Target Of Complex Research Articles

The Complexity of State-Led Housing Planning: Lessons from Implementation in Southern California

California’s current housing planning system is comprised of a complex housing target allocation mechanism and enforcement mechanisms to ensure that local governments effectively accommodate the development of the allocated housing units. This study illustrates the complexity in California’s planning requirements and discusses the implications for implementation. Drawing on interview data and observations of public events, this study also reveals implementation challenges perceived by front-line workers. This study contributes to the planning and policy implementation literature by addressing the implementation of complex rules in the context of top-down planning.

Rictor, an mTORC2 Protein, Regulates Murine Lymphatic Valve Formation Through the AKT-FOXO1 Signaling.

Lymphatic valves are specialized structures in collecting lymphatic vessels and are crucial for preventing retrograde lymph flow. Mutations in valve-forming genes have been clinically implicated in the pathology of congenital lymphedema. Lymphatic valves form when oscillatory shear stress from lymph flow signals through the PI3K/AKT pathway to promote the transcription of valve-forming genes that trigger the growth and maintenance of lymphatic valves. Conventionally, in many cell types, AKT is phosphorylated at Ser473 by the mTORC2 (mammalian target of rapamycin complex 2). However, mTORC2 has not yet been implicated in lymphatic valve formation. In vivo and in vitro techniques were used to investigate the role of Rictor, a critical component of mTORC2, in lymphatic endothelium. Here, we showed that embryonic and postnatal lymphatic deletion of Rictor, a critical component of mTORC2, led to a significant decrease in lymphatic valves and prevented the maturation of collecting lymphatic vessels. RICTOR knockdown in human dermal lymphatic endothelial cells not only reduced the level of activated AKT and the expression of valve-forming genes under no-flow conditions but also abolished the upregulation of AKT activity and valve-forming genes in response to oscillatory shear stress. We further showed that the AKT target, FOXO1 (forkhead box protein O1), a repressor of lymphatic valve formation, had increased nuclear activity in Rictor knockout mesenteric lymphatic endothelial cells in vivo. Deletion of Foxo1 in Rictor knockout mice restored the number of valves to control levels in lymphatic vessels of the ear and mesentery. Our work identifies a novel role for RICTOR in the mechanotransduction signaling pathway, wherein it activates AKT and prevents the nuclear accumulation of the valve repressor, FOXO1, which ultimately enables the formation and maintenance of lymphatic valves.

Chemical control of Alternaria and Corynespora leaf spot complex in Bt cotton

Cotton is an important cash crop of India as well as Gujarat, enjoying the pre-eminent status as 'White gold' and 'King of Fibres'. Cotton is widely affected by many diseases including Alternaria leaf spot and target spot or Corynespora leaf spot caused by Alternaria alternata and Corynespora cassiicola, respectively. The main objective of the study was to investigate the effectiveness of fungicides against leaf spot complex (Alternaria leaf spot and target spot) of Bt cotton. The field experiment was conducted during Kharif 2022 at Plant Pathological Research Farm, Department of Plant Pathology, BA College of Agriculture, Anand Agricultural University Anand, Gujarat. Fungicides were applied two times at 15 days interval after initiation of disease and results showed that among the tested treatments including control, Azoxystrobin 18.2% + Difenoconazole 11.4% SC recorded significantly lowest disease intensity (18.50% and 17.92%) as compared to control (50.75% and 46.85%), with highest disease control (63.54% and 61.73%) for Alternaria leaf spot and target spot respectively. The highest yield (1968 kg ha ) and ICBR (1:10.62) was -1 recorded in Azoxystrobin 18.2% + Difenoconazole 11.4% SC. The next best treatment found in terms of disease control was Tebuconazole 50% + Trifloxystrobin 25% WG. So in nutshell it was found that readymix fungicides were found best and also cost effective in managing both the diseases.. KEYWORDS :Alternaria alternata, Corynespora cassiicola, leaf spot, fungicides

A Hybrid SI-FDTD Method to Analyze Scattering Fields From Underwater Complex Targets

A Hybrid SI-FDTD Method to Analyze Scattering Fields From Underwater Complex Targets

The yeast VAPs Scs2 and Scs22 are required for NVJ integrity and micronucleophagy

Microautophagy degrades cargos in the vacuole by direct engulfment of the vacuolar membrane. Micronucleophagy selectively degrades a portion of the nucleus in budding yeast. The vacuole contacts the nucleus via the nucleus–vacuole junction (NVJ), and in micronucleophagy a portion of the nucleus containing nucleolar proteins is made to protrude into the vacuole at the NVJ, followed by abscission and degradation. Microautophagy and micronucleophagy are induced by inactivation of target of rapamycin complex 1 (TORC1) protein kinase after nutrient starvation. Here, we show that the VAMP-associated proteins (VAPs) Scs2 and its paralog Scs22 are required for NVJ integrity and micronucleophagic degradation of nucleolar proteins. On the other hand, nucleolar dynamics prerequisite for micronucleophagy were not impaired in VAP mutant cells. Finally, yeast VAPs were critical for viability during prolonged nutrient starvation. This study sheds light on the emerging role of VAP in adaptation in responses to nutrient starvation.

