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Background: Standard high-frequency deep brain stimulation (HF-DBS) at the subthalamic nucleus (STN) is less effective for lower-limb motor dysfunctions in Parkinson’s disease (PD) patients. However, the effects of very low frequency (VLF; 4 Hz)-DBS on lower-limb movement and motor cortical oscillations have not been compared. Objective: To compare the effects of VLF-DBS and HF-DBS at the STN on a lower-limb pedaling motor task and motor cortical oscillations in patients with PD and with and without freezing of gait (FOG). Methods: Thirteen PD patients with bilateral STN-DBS performed a cue-triggered lower-limb pedaling motor task with electroencephalography (EEG) in OFF-DBS, VLF-DBS (4 Hz), and HF-DBS (120-175 Hz) states. We performed spectral analysis on the preparatory signals and compared GO-cue-triggered theta and movement-related beta oscillations over motor cortical regions across DBS conditions in PD patients and subgroups (PDFOG–and PDFOG+). Results: Both VLF-DBS and HF-DBS decreased the linear speed of the pedaling task in PD, and HF-DBS decreased speed in both PDFOG–and PDFOG+. Preparatory theta and beta activities were increased with both stimulation frequencies. Both DBS frequencies increased motor cortical theta activity during pedaling movement in PD patients, but this increase was only observed in PDFOG + group. Beta activity was not significantly different from OFF-DBS at either frequency regardless of FOG status. Conclusion: Results suggest that VL and HF DBS may induce similar effects on lower-limb kinematics by impairing movement speed and modulating motor cortical oscillations in the lower frequency band.

Objectives: The present study investigates whether space syntax offers appropriate tools for identifying risks of aggression, interventional opportunities, and environmental design strategies to reduce the risk of Type II violence in emergency departments. Background: Although healthcare workers are a relatively small percentage of the U.S. workforce, they sustain almost 75% of workplace assaults. Poor environmental design has been identified as an antecedent to aggression by patients and/or their companions. Method: Guided by Rational Choice Theory, Lifestyle Exposure Theory, Routine Activity Theory, and Crime Prevention through Environmental Design (CPTED), the study uses five visibility graph analysis (VGA) measures: visibility, control, controllability, mean visual depth, and occlusivity. Three U.S. hospital-based emergency departments were selected. First, a VGA was performed on all three layouts. A second VGA was performed after excluding unconnected spaces, and a third was performed on key patient and staff areas. Last, a fourth VGA was conducted after performing physical modifications to the three departments. Results: Statistical analysis revealed significant differences in VGA measures not only between different layouts but also between the original and modified layouts. Specifically, small changes created by architectural features can affect visual access and exposure as measured by space syntax. Alcove-style spaces in key staff areas are also associated with limited visual control of the local environment. Typically, in smaller zones, central staff workstations afford better control of patient spaces. Conclusion: This study shows that space syntax analysis is a useful tool for identifying risks of aggression in hospital spaces and for identifying interventional opportunities.

Many Pacific salmon populations are returning from sea at younger ages and smaller sizes. Hatchery culture, management practices, and environmental factors influence juvenile release size and emigration timing, which in turn affect important demographic characteristics in returning adults. We analyzed data from approximately 345,000 tagged spring Chinook Salmon juveniles exiting Cle Elum Supplementation and Research Facility (Yakima River, Washington, USA) acclimation sites over thirteen brood years (2002–2014), evaluating smolt size, emigration timing, river flow, juvenile survival, and age-at-return. We observed a relationship between size and volitional exit timing of smolts from acclimation sites, with larger fish tending to emigrate earlier than smaller fish. Early emigration was also coincident with lower river flows near acclimation sites. Later emigration timing was correlated with an increase in apparent survival of juveniles to Bonneville Dam (500–530 km downstream of acclimation sites), but also with a lower rate of survival to return from sea. In general, for juveniles successfully emigrating downstream of Bonneville Dam, age-at-return increased with decreasing juvenile fish size and later emigration timing. Our results support a growing body of evidence that hatchery practices may result in larger smolts that tend to return at younger ages. Given the biological and economic consequences of younger age-at-maturation, methods to reverse this trend should be further explored and implemented.

