Spatial Regulation Research Articles

N-cadherin and β1 integrin coordinately regulate growth plate cartilage architecture.

Spatial and temporal regulation of chondrocyte maturation in the growth plate drives growth of many bones. One essential event to generate the ordered cell array characterizing growth plate cartilage is the formation of chondrocyte columns in the proliferative zone via 90-degree rotation of daughter cells to align with the long axis of the bone. Previous studies have suggested crucial roles for cadherins and integrin β1 in column formation. The purpose of this study was to determine the relative contributions of cadherin- and integrin-mediated cell adhesion in column formation. Here we present new mechanistic insights generated by application of live time-lapse confocal microscopy of cranial base explant cultures, robust genetic mouse models, and new quantitative methods to analyze cell behavior. We show that conditional deletion of either the cell-cell adhesion molecule Cdh2 or the cell-matrix adhesion molecule Itgb1 disrupts column formation. Compound mutants were used to determine a potential reciprocal regulatory interaction between the two adhesion surfaces and identified that defective chondrocyte rotation in a N-cadherin mutant was restored by a heterozygous loss of integrin β1. Our results support a model for which integrin β1, and not N-cadherin, drives chondrocyte rotation and for which N-cadherin is a potential negative regulator of integrin β1 function.

A dynamic bactofilin cytoskeleton cooperates with an M23 endopeptidase to control bacterial morphogenesis

Bactofilins have emerged as a widespread family of cytoskeletal proteins with important roles in bacterial morphogenesis, but their precise mode of action is still incompletely understood. In this study, we identify the bactofilin cytoskeleton as a key regulator of cell growth in the stalked budding alphaproteobacterium Hyphomonas neptunium. We show that, in this species, bactofilin polymers localize dynamically to the stalk base and the bud neck, with their absence leading to unconstrained growth of the stalk and bud compartments, indicating a central role in the spatial regulation of cell wall biosynthesis. Database searches reveal that bactofilin genes are often clustered with genes for cell wall hydrolases of the M23 peptidase family, suggesting a functional connection between these two types of proteins. In support of this notion, we find that the H. neptunium M23 peptidase homolog LmdC interacts directly with bactofilin in vitro and is required for proper cell shape in vivo. Complementary studies in the spiral-shaped alphaproteobacterium Rhodospirillum rubrum again reveal a close association of its bactofilin and LmdC homologs, which co-localize at the inner curve of the cell, modulating the degree of cell curvature. Collectively, these findings demonstrate that bactofilins and M23 peptidases form a conserved functional module that promotes local changes in the mode of cell wall biosynthesis, thereby driving cell shape determination in morphologically complex bacteria.

A dynamic bactofilin cytoskeleton cooperates with an M23 endopeptidase to control bacterial morphogenesis.

Bactofilins have emerged as a widespread family of cytoskeletal proteins with important roles in bacterial morphogenesis, but their precise mode of action is still incompletely understood. In this study, we identify the bactofilin cytoskeleton as a key regulator of cell growth in the stalked budding alphaproteobacterium Hyphomonas neptunium. We show that, in this species, bactofilin polymers localize dynamically to the stalk base and the bud neck, with their absence leading to unconstrained growth of the stalk and bud compartments, indicating a central role in the spatial regulation of cell wall biosynthesis. Database searches reveal that bactofilin genes are often clustered with genes for cell wall hydrolases of the M23 peptidase family, suggesting a functional connection between these two types of proteins. In support of this notion, we find that the H. neptunium M23 peptidase homolog LmdC interacts directly with bactofilin in vitro and is required for proper cell shape in vivo. Complementary studies in the spiral-shaped alphaproteobacterium Rhodospirillum rubrum again reveal a close association of its bactofilin and LmdC homologs, which co-localize at the inner curve of the cell, modulating the degree of cell curvature. Collectively, these findings demonstrate that bactofilins and M23 peptidases form a conserved functional module that promotes local changes in the mode of cell wall biosynthesis, thereby driving cell shape determination in morphologically complex bacteria.