Osteoclasts control endochondral ossification via regulating acetyl-CoA availability

Osteoclast is critical in skeletal development and fracture healing, yet the impact and underlying mechanisms of their metabolic state on these processes remain unclear. Here, by using osteoclast-specific small GTPase Rheb1-knockout mice, we reveal that mitochondrial respiration, rather than glycolysis, is essential for cathepsin K (CTSK) production in osteoclasts and is regulated by Rheb1 in a mechanistic target of rapamycin complex 1 (mTORC1)-independent manner. Mechanistically, we find that Rheb1 coordinates with mitochondrial acetyl-CoA generation to fuel CTSK, and acetyl-CoA availability in osteoclasts is the central to elevating CTSK. Importantly, our findings demonstrate that the regulation of CTSK by acetyl-CoA availability is critical and may confer a risk for abnormal endochondral ossification, which may be the main cause of poor fracture healing on alcohol consumption, targeting Rheb1 could successfully against the process. These findings uncover a pivotal role of mitochondria in osteoclasts and provide a potent therapeutic opportunity in bone disorders.

Synthesis of Para-Acetylated Functionalized Ni(II)-POCOP Pincer Complexes and Their Cytotoxicity Evaluation Against Human Cancer Cell Lines.

A series of three Ni(II)-POCOP complexes para-functionalized with an acetoxyl fragment were synthesized. All complexes (2 a-c) were fully characterized through standard analytical techniques. The molecular structure of complex 2 b was unambiguously determined by single-crystal X-ray diffraction, revealing that the metal center is situated in a slightly distorted square-planar environment. Additionally, the acetoxy fragment at the para-position of the phenyl ring was found to be present. The in vitro cytotoxic activity of all complexes was assessed on six human cancer cell lines. Notably, complex 2 b exhibited selective activity against K-562 (chronic myelogenous leukemia) and MCF-7 (mammary adenocarcinoma) with IC50 values of 7.32±0.60 μM and 14.36±0.02 μM, respectively. Furthermore, this compound showed negligible activity on the healthy cell line COS-7, highlighting the potential therapeutic application of 2 b. The cytotoxic evaluations were further complemented with molecular docking calculations to explore the potential biological targets of complex 2 b, revealing interactions with cluster differentiation protein 1a (CD1 A, PDB: 1xz0) for K-562 and with the progesterone receptor for MCF-7.

Design of Synthetic Strategies towards Sulfur Containing Scaffolds

AbstractThe utilization of sulfur heterocycles in organic synthesis has attracted significant attention due to their wide-ranging applications. This review showcases the syntheses of diverse sulfur heterocycles embedded with amino acid derivatives, polycycles, spirocycles, cyclophanes, and other complex scaffolds. The reported methods extend beyond compound synthesis and highlight the use of different sulfur reagents for constructing sulfur heterocycles. This Review also discusses the utility of a variety of sulfur-containing starting materials for the generation of complex target molecules.1 Introduction2 Potassium Thioacetate3 Thiazolidine-2,4-dione4 Rhodanines5 Sodium Sulfide6 Thiotetronic Acid7 Thiadiazoles8 Thiophene9 Rongalite10 Sulfur Dioxide11 Divinyl Sulfone12 Sulfur Heterocycles Based on Boronic Acids13 Miscellaneous14 Summary

Superoxide dismutase 1 mediates adaptation to the tumor microenvironment of glioma cells via mammalian target of rapamycin complex 1

