Thermal camouflage and cloaking can transform an actual heat signature into a pre‐controlled one. A viable recipe for controlling and manipulating heat signatures using thermal metamaterials to ...empower cloaking and camouflage in heat conduction is demonstrated. The thermal signature of the object is thus metamorphosed and perceived as multiple targets with different geometries and compositions, with the original object cloaked.
The remarkable aliphatic C–H hydroxylations catalyzed by the heme-containing enzyme, cytochrome P450, have attracted sustained attention for more than four decades. The effectiveness of P450 enzymes ...as highly selective biocatalysts for a wide range of oxygenation reactions of complex substrates has driven chemists to develop synthetic metalloporphyrin model compounds that mimic P450 reactivity. Among various known metalloporphyrins, manganese derivatives have received considerable attention since they have been shown to be versatile and powerful mediators for alkane hydroxylation and olefin epoxidation. Mechanistic studies have shown that the key intermediates of the manganese porphyrin-catalyzed oxygenation reactions include oxo- and dioxomanganese(V) species that transfer an oxygen atom to the substrate through a hydrogen abstraction/oxygen recombination pathway known as the oxygen rebound mechanism. Application of manganese porphyrins has been largely restricted to catalysis of oxygenation reactions until recently, however, due to ultrafast oxygen transfer rates. In this Account, we discuss recently developed carbon–halogen bond formation, including fluorination reactions catalyzed by manganese porphyrins and related salen species. We found that biphasic sodium hypochlorite/manganese porphyrin systems can efficiently and selectively convert even unactivated aliphatic C–H bonds to C–Cl bonds. An understanding of this novel reactivity derived from results obtained for the oxidation of the mechanistically diagnostic substrate and radical clock, norcarane. Significantly, the oxygen rebound rate in Mn-mediated hydroxylation is highly correlated with the nature of the trans-axial ligands bound to the manganese center (L–MnVO). Based on the ability of fluoride ion to decelerate the oxygen rebound step, we envisaged that a relatively long-lived substrate radical could be trapped by a Mn–F fluorine source, effecting carbon–fluorine bond formation. Indeed, this idea led to the discovery of the first Mn-catalyzed direct aliphatic C–H fluorination reactions utilizing simple, nucleophilic fluoride salts. Mechanistic studies and DFT calculations have revealed a trans-difluoromanganese(IV) species as the key fluorine transfer intermediate. In addition to catalyzing normal 19F-fluorination reactions, manganese salen complexes were found to enable the incorporation of radioactive 18F fluorine via C–H activation. This advance represented the first direct Csp3 –H bond 18F labeling with no-carrier-added 18Ffluoride and facilitated the late-stage labeling of drug molecules for PET imaging. Given the high reactivity and enzymatic-like selectively of metalloporphyrins, we envision that this new Heteroatom-Rebound Catalysis (HRC) strategy will find widespread application in the C–H functionalization arena and serve as an effective tool for forming new carbon–heteroatom bonds at otherwise inaccessible sites in target molecules.
An efficient protocol for the selective fluorination of benzylic CH bonds is described. The process is catalyzed by manganese salen complexes and uses nucleophilic fluorine sources, such as ...triethylamine trihydrofluoride and KF. Reaction rates are sufficiently high (30 min) to allow adoption for the incorporation of 18F fluoride sources for PET imaging applications.
Purpose The AUA (American Urological Association) QIPS (Quality Improvement and Patient Safety) committee created a white paper on the diagnosis and management of nonneurogenic chronic urinary ...retention. Materials and Methods Recommendations for the white paper were based on a review of the literature and consensus expert opinion from the workgroup. Results The workgroup defined nonneurogenic chronic urinary retention as an elevated post-void residual of greater than 300 mL that persisted for at least 6 months and documented on 2 or more separate occasions. It is proposed that chronic urinary retention should be categorized by risk (high vs low) and symptomatology (symptomatic versus asymptomatic). High risk chronic urinary retention was defined as hydronephrosis on imaging, stage 3 chronic kidney disease or recurrent culture proven urinary tract infection or urosepsis. Symptomatic chronic urinary retention was defined as subjectively moderate to severe urinary symptoms impacting quality of life and/or a recent history of catheterization. A treatment algorithm was developed predicated on stratifying patients with chronic urinary retention first by risk and then by symptoms. The proposed 4 primary outcomes that should be assessed to determine effectiveness of retention treatment are 1) symptom improvement, 2) risk reduction, 3) successful trial of voiding without catheterization, and 4) stability of symptoms and risk over time. Conclusions Defining and categorizing nonneurogenic chronic urinary retention, creating a treatