Multiple Migration Research Articles

Navigating Geoeducational Dilemmas: Singapore as a Migration Hub for Students from China

In a post-pandemic world of escalating tensions between China and the West, increasing numbers of students from China are eschewing Western destinations for places in Asia, including Singapore. For these migrants, this Chinese-majority city-state has emerged as an important geoeducational hub between China and the West. A portmanteau of geopolitics and education, the term geoeducational refers to the reciprocal effects of both. Employing an anthropological approach, this article theorizes the geoeducational as a crucial subdomain of the geosocial—a concept proposed by geographers to analyze how social subjects and spaces are influenced by and impact geopolitics and geoeconomics. Using ethnographic interviews and observations, I argue that Singapore's emergent junctional position helps Chinese student migrants navigate their geoeducational dilemmas. These dilemmas are conditioned by rising US-China superpower competition amid economic stagnation in China and growing xenophobia in the West. Under these conditions, many students see Singapore as a safe liminal place from which they can pursue security, flexibility, freedom, cultural belonging, and family togetherness—by "springboarding" to the West, returning to China, or remaining in Singapore. This article contributes to the mobilities turn in education studies and enhances understanding of multiple migration—migration characterized by multiple changes in destination—by analyzing the interplay between domestic and transnational movements. The geoeducational lens it develops is useful for illuminating international student mobilities cross-culturally and comparatively as well as investigating their systematic interrelationships, including implications for demographic change, brain drain and gain, university financing and rankings, and hypercompetition in a time of eroding meritocracy.

Plasma levels of matrix metalloproteinases in early psychosis, anxiety and depression: Evidence from the ALSPAC cohort

BackgroundConverging evidence supports the role of Matrix Metalloproteinases (MMPs) in psychiatric disorders. Originally identified as regulators of the extracellular matrix (ECM), MMPs’ functions span multiple processes, including inflammation, synaptic plasticity, neuronal migration, and blood–brain barrier maintenance. Tissue Inhibitors of Metalloproteinases (TIMPs) are major regulators of MMPs. In the present study we examined the associations of plasma MMPs and TIMPs with mental disorders in young adults aged 24 years in the Avon Longitudinal Study of Parents and Children (ALSPAC). MethodsThe present study was a nested case control study within the Avon Longitudinal Study of Parents and Children and comprised 374 participants who met criteria for psychiatric disorders (35 met the criteria for psychotic disorder, 201 for mild/moderate depressive disorder, and 266 for generalised anxiety disorder) and 401 controls. All cases and controls had were selected from the group of 4019 participants who had attended at age 24 years, completed psychiatric assessments and provided plasma samples. Plasma concentrations of MMP2, MMP3, MMP9 and TIMP-4 were quantified using proximity extension assays available on Olink® Cardiovascular Panel III. Logistic regression analysis compared standardised MMPs and TIMPs levels in cases and controls. Models were adjusted for sex, body mass index, and cigarette smoking. ResultsThere was evidence for an association between MMP3 and depressive disorder (Odds ratio [OR] 1.35, 95 % confidence interval [CI] 1.06–1.73). There was evidence for an association between TIMP4 and depressive disorder (OR 1.51, 95 % CI 1.22–1.88) and generalised anxiety disorder (OR 1.43, 95 % CI 1.19–1.72). There was no evidence for an association between MMPs and psychotic disorders. ConclusionsThe study revealed that 24-year-olds with depressive and anxiety disorders exhibited elevated plasma concentrations of TIMP-4 compared to controls. There was evidence for an association between MMP3 and depressive disorder. These findings provide further support for the involvement of metalloproteinases as biomarkers in the pathophysiology of mental disorders during early adulthood.