In glioblastoma (GB) cells oxidative stress is induced by both, conditions of the tumor microenvironment as well as by therapeutic interventions. Upregulation of superoxide dismutase 1 (SOD1), a key enzyme for oxidative defense and downstream target of mammalian target of rapamycin complex 1 (mTORC1) is a candidate mechanism to sustain survival and proliferation of tumor cells. SOD1 was inhibited by shRNA mediated gene suppression, CRISPR/Cas9 knockout and pharmacological inhibition in human (primary) GB cells. SOD1 activity was determined by SOD1/2 activity assay. ROS levels, cell death and the NADPH/NADP-ratio were measured under normal and starvation conditions. To study the mTORC1-SOD1 axis, mTORC1 activated TSC2 knockdown cells (TSC2sh) were analyzed. Genetic and pharmacological inhibition of SOD1 correlated with decreased SOD1 activity, increased ROS and enhanced the sensitivity of glioma cells towards starvation- and hypoxia-induced cell death. This was accompanied by a decreased NADPH/NADP-ratio. Furthermore, combination therapy of SOD1 and mTORC1 inhibition partially rescued the protective effect of mTORC1 inhibitor monotherapy. SOD1 mediates adaptation of GB cells to stress conditions in the tumor microenvironment in a mTORC1-dependent manner. Moreover, SOD1 activation contributes to the cell death resistance conferred by mTORC1 inhibitors under hypoxic conditions.

Animal amino acid sensor.

Cell growth and metabolism necessitate the involvement of amino acids, which are sensed and integrated by the mammalian target of rapamycin complex 1 (mTORC1). However, the molecular mechanisms underlying amino acid sensing remain poorly understood. Research indicates that amino acids are detected by specific sensors, with the signals being relayed to mTORC1 indirectly. This paper reviews the structures and biological functions of the amino acid sensors identified thus far. Additionally, it evaluates the potential role these sensors play in the developmental changes of the livestock production.

A complex network-based transmission mechanism and target control method for reducing carbon emission

To achieve carbon neutrality for China, the transmission mechanism, path, diffusion effect,and allocation of Emission Reduction Targets (ERT) among industries must be investigated. Setting short-term ERT will create a reverse pressure mechanism for the industry's carbon reduction, ensuring the achievement of carbon emission control target. However, few studies have explored how to influence the entire system by controlling key industries from the perspective of network control. Therefore, this study investigates Inter-industry Carbon Emission Transfer (ICET) in China from 1997 to 2017,and found that ICET can achieve fair distribution of ERT. Inspired by the controllability theory of complex networks to integrate the driving factors, the transmission paths, diffusion effects, and allocation of ERT into a unified analytical framework. Then, breaking the traditional top-down hierarchical decomposition mechanism and transforming it into a bottom-up target forcing mechanism, a decomposition algorithm for the total control target was proposed.The results reveal that ICET accounts for the majority of carbon emission. The characteristics of network structure have a significant impact on the ICET.Different industries have varying control capabilities. Compared with industry-wide control, target control on the Minimum Control Industry Set (MCMCS) has a slightly worse emission reduction effect, but the economic loss is smaller, making it an effective policy choice.

Zigzag path connects two Monte Carlo samplers: Hamiltonian counterpart to a piecewise deterministic Markov process

Zigzag and other piecewise deterministic Markov process samplers have attracted significant interest for their non-reversibility and other appealing properties for Bayesian posterior computation. Hamiltonian Monte Carlo is another state-of-the-art sampler, exploiting fictitious momentum to guide Markov chains through complex target distributions. We establish an important connection between the zigzag sampler and a variant of Hamiltonian Monte Carlo based on Laplace-distributed momentum. The position and velocity component of the corresponding Hamiltonian dynamics travels along a zigzag path paralleling the Markovian zigzag process; however, the dynamics is non-Markovian in this position-velocity space as the momentum component encodes non-immediate pasts. This information is partially lost during a momentum refreshment step, in which we preserve its direction but re-sample magnitude. In the limit of increasingly frequent momentum refreshments, we prove that Hamiltonian zigzag converges strongly to its Markovian counterpart. This theoretical insight suggests that, when retaining full momentum information, Hamiltonian zigzag can better explore target distributions with highly correlated parameters by suppressing the diffusive behavior of Markovian zigzag. We corroborate this intuition by comparing performance of the two zigzag cousins on high-dimensional truncated multivariate Gaussians, including a 11,235-dimensional target arising from a Bayesian phylogenetic multivariate probit modeling of hiv virus data.

Optimal Control of Material Microstructures

Abstract In this paper, we consider the optimal control of material microstructures. Such material microstructures are modeled by the so-called phase-field model. We study the underlying physical structure of the model and propose a data-based approach for its optimal control, along with a comparison to the control using a state-of-the-art reinforcement learning (RL) algorithm. Simulation results show the feasibility of optimally controlling such microstructures to attain desired material properties and complex target microstructures.

Aged Brain Metabolomics Study by Metabolic Profiling Analysis of Amino Acids, Organic Acids, and Fatty Acids in Cortex, Cerebellum, Hypothalamus, and Hippocampus of Rats.