Background Although many studies have shown abnormalities in brain structure and function in people with Parkinson’s disease (PD), we still have a poor understanding of how brain structure and function relates to freezing of gait (FOG). Graph theory analysis of electroencephalography (EEG) can explore the relationship between brain network structure and gait function in PD. Methods Scalp EEG signals of 83 PD (42 PDFOG+ and 41 PDFOG−) and 42 healthy controls were recorded in an eyes-opened resting-state. The phase lag index was calculated for each electrode pair in different frequency bands, but we focused our analysis on the theta-band and performed global analyses along with nodal analyses over a midfrontal channel. The resulting connectivity matrices were converted to weighted graphs, whose structure was characterized using strength and clustering coefficient measurements, our main outcomes. Results We observed increased global strength and increased global clustering coefficient in people with PD compared to healthy controls in the theta-band, though no differences were observed in midfrontal nodal strength and midfrontal clustering coefficient. Furthermore, no differences in global nor midfrontal nodal strength nor global clustering coefficients were observed between PDFOG+ and PDFOG− in the theta-band. However, PDFOG+ exhibited a significantly diminished midfrontal nodal clustering coefficient in the theta-band compared to PDFOG−. Furthermore, FOG scores were negatively correlated with midfrontal nodal clustering coefficient in the theta-band. Conclusion The present findings support the involvement of midfrontal theta oscillations in FOG symptoms in PD and the sensitivity of graph metrics to characterize functional networks in PDFOG+.

In view of increasing globalization, the ongoing promotion of foreign direct investment and the lack of comparative literature on how water property rights are changing in the global South, this article asks: How have property rights in water evolved through investor-State contracts on mineral, petroleum and land issues in Africa and Asia? We analyse 80 publicly available contracts—22 minerals, 40 petroleum and 18 land—of 34 African and 19 Asian countries. We find that: (i) in addition to a State's water law, water allocation is also implicitly governed by contracts and international investment treaties; (ii) States de facto privatize water by allocating quasi-property rights through the granting of contracts to foreign international investors; (iii) such waters exploited by virtue of contracts reduce the ability of States to regulate water during the term of the contract especially as investors' water use is protected by bilateral investment treaties and potential compensation claims; and (iv) the need of the State to increasingly adaptively govern water as the impacts of climate change on water become more noticeable will be challenged by the long-term quasi property rights granted by States to investors in such contracts.

The TRI-POL project explores the triangle of interactive relationships between affective and ideological polarisation, political distrust, and the politics of party competition. In this project there are two complementary groups of datasets with individual-level survey data and digital trace data collected in five countries: Argentina, Chile, Italy, Portugal and Spain. These datasets are comprised of three waves carried out over a six-month period between late September 2021 and April 2022. In addition, the survey datasets include a series of experiments embedded in the different waves that examine social exposure, polarisation framing, and social sorting. The digital trace datasets include variables on individuals’ behaviours and exposure to information received via digital media and social media. This data was collected using a combination of tracking technologies that the interviewees installed in their different devices. This digital trace data is matched with the individual-level survey data. These datasets are especially useful for researchers who wish to explore dynamics of polarisation, political attitudes, and political communication. The authors would like to express their gratitude to other members of the original research team that participated in one way or another in the design and implementation of the different waves of the survey: Ryan Carlin, Gregory Love, Noam Lupu, Pedro Magalhaes, Melanie Revilla, and Luana Russo. The authors would also like to thank all respondents who participated in the survey. This research was supported by competitive grant funding from the Spanish Ministry of Science and Innovation, “Proyectos de I+D+i”, Title: "El triángulo de polarización, confianza política y competencia política: Comprendiendo sus dinámicas en las democracias contemporáneas", (Code: PID2019-106867RB-I00 /AEI/10.13039/501100011033 (2020-2024), Principal Investigator: Mariano Torcal). Additional funding provided through Ayudas Fundación BBVA a Equipos de Investigación Cientifica en Economía y Sociedad Digital 2019, Project Title: "El triángulo de polarización, confianza política y comunicación política: comprendiendo sus dinámicas en las democracias contemporáneas" (Principal Investigator: Mariano Torcal). The views expressed herein are those of the authors and are not necessarily those of the Spanish Ministry of Science and Innovation or the Fundación BBVA. The PI of the project is also grateful for the funding provided by the Advanced Research Fellowship Programme ICREA, funded by the Catalonian Government. Other contributors include funding from the Political Science Department at the University of Mississippi (PI: Gregory J. Love), the Georgia State University Provost Faculty Fellowship and Center for Human Rights and Democracy funded project “Polarization, Political Competition, and Interpersonal Trust” (PI: Ryan Carlin), the Centre for Social Conflict and Cohesion Studies and the Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias (Fondap) de la Agencia Nacional de Investigación y Desarrollo del Gobierno de Chile (Proyecto #15130009, PI: Matias Bargsted) and Vanderbilt University (PI: Noam Lupu).