Atomic-level direct imaging for Cu(I) multiple occupations and migration in 2D ferroelectric CuInP2S6

CuInP2S6 (CIPS) is an emerging 2D ferroelectric material known for disrupting spatial inversion symmetry due to Cu(I) position switching. Its ferroelectricity strongly relies on the Cu(I) atom/ion occupation ordering and dynamics. Nevertheless, the accurate Cu(I) occupations and correlated migration dynamics under the externally applied energy, which are key to unlocking ferroelectric properties, remain controversial and unresolved. Herein, an atomic-level direct imaging through aberration-corrected scanning transmission electron microscopy is performed to precisely trace the Cu(I) dynamic behaviours under electron-beam irradiation along (100)-CIPS. It clearly demonstrates that Cu(I) possesses multiple occupations, and Cu(I) could migrate to the lattice, vacancy, interstitial and interlayer sites between the InS6 octahedral skeletons of CIPS to form local CuxInP2S6 (x = 2-4) structure. Cu(I) multi-occupations induced lattice stress results in a layer sliding along the b-axis direction generating a sliding size of 1/6 b lattice constant. The CuxInP2S6 (x = 2-4) exists in a type of dynamic structure, only metastable with electron dose over 50 e− Å−2, thus generating a dynamic process of CuxInP2S6(x=2−4)⇌CuInP2S6\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\mbox{C}}{{\\mbox{u}}}_{x}{\\mbox{In}}{{\\mbox{P}}}_{2}{{\\mbox{S}}}_{6}(x=2-4)\\rightleftharpoons {\\mbox{CuIn}}{{\\mbox{P}}}_{2}{{\\mbox{S}}}_{6}$$\\end{document}, a completely unreported phenomenon. These findings shed light on the unveiled mechanism underlying Cu(I) migration in CIPS, providing crucial insights into the fundamental processes that govern its ferroelectric properties.

Request Deadline Split and Interference‐Aware Request Migration in Edge Cloud

ABSTRACTEdge computing extends computing resources from the data center to the edge of the network to better handle latency‐sensitive tasks. However, with the rise of the Internet of Things, edge devices with limited processing capabilities face difficulties in executing requests with fluctuating request peaks. In order to meet the deadline constraints of latency‐sensitive tasks, a feasible solution is to offload some latency‐sensitive tasks to other nearby edge devices. This article studies the problem of request migration in edge computing systems and minimizes the request deadline violation rate based on actual online arrival patterns, performance interference phenomena, and deadline constraints. Since a request contains multiple services and request migration will lead to changes in server resource competition pressure, we split the problem into three sub‐problems, dividing the request deadline to determine the maximum response time of the service, determining the performance of the service under different resource pressures and the request migration strategies. To this end, we propose two deadline splitting methods, a performance interference model under multi‐resource pressure, and two heuristic request migration strategies. Since this article considers online edge scenarios, the number and type of requests are black boxes. We conduct simulation experiments and find that our method has only one‐third the number of request violations of other methods.

Predictive Model for Cell Positioning during Periodic Lateral Migration in Spiral Microchannels.

The periodic lateral migration of submicrometer cells is the primary factor leading to low precision in a spiral microchannel during cell isolation. In this study, a mathematical predictive model (PM) is derived for the lateral position of cells during the periodic lateral migration process. We analyze the relationship of migration period, migration width, and starting point of lateral migration with microchannel structure and flow conditions and determine the empirical coefficients in PM. Results indicate that the aspect ratio of the microchannel and the Reynolds number (Re) are key factors that influence the periodicity of the cell lateral migration. The lateral migration width is jointly affected by Re, the cell blockage ratio, and the microchannel curvature radius. The inlet structure of the microchannel and the ratio of the cell sample to the sheath flow rate are critical parameters for regulating the initial position. Moreover, the structure of the pressure field at the inlet constrains the distribution range of the starting point of the lateral migration. Regardless of whether the particles/cells undergo 0.5, 1, or multiple lateral migration cycles, the lateral positions predicted by PM align well with the experimental observations, thus verifying the accuracy of PM. This research helps to elucidate the characteristics of periodic lateral migration of cells in spiral microchannels and can provide practical guidance for the development and optimization of miniature spiral microchannel chips for precise cell isolation.