The Role of the Public Works and Spatial Planning Department in the Spatial Plan Local Regulations of Asahan Regency

This study focuses on the Public Works and Spatial Planning Office's role in the existing Spatial Planning Regional Regulation in Asahan Regency, especially in its amendments. The changes are intended to harmonize, synchronize and harmonize the spatial planning regulations that the Regional Government of North Sumatra Province has issued. The research method used is the empirical method, considering the Settlement of the Formation of the Civil Code, and the empirically symptomatic law. These, namely various legal factors influence it, so the study will lead to the role of organizations and legal institutions when enforcing the law. The results show that changes to the Asahan District Civil Code have been implemented based on the proposals from the PUPR Service so that the role of the PPUPR Office has been achieved, namely planning, informative, and indicative. For implementation, there are also obstacles encountered, such as the limited budget ceiling, the issuance of changes to the Procedure for the Implementation of Strategic Environmental Studies (KLHS), the limited number of employees in the field of spatial planning who have spatial planning legal competence and the lack of financial support for education and training in the field of spatial planning by local governments.

KAJIAN DINAMIKA PERATURAN DAN KEBIJAKAN PENATAAN RUANG TERHADAP MUATAN PERATURAN DAERAH TENTANG RENCANA TATA RUANG WILAYAH KABUPATEN NIAS BARAT

The implementation of spatial use, the dynamics of development as well as the development of the strategic environment in recent years, have often influenced the implementation of the West Nias RTRW as a reference in development. This sometimes causes an imbalance in the arrangement of a space or region. This paper aims to review the suitability of the content of the West Nias RTRW with regulations and policies related to spatial planning. Based on the results of the study, it is concluded that it is necessary to renew the technical material for the RTRW of West Nias Regency by adjusting the dynamics of the latest spatial planning regulations and policies. It is also hoped that there will be serious attention from the local government regarding the sustainability of funding to the stage of stipulation of the Regional Regulation on the revision of the RTRW, as well as the placement of human resources with a spatial planning background in technical OPD.Keywords: spatial planning, RTRW revision, West Nias Regency

Light-inducible protein degradation in E. coli with the LOVdeg tag.

Molecular tools for optogenetic control allow for spatial and temporal regulation of cell behavior. In particular, light-controlled protein degradation is a valuable mechanism of regulation because it can be highly modular, used in tandem with other control mechanisms, and maintain functionality throughout growth phases. Here, we engineered LOVdeg, a tag that can be appended to a protein of interest for inducible degradation in Escherichia coli using blue light. We demonstrate the modularity of LOVdeg by using it to tag a range of proteins, including the LacI repressor, CRISPRa activator, and the AcrB efflux pump. Additionally, we demonstrate the utility of pairing the LOVdeg tag with existing optogenetic tools to enhance performance by developing a combined EL222 and LOVdeg system. Finally, we use the LOVdeg tag in a metabolic engineering application to demonstrate post-translational control of metabolism. Together, our results highlight the modularity and functionality of the LOVdeg tag system and introduce a powerful new tool for bacterial optogenetics.

Light-inducible protein degradation in E. coli with the LOVdeg tag

Molecular tools for optogenetic control allow for spatial and temporal regulation of cell behavior. In particular, light-controlled protein degradation is a valuable mechanism of regulation because it can be highly modular, used in tandem with other control mechanisms, and maintain functionality throughout growth phases. Here, we engineered LOVdeg, a tag that can be appended to a protein of interest for inducible degradation in Escherichia coli using blue light. We demonstrate the modularity of LOVdeg by using it to tag a range of proteins, including the LacI repressor, CRISPRa activator, and the AcrB efflux pump. Additionally, we demonstrate the utility of pairing the LOVdeg tag with existing optogenetic tools to enhance performance by developing a combined EL222 and LOVdeg system. Finally, we use the LOVdeg tag in a metabolic engineering application to demonstrate post-translational control of metabolism. Together, our results highlight the modularity and functionality of the LOVdeg tag system and introduce a powerful new tool for bacterial optogenetics.

Identification of a Chondrocyte-Specific Enhancer in the Hoxc8 Gene.

