection rate for R. raoultii and R. slovaca in Dermacentor marginatus was 10% and 4%, respectively, and for R. aeschlimannii in Haemaphysalis sulcata and Hyalomma spp. it was 1.9% and 20%, respectively.

In this paper, we describe an environment monitoring and control system for fish farming applications. This system can receive sensor data in proprietary format and map it to a standard data model. All sensor data and control commands can be accessed via well defined HTTP RESTful interfaces. With this interface, historical data and statistics can be easily accessed and application development time can be greatly shortened.