In Vitro Experiment Present ROCK2 Inhibition Promotes the Therapeutic Effect of Bevacizumab in the Treatment of Glioblastoma Multiforme

Objective Gliomas are a general designation for neuroepithelial tumors derived from the glial cells of the central nervous system. According to the histopathological and immunohistochemical features, the World Health Organization classifies gliomas into four grades. Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor that has been approved for the treatment of glioblastoma multiforme (GBM) as a second-line therapy. However, its efficacy remains limited. Rho/Rho-associated kinase (ROCK) is a downstream molecule of small guanosine triphosphatases (GTPases) that regulates multiple cellular processes, including motility, migration, and proliferation. Thus, ROCK has been regarded as a therapeutic target for cardiovascular diseases, neurological diseases, immune diseases, and cancer, and ROCK inhibitors have high potential clinical value. Methods Viability rate of cells was detected using MTT assay, and apoptosis of cells was detected using FACS. Expression of target genes and proteins was detected using qPCR and western blotting analysis. Concentration of cytokines was detected using ELISA methods. Results Viability and migration of GBM cells were reduced after bevacizumab treatment and that these effects were enhanced by ROCK2 inhibition. We further found that ROCK2 inhibition promoting the effect of bevacizumab was mainly mediated by the RhoA/ROCK2 pathway, further inducing apoptosis in GBM cells. In addition, we found that angiogenesis and degradation of cellular matrix-related cytokines were reduced by ROCK2 inhibition. Conclusions ROCK2 inhibition contributes to the therapeutic effects of bevacizumab.

From the Iranian Plateau into the heart of the Eurasian steppe belt: The phylogeography of Sisymbrium polymorphum (Brassicaceae)

The Eurasian steppe belt is the largest grassland region in the world. The flora of this belt varies greatly between its regions, and its individual elements have different spatiotemporal evolutionary histories. The main aim of this study was to investigate the phylogeographic pattern of a prominent plant steppe element. We genetically characterized 136 accessions of Sisymbrium polymorphum collected from field and herbarium surveys using a multi-locus approach. We dated the resulting phylogenetic trees and employed rooted TCS network methods to estimate the evolutionary history of individual genetic markers. The majority of haplo- and ribotypes showed restricted geographic distributions. Stem age of S. polymorphum was estimated to be in the early Pliocene, while its crown age was estimated to be in the late Pliocene. We hypothesize that this plant was introduced to the Eurasian steppe belt through the Kopet Dagh mountain chain over the Turanian lowlands via multiple migration events. Time frame along the migration route was limited by the retreat of the Paratethys at the end of the Pliocene and the Akchagyl transgression of the Caspian Sea at the beginning of the Pleistocene. No additional evidence was found to suggest any further migration events occurred. The Akchagyl transgression acted as a physiogeographical barrier in two ways. Firstly, it restricted the time window for immigration from the Iranian Plateau into the Eurasian steppe, and secondly, it temporarily blocked intra-steppe migration routes between the western and eastern parts of the Eurasian steppe.

MiR-494-3p regulates skin fibroblast activities by mediating fibromodulin production.

Skin wound healing is a well-coordinated process in which various cells and factors participate, during which fibroblast exhibits a critical role by exerting its multiple activities, including proliferation, migration, invasion, and differentiation. Previous studies have identified that fibromodulin (FMOD) could enhance dermal wound healing by promoting skin fibroblast activities, but little is known about its upstream regulator. We occasionally found that FMOD expression was downregulated in skin fibroblast by transforming growth factor-β1 treatment. It was hypothesized that microRNAs (miRNA) in skin fibroblast could downregulate FMOD production and blocking them would increase FMOD expression, as well as promote skin wound healing. Here, by utilizing combined analysis of miRNA microarray from the Gene Expression Omnibus database and miRNA targets prediction, we successfully identified a miRNA, termed miR-494-3p, could regulate FMOD production in human skin fibroblast (BJ fibroblast). The functional analysis revealed that miR-494-3p mimics could inhibit BJ fibroblast migration and invasion but not proliferation and differentiation, while miR-494-3p inhibition markedly promotes migration, invasion, and differentiation of BJ fibroblast. Moreover, we established FMOD overexpression (OE) and knockout BJ fibroblast. We found that FMOD OE could rescue the inhibitory effects of miR-494-3p mimics on the migration and invasion of BJ fibroblast. In contrast, the miR-494-3p inhibitor transfection could not enhance migration, invasion, and differentiation of FMOD KO BJ fibroblast. Together, our results suggest that miR-494-3p may be a potential target for skin wound management via regulating FMOD production.

ETS1 and RBPJ transcriptionally regulate METTL14 to suppress TGF-β1-induced epithelial-mesenchymal transition in human bronchial epithelial cells

Asthma is a chronic respiratory disease characterized by airway inflammation and remodeling. Epithelial-mesenchymal transition (EMT) of bronchial epithelial cells is considered to be a crucial player in asthma. Methyltransferase-like 14 (METTL14), an RNA methyltransferase, is implicated in multiple pathological processes, including EMT, cell proliferation and migration. However, the role of METTL14 in asthma remains uncertain. This research aimed to explore the biological functions of METTL14 in asthma and its underlying upstream mechanisms. METTL14 expression was down-regulated in asthmatic from three GEO datasets (GSE104468, GSE165934, and GSE74986). Consistent with this trend, METTL14 was decreased in the lung tissues of OVA-induced asthmatic mice and transforming growth factor-β1 (TGF-β1)-stimulated human bronchial epithelial cells (Beas-2B) in this study. Overexpression of METTL14 caused reduction in mesenchymal markers (FN1, N-cad, Col-1 and α-SMA) in TGF-β1-treated cells, but caused increase in epithelial markers (E-cad), thus inhibiting EMT. Also, METTL14 suppressed the proliferation and migration ability of TGF-β1-treated Beas-2B cells. Two transcription factors, ETS1 and RBPJ, could both bind to the promoter region of METTL14 and drive its expression. Elevating METTL14 expression could reversed EMT, cell proliferation and migration promoted by ETS1 or RBPJ deficiency. These results indicate that the ETS1/METTL14 and RBPJ/METTL14 transcription axes exhibit anti-EMT, anti-proliferation and anti-migration functions in TGF-β1-induced bronchial epithelial cells, implying that METTL14 may be considered an alternative candidate target for the treatment of asthma.

Stay, leave late, leave early, return, or move onward? Interprovincial migration decisions of older adults in China, 2000–2005 and 2010–2015

AbstractExisting studies on the migration of older adults in China have tended to treat older migration as a one‐off activity and have failed to investigate the multiple processes involved. Based on the microdata samples of the 1% national population sample surveys in 2005 and 2015, this study examines the effect of regional and personal attributes on older adults' two‐phase migration decisions. In the first phase, older adults decide whether to leave the province of household registration, while in the second phase, they decide to stay in the same province, return to the province of household registration, or move onward to a new province. In the first phase of migration, older adults' decisions were affected by several regional amenities, including medical services, public green areas, air pollution, and temperature differences. In the second phase of migration, older adults who had decided to remain in the first phase tended to leave provinces with a lower cost of living, fewer public green areas, and more extreme temperature differences. Older adults who, in the first phase, had moved to a new province with fewer medical services, more severe air pollution, and larger temperature differences were more likely to return to their province of household registration in the second phase in 2000‐2005, while those residing in provinces with more extreme temperature differences tended to move onward to a new province in 2010‐2015. This study enhances our understanding of the heterogeneity of older migration in China by disentangling the complexity of multiple migration processes.

Multiple contamination sources, pathways and conceptual model of complex buried karst water system:constrained by hydrogeochemistry and δ2H, δ18O, δ34S, δ13C and 87Sr/86Sr isotopes

Karst groundwater contamination has emerged as a worldwide environmental and health hazard. Karst aquifers, even for the buried karst systems, have strong contamination sensitivity and great pollution risk due to the good pipe fracture connectivity. The large burial depth and invisible hydrologic connectivity pose a challenge for the diagnosis of the contamination sources and identification of the contamination pathways of buried karst aquifers. To address it, a comprehensive application of hydrogeological and hydrogeochemical investigation combined with multiple isotopes (δ2H, δ18O, δ34S, δ13C and 87Sr/86Sr) were performed to elucidate the multiple contamination sources and migration pathways of contaminants in Jinci Spring, a complex buried karst water system. The results obtained highlight that the hydrological connectivity and source availability determine the specific contamination process in buried karst aquifer. Karst aquifer under the river channel is observed to be influenced by the vertical infiltration of polluted river water as indicated by elevated chloride levels (mean 79.4 mg/L) and higher δ2H (mean −8.8 ‰) and δ18O (mean −64.5 ‰) values. Evidenced by the excess of sulfate (mean: 1454 mg/L) and depleted δ34S (mean: −1.6 ‰), the lower karst aquifer may receive the leaking recharge of the mining waste water in the overlying coal seams. The occurrence of nitrate in karst water may be induced by reverse recharge from neighboring confined quaternary aquifers, indicated by the elevated nitrate concentration (15.0–50.8 mg/L) with high 87Sr/86Sr ratios (mean 0.7124). Our findings suggest that over-pumping of deep karst waters may produce additional pollution sources by altering the natural recharge relationship between montanic karst waters and the neighboring pore waters within the basin. Research in this paper improves our understanding of groundwater pollution and hydrological connectivity in buried carbonate aquifers and the protection of karst water resources.

The roles of different migration mechanisms in the transport of H2O–CH4 gas mixture in shales

Studying the roles of different migration mechanisms in shale matrix gas transport is beneficial for shale gas extraction and CO2 sequestration. The roles of different transport mechanisms in shale H2O–CH4 gas mixture transport were investigated considering their contributions to fluid flux. A permeability model coupling multiple gas migration mechanisms was developed by combining the pore network-related effective medium approximation, which was validated using process data from simultaneous H2O–CH4 transport in shales. The results showed that the gas transport mechanisms dominating methane and water vapor migration in shale differed. Slip flow and Knudsen diffusion contributed approximately 99% to methane migration. Water vapor surface diffusion as well as slip flow and Knudsen diffusion primarily contributed to the water vapor permeability before and after a time point, respectively. Water vapor and methane permeability generally decreased with time. The equilibrium water vapor and methane permeabilities ranged from 2.7699×10−22–12.312×10−22 m2 and 0.2640×10−21–4.9036×10−21 m2, respectively. The methane surface diffusion permeability increased slowly with time before approaching methane monolayer adsorption (before ∼100 s). An increase in relative humidity (approximately 300–3600 s) can promote the transport of water vapor. Water vapor and methane adsorption, especially the condensation of adsorbed water, could largely explain the decrease in shale gas permeability.

Seismic migration of water‐bottom‐related multiples accelerated by random phase‐encoding strategy

AbstractMarine seismic multiples contain more structure information than primaries and should be considered in migrations. However, multiple migrations suffer from severe crosstalks generated by interferences among undesirable multiples. It has been proven that the water‐bottom‐related multiple migration can suppress crosstalks greatly. However, if all associated consecutive‐order multiples are considered, the computation cost is extremely high. To settle this issue, a phase‐encoding‐based multiple migration is proposed. Supergathers are first created by randomly phase‐encoding consecutive‐order multiples and stacking‐encoded multiples. By migrating supergathers, the proposed method can fulfil migrations of all order multiples simultaneously, thereby reducing the computation cost significantly. We use a three‐layer model and the Pluto 1.5 model for numerical comparisons. The results reveal that the method can retrieve high‐quality images and increase computation efficiency considerably.

Endolysosomal transient receptor potential mucolipins and two-pore channels: implications for cancer immunity.

Past research has identified that cancer cells sustain several cancer hallmarks by impairing function of the endolysosomal system (ES). Thus, maintaining the functional integrity of endolysosomes is crucial, which heavily relies on two key protein families: soluble hydrolases and endolysosomal membrane proteins. Particularly members of the TPC (two-pore channel) and TRPML (transient receptor potential mucolipins) families have emerged as essential regulators of ES function as a potential target in cancer therapy. Targeting TPCs and TRPMLs has demonstrated significant impact on multiple cancer hallmarks, including proliferation, growth, migration, and angiogenesis both in vitro and in vivo. Notably, endosomes and lysosomes also actively participate in various immune regulatory mechanisms, such as phagocytosis, antigen presentation, and the release of proinflammatory mediators. Yet, knowledge about the role of TPCs and TRPMLs in immunity is scarce. This prompts a discussion regarding the potential role of endolysosomal ion channels in aiding cancers to evade immune surveillance and destruction. Specifically, understanding the interplay between endolysosomal ion channels and cancer immunity becomes crucial. Our review aims to comprehensively explore the current knowledge surrounding the roles of TPCs and TRPMLs in immunity, whilst emphasizing the critical need to elucidate their specific contributions to cancer immunity by pointing out current research gaps that should be addressed.

