Conventional views of the tunica adventitia as a poorly organized layer of vessel wall composed of fibroblasts, connective tissue, and perivascular nerves are undergoing revision. Recent studies ...suggest that the adventitia has properties of a stem/progenitor cell niche in the artery wall that may be poised to respond to arterial injury. It is also a major site of immune surveillance and inflammatory cell trafficking and harbors a dynamic microvasculature, the vasa vasorum, that maintains the medial layer and provides an important gateway for macrophage and leukocyte migration into the intima. In addition, the adventitia is in contact with tissue that surrounds the vessel and may actively participate in exchange of signals and cells between the vessel wall and the tissue in which it resides. This brief review highlights recent advances in our understanding of the adventitia and its resident progenitor cells and discusses progress toward an integrated view of adventitial function in vascular development, repair, and disease.
Immune-related RECIST (irRECIST) were designed to capture atypical responses seen with immunotherapy. We hypothesized that, in patients with metastatic clear cell renal cell carcinoma (mccRCC), ...candidate biomarkers for nivolumab response would show improved association with clinical endpoints capturing atypical responders (irRECIST) compared with standard clinical endpoints (RECISTv1.1).
Endpoints based on RECISTv1.1 objective response rate (ORR)/progression-free survival (PFS) or irRECIST immune-related ORR (irORR)/immune-related PFS (irPFS) were compared in patients enrolled in the CheckMate-010 trial. Pretreatment tumors were analyzed by PD-L1 and PD-L2 IHC, and by multiplex immunofluorescence for CD8, PD-1, TIM-3, and LAG-3. T-cell activation signatures were assessed by RNA sequencing.
Median irPFS was significantly longer than median PFS. irORR was not significantly different from ORR, but immune-related progressive disease (irPD) rate was significantly lower than progressive disease (PD) rate. Tumor cell (TC) PD-L1 expression was not associated with PFS or ORR, but patients with TC PD-L1 ≥1% had longer median irPFS and higher irORR. High percentage of CD8
tumor-infiltrating cells (TIC) that are PD-1
TIM-3
LAG-3
(% CD8
PD-1
TIM-3
LAG-3
TIC) correlated with high levels of T-cell activation and was associated with longer median irPFS and higher irORR. Notably, combination of TC PD-L1 expression with % CD8
PD-1
TIM-3
LAG-3
TIC identified three groups of patients for which irPFS and irORR were significantly different.
Atypical responders to nivolumab were identified in the CheckMate-010 trial. We observed improved association of candidate biomarkers for nivolumab response with endpoints defined by irRECIST compared with RECISTv1.1. TC PD-L1 expression in combination with PD-1 expression on CD8
TIC may predict outcome on nivolumab in mccRCC.
Bisphenol-A (BPA) and methoxychlor (MXC), two endocrine-disrupting chemicals (EDCs) with estrogenic and antiandrogenic effects, disrupt the reproductive system. BPA has profound effects on ...luteinizing hormone (LH) surge amplitude, and MXC has profound effects on on LH surge timing in sheep. The neural mechanisms involved in the differential disruption of the LH surge by these two EDCs remain to be elucidated. We tested the hypothesis that the differential effects of BPA and MXC on LH surge system involved changes in hypothalamic gonadotropin-releasing hormone (GnRH) and estrogen receptors (ESR), ESR1 and ESR2, mRNA expression. Pregnant sheep were given daily injections of cottonseed oil (controls), MXC, or BPA (5
mg/kg/day) from day 30 to 90 of gestation (term 147
d). Offspring from these animals were euthanized as adults, during the late follicular phase following synchronization of estrus with prostaglandin F
2α, just before the expected onset of preovulatory LH surge and changes in mRNA expression of hypothalamic GnRH, ESR1, and ESR2 quantified following
in situ hybridization. GnRH mRNA expression was significantly lower in both groups of EDC-treated females compared to controls. ESR1 expression was increased in prenatal BPA- but not MXC-treated females in medial preoptic area relative to controls. In contrast, ESR2 expression was reduced in the medial preoptic area of both EDC-treated groups. Differences in expression of ESR1/ESR2 receptors may contribute to the differential effects of BPA and MXC on the LH surge system. These findings provide support that prenatal exposure to EDCs alters the neural developmental trajectory leading to long-term reproductive consequences in the adult female.