Search

Supplemental Digital Content is Available in the Text.

Decompressive craniectomies (DCs) are routinely performed neurosurgical procedures to emergently treat increased intracranial pressure secondary to multiple aetiologies, such as subdural haematoma, epidural haematoma, or malignant oedema in the setting of acute infarction. The DC procedure typically induces epidural fibrosis post-cranial resection, resulting in adherence of the dura to both the brain internally and skin flap externally. This becomes especially problematic in the setting of skull flap replacement for cranioplasty as adherences can lead to bridging vein tear, damage to the underlying brain cortex, and other postoperative complications. Dural adjuvants, which can contribute to decreased rate of adherence formation, can thereby reduce both postoperative cranioplasty complications and operative duration. Dehydrated human amnion/chorion membrane (DHACM) allografts (AMNIOFIX, MIMEDX Group Inc., US) have been shown to reduce the rate of dural scar tissue formation in re-exploration of posterior lumbar interbody fusion operations which require entry into the epidural space. The purpose of this study was to evaluate whether or not the use of DHACM in the setting of emergent craniectomies decreased the rate of dural adhesion formation and subsequent cranioplasty complications. Patients (n=7) who underwent emergent craniectomy and intraoperative placement of DHACM were evaluated during replacement of either an autologous skull cap or a custom-made implant, at which point the degree of adhesions was qualitatively assessed. Placement of DHACM below and on top of the dura resulted in negligible adhesion being found during the defect exposure, and there were no intraoperative complications during cranioplasties. Reported estimated blood loss across the seven patients averaged 64.2ml, total operative time averaged 79.2 minutes, and time dedicated to exposing defect for bone flap placement was <3 minutes.

ABSTRACTWhat does it mean to be a veteran, and how does serving in the armed forces condition how veterans view their sense of identity? In a national survey sample with an oversample of veterans, I find that veterans have a stronger sense of identity as a veteran, measured in terms of self-identification as both a veteran and a feeling of closeness to the veteran group, compared to civilians. I also find that, among military veterans, combat experience and valuing time in the military leads to higher veteran identity. Moreover, I find that even some non-military members report a greater sense of identity with veterans than others. I compare the effect of this “veteran” identity to that of partisan identity and find that, for most veterans, there is a greater sense of attachment to the veteran identity than to their partisan identity. Finally, I find that veteran identity has an important, independent influence on veterans’ and civilians’ views on military spending. These findings suggest that there is a veteran identity that military members and civilians attach themselves to that is stronger than partisanship for some individuals and is associated with certain policy positions.

Objective Herein we describe the development, implementation, and growth of our Vascular Research Training Program (VRTP), emphasizing the intentional involvement of medical students in clinical research.Methods We developed a VRTP focusing on medical student engagement to encompass 4 pillars: ownership, mentorship, experience, and independence within the research process. The program is organized by clinical projects with an attending surgeon, surgical trainee (fellow or resident), and medical student comprising each research project team. The VRTP program sought to facilitate a culture of learning, accountability, and mentorship to engage and encourage medical student involvement in clinical research.Results We reviewed the productivity of our current vascular surgery faculty by reviewing divisional records of faculty publications and conducting a literature search for the period of 2012 to 2019. The pre-VRTP model produced 13 included manuscripts in 2012-2015 (3.25 per year), while the implemented VRTP model yielded 43 articles (10.75 per year) from 2016-2019. There was no significant change in the impact factor (pre-VRTP mean ± SD was 1.8 ± 1.0 vs 2.2 ± 1.1, P= .17). Medical student productivity rose from 1.3 to 2.7 publications, with a similar rise in the number of students participating in more than one manuscript from 2 to 14.Conclusions Deliberate involvement of medical trainees as a member of the clinical research team has the potential to generate subsequent increases in research productivity and effective mentorships. Academic surgical divisions should consider organized and intentional involvement of medical students as an essential component of clinical research.