Ouabain modulates collective cell migration via a Na,K-ATPase activated Ca2+ signal pathway

Collective cell migration is important for many physiological and pathological processes. Ouabain, a cardiotonic steroid and specific ligand to Na,K-ATPase, has been reported to modulate collective cell migration, inhibiting it in cancer cells, and increasing it in normal cells. However, it is not clear what the mechanism is behind this difference in response. It is well-documented that ouabain blocks the pump function of Na,K-ATPase. At low concentrations this activates on the cellular level a Ca2+ mediated signaling chain with multiple downstream effects, including adhesion and migration pathways. At higher concentrations the inhibition of Na+ and K+ transport dominates the effect on the cellular level. We hypothesize that the difference in migration response of cancer and normal cells to ouabain is due to a difference in the Ca2+ signaling response. We further hypothesize that the spread and amplification of Ca2+signals between cells via gap junctions is upregulated by ouabain. To test the hypothesis, we made scratch assays in cultures of MDCK cells and studied migration rate and Ca2+signaling. 10 nM ouabain increases the migration rate, an effect that is inhibited by 2-APB, that blocks the IP3R Ca2+ release from ER. The effect on migration is also blocked by KN-93 that inhibits Ca2+ activated CAMKII. Interestingly, ouabain at 200 nM concentration decreased the migration rate compared to untreated cells. To analyze the strength of intercellular communication we analyzed the spread and synchronicity of spontaneous Ca2+ signals between neighboring cells. For this we used MDCK cells stable transfected with the Ca2+ sensitive fluorescent protein GCamp6f. Cells were treated with vehicle, ouabain 10 nM, or heptanol (blocks gap junctions). Timelapse Ca2+ imaging for 10-30 minutes was done. Machine learning based image analysis with Cellpose was then used to segment cells, followed by cross correlation of the integrated Ca2+signals from neighboring cells. Despite findings from previous phosphoproteomic studies indicating that there should be an upregulation of gap junctions, no conclusive differences in intercellular signaling could be identified for the different treatments. Finally, we made high resolution imaging of cells immunolabeled for vinculin and FAK, two proteins that are involved in migration and adhesion. We found ouabain correlated effects on the localization of vinculin and FAK with a polarized and concentrated localization after high dose ouabain, compared to a diffuse and unpolarized localization after low dose ouabain. Taken together we suggest that low dose ouabain via Na,K-ATPase triggers a Ca2+ signal that destabilize cell adhesions and that this is an important mechanism contributing to the observed upregulation of cell migration. Marta and Gunnar V Philipson's foundation, and VR 2020-05347 (Swedish Research Council). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mexican hospitality migrants and the spatial and geographic regulation of mobility

Mobility (and control over it) is partially mediated by migrant capital and how it is evaluated across time and space. This study draws on the concept of multiple migration – wherein migration is viewed as potentially multidirectional and open-ended over the life course – to examine the plight of male, Mexican hospitality staff globally on the move. These participants are unique in that they had experience working as hospitality staff in different countries under different legal classifications. In the US they were undocumented, in Mexico they were deported nationals, and in Canada they were received as temporary migrant workers. Their accounts bring different mobilities – illegal, forced, contract, and returned – under one analytical frame to illuminate how mobilities are spatially and geographically regulated. As the article details, their mobility depended on the resources they accrued during migration and whether these resources could be converted into relevant capital, with class, gender and race significant mediating factors. When contextualised, their accounts offer unique insights into immigration controls, transnational labour regimes, political economy and how access to capital shapes gendered identities and hierarchies. Their evaluations vis-à-vis other (global) workers also mediated their legal incorporation, governed by normative ideals that shape prospects and life outcomes in the current economy.