Hox genes encode transcription factors whose roles in patterning animal body plans during embryonic development are well-documented. Multiple studies demonstrate that Hox genes continue to act in adult cells, in normal differentiation, in regenerative processes, and, with abnormal expression, in diverse types of cancers. However, surprisingly little is known about the regulatory mechanisms that govern Hox gene expression in specific cell types, as they differentiate during late embryonic development, and in the adult organism. The murine Hoxc8 gene determines the identity of multiple skeletal elements in the lower thoracic and lumbar region and continues to play a role in the proliferation and differentiation of cells in cartilage as the skeleton matures. This study was undertaken to identify regulatory elements in the Hoxc8 gene that control transcriptional activity, specifically in cartilage-producing chondrocytes. We report that an enhancer comprising two 416 and 224 bps long interacting DNA elements produces reporter gene activity when assayed on a heterologous transcriptional promoter in transgenic mice. This enhancer is distinct in spatial, temporal, and molecular regulation from previously identified regulatory sequences in the Hoxc8 gene that control its expression in early development. The identification of a tissue-specific Hox gene regulatory element now allows mechanistic investigations into Hox transcription factor expression and function in differentiating cell types and adult tissues and to specifically target these cells during repair processes and regeneration.

Modified hybrid B-spline estimation based on spatial regulator tensor network for burger equation with nonlinear fractional calculus

In this paper, a modified hybrid B-spline approximation based on spatial regulator tensor network (MHBA-SRTN) is proposed for solving the application and the feasibility problems of fractional calculus-based Burger equation. The main innovation points include: (1) a dual singular kernel based fractional derivative operator is employed on the Burger’s equation with external force term to analyze the solutions and properties under perturbation condition for further realism simulation; (2) a modified hybrid B-spline basis function and its corresponding topological tensor network structure are further proposed to solve the provided Burger’s equation with more favorable approximation accuracy and solution uniqueness; (3) the tensor network transformed the hybrid B-spline construction process into the tensor solving with the introduced spatially regulated tensor network decomposition for a more robust solution procedure; (4) an acceleration approach for decomposition process is introduced to significantly reduce its computational and storage complexity. Extensive experiments are also carried out to verify the performance of MHBA-SRTN.

Recurrent symmetrical bendings cause dwarfing in Hydrangea through spatial molecular regulation of xylem cell walls.

Environmental prejudices progressively lead to the ban of dwarfing molecules in agriculture, and alternatives are urgently required. Mechanical stimulation (MS) is a promising, eco-friendly, and economical technique, but some responses to mechanical stimulation vary from one plant species to another. Additionally, as more frequent and violent wind episodes are forecasted under global climate change, knowledge of plant responses to stimuli mimicking wind sways is decisive for agriculture. However, little is known about plant mechanosensitive responses after long-term, recurrent MS. Here, the effects of 3-week, recurrent, symmetrical bendings (1 or 12 per day) in Hydrangea macrophylla stems are examined. Bendings repressed internode elongation and leaf area development, whereas the diametrical growth of the basal internode is increased. Responses were dose-dependent, and no desensitization was observed during the 3 weeks of treatment. MS was almost as efficient as daminozide for plant dwarfing, and it improved stem robustness. Histological and molecular responses to MS were spatially monitored and were concordant with ongoing primary or secondary growth in the internodes. Our molecular data provide the first knowledge on the molecular paths controlled by mechanical loads in Hydrangea and revealed for the first time the involvement of XYP1 in thigmomorphogenetic responses. MS still had a transcriptional impact 48 h after the last bending session, promoting the expression of XYP1, FLA11, and CAD1 while repressing the expression of EXP3 and XTH33 homologs in accordance with xylogenesis, cell wall thickening, and lignin deposition in the xylem of basal internodes. In upper elongating internodes, repression of XYP1, CAD1, SAMS1, and CDC23 homologs is correlated with ongoing primary, even though stunted, growth. For producers, our findings highlight the potential of MS as a sustainable and economical option for controlling plant compactness in Hydrangea and show valuable reinforcement of stem strength.