Aging is a progressive process characterized by weakness in brain function. Although metabolomics studies on the brain related with aging have been conducted, it is not yet fully understood. A systematic metabolomics study was performed to search for biomarkers and monitor altered metabolism in various brain tissues of the cortex, cerebellum, hypothalamus, and hippocampus of young (8 months old) and old rats (22 months old). Simultaneous profiling analysis of amino acids (AAs), organic acids (OAs), and fatty acids (FAs) in the brain tissues of young and old rats were performed by gas chromatography-tandem mass spectrometry. Under optimal conditions, AA, OA, and FA profiling methods showed good linearity (r ≥0.995) with limit of detection of ≤30 and 73.2 ng and limit of quantification of ≤90.1 and 219.5 ng, respectively. Repeatability varied from 0.4 to 10.4 and 0.8 to 14.8% relative standard deviation and accuracy varied from -11.3 to 10.3 and -12.8 to 14.1% relative error, respectively. In the profiling analysis, total 32, 43, 45, and 30 metabolites were determined in cortex, cerebellum, hypothalamus, and hippocampus, respectively. In statistical analysis, eight AAs (alanine, valine, leucine, isoleucine, threonine, serine, proline, and phenylalanine) in the cortex and four metabolites (alanine, phenylalanine, 3-hydoxypropionic acid, and eicosadienoic acid) in the cerebellum were significantly evaluated (Q-value <0.05, variable importance in projection scores ≥1.0). In all brain tissues, the score plots of orthogonal partial least square discriminant analysis were clearly separated between the young and old groups. Metabolomics results indicate that mechanistic targets of rapamycin complex 1, branched chain-amino acid, and energy metabolism are related to inflammation and mitochondrial dysfunction in the brain during aging. Thus, these results may explain the characteristic metabolism of brain aging.

Targeting spinal mechanistic target of rapamycin complex 2 alleviates inflammatory and neuropathic pain.

The development and maintenance of chronic pain involves the reorganization of spinal nociceptive circuits. The mechanistic target of rapamycin complex 2 (mTORC2), a central signaling hub that modulates both actin-dependent structural changes and mTORC1-dependent mRNA translation, plays key roles in hippocampal synaptic plasticity and memory formation. However, its function in spinal plasticity and chronic pain is poorly understood. Here we show that pharmacological activation of spinal mTORC2 induces pain hypersensitivity, whereas its inhibition, using downregulation of the mTORC2-defining component Rictor, alleviates both inflammatory and neuropathic pain. Cell-type-specific deletion of Rictor showed that the selective inhibition of mTORC2 in a subset of excitatory neurons impairs spinal synaptic potentiation and alleviates inflammation-induced mechanical and thermal hypersensitivity, and nerve injury-induced heat hyperalgesia. The ablation of mTORC2 in inhibitory interneurons strongly alleviated nerve injury-induced mechanical hypersensitivity. Our findings reveal the role of mTORC2 in chronic pain and highlight its cell-type-specific functions in mediating pain hypersensitivity in response to peripheral inflammation and nerve injury.

Normalizing flows as an enhanced sampling method for atomistic supercooled liquids

Abstract Normalizing flows can transform a simple prior probability distribution into a more complex target distribution. Here, we evaluate the ability and efficiency of generative machine learning methods to sample the Boltzmann distribution of an atomistic model for glass-forming liquids. This is a notoriously difficult task, as it amounts to ergodically exploring the complex free energy landscape of a disordered and frustrated many-body system. We optimize a normalizing flow model to successfully transform high-temperature configurations of a dense liquid into low-temperature ones, near the glass transition. We perform a detailed comparative analysis with established enhanced sampling techniques developed in the physics literature to assess and rank the performance of normalizing flows against state-of-the-art algorithms. We demonstrate that machine learning methods are very promising, showing a large speedup over conventional molecular dynamics. Normalizing flows show performances comparable to parallel tempering and population annealing, while still falling far behind the swap Monte Carlo algorithm. Our study highlights the potential of generative machine learning models in scientific computing for complex systems, but also points to some of its current limitations and the need for further improvement.

Rag-Ragulator is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway.