Evaluating streamflow and temperature effects on Bull Trout migration and survival with linear spatial capture–recapture models

AbstractObjectiveIn the U.S. Pacific Northwest, climate change is increasing air temperatures, decreasing warm season (April–September) streamflow, and increasing cool season (October–March) streamflow. Warmer water temperatures may alter conditions for migratory coldwater fishes like the Bull Trout Salvelinus confluentus. Consequently, an understanding of Bull Trout migration and survival is critical for species conservation and restoration. In the Salmon River basin, Idaho, 1992 and 1993 transpired to be two of the most opposing extreme years among the past three decades for warm season water temperature and streamflow. These extremes provided a unique opportunity to retrospectively compare Bull Trout survival and migration under potential climate change scenarios.MethodsWe evaluated prespawning and postspawning migrations and survival of fluvial Bull Trout that were radio‐tagged and tracked from 1992 to 1994. We used a Cormack–Jolly–Seber linear spatial capture–recapture model to simultaneously model the migration and survival of radio‐tagged prespawn (n = 58) and postspawn (n = 23) Bull Trout among weeks and river reaches with streamflow, water temperature, and habitat covariates.ResultMost individual prespawning migrations were similar among tagged fish, whereas postspawn fish adopted multiple migration and overwintering strategies. Movements of prespawn Bull Trout were larger when (1) weekly average daily maximum streamflow increased and (2) weekly average daily maximum water temperature increased. The model estimated that at least 52% of spawners survived to spawning, and mean weekly prespawning apparent survival was higher in the low‐streamflow year (1992) than in the year with higher and more variable streamflow (1993). Survival of 1992–1994 fish during the 38‐week postspawning period was intermediate to that in the prespawning period. Detections of prespawn Bull Trout were generally higher at sites with more complex habitats, less large woody debris, and fewer undercut banks.ConclusionWe found that the prespawn life stage can represent a shorter time frame (14–18 weeks) with increased mortality compared to the longer postspawning period (38 weeks). Bull Trout apparent survival increased with lower streamflow variability, indicating that expected future changes in climate may adversely affect Bull Trout.

Abstract 2731: CCR5-001, a novel drug Fc-conjugate (DFC) targeting CCR5, demonstrates potent efficacy in a colorectal cancer mouse model

Abstract Background The approval of immune checkpoint inhibitors (ICI) such as PD-(L)1 inhibitors has revolutionized cancer therapy and established a role for immune effector cells, most notably CD8+ T cells, in tumor control and destruction. While anti-PD-(L)1 therapy has demonstrated durable responses, only a small subset of patients benefit and respond to therapy. CCR5 is expressed on multiple immune cells (e.g. myeloid-derived suppressor cells) and CCR5-dependent migration of these cells contribute to an immune-suppressive tumor microenvironment (TME) thereby limiting response to ICI therapy. In addition, expression of CCR5 on cancer cells has been linked to increased metastasis and resistance to ICI therapy. Upregulation of CCL5/CCR5 has been associated with poor outcomes in multiple solid tumor indications, including colorectal cancer (CRC). Therefore, targeting CCR5 has the potential to increase response rates to ICI therapy and improve outcomes. Herein, we describe a first-in-class CCR5 targeting DFC, CCR5-001, a multivalent conjugate of a potent, small molecule CCR5 antagonist conjugated to an immune-silent proprietary human IgG1 Fc. This CCR5 targeting DFC has the potential to improve responses to ICI therapy by preventing pro-tumorigenic reprogramming of the TME induced by CCL5/CCR5 expressing tumor and myeloid cells. Methods Binding of CCR5-001 to hCCR5 was measured by surface plasmon resonance (SPR) and to CCR5+ PathHunter cells (DiscoverX) by flow cytometry. Functional activity was determined in CCR5+ PathHunter β-arrestin assay with CCL3 to induce CCR5 signaling according to manufacturer’s instructions. Efficacy was determined in an immune-competent syngeneic mouse model using the CRC cell line, MC38. CCR5-001 was dosed at 20 mg/kg twice per week for two weeks. Tumor volumes were recorded and statistical analysis was conducted by t-test (Mann-Whitney) or two-way ANOVA in Prism. Results CCR5-001 displayed a KD of 4.2 nM to immobilized hCCR5 by SPR and IC50 of 0.63-0.98 nM for binding to engineered CCR5+ PathHunter cells. This high affinity binding translated to potent functional inhibition of CCL3-induced CCR5 signaling with an IC50 of 12.7 nM in CCR5+ cell-based assay. CCR5-001 demonstrated potent, statistically significant (p = 0.0052) tumor growth inhibition of 76% by day 13 in a syngeneic mouse model. Conclusions CCR5-001 demonstrated potent CCR5 binding and functional inhibition of CCR5 signaling in cell-based assays. The in vitro activity translated to robust efficacy as a monotherapy in a syngeneic mouse model. Based on these results and other emerging data, CCR5-001 represents an exciting new avenue for targeting CCR5 with DFCs in solid cancers where the pathology is driven by the CCR5/CCL5 axis. Citation Format: Simon Döhrmann, James Levin, Nicholas Dedeic, Amanda Almaguer, Doug Zuill, Elizabeth Abelovski, Jeffrey B. Locke, Joanne Fortier, Maria Hernandez, Qiping Zhao, Karin Amundson, Madison Moniz, Hongyuan Chen, Dhanya Panickar, Thanh Lam, Grayson Hough, Thomas P. Brady, Allen Borchardt, Jason N. Cole, Leslie W. Tari. CCR5-001, a novel drug Fc-conjugate (DFC) targeting CCR5, demonstrates potent efficacy in a colorectal cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2731.