Genetic variation of immune genes is an important component of genetic diversity. Major histocompatibility complex (MHC) genes have been put forward as a model for studying how genetic diversity is maintained and geographically distributed in wild populations. Pathogen-mediated selection processes (i.e., heterozygosity advantage, rare-allele advantage or fluctuating selection) and demography are believed to generate and maintain the extreme diversity of MHC genes observed. However, establishing the relative importance of the different proposed mechanisms has proved extremely difficult, but heterozygote advantage is expected to be more detectable when multiple pathogens are considered simultaneously. Here, we test whether MHC diversity in three amphibian species (Ichthyosaura alpestris, Pleurodeles waltl,andPelophylax perezi) is driven by pathogen-mediated selection. We examined the relationship between the individual MHC class II exon variability with individual infection status (infected or not), infection intensity, and co-infection of two main amphibian pathogens:Batrachochytrium dendrobatidis(Bd) andRanavirussp. (Rv). We found higher MHC class II exon 2 allelic diversity inI.alpestrisandP. perezithan inP.waltlbut no significant differences in allele frequencies between infection groups. We also observed significant differences inBdinfection intensity betweenBdinfected individuals and co-infected individuals depending on the number of MHC loci that an individual carries. ForI. alpestris, we show stronger evidence for MHC associations with infection intensity and status when individuals carry specific alleles and supertypes. Our results suggest that studying the association between MHC genes and single and co-infected individuals might provide new insights into host-parasite evolution and a better understanding of evolutionary mechanisms driven by MHC diversity.

Supplementary Figure from Midkine Promotes Metastasis and Therapeutic Resistance via mTOR/RPS6 in Uveal Melanoma

Uveal melanoma is a rare form of melanoma that originates in the eye, exerts widespread therapeutic resistance, and displays an inherent propensity for hepatic metastases. Because metastatic disease is characterized by poor survival, there is an unmet clinical need to identify new therapeutic targets in uveal melanoma. Here, we show that the pleiotropic cytokine midkine is expressed in uveal melanoma. Midkine expression in primary uveal melanoma significantly correlates with poor survival and is elevated in patients that develop metastatic disease. Monosomy 3 and histopathologic staging parameters are associated with midkine expression. In addition, we demonstrate that midkine promotes survival, migration across a barrier of hepatic sinusoid endothelial cells and resistance to AKT/mTOR inhibition. Furthermore, midkine is secreted and mediates mTOR activation by maintaining phosphorylation of the mTOR target RPS6 in uveal melanoma cells. Therefore, midkine is identified as a uveal melanoma cell survival factor that drives metastasis and therapeutic resistance, and could be exploited as a biomarker as well as a new therapeutic target.Implications:Midkine is identified as a survival factor that drives liver metastasis and therapeutic resistance in melanoma of the eye.