The mechanistic target of rapamycin complex 1 (mTORC1) pathway regulates cell growth and metabolism in response to many environmental cues, including nutrients. Amino acids signal to mTORC1 by modulating the guanine nucleotide loading states of the heterodimeric Rag GTPases, which bind and recruit mTORC1 to the lysosomal surface, its site of activation. The Rag GTPases are tethered to the lysosome by the Ragulator complex and regulated by the GATOR1, GATOR2, and KICSTOR multiprotein complexes that localize to the lysosomal surface through an unknown mechanism(s). Here, we show that mTORC1 is completely insensitive to amino acids in cells lacking the Rag GTPases or the Ragulator component p18. Moreover, not only are the Rag GTPases and Ragulator required for amino acids to regulate mTORC1, they are also essential for the lysosomal recruitment of the GATOR1, GATOR2, and KICSTOR complexes, which stably associate and traffic to the lysosome as the "GATOR" supercomplex. The nucleotide state of RagA/B controls the lysosomal association of GATOR, in a fashion competitively antagonized by the N terminus of the amino acid transporter SLC38A9. Targeting of Ragulator to the surface of mitochondria is sufficient to relocalize the Rags and GATOR to this organelle, but not to enable the nutrient-regulated recruitment of mTORC1 to mitochondria. Thus, our results reveal that the Rag-Ragulator complex is the central organizer of the physical architecture of the mTORC1 nutrient-sensing pathway and underscore that mTORC1 activation requires signal transduction on the lysosomal surface.

Ligand-free biodegradable poly(beta-amino ester) nanoparticles for targeted systemic delivery of mRNA to the lungs

Non-viral nanoparticles (NPs) have seen heightened interest as a delivery method for a variety of clinically relevant nucleic acid cargoes in recent years. While much of the focus has been on lipid NPs, non-lipid NPs, including polymeric NPs, have the possibility of improved efficacy, safety, and targeting, especially to non-liver organs following systemic administration. A safe and effective systemic approach for intracellular delivery to the lungs could overcome limitations to intratracheal/intranasal delivery of NPs and improve clinical benefit for a range of diseases including cystic fibrosis. Here, engineered biodegradable poly (beta-amino ester) (PBAE) NPs are shown to facilitate efficient delivery of mRNA to primary human airway epithelial cells from both healthy donors and individuals with cystic fibrosis. Optimized NP formulations made with differentially endcapped PBAEs and systemically administered in vivo lead to high expression of mRNA within the lungs in BALB/c and C57 B/L mice without requiring a complex targeting ligand. High levels of mRNA-based gene editing were achieved in an Ai9 mouse model across bronchial, epithelial, and endothelial cell populations. No toxicity was observed either acutely or over time, including after multiple systemic administrations of the NPs. The non-lipid biodegradable PBAE NPs demonstrate high levels of transfection in both primary human airway epithelial cells and in vivo editing of lung cell types that are targets for numerous life-limiting diseases particularly single gene disorders such as cystic fibrosis and surfactant deficiencies.

DSS1 restrains BRCA2’s engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis

DSS1, essential for BRCA2-RAD51 dependent homologous recombination (HR), associates with the helical domain (HD) and OB fold 1 (OB1) of the BRCA2 DSS1/DNA-binding domain (DBD) which is frequently targeted by cancer-associated pathogenic variants. Herein, we reveal robust ss/dsDNA binding abilities in HD-OB1 subdomains and find that DSS1 shuts down HD-OB1’s DNA binding to enable ssDNA targeting of the BRCA2-RAD51 complex. We show that C-terminal helix mutations of DSS1, including the cancer-associated R57Q mutation, disrupt this DSS1 regulation and permit dsDNA binding of HD-OB1/BRCA2-DBD. Importantly, these DSS1 mutations impair BRCA2/RAD51 ssDNA loading and focus formation and cause decreased HR efficiency, destabilization of stalled forks and R-loop accumulation, and hypersensitize cells to DNA-damaging agents. We propose that DSS1 restrains the intrinsic dsDNA binding of BRCA2-DBD to ensure BRCA2/RAD51 targeting to ssDNA, thereby promoting optimal execution of HR, and potentially replication fork protection and R-loop suppression.

Multi-Person Action Recognition Based on Millimeter-Wave Radar Point Cloud

Human action recognition has many application prospects in human-computer interactions, innovative furniture, healthcare, and other fields. The traditional human motion recognition methods have limitations in privacy protection, complex environments, and multi-person scenarios. Millimeter-wave radar has attracted attention due to its ultra-high resolution and all-weather operation. Many existing studies have discussed the application of millimeter-wave radar in single-person scenarios, but only some have addressed the problem of action recognition in multi-person scenarios. This paper uses a commercial millimeter-wave radar device for human action recognition in multi-person scenarios. In order to solve the problems of severe interference and complex target segmentation in multiplayer scenarios, we propose a filtering method based on millimeter-wave inter-frame differences to filter the collected human point cloud data. We then use the DBSCAN algorithm and the Hungarian algorithm to segment the target, and finally input the data into a neural network for classification. The classification accuracy of the system proposed in this paper reaches 92.2% in multi-person scenarios through experimental tests with the five actions we set.