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The knee flexion angle is an important measurement for studies of the human gait. Running is a common activity with a high risk of knee injury. Studying the running gait in realistic situations is ...challenging because accurate joint angle measurements typically come from optical motion-capture systems constrained to laboratory settings. This study considers the use of shank and thigh inertial sensors within three different filtering algorithms to estimate the knee flexion angle for running without requiring sensor-to-segment mounting assumptions, body measurements, specific calibration poses, or magnetometers. The objective of this study is to determine the knee flexion angle within running applications using accelerometer and gyroscope information only. Data were collected for a single test participant (21-year-old female) at four different treadmill speeds and used to validate the estimation results for three filter variations with respect to a Vicon optical motion-capture system. The knee flexion angle filtering algorithms resulted in root-mean-square errors of approximately three degrees. The results of this study indicate estimation results that are within acceptable limits of five degrees for clinical gait analysis. Specifically, a complementary filter approach is effective for knee flexion angle estimation in running applications.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Members of the highly related TEF-1 (transcriptional enhancer factor-1) family (also known as TEAD, for TEF-1, TEC1, ABAA domain) bind to MCAT (muscle C, A and T sites) and A/T-rich sites in ...promoters active in cardiac, skeletal and smooth muscle, placenta, and neural crest. TEF-1 activity is regulated by interactions with transcriptional co-factors p160, TONDU (Vgl-1, Vestigial-like protein-1), Vgl-2 and YAP65 (Yes-associated protein 65 kDa). The strong transcriptional co-activator YAP65 interacts with all TEF-1 family members, and, since YAP65 is related to TAZ (transcriptional co-activator with PDZ-binding motif), we wanted to determine if TAZ also interacts with members of the TEF-1 family. In the present study, we show by GST (glutathione S-transferase) pull-down assays, by co-immunoprecipitation and by modified mammalian two-hybrid assays that TEF-1 interacts with TAZ in vitro and in vivo. Electrophoretic mobility-shift assays with purified TEF-1 and GST-TAZ fusion protein showed that TAZ interacts with TEF-1 bound to MCAT DNA. TAZ can interact with endogenous TEF-1 proteins, since exogenous TAZ activated MCAT-dependent reporter promoters. Like YAP65, TAZ interacted with all four TEF-1 family members. GST pull-down assays with increasing amounts of 35STEF-1 and 35SRTEF-1 (related TEF-1) showed that TAZ interacts more efficiently with TEF-1 than with RTEF-1. This differential interaction also extended to the interaction of TEF-1 and RTEF-1 with TAZ in vivo, as assayed by a modified mammalian two-hybrid experiment. These data show that differential association of TEF-1 proteins with transcriptional co-activators may regulate the activity of TEF-1 family members.
Island environments have the potential to change evolutionary trajectories of morphological traits in species relative to their mainland counterparts due to habitat and resource differences, or by ...reductions in the intensity of social or sexual selection. Latitude, island size, and isolation may further influence trait evolution through biases in colonization rates. We used a global dataset of passerine plumage color as a model group to identify selective pressures driving morphological evolution of island animals using phylogenetically-controlled analyses. We calculated chromaticity values from red and blue scores extracted from images of the majority of Passeriformes and tested these against the factors hypothesized to influence color evolution. In contrast to predictions based on sexual and social selection theory, we found consistent changes in island female color (lower red and higher blue chromaticity), but no change in males. Instead, island size and distance from mainland and other islands influenced color in both sexes, reinforcing the importance of island physiognomy in shaping evolutionary processes. Interactions between ecological factors and latitude also consistently influenced color for both sexes, supporting a latitudinal gradient hypothesis. Finally, patterns of color evolution varied among families, indicating taxon-specific microevolutionary processes in driving color evolution. Our results show island residency influences color evolution differently between sexes, but the patterns in both sexes are tempered by ecological, island characteristics, and phylogenetic effects that further vary in their importance among families. The key role of environmental factors in shaping bird plumage on islands further suggests a reduced importance of sexual and social factors in driving color evolution.