The PTEN gene negatively regulates the oncogenic PI3K-AKT pathway by encoding a lipid and protein phosphatase that dephosphorylates lipid phosphatidylinositol-3,4,5-triphosphate (PIP3) resulting in the inhibition of PI3K and downstream inhibition of AKT. Overexpression of PTEN in mice leads to a longer lifespan compared to control littermates, although the mechanism is unknown. Here, we provide evidence that young adult PTENOE mice exhibit many characteristics shared by other slow-aging mouse models, including those with mutations that affect GH/IGF1 pathways, calorie-restricted mice, and mice treated with anti-aging drugs. PTENOE white adipose tissue (WAT) has increased UCP1, a protein linked to increased thermogenesis. WAT of PTENOE mice also shows a change in polarization of fat-associated macrophages, with elevated levels of arginase 1 (Arg1, characteristic of M2 macrophages) and decreased production of inducible nitric oxide synthase (iNOS, characteristic of M1 macrophages). Muscle and hippocampus showed increased expression of the myokine FNDC5, and higher levels of its cleavage product irisin in plasma, which has been linked to increased conversion of WAT to more thermogenic beige/brown adipose tissue. PTENOE mice also have an increase, in plasma and liver, of GPLD1, which is known to improve cognition in mice. Hippocampus of the PTENOE mice has elevation of both BDNF and DCX, indices of brain resilience and neurogenesis. These changes in fat, macrophages, liver, muscle, hippocampus, and plasma may be considered “aging rate indicators” in that they seem to be consistently changed across many of the long-lived mouse models and may help to extend lifespan by delaying many forms of late-life illness. Our new findings show that PTENOE mice can be added to the group of long-lived mice that share this multi-tissue suite of biochemical characteristics.

The development of ligands for biological targets is critically dependent on the identification of sites on proteins that bind molecules with high affinity. A set of compounds, called FragLites, can identify such sites, along with the interactions required to gain affinity, by X-ray crystallography. We demonstrate the utility of FragLites in mapping the binding sites of bromodomain proteins BRD4 and ATAD2 and demonstrate that FragLite mapping is comparable to a full fragment screen in identifying ligand binding sites and key interactions. We extend the FragLite set with analogous compounds derived from amino acids (termed PepLites) that mimic the interactions of peptides. The output of the FragLite maps is shown to enable the development of ligands with leadlike potency. This work establishes the use of FragLite and PepLite screening at an early stage in ligand discovery allowing the rapid assessment of tractability of protein targets and informing downstream hit-finding.

Patients requiring emergent vascular surgery often undergo transfer from one facility to another for definitive surgical care. In this study, we analyzed morbidity and mortality in patients presenting for emergent lower extremity thrombectomy and embolectomy in the transferred and nontransferred populations.

ABSTRACTMice deficient in GHR (growth hormone receptor; ghrKO) have a dramatic lifespan extension and elevated levels of hepatic chaperone-mediated autophagy (CMA). Using quantitative proteomics to identify protein changes in purified liver lysosomes and whole liver lysates, we provide evidence that elevated CMA in ghrKO mice downregulates proteins involved in ribosomal structure, translation initiation and elongation, and nucleocytosolic acetyl-coA production. Following up on these initial proteomics findings, we used a cell culture approach to show that CMA is necessary and sufficient to regulate the abundance of ACLY and ACSS2, the two enzymes that produce nucleocytosolic (but not mitochondrial) acetyl-coA. Inhibition of CMA in NIH3T3 cells has been shown to lead to aberrant accumulation of lipid droplets. We show that this lipid droplet phenotype is rescued by knocking down ACLY or ACSS2, suggesting that CMA regulates lipid droplet formation by controlling ACLY and ACSS2. This evidence leads to a model of how constitutive activation of CMA can shape specific metabolic pathways in long-lived endocrine mutant mice.Abbreviations:CMA: chaperone-mediated autophagy; DIA: data-independent acquisition; ghrKO: growth hormone receptor knockout; GO: gene ontology; I-WAT: inguinal white adipose tissue; KFERQ: a consensus sequence resembling Lys-Phe-Glu-Arg-Gln; LAMP2A: lysosomal-associated membrane protein 2A; LC3-I: non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; PBS: phosphate-buffered saline; PI3K: phosphoinositide 3-kinase

