Abstract
Within the dynamically cold low-inclination portion of the Classical Kuiper Belt, there exists a population of weakly bound binary systems with a number of unusual properties, most notable ...of which is their extremely wide orbital separations—beyond 7% of their Hill radii. The stability and evolution of these ultrawide Trans-Neptunian binaries (TNBs) have, in the past, been studied extensively under the assumption that the primary evolving mechanisms are interactions between the binary components and impacting Trans-Neptunian Objects (TNOs). Here, we instead study their evolution as driven by the gravitational perturbations of close passing but nonimpacting TNOs. By simulating these passages, we show that the aggregate effects of encounters over billions of years have a significant effect on Kuiper Belt binary evolution. Such processes can lead to tight binaries widening significantly over time, approaching and sometimes surpassing the separation of the widest known TNBs. We also find that the eccentricity and inclination distributions of observed ultrawide TNBs can be sampled from such widened binaries. While we are unable to produce enough wide binaries to explain their abundance, the orbital properties of ones we do produce are consistent with known wide binaries.
•Ro 63-1908 blocks acquisition of methamphetamine CPP in male rats.•Ro 63-1908 attenuates acquisition of methamphetamine CPP in female rats.•Ro 63-1908 does not block expression of ...methamphetamine-induced place preference.•Ro 63-1908 (1.0 mg/kg) enhances the locomotor-stimulant effects of methamphetamine.•Ro 63-1908 was neither rewarding nor aversive when administered alone.
Methamphetamine abuse has increased significantly in recent years. Currently, there are no FDA-approved pharmacotherapies for the treatment of methamphetamine use disorder. The goal of the current study was to determine if the N-methyl-d-aspartate (NMDA) GluN2B-selective antagonist Ro 63-1908 can block the conditioned rewarding effects of methamphetamine as assessed in conditioned place preference (CPP).
Two main experiments were conducted. In the first experiment, male (n = 24) and female (n = 24) rats received either vehicle or Ro 63-1908 (1.0–10.0 mg/kg) 30 min prior to the posttest to determine if blocking the GluN2B subunit attenuates expression of methamphetamine CPP. In the second experiment, male (n = 18) and female (n = 18) rats received either vehicle or Ro 63-1908 (1.0 or 3.0 mg/kg) 30 min prior to each conditioning session to determine if blocking the GluN2B subunit attenuates acquisition of methamphetamine CPP.
Ro 63-1908 (3.0 mg/kg) blocked acquisition of methamphetamine CPP in male rats, but only attenuated CPP in female rats. Ro 63-1908 did not alter expression of CPP in either sex. Increasing the dose of Ro 63-1908 (10.0 mg/kg) failed to block acquisition of CPP in an additional group of female rats (n = 6). A control experiment showed that Ro 63-1908 (3.0 mg/kg) did not produce CPP or conditioned place aversion in male rats (n = 6) or in female rats (n = 6).
The results of this study show that Ro 63-1908 is able to decrease the conditioned rewarding effects of methamphetamine.
Metabotropic glutamate receptor 1 (mGluR1) blockade has been shown to decrease impulsive choice, as measured in delay discounting. However, several variables are known to influence an animal’s ...discounting, including sensitivity to delayed reinforcement and sensitivity to reinforcer magnitude. The goal of this experiment was to determine the effects of mGluR1, as well as mGluR5, antagonism on these parameters. Forty Sprague Dawley rats were trained in delay discounting, in which consistently choosing a small, immediate reward reflects impulsive choice. For half of the rats, the delay to the large reinforcer increased across blocks of trials, whereas the delay decreased across the session for half of the rats. Following training, half of the rats received injections of the mGluR1 antagonist JNJ 16259685 (JNJ; 0, 0.1, 0.3, or 1.0mg/kg; i.p), and half received injections of the mGluR5 antagonist MPEP (0, 1.0, 3.0, or 10.0mg/kg; i.p.). Administration of JNJ increased sensitivity to delayed reinforcement (i.e., promoted impulsive choice), regardless of which schedule was used. However, the order in which delays were presented modulated the effects of JNJ on sensitivity to reinforcer magnitude. Specifically, JNJ decreased sensitivity to reinforcer magnitude in rats trained on the descending schedule only. MPEP did not alter sensitivity to reinforcer magnitude or sensitivity to delayed reinforcement. These results show that mGluR1 is an important mediator of impulsive choice, and they provide further evidence that delay order presentation is an important variable that influences drug effects in delay discounting.