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Estrogenic signaling shapes and modifies daily and circadian rhythms, the disruption of which has been implicated in psychiatric, neurologic, cardiovascular, and metabolic disease, among others. ...However, the activational mechanisms contributing to these effects remain poorly characterized. To determine the activational impact of estrogen on daily behavior patterns and differentiate between the contributions of the estrogen receptors ESR1 and ESR2, ovariectomized adult female mice were administered estradiol, the ESR1 agonist propylpyrazole triol, the ESR2 agonist diarylpropionitrile, or cholesterol (control). Animals were singly housed with running wheels in a 12-hour light, 12-hour dark cycle or total darkness. Estradiol increased total activity and amplitude, consolidated activity to the dark phase, delayed the time of peak activity (acrophase of wheel running), advanced the time of activity onset, and shortened the free running period (τ), but did not alter the duration of activity (α). Importantly, activation of ESR1 or ESR2 differentially impacted daily and circadian rhythms. ESR1 stimulation increased total wheel running and amplitude and reduced the proportion of activity in the light vs the dark. Conversely, ESR2 activation modified the distribution of activity across the day, delayed acrophase of wheel running, and advanced the time of activity onset. Interestingly, τ was shortened by estradiol or either estrogen receptor agonist. Finally, estradiol-treated animals administered a light pulse in the early subjective night, but no other time, had an attenuated response compared with controls. This decreased phase response was mirrored by animals treated with diarylpropionitrile, but not propylpyrazole triol. To conclude, estradiol has strong activational effects on the temporal patterning and expression of daily and circadian behavior, and these effects are due to distinct mechanisms elicited by ESR1 and ESR2 activation.
Brachy
dactyly type
B (BDB) is characterized by terminal deficiency of fingers and toes, which is caused by heterozygous truncating mutations in the
receptor tyrosine kinase–like
orphan
receptor 2 (
...ROR2) in the majority of patients. In a subset of ROR2-negative patients with BDB, clinically defined by the additional occurrence of proximal symphalangism and carpal synostosis, we identified six different point mutations (P35A, P35S, A36P, E48K, R167G, and P187S) in the bone morphogenetic protein (BMP) antagonist NOGGIN (NOG). In contrast to previously described loss-of-function mutations in
NOG, which are known to cause a range of conditions associated with abnormal joint formation but without BDB, the newly identified BDB mutations do not indicate a major loss of function, as suggested by calculation of free-binding energy of the modeled NOG-GDF5 complex and functional analysis of the micromass culture system. Rather, they presumably alter NOG’s ability to bind to BMPs and growth-differentiation factors (GDFs) in a subtle way, thus disturbing the intricate balance of BMP signaling. The combined features observed in this phenotypic subtype of BDB argue for a functional connection between BMP and ROR2 signaling and support previous findings of a modulating effect of ROR2 on the BMP-receptor pathway through the formation of a heteromeric complex of the receptors at the cell surface.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Originating in Glacier Park, Montana, the transboundary St. Mary River has provided a focus for international water sharing for a century. It was dammed and diverted in the USA, and more extensively ...in Alberta, where it supports Canada's centre for agricultural irrigation. Following water withdrawals, the riparian cottonwoods (Populus angustifolia) collapsed, and we assessed the woodland decline downstream from the St. Mary Dam, through eight sets of aerial photographs over seven decades. These revealed 88% woodland loss from 1951 to 1999 (R2 = 0.984), including a steeper decline with the 1980s drought. Following the implementation of an environmental flow regime that increased minimum flows after 1993, the remnant woodlands were stabilized, with a slight recovery by 2022. Analyses of the historical hydrology revealed compound contributions to the woodland mortality. (1) Annual river flows declined with increasing water diversion, and (2) late summer flows were particularly depleted. (3) Dam operations resulted in abrupt stage recessions and irregular spikes. (4) Accompanying climate warming, the spring snowmelt advanced and late summer flows declined. (5) The greatest climatic influence involved multiple‐year clusters with high versus low flows, corresponding with the Pacific decadal oscillation (PDO) from 1920 to 1990 (R2 = 0.365), but less coupled thereafter. This long‐term study demonstrates the coordination between hydroclimatic variation, water management and the fate of riparian woodlands, which reveal ecosystem health. An environmental flow regime provided benefit, and for other regulated rivers in dry ecoregions, we recommend functional flow regimes that provide sufficient minimum flows and avoid abrupt flow recession or irregular spikes.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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