IMPORTANCE: Recognizing segmental infantile hemangioma (IH) patterns is important for risk stratification and provides clues to pathogenesis. Previously, segmental hemangiomas were mapped to 4 facial regions, 3 corresponding to known facial metameres. OBJECTIVES: To refine existing maps of facial segmental IHs, examine so-called indeterminate hemangiomas as they relate to known segmental patterns, and define a novel pattern of segmental scalp hemangiomas. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study was conducted at 4 pediatric dermatology centers (University of California, San Francisco; Indiana University; Medical College of Wisconsin; and Northwestern University/Ann & Robert H. Lurie Children’s Hospital of Chicago) using photographic archives of patients younger than 12 years with segmental and indeterminate hemangiomas on the face and scalp. Clinical images were used to map hemangioma distribution onto standardized facial templates. Heat map densiometry identified recurrent patterns that were compared with previously published patterns of facial segmental hemangiomas. Patterns of indeterminate hemangiomas were compared with those of segmental hemangiomas. Data collection took place in 2017, and analysis took place from 2017 to 2019. MAIN OUTCOMES AND MEASURES: Distribution and patterning of segmental and indeterminate IHs of the face and scalp. RESULTS: A total of 549 IHs were mapped. The borders of the frontotemporal (S1) and frontonasal (S4) segments agreed with previous segmental maps; however, the maxillary (S2) and mandibular (S3) segment borders differed with respect to the preauricular skin. In contrast with previous reports, preauricular skin segregated with the mandibular (S3) rather than the maxillary (S2) segment. Indeterminate hemangiomas occurred within and respected the same borders as segmental hemangiomas. Hemangiomas on the lateral scalp commonly occurred in a C shape extending from the posterior auricular region. CONCLUSIONS AND RELEVANCE: This cohort study provides an updated map of facial segmental IHs with redefined maxillary (S2) and mandibular (S3) segment borders. It provides evidence that indeterminate hemangiomas are partial segmental hemangiomas respecting anatomic boundaries of their larger segmental counterparts. A newly recognized C-shaped pattern of segmental scalp hemangioma is reported.

NF-κB-inducing kinase (NIK) is a key enzyme in the noncanonical NF-κB pathway, of interest in the treatment of a variety of diseases including cancer. Validation of NIK as a drug target requires potent and selective inhibitors. The protein contains a cysteine residue at position 444 in the back pocket of the active site, unique within the kinome. Analysis of existing inhibitor scaffolds and early structure–activity relationships (SARs) led to the design of C444-targeting covalent inhibitors based on alkynyl heterocycle warheads. Mass spectrometry provided proof of the covalent mechanism, and the SAR was rationalized by computational modeling. Profiling of more potent analogues in tumor cell lines with constitutively activated NIK signaling induced a weak antiproliferative effect, suggesting that kinase inhibition may have limited impact on cancer cell growth. This study shows that alkynyl heterocycles are potential cysteine traps, which may be employed where common Michael acceptors, such as acrylamides, are not tolerated.

In a contribution to a symposium on Nick Barber’s book, The Principles of Constitutionalism, I argue that Barber is right to explain the principles of constitutionalism by reference to the purpose of a state, but I defend a restatement of that purpose. Barber says that it is to advance the well-being of the citizens. I argue that the purpose is more open-ended: it is to make the political community a good one. The state has duties that are not grounded in the well-being of its citizens, and it may legitimately pursue good public purposes that do not advance its citizens’ well-being. The state is forits citizens, not primarily in the sense that it is there to make them better off, but in the sense that it is a way for citizens(and not for outsiders) to act as an organized community.

ABSTRACTPTEN is a negative modulator of the INS-PI3K-AKT pathway and is an essential regulator of metabolism and cell growth. PTEN is one of the most commonly mutated tumor suppressors in cancer. However, PTEN overexpression extends the lifespan of both sexes of mice. We recently showed that PTEN is necessary and sufficient to activate chaperone-mediated autophagy (CMA) in the mouse liver and cultured cells. Selective protein degradation via CMA is required to suppress glycolysis and fatty acid synthesis when PTEN is overexpressed. Thus, activation of CMA downstream of PTEN might modulate health and metabolism through selective degradation of key metabolic enzymes.

