Long-term solid-organ allografts typically develop diffuse arterial intimal lesions (graft arterial disease; GAD), consisting of smooth-muscle cells (SMC), extracellular matrix and admixed ...mononuclear leukocytes. GAD eventually culminates in vascular stenosis and ischemic graft failure. Although the exact mechanisms are unknown, chronic low-level alloresponses likely induce inflammatory cells and/or dysfunctional vascular wall cells to secrete growth factors that promote SMC intimal recruitment, proliferation and matrix synthesis. Although prior work demonstrated that the endothelium and medial SMCs lining GAD lesions in cardiac allografts are donor-derived, the intimal SMC origin could not be determined. They are generally presumed to originate from the donor media, leading to interventions that target donor medial SMC proliferation, with limited efficacy. However, other reports indicate that allograft vessels may contain host-derived endothelium and SMCs (refs. 8,9). Moreover, subpopulations of bone-marrow and circulating cells can differentiate into endothelium, and implanted synthetic vascular grafts are seeded by host SMCs and endothelium. Here we used murine aortic transplants to formally identify the source of SMCs in GAD lesions. Allografts in beta-galactosidase transgenic recipients showed that intimal SMCs derived almost exclusively from host cells. Bone-marrow transplantation of beta-galactosidase--expressing cells into aortic allograft recipients demonstrated that intimal cells included those of marrow origin. Thus, smooth-muscle--like cells in GAD lesions can originate from circulating bone--marrow-derived precursors.
Resting-state functional connectivity, as measured by functional magnetic resonance imaging (fMRI), is often treated as a trait, used, for example, to draw inferences about individual differences in ...cognitive function, or differences between healthy or diseased populations. However, functional connectivity can also depend on the individual's mental state. In the present study, we examined the relative contribution of state and trait components in shaping an individual's functional architecture. We used fMRI data from a large, population-based human sample (N = 587, age 18-88 years), as part of the Cambridge Centre for Aging and Neuroscience (Cam-CAN), which were collected in three mental states: resting, performing a sensorimotor task, and watching a movie. Whereas previous studies have shown commonalities across mental states in the average functional connectivity across individuals, we focused on the effects of states on the pattern of individual differences in functional connectivity. We found that state effects were as important as trait effects in shaping individual functional connectivity patterns, each explaining an approximately equal amount of variance. This was true when we looked at aging, as one specific dimension of individual differences, as well as when we looked at generic aspects of individual variation. These results show that individual differences in functional connectivity consist of state-dependent aspects, as well as more stable, trait-like characteristics. Studying individual differences in functional connectivity across a wider range of mental states will therefore provide a more complete picture of the mechanisms underlying factors such as cognitive ability, aging, and disease.
The brain's functional architecture is remarkably similar across different individuals and across different mental states, which is why many studies use functional connectivity as a trait measure. Despite these trait-like aspects, functional connectivity varies over time and with changes in cognitive state. We measured connectivity in three different states to quantify the size of the trait-like component of functional connectivity, compared with the state-dependent component. Our results show that studying individual differences within one state (such as resting) uncovers only part of the relevant individual differences in brain function, and that the study of functional connectivity under multiple mental states is essential to disentangle connectivity differences that are transient versus those that represent more stable, trait-like characteristics of an individual.
Scientific research has been changing medical practice at an increasing pace. To keep up with this change, physicians of the future will need to be lifelong learners with the skills to engage with ...emerging science and translate it into clinical care. How medical schools can best prepare students for ongoing scientific change remains unclear. Adding to the challenge is reduced time allocated to basic science in curricula and rapid expansion of relevant scientific fields. A return to science with greater depth after clinical clerkships has been suggested, although few schools have adopted such curricula and implementation can present challenges. The authors describe an innovation at Harvard Medical School, the Advanced Integrated Science Courses (AISCs), which are taken after core clerkships. Students are required to take 2 such courses, which are offered in a variety of topics. Rather than factual content, the learning objectives are a set of generalizable skills to enable students to critically evaluate emerging research and its relationship to medical practice. Making these generalizable skills the defining principle of the courses has several important advantages: it allows standardization of acquired skills to be combined with diverse course topics ranging from basic to translational and population sciences; students can choose courses and projects aligned with their interests, thereby enhancing engagement, curiosity, and career relevance; schools can tailor course offerings to the interests of local faculty; and the generalizable skills delineate a unique purpose of these courses within the overall medical school curriculum. For the 3 years AISCs have been offered, students rated the courses highly and reported learning the intended skill set effectively. The AISC concept addresses the challenge of preparing students for this era of rapidly expanding science and should be readily adaptable to other medical schools.
Perivascular fibrosis, characterized by increased amount of connective tissue around vessels, is a hallmark for vascular disease. Ang II (angiotensin II) contributes to vascular disease and end-organ ...damage via promoting T-cell activation. Despite recent data suggesting the role of T cells in the progression of perivascular fibrosis, the underlying mechanisms are poorly understood.
TF (transcription factor) profiling was performed in peripheral blood mononuclear cells of hypertensive patients. CD4-targeted KLF10 (Kruppel like factor 10)-deficient (
; TKO) and CD4-Cre (
; Cre) control mice were subjected to Ang II infusion. End point characterization included cardiac echocardiography, aortic imaging, multiorgan histology, flow cytometry, cytokine analysis, aorta and fibroblast transcriptomic analysis, and aortic single-cell RNA-sequencing.