Dendritic cell (DC) migration to draining lymph nodes (dLNs) is a slow process that is believed to begin with DCs approaching and entering into afferent lymphatic capillaries. From capillaries, DCs ...slowly crawl into lymphatic collectors, where lymph flow induced by collector contraction supports DC detachment and thereafter rapid, passive transport to dLNs. Performing a transcriptomics analysis of dermal endothelial cells, we found that inflammation induces the degradation of the basement membrane (BM) surrounding lymphatic collectors and preferential up-regulation of the DC trafficking molecule VCAM-1 in collectors. In crawl-in experiments performed in ear skin explants, DCs entered collectors in a CCR7- and β1 integrin-dependent manner. In vivo, loss of β1-integrins in DCs or of VCAM-1 in lymphatic collectors had the greatest impact on DC migration to dLNs at early time points when migration kinetics favor the accumulation of rapidly migrating collector DCs rather than slower capillary DCs. Taken together, our findings identify collector entry as a critical mechanism enabling rapid DC migration to dLNs in inflammation.
Aim
Pelvic exenteration surgery is an umbrella term for a multitude of operative techniques for locally advanced and recurrent pelvic malignancy. Currently, there is heterogeneity in the operative ...description that limits the interpretation of patient outcome and collaboration between units through standardized data collection. Our study aims to develop a consensus lexicon to describe the operative components of extended and exenteration pelvic surgery.
Method
This study adopted a mixed‐methods approach using semi‐structured interviews, questionnaires, focus groups and validation exercises involving pelvic exenteration experts from centres in the UK. Qualitative data were collected, and descriptive statistics are presented.
Results
We identified eight headings with 32 subheadings that encompass all components of the extent of the potential surgery. The lexicon was validated by 15 UK specialists. A ‘high‐complexity pelvic exenteration’ was defined as encompassing ‘conventional pelvic exenteration’ with the extension of surgery to remove bony structures or the structures in the pelvic sidewall. Pelvic sidewall structures include major vessels, sciatic nerves and/or bone. Bony structures include the sacrum and/or pubic bones.
Conclusion
This pelvic exenteration lexicon will permit classification of the surgical approach used that will improve data synthesis, allow more accurate activity recording for audit and ultimately improved outcomes for patients.
Background Although chronic kidney disease (CKD) is a highly prevalent condition among older adults with diabetes, the associations between health-related quality of life (HRQoL) and severity of CKD ...in this population are not well understood. The objective of this study was to assess HRQoL and depressive symptoms across estimated glomerular filtration rate (eGFR) stages. Study Design Cross-sectional. Setting & Participants 5,805 members of Kaiser Permanente Northern California, 60 years or older with diabetes, from the 2005-2006 Diabetes Study of Northern California (DISTANCE) survey. Predictor eGFR categories were defined as ≥90 (referent category), 75-89, 60-74, 45-59, 30-44, or ≤29 mL/min/1.73 m2. Outcomes HRQoL was measured using the modified Short Form−8 Physical Component Summary (PCS) and Mental Component Summary (MCS) scores. Depressive symptoms were measured using the Patient Health Questionnaire−8. Results In unadjusted linear regression analyses, physical (PCS) and mental (MCS) HRQoL scores were significantly lower with worsening eGFR level. However, after adjustment for sociodemographics, diabetes duration, obesity, and cardiovascular comorbid conditions and taking into account interactions with proteinuria, none of the eGFR categories was significantly or substantively associated with PCS or MCS score. In both unadjusted and adjusted analyses, higher risk of depressive symptoms was observed in respondents with eGFR ≤29 mL/min/1.73 m2 (relative risk, 2.02; 95% CI, 1.10-3.71; P < 0.05) compared with the referent group. However, this eGFR-depression relationship was no longer significant after adjusting for hemoglobin level. Limitations Participants are part of a single health care delivery system. Conclusions Our findings suggest the need for greater attention to and potential interventions for depression in patients with reduced eGFR.