People with HIV (PWH) have persistently elevated levels of inflammation and immune activation despite suppressive antiretroviral therapy (ART), with specific biomarkers showing associations with non-AIDS-defining morbidities and mortality. We investigated the potential role of the HIV-specific adaptive immune response, which also persists under ART, in driving levels of these clinically relevant biomarkers.Cohort-based study.HIV-specific IFN-γ-producing T-cell responses and antibody concentrations were measured in blood at study entry in the ACTG A5321 cohort, following a median of 7 years of suppressive ART. HIV persistence measures including cell-associated (CA)-DNA, CA-RNA, and plasma HIV RNA (single-copy assay) were also assessed at study entry. Plasma inflammatory biomarkers and T-cell activation and cycling were measured at a pre-ART time point and at study entry.Neither the magnitudes of HIV-specific T-cell responses nor HIV antibody levels were correlated with levels of the inflammatory or immune activation biomarkers, including hs-CRP, IL-6, neopterin, sCD14, sCD163, TNF-α, %CD38 + HLA-DR + CD8 + and CD4 + cells, and %Ki67 + CD8 + and CD4 + cells - including after adjustment for pre-ART biomarker level. Plasma HIV RNA levels were modestly correlated with CD8 + T-cell activation ( r = 0.25, P = 0.027), but other HIV persistence parameters were not associated with these biomarkers. In mediation analysis, relationships between HIV persistence parameters and inflammatory biomarkers were not influenced by either HIV-specific T-cell responses or antibody levels.Adaptive HIV-specific immune responses do not appear to contribute to the elevated inflammatory and immune activation profile in persons on long-term ART.

Este artículo de investigación se encuentra disponible en la siguiente URL: https://www.revistanefrologia.com/es-pdf-S0211699521001570 En este artículo de investigación también participan: Ramón A. García-Trabanino, Miguel Hueso, Pedro Trinidad, Aquiles Jara, Mónica Furlano, Rosana Gelpi, Ana Vila-Santandreu, César A. Restrepo, Maya Sánchez-Baya, Carolt Arana, Marián Goicoechea, Verónica Coll, Julián Segura, Orlando Gutiérrez, Kamyar Kalantar-Zadeh, Emilio Sánchez y Alejandro Ferreiro.

Clinical research to achieve antiretroviral therapy-free remission requires quantitative assays of the HIV-1 reservoir. Intact proviral DNA (IPD) measurement has greater throughput than the quantitative viral outgrowth assay (QVOA). In 25 individuals with well-documented long-term viral suppression, IPD levels and infectious units per million CD4+ T cells by QVOA strongly correlated (r = 0.59, P = .002), and IPD correlated with total cell-associated HIV-1 DNA and cell-associated HIV-1 RNA (r = 0.62 and r = 0.59, P ≤ .002). IPD may provide an accessible marker of inducible replication-competent virus, total numbers of infected cells, and cellular expression of HIV-1 RNA.

Many species of insects show phenotypically plastic dispersal traits in response to suboptimal environmental conditions. These polyphenetic traits can have large impacts on the population dynamics of the dispersing insects. Therefore, it is important to understand what environmental factors affect the development of dispersal traits and how these factors affect population dynamics via immigration/emigration.Pea aphids (Acyrthosiphon pisum) exhibit a polyphenetic wing dimorphism in which individuals are either winged (alate) or not (apterous). The production of alate offspring is determined by environmental cues experienced by the mother. Environmental factors associated with these cues have been intensively studied, with crowding, host plant quality, natural enemies, and fungal infection being shown to affect the production of pea aphid alates under controlled laboratory conditions. Nonetheless, environmental factors affecting alate production have rarely been studied in field populations of pea aphids.Using data from a three-year study of alate production in 5-9 alfalfa (lucerne) fields, we examined the effects of (i) pea aphid abundance, (ii) host plant maturity, (iii) temperature, (iv) predator and herbivore abundance, (v) parasitism, and (vi) entomopathic fungal incidence. In twice-weekly samples taken over the growing season, alate production ranged from 0 to 83% of the nymphal population.Pea aphid abundance, temperature, and alfalfa maturity together explained 67% of the variation in alate production. The other factors we investigated explained little variation. These results suggest there is a limited number of key environmental factors that consistently predict changes in alate production in field populations, while many factors identified in lab studies may be unimportant. Our results highlight the value of investigating factors affecting the expression of plastic traits in insect species at a broad spatiotemporal scale and under natural conditions.