The effects of domestication selection on fitness are of serious concern in hatchery‐reared anadromous salmonids, which often experience selection for rapid growth and associated deviations from natural agonistic and feeding behaviors. The high rations that are used to raise age‐1 smolts and the reduced rations that are used to produce age‐2 smolts potentially result in very different behavioral tactics and social dynamics of competition in hatchery tanks. Consequently, steelhead Oncorhynchus mykisshatchery programs with recovery or conservation goals may need to change their aquaculture practices to minimize domestication selection. This study investigated how the feeding rate (proportion of presented food items that were successfully captured) and relative competitive ability (ability to monopolize food items in small groups) of age‐1 and age‐2 steelhead corresponded to feeding location (surface or bottom) and growth rate in hatchery rearing tanks. We raised steelhead from a common broodstock to smolt at age 1 or age 2 by manipulating their rations (age‐1 fish received the high ration, age‐2 the low ration). The fish in the age‐1 treatment had a lower feeding rate than did those in the age‐2 treatment. Feeding rate was positively correlated with both body size and with growth rate in the rearing tanks at both rations. The age‐2 steelhead were more likely to be detected at a single feeding location than were the age‐1 fish, which were more frequently detected at both locations. The more competitive age‐1 fish were more frequently detected at both feeding locations, and the less competitive fish were detected at only one location. Relative competitive ability was not associated with feeding location in the age‐2 treatment, nor was it associated with growth rate in either treatment. Age‐2 steelhead that were detected only at the bottom or at both feeding locations had higher growth rates than those that were detected only at the surface, suggesting greater scramble competition near the point of food delivery under the restricted ration. Feeding location was not associated with growth rate in the age‐1 treatment. The results indicate that ration directly affects feeding rate and that ration and relative competitive ability interact to influence feeding rate. Because feeding rate was positively associated with growth rate at both ration levels in the hatchery tanks, behaviors that are associated with feeding motivation may be an important trait under selection in salmonid hatcheries.

ABSTRACTChaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis. CMA modulates proteomic organization through selective protein degradation, with targets including metabolic enzymes, cell growth regulators, and neurodegeneration-related proteins. CMA activity is low in ad libitum-fed rodents but is increased by prolonged fasting. AKT negatively regulates CMA at the lysosomal membrane by phosphorylating and inhibiting the CMA regulator GFAP. We have previously reported that long-lived Pou1f1/Pit1mutant (Snell) mice and ghr(growth hormone receptor) knockout mice (ghrKO) have lower AKT activity when fed compared to littermate controls, suggesting the hypothesis that these mice have increased baseline CMA activity. Here, we report that liver lysosomes from fed Snell dwarf mice and ghrKO mice have decreased GFAP phosphorylation and increased CMA substrate uptake activity. Liver lysosomes isolated from fed Snell dwarf mice and ghrKO mice injected with the protease inhibitor leupeptin had increased accumulation of endogenous CMA substrates, compared to littermate controls, suggesting an increase in CMA in vivo. Mice with liver-specific ablation of GH (growth hormone) signaling did not have increased liver CMA, suggesting that a signaling effect resulting from a loss of growth hormone in another tissue causes enhanced CMA in Snell dwarf and ghrKO mice. Finally, we find Snell dwarf mice have decreased protein levels (in liver and kidney) of CIP2A, a well-characterized CMA target protein, without an associated change in Cip2amRNA. Collectively, these data suggest that CMA is enhanced downstream of an endocrine change resulting from whole-body ablation of GH signaling.Abbreviations:CMA: chaperone-mediated autophagy; GH: growth hormone; ghrKO: growth hormone receptor knockout; LAMP2A: splice variant 1 of Lamp2transcript; LC3-I: non-lipidated MAP1LC3; LC3-II: lipidated MAP1LC3; Li-ghrKO: liver-specific ghrknockout; MA: macroautophagy; MTORC1: mechanistic target of rapamycin kinase complex 1; MTORC2: mechanistic target of rapamycin kinase complex 2; PBS: phosphate-buffered saline.