The Principles of Land Use in The Morphological Dimension of Spatial Management in An Urban Area of The Province of South Sulawesi (Socio-Legal Review)

Purpose: This study aims to analyze and explain the principles of land use within the dimensions of spatial morphology in urban development patterns in South Sulawesi Province and their relevance to spatial strategy. It also aims to analyze and explain factors affecting urban development patterns in the province concerning spatial strategy. Theoretical framework: Sustainable urban land use emphasizes balancing economic growth, environmental preservation, and social equity. It includes long-term resource sustainability, biodiversity conservation, and climate-resilient communities. Effective urban planning should prioritize inclusivity, community involvement, and sustainable transportation for accessible and functional cities. Regional development theory highlights coordinated policies for sustainable economic growth, environmental protection, and social well-being, including diversifying the local economy and enhancing education and healthcare access. Holistic regional development integrates economic, environmental, and social factors, laying the groundwork for responsible land use. Methods: The research was conducted in five Regency/cities in South Sulawesi: Makassar, Gowa, Pangkaje'ne and Islands, Soppeng, and Palopo, with 80 respondents selected through purposive sampling. The study employed descriptive analysis with qualitative and quantitative approaches. Findings: The findings conclude that the principles of land use in South Sulawesi are less than optimally used as guidelines for urban development despite being incorporated into the spatial planning of the Province and Regency/Cities. Practical implications: The implementation of urban development patterns is suboptimal in coordination with urban spatial plans of the Province and Districts. Legal factors, facilities, legal awareness, and the environment positively influence development patterns, while coordination has a negative impact. Originality/Value: The study recommends revising or issuing spatial planning regulations following Law No. 26 of 2007. Consistent supervision, control, and sanctioning by local governments in urban development in South Sulawesi. Enhancement of facilities for the supervision and control of spatial planning. Increasing public legal awareness through the socialization of spatial arrangement regulations. Inter-agency coordination in urban development through a One-Stop Service Office for optimal access to land use permission and spatial planning following the spatial plans of the Regency/Cities.

Aging disrupts spatiotemporal regulation of germline stem cells and niche integrity.

A major factor driving stem cell decline is stem cell niche aging, but its molecular mechanism remains elusive. We use the Caenorhabditis elegans distal tip cell (DTC), the mesenchymal niche that employs Notch signaling to regulate germline stem cells (GSCs), as an in vivo niche aging model and delineate the molecular details of the DTC/niche aging process. Here, we demonstrate that a drastic decrease in C. elegans germline fecundity, which begins even in early adulthood, is mainly due to an age-induced disruption in spatial regulation of Notch-dependent transcription in the germline combined with a moderate reduction in Notch transcription at both tissue and cellular levels. Consequently, the Notch-responsive GSC pool shifts from the distal end of the gonad to a more proximal region, disrupting the distal-to-proximal germline polarity. We find that this GSC pool shift is due to a dislocation of the DTC/niche nucleus, which is associated with age-induced changes in the structure and morphology of the DTC/niche. Our findings reveal a critical link between physiological changes in the aging niche, their consequences in stem cell regulation, and germline tissue functions.

The Spatial and Governance Dilemma of Small and Medium-Sized Italian Ports (SMPs): Maritime Spatial Planning (MSP) as a Potential Response

The Italian coast has about 700 ports, which are different in typology, dimension, role, and ownership. Historically, this has led to the significant fragmentation of governance and space and a lack of cooperation that ports and cities still experience today. Among all ports, small and medium-sized ports (SMPs), such as marinas, small touristic harbors, and moorings, are the most affected. Unlike the main ports, where spatial and strategic regulation planning fall under the port authority’s responsibilities, SMPs are a combination of public and private management and are, therefore, excluded from national and regional planning and larger strategies. Improving SMPs’ cooperation at the regional level can drive more effective sustainable management among related activities (tourism and the fishing sector) and reduce pressures on the land–sea interaction (LSI). In filling the gaps, this article challenges the existing legal framework, planning tools, approaches, and initiatives and may pave the way to establishing a better-integrated national governance for SMPs. In conclusion, this paper identifies two main opportunities that can support the steady establishment of governance and the systematic harmonized development of these SMPs. The first one is offered by maritime spatial planning (MSP) as a strategic and legal tool whereby SMPs are recognized and, if financially supported, could find incentives and measures for their development. The second one is through European projects, programs, and initiatives such as Framesport as drivers in establishing a common ground among public and private interests and as a cooperation engine at a local scale.