Afferent lymphatic vessels contribute to immunity by transporting antigen and leukocytes to draining lymph nodes (LNs) and are emerging as new players in the regulation of peripheral tolerance. ...Performing intravital microscopy in inflamed murine ear skin we found that migrating dendritic cells (DCs) and antigen-experienced effector T cells spend considerable time arresting or clustering within afferent lymphatic capillaries. We also observed that intralymphatic T cells frequently interacted with DCs. When imaging polyclonal T cells during an ongoing contact-hypersensitivity response, most intralymphatic DC-T cell interactions were short-lived. Conversely, during a delayed-type-hypersensitivity response, cognate antigen-bearing DCs engaged in long-lived MHCII-(I-A/I-E)-dependent interactions with antigen-specific T cells. Long-lived intralymphatic DC-T cell interactions reduced the speed of DC crawling but did not delay overall DC migration to draining LNs. While further consequences of these intralymphatic interactions still need to be explored, our findings suggest that lymphatic capillaries represent a unique compartment in which adaptive immune interaction and modulation occur.
Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule that supports T cell activation, leukocyte migration, and (lymph)angiogenesis and has been shown to contribute to the ...pathology of various immune-mediated disorders, including asthma and corneal graft rejection. In contrast to monoclonal antibodies (mAbs) targeting ALCAM's T cell expressed binding partner CD6, no ALCAM-targeting mAbs have thus far entered clinical development. This is likely linked with the broad expression of ALCAM on many different cell types, which increases the risk of eliciting unwanted treatment-induced side effects upon systemic mAb application. Targeting ALCAM in surface-exposed tissues, such as the lungs or the cornea, by a topical application could circumvent this issue. Here, we report the development of various stability- and affinity-improved anti-ALCAM mAb fragments with cross-species reactivity towards mouse, rat, monkey, and human ALCAM. Fragments generated in either mono- or bivalent formats potently blocked ALCAM-CD6 interactions in a competition ELISA, but only bivalent fragments efficiently inhibited ALCAM-ALCAM interactions in a leukocyte transmigration assay. The different fragments displayed a clear size-dependence in their ability to penetrate the human corneal epithelium. Furthermore, intranasal delivery of anti-ALCAM fragments reduced leukocyte infiltration in a mouse model of asthma, confirming ALCAM as a target for topical application in the lungs.
Cell migration plays a vital role in both health and disease. It is driven by reorganization of the actin cytoskeleton, which is regulated by actin-binding proteins cofilin and profilin. ...Stress-inducible phosphoprotein 1 (STIP1) is a well-described co-chaperone of the Hsp90 chaperone system, and our findings identify a potential regulatory role of STIP1 in actin dynamics. We show that STIP1 can be isolated in complex with actin and Hsp90 from HEK293T cells and directly interacts with actin in vitro via the C-terminal TPR2AB-DP2 domain of STIP1, potentially due to a region spanning two putative actin-binding motifs. We found that STIP1 could stimulate the in vitro ATPase activity of actin, suggesting a potential role in the modulation of F-actin formation. Interestingly, while STIP1 depletion in HEK293T cells had no major effect on total actin levels, it led to increased nuclear accumulation of actin, disorganization of F-actin structures, and an increase and decrease in cofilin and profilin levels, respectively. This study suggests that STIP1 regulates the cytoskeleton by interacting with actin, or via regulating the ratio of proteins known to affect actin dynamics.
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