Long-term consequences of human immunodeficiency virus (HIV) are likely the result of persistent inflammation and immune dysfunction of which cytomegalovirus (CMV) is a known contributor. We leveraged 2 AIDS Clinical Trials Group clinical trials exploring the effects of immune modulators (ruxolitinib and sirolimus) on inflammation in people with HIV on antiretroviral therapy to determine whether these interventions affected CMV shedding at various mucosal sites. Analyzing 635 mucosal samples collected, we found no significant difference in CMV levels across study arms or time points. Men had more CMV shedding than women. We did confirm an association between higher CMV DNA and immune markers associated with HIV persistence and HIV-associated mortality rates.

HIV post-treatment controllers (PTCs) are rare individuals who maintain low levels of viremia after stopping antiretroviral therapy (ART). Understanding the mechanisms of HIV post-treatment control will inform development of strategies aiming at achieving HIV functional cure. In this study, we evaluated 22 PTCs from 8 AIDS Clinical Trials Group (ACTG) analytical treatment interruption (ATI) studies who maintained viral loads ≤400 copies/mL for ≥24 wk. There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen (HLA) alleles between PTCs and post-treatment noncontrollers (NCs, n = 37). Unlike NCs, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA (CA-RNA) and intact proviral DNA assay (IPDA) during analytical treatment interruption (ATI). Immunologically, PTCs demonstrated significantly lower CD4 + and CD8 + T cell activation, lower CD4 + T cell exhaustion, and more robust Gag-specific CD4 + T cell responses and natural killer (NK) cell responses. Sparse partial least squares discriminant analysis (sPLS-DA) identified a set of features enriched in PTCs, including a higher CD4 + T cell% and CD4 + /CD8 + ratio, more functional NK cells, and a lower CD4 + T cell exhaustion level. These results provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.

Maternal separation is a widely used animal model to study early life adversity in offspring. However, only a few studies have focused on the impact of disrupting the maternal bond from the mother's perspective. Such studies reveal alterations in behavior, whereas the underlying neuroendocrine mechanisms remain largely unknown. In this study, we compared the consequences of daily brief maternal separation (BMS; 15 min) versus long maternal separation (LMS; 180 min) during the first week postpartum with respect to behavioral and neuroendocrine changes in lactating Sprague–Dawley dams. Mothers were tested for their maternal care before and after separation, maternal motivation to retrieve pups, as well as anxiety-related and stress-coping behaviors. In addition, we analyzed their basal plasma corticosterone levels and oxytocin receptor binding in selected brain regions of the limbic system and maternal network. LMS dams showed higher levels of behavioral alterations compared to BMS and non-maternally separated (NMS) dams, including increased licking and grooming of the pups and decreased maternal motivation. Anxiety-related behavior was not affected by either separation paradigm, whereas passive stress-coping behavior tended to increase in the LMS group. Plasma corticosterone concentrations were not different between groups. Oxytocin receptor binding was higher in the medial preoptic area and tended to be higher in the prelimbic cortex of LMS dams, only. Our results demonstrate that especially daily prolonged maternal separation impacts on the mothers' behavior and oxytocin system, which suggests that enhanced oxytocin receptor binding could be a compensatory mechanism for potentially decreased central oxytocin release due to limited pup contact.

A critical legal issue in water governance is who owns and who holds property rights in water. Hence, we address the question: How has the state of legal knowledge on private property rights in water evolved worldwide, and how are these rights embedded in the current existing legal constructions? In answering the question, this article reviews the legal literature to: (i) understand the current state of water ownership and water property rights in the main legal systems, (ii) understand and capture how private water “property” rights are embedded in the existing legal constructions; and (iii) reflect on the application of these rights in practice. We conclude: (a) While most states have placed water in the public domain, past statutory systems of water rights are difficult to abolish, and increasingly Indigenous peoples are successfully demanding recognition of, and reclaiming their water rights. (b) States are (re)allocating water rights through statutory mechanisms, including clearly defined bundle-of-rights. And (c), while the state ostensibly controls the water, the allocation of water through historic and new statutory instruments “encroaches” on state water ownership, and has created confusion affecting the state's power to adaptively govern the water. This confusion reflects the tension between the need of states to own and govern water in the public interest, the rights of Indigenous peoples to their water, with the need of agriculture and industries to have reliable supplies of water, leading to water use rights that imply “quasi-property” rights in water.