Reversible polarity-switch of thin-layer chromatography by photo-induction with multi-regulation in spatial dimension

Generally, thin-layer chromatography always undertakes the indispensable role in rapid screening and identification of specific compounds. Stationary phase is the core part of thin-layer chromatography with fixed property, which leading to the limitations of separation mode of only regulating the composition of mobile phase. This work was an attempt to fabricate the unique photosensitive thin-layer chromatography to make up the above major drawback. 4-[3-(Triethoxysilyl)propoxy]azobenzene (azo-PTES) was synthesized as photosensitive modifier to fabricate the photosensitive stationary phase, and the transformation of cis-trans structure of azo-PTES proceeds along with polarity difference under 365 nm and 473 nm irradiation. Based on this, the proposed photosensitive thin-layer chromatography shows the reversible switch of polarity of stationary phase by photoinduction, followed by the deserved reversible separation behavior. Furthermore, multi-regulation in spatial dimension was achieved based on the high freedom of spatial regulation of photoinduction, which brings about the integration of stationary phase with different polarity, just by photoinduction. The concept of photosensitive thin-layer chromatography provides new idea for improving separation efficiency and developing multi-dimensional thin-layer chromatography on the one plate.

Spatial IMA1 regulation restricts root iron acquisition on MAMP perception.

Iron is critical during host-microorganism interactions1-4. Restriction of available iron by the host during infection is an important defence strategy, described as nutritional immunity5. However, this poses a conundrum for externally facing, absorptive tissues such as the gut epithelium or the plant root epidermis that generate environments that favour iron bioavailability. For example, plant roots acquire iron mostly from the soil and, when iron deficient, increase iron availability through mechanisms that include rhizosphere acidification and secretion of iron chelators6-9. Yet, the elevated iron bioavailability would also be beneficial for the growth of bacteria that threaten plant health. Here we report that microorganism-associated molecular patterns such as flagellin lead to suppression of root iron acquisition through a localized degradation of the systemic iron-deficiency signalling peptide Iron Man 1 (IMA1) in Arabidopsis thaliana. This response is also elicited when bacteria enter root tissues, but not when they dwell on the outer root surface. IMA1 itself has a role in modulating immunity in root and shoot, affecting the levels of root colonization and the resistance to a bacterial foliar pathogen. Our findings reveal an adaptive molecular mechanism of nutritional immunity that affects iron bioavailability and uptake, as well as immune responses.

Ligand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors

The presynaptic serotonin transporter (SERT) clears extracellular serotonin following vesicular release to ensure temporal and spatial regulation of serotonergic signalling and neurotransmitter homeostasis. Prescription drugs used to treat neurobehavioral disorders, including depression, anxiety, and obsessive-compulsive disorder, trap SERT by blocking the transport cycle. In contrast, illicit drugs of abuse like amphetamines reverse SERT directionality, causing serotonin efflux. Both processes result in increased extracellular serotonin levels. By combining molecular dynamics simulations with biochemical experiments and using a homologous series of serotonin analogues, we uncovered the coupling mechanism between the substrate and the transporter, which triggers the uptake of serotonin. Free energy analysis showed that only scaffold-bound substrates could initiate SERT occlusion through attractive long-range electrostatic interactions acting on the bundle domain. The associated spatial requirements define substrate and inhibitor properties, enabling additional possibilities for rational drug design approaches.

Magnetically assembled endothelial cell-coated spheroid for vascularization

3D spheroids are used as a therapeutic strategy and transplanted in vivo owing to their ability to better mimic the microphysiological environment that is crucial for the transplants to be able to engraft and vascularize for their long-term survival and functionalization in the host tissue. Among various methods of fabricating spheroids, the utilization of magnetic force enables rapid cell aggregation and spatial regulation. Encapsulating a magnetic spheroid with endothelial cells paves the way toward vascularization. Here, we magnetically bioprinted vascular assembly by coating magnetic spheroids with the magnetic nanoparticles (MNPs)-internalized vascular endothelial cells. MNPs-internalized mouse myoblasts cells (C2C12) were magnetically aggregated by placing a neodymium magnet under a well plate and then encapsulated by MNPs-internalized human umbilical vein endothelial cells (HUVECs). Internalization of MNPs did not hinder cell viability and vascularization-related gene expression, and the transplant of the vascular assemblies could sprout and be engrafted into the host tissue within three days. As these vascular assemblies are easily fabricated by coating spheroids with MNPs-internalized endothelial cells and controlled by a magnetic force, they may be used for engraftment and vascularization in various applications with spheroids with different functions.