Efficient charge-transfer (CT) phosphorescence in the near-IR (NIR) spectral region is reported for four substituted Ru-(R-dipyrrinato) complexes, [Ru(bpy)2(R-dipy)](PF6), where bpy is 2,2′-bipyridine and the substituent R is phenyl (ph), 2,4,6-trimethylphenyl, 4-carboxyphenyl (HOOC-ph), or 4-pyridinyl. The experimentally determined phosphorescence efficiency, ιem(p)= kRAD(p)/(νem(p))3(where kRAD(p)and νem(p)are the phosphorescence rate constant and the phosphorescence frequency, respectively), of the [Ru(bpy)2(R-dipy)]+complexes was approximately double that of [Ru(bpy)(Am)4]2+complexes (Am = ammine ligand) in the NIR region. Density functional theory (DFT) modeling indicated two strikingly different electronic configurations of the triplet emitting state (Te) in the two types of complexes. The Teof [Ru(bpy)2(R-dipy)]+complexes shows a CT-type corresponding to the metal-to-ligand charge transfer (MLCT)-(Ru-(R-dipy)) and the ππ*-(R-dipy) moiety configurations, and the Testate in the [Ru(bpy)(Am)4]2+complexes corresponds to an approximately MLCT excited state consisting of mostly MLCT-(Ru-bpy) with a minimal ππ*(bpy) contribution. DFT modeling also indicated that the low-energy singlet excited states in the Tegeometry (Sn(T)) of the [Ru(bpy)2(ph-dipy)]+complex consist of numerous CT-Sn(T)-type states of the Ru-dipy and Ru-bpy moieties, whereas the [Ru(bpy)(Am)4]2+ions show quite simple MLCT-Sn(T)-type states of the Ru-bpy moiety. Based on experimental observations, DFT modeling, and the plain spin–orbit coupling (SOC) principle, we conclude that the remarkably high ιem(p)amplitudes of the [Ru(bpy)2(R-dipy)]+complexes relative to those of [Ru(bpy)(Am)4]2+complexes can be attributed to the relatively substantial contribution of intrinsic SOC-mediated intensity stealing from the numerous low-energy CT-type Sn(T)states.

Endovascular treatment of mesenteric lesions has become increasingly prevalent. Mesenteric bypass, however, remains the optimal treatment in the cases of chronic mesenteric ischemia (CMI) in young, medically fit patients given its durability. Endarterectomy has gone by the wayside, but in certain situations, this technique remains surgically relevant and should still be used. Herein, we present 2 cases of distal superior mesenteric artery (SMA) endarterectomy for mesenteric revascularization.

A 55-year-old woman with COPD, heart failure with preserved ejection fraction (congestive heart failure), diabetes mellitus, and hypertension presented with baseline dyspnea at rest that had worsened over the last week. She reported associated runny nose, congestion, and cough productive of green sputum. She smoked six cigarettes per day and denied alcohol, drugs, or occupational exposure. She was admitted and initiated on treatment for acute exacerbation of COPD; however, her condition did not improve with steroid, ceftriaxone, and nebulized albuterol and budesonide treatments. She had been diagnosed with asthma and COPD without ever undergoing pulmonary function testing. She presented 11 times to the ED with six hospital admissions in the last 1.5 years for worsening dyspnea at rest, wheezing, and lower extremity edema deemed secondary to exacerbation of her COPD or congestive heart failure. She reported medication compliance, which included fluticasone-vilanterol, tiotropium bromide, and furosemide. She repeatedly demonstrated mild vascular congestion on imaging without hyperinflation, a normal to mildly elevated brain natriuretic peptide (<10 to 200 pg/mL), and dyspnea without hypoxia. She was treated normally for both COPD and congestive heart failure exacerbations simultaneously with methylprednisolone, albuterol, and furosemide with rapid improvement over the course of 1 to 2 days. No significant improvement was noted with steroid therapy, despite receiving them as an inpatient and outpatient. At the time of discharge, her symptoms would be at her baseline.

Siderophores are small-molecule high-affinity multidentate chelators selective for ferric iron that are produced by pathogenic microbes to aid in nutrient sequestration and enhance virulence. In Gram-positive bacteria, the currently accepted paradigm in siderophore-mediated iron acquisition is that effluxed metal-free siderophores extract ferric iron from biological sources and the resulting ferric siderophore complex undergoes diffusion-controlled association with a surface-displayed siderophore-binding protein (SBP) followed by ABC permease-mediated translocation across the cell envelope powered by ATP hydrolysis. Here we show that a more efficient paradigm is possible in Gram-positive bacteria where extracellular metal-free siderophores associate directly with apo-SBPs on the cell surface and serve as non-covalent cofactors that enable the holo-SBPs to non-reductively extract ferric iron directly from host metalloproteins with so-called “ferrichelatase” activity. The resulting SBP-bound ferric siderophore complex is ready for import through an associated membrane permease and enzymatic turnover is achieved through cofactor replacement from the readily available pool of extracellular siderophores. This new “iron shuttle” model closes a major knowledge gap in microbial iron acquisition and defines new roles of the siderophore and SBP as cofactor and enzyme, respectively, in addition to the classically accepted roles as a transport substrate and receptor pair. We propose the formal name “siderophore-dependent ferrichelatases” for this new class of catalytic SBPs.