TF profiling identified increased
expression in hypertensive human subjects and in CD4+ T cells in Ang II-treated mice. TKO mice showed enhanced perivascular fibrosis, but not interstitial fibrosis, in aorta, heart, and kidney in response to Ang II, accompanied by alterations in global longitudinal strain, arterial stiffness, and kidney function compared with Cre control mice. However, blood pressure was unchanged between the 2 groups. Mechanistically, KLF10 bound to the IL (interleukin)-9 promoter and interacted with HDAC1 (histone deacetylase 1) inhibit IL-9 transcription. Increased IL-9 in TKO mice induced fibroblast intracellular calcium mobilization, fibroblast activation, and differentiation and increased production of collagen and extracellular matrix, thereby promoting the progression of perivascular fibrosis and impairing target organ function. Remarkably, injection of anti-IL9 antibodies reversed perivascular fibrosis in Ang II-infused TKO mice and C57BL/6 mice. Single-cell RNA-sequencing revealed fibroblast heterogeneity with activated signatures associated with robust ECM (extracellular matrix) and perivascular fibrosis in Ang II-treated TKO mice.
CD4+ T cell deficiency of
exacerbated perivascular fibrosis and multi-organ dysfunction in response to Ang II via upregulation of IL-9.
or IL-9 in T cells might represent novel therapeutic targets for treatment of vascular or fibrotic diseases.
Anthracyclines are cardiotoxic; however, there are limited data characterizing the serial changes in cardiac structure and function after anthracyclines. The aim of this study was to use cardiac ...magnetic resonance to characterize anthracycline-induced cardiotoxicity in mice.
This was a longitudinal cardiac magnetic resonance and histological study of 45 wild-type male mice randomized to doxorubicin (n=30, 5 mg/kg of doxorubicin/week for 5 weeks) or placebo (n=15). A cardiac magnetic resonance was performed at baseline and at 5, 10, and 20 weeks after randomization. Measures of primary interest included left ventricular ejection fraction, myocardial edema (multiecho short-axis spin-echo acquisition), and myocardial fibrosis (Look-Locker gradient echo). In doxorubicin-treated mice versus placebo, there was an increase in myocardial edema at 5 weeks (T2 values of 32±4 versus 21±3 ms; P<0.05), followed by a reduction in left ventricular ejection fraction (54±6 versus 63±5%; P<0.05) and an increase in myocardial fibrosis (extracellular volume of 0.34±0.03 versus 0.27±0.03; P<0.05) at 10 weeks. There was a strong association between the early (5 weeks) increase in edema and the subacute (10 weeks) increase in fibrosis (r=0.90; P<0.001). Both the increase in edema and fibrosis predicted the late doxorubicin-induced mortality in mice (P<0.001).
Our data suggest that, in mice, anthracycline-induced cardiotoxicity is associated with an early increase in cardiac edema and a subsequent increase in myocardial fibrosis. The early increase in edema and subacute increase in fibrosis are strongly linked and are both predictive of late mortality.
Long-term outcomes after face transplantation are rarely reported in the scientific literature. Here we present outcome data of a partial face allograft recipient 10 years after transplantation.
...Medical records were reviewed for functional and psychosocial outcomes as well as complications. Histopathologic analyses of autopsy tissues and characterization of skin immune cells were performed.
The patient retained long-term motor and sensory function, though with a noticeable drop in sensory function after year 5. Social reintegration of the patient was marked by reconnection with his family and participation in public social activities. Immunosuppressive therapy consisted of tacrolimus (target levels 6–8 ng/mL after the first year), mycophenolate, and prednisone, while steroids were completely weaned between years 1 and 7. One acute cellular rejection episode of grade II or higher occurred on average per year and led to chronic skin changes (papillary dermal sclerosis with superficial hyalinization, epidermal thinning with loss of rete ridges, perieccrine fibrosis), but the allograft vessels, muscles, adipose tissue, and bone were spared. Allograft skin was characterized by increased number of CD4+ TNF-α/IL17A producing T-cells as compared with native skin. Long-term kidney function was maintained at 60 mL/min estimated glomerular filtration rate. Unfortunately, the preexisting hepatitis C virus infection with liver cirrhosis was resistant to 3 treatments with new direct-acting antivirals and eventually hepatocellular carcinoma developed, causing the patient’s death 10 years after transplantation.
This report suggests that face transplants can maintain their function for at least 10 years. Chronic skin changes can occur independently of allograft vasculopathy.
The control of voluntary movement changes markedly with age. A critical component of motor control is the integration of sensory information with predictions of the consequences of action, arising ...from internal models of movement. This leads to sensorimotor attenuation-a reduction in the perceived intensity of sensations from self-generated compared with external actions. Here we show that sensorimotor attenuation occurs in 98% of adults in a population-based cohort (n=325; 18-88 years; the Cambridge Centre for Ageing and Neuroscience). Importantly, attenuation increases with age, in proportion to reduced sensory sensitivity. This effect is associated with differences in the structure and functional connectivity of the pre-supplementary motor area (pre-SMA), assessed with magnetic resonance imaging. The results suggest that ageing alters the balance between the sensorium and predictive models, mediated by the pre-SMA and its connectivity in frontostriatal circuits. This shift may contribute to the motor and cognitive changes observed with age.
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