Decoding the spatiotemporal regulation of transcription factors during human spinal cord development

The spinal cord is a crucial component of the central nervous system that facilitates sensory processing and motor performance. Despite its importance, the spatiotemporal codes underlying human spinal cord development have remained elusive. In this study, we have introduced an image-based single-cell transcription factor (TF) expression decoding spatial transcriptome method (TF-seqFISH) to investigate the spatial expression and regulation of TFs during human spinal cord development. By combining spatial transcriptomic data from TF-seqFISH and single-cell RNA-sequencing data, we uncovered the spatial distribution of neural progenitor cells characterized by combinatorial TFs along the dorsoventral axis, as well as the molecular and spatial features governing neuronal generation, migration, and differentiation along the mediolateral axis. Notably, we observed a sandwich-like organization of excitatory and inhibitory interneurons transiently appearing in the dorsal horns of the developing human spinal cord. In addition, we integrated data from 10× Visium to identify early and late waves of neurogenesis in the dorsal horn, revealing the formation of laminas in the dorsal horns. Our study also illuminated the spatial differences and molecular cues underlying motor neuron (MN) diversification, and the enrichment of Amyotrophic Lateral Sclerosis (ALS) risk genes in MNs and microglia. Interestingly, we detected disease-associated microglia (DAM)-like microglia groups in the developing human spinal cord, which are predicted to be vulnerable to ALS and engaged in the TYROBP causal network and response to unfolded proteins. These findings provide spatiotemporal transcriptomic resources on the developing human spinal cord and potential strategies for spinal cord injury repair and ALS treatment.

Epigenetic regulation in cancer therapy: From mechanisms to clinical advances

AbstractEpigenetic regulation refers to the alteration of gene expression independent of changes in DNA sequence. It involves chemical modifications such as DNA methylation, histone methylation, and histone acetylation, which are regulated by a coordinated interplay of various regulators to ensure precise spatial and temporal regulation of gene expression. Epigenetic aberrations are commonly observed in cancer and are considered as hallmarks of cancer. In recent years, small molecules targeting specific epigenetic regulators have been developed and are demonstrating promising therapeutic potential in preclinical and clinical trials for cancer treatment. In this review, we summarize the essential regulatory mechanisms and dysfunctions of epigenetic regulators involved in DNA methylation, histone methylation, and histone acetylation during tumor development and progression. Moreover, we discuss the current advances and challenges in cancer epigenetic therapy that target these mechanisms in both hematologic malignancies and solid tumors. Finally, we discuss the potential of combining epigenetic drugs with other therapies, including chemotherapy, radiotherapy, targeted therapy, and immunotherapy, as a promising approach for cancer treatment. Overall, we aim to enhance the understanding of epigenetic regulation in cancer therapy and explore targeted therapeutic strategies based on these mechanisms, to ultimately advance cancer therapy and improve patient prognosis.

How do the “Pastoral Children” transform into Modern Students? Reflections from the perspectives of cultural reproduction and cultural acculturation

Education serves as one of the most potent means to promote equity and justice, yet concurrently functions as a powerful mechanism for the reproduction of inequity and injustice. This study integrates the theories of cultural reproduction and cultural acculturation, combining macro-level structural considerations with micro-level agency perspectives to explore the regeneration mechanism of educational equity. Utilizing interview methods, data were collected from 83 students, 48 teachers, 25 parents, 26 education administrators, 12 leaders in education administration, and 9 local cultural elites in Kangding City, a central urban area for China's ethnic minorities. The findings indicate that minority working-class students from traditional communities, upon entering urban schools where the predominant culture is modern mainstream, face significant challenges related to strict temporal and spatial regulations, as well as the intense clash between the inward-seeking spiritual foundations of traditional culture and the outward-seeking demands of modern mainstream culture. This results in a profound cultural interruption and even conflict during the process of cultural reproduction, as students strive to master the new cultural capital taught in schools, facilitating cross-cultural adaptation and transforming into genuine modern students. Following cultural adaptation, new issues of cultural identity arise, leading students into a dilemma of self-reflection within diverse contexts and even fostering a dual alienation from both modern mainstream society and traditional communities. All these aspects underscore the imbalance in power relations between urban schools in marginalized communities, which, in teaching cultural capital and reinforcing social control, deviate to some extent from their original intent of addressing educational equity issues.