Deguelin inhibits the proliferation of human multiple myeloma cells by inducing apoptosis and G2/M cell cycle arrest: Involvement of Akt and p38 MAPK signalling pathway.

Deguelin exhibits antiproliferative activity against various cancer cell types. Previous studies have reported that deguelin exhibits pro-apoptotic activity against human cancer cells. The current study aimed at further elaborating the anticancer effects of deguelin against multiple myeloma cells. Cell growth estimations were made through MTT assay. Phase contrast microscopy was used for the analysis of the viability of multiple myeloma cells. Colony formation from multiple myeloma cells was studied using a clonogenic assay. Antioxidative assays for determining levels of glutathione (GSH) and superoxide dismutase (SOD) were carried out after treating multiple myeloma cells with deguelin. The apoptosis of multiple myeloma cells was studied using AO/EB and Annexin V-FITC/PI staining methods. Multiple myeloma cell cycle analysis was performed through flow cytometry. mRNA expression levels were depicted using qRT-PCR. Migration and invasion of multiple myeloma cells were determined with the wound-healing and transwell assays, respectively. Deguelin specifically inhibited the multiple myeloma cell growth while the normal plasma cells were minimally affected. Multiple myeloma cells when treated with deguelin exhibited remarkably lower viability and colony-forming ability. Multiple myeloma cells treated with deguelin produced more SOD and had higher GSH levels. The multiple myeloma cell growth, migration, and invasion were significantly declined by in vitro administration of deguelin. In conclusion, deguelin treatment, when applied in vitro, induced apoptotic cell death and resulted in mitotic cessation at the G2/M phase through modulation of cell cycle regulatory mRNAs in multiple myeloma cells.

Study on formation mechanism of mud-inclusion-type underground debris flows using natural caving method

This study aimed to investigate the formation mechanism of the mud-inclusion-type underground debris flows of natural caving underground mines. The characteristics of fine moraine particles flowing through the coarse-grained ore bed were used to analyze the formation process of mud inclusions in the caving ore bed through a physical model test. Based on the movement behavior of the mud inclusions of moraine in the caving ore bed, a formation-mechanism generalized model of underground debris flows with mud inclusions was established. The model was used to examine the formation mechanism of mud-inclusion-type underground debris flows in natural caving. The results showed that the fine moraine particles had good cross-flow characteristics in the process of drawing coarse-grained ore. The accumulation of fine moraine in the ore bed was a prerequisite for the formation of mud inclusions, and the fluid inclusions were formed by a mixture of the particles with the infiltrated water. When mud inclusions in moraine are affected by many factors, such as ore-drawing vibrations, blasting vibrations, and groundwater, the inclusions undergo multiple migration–stop–migration cycles, resulting in separation or fusion. However, the inclusions are released along the optimal random pore path to the outlet, forming a certain scale of underground debris flows accidents. The accuracy and reliability of the formation mechanism were verified through geophysical explorations based on the equivalent inverse flux transient electromagnetic method. This study not only broadens the research on debris flow, but also provides theoretical guidance for the prevention and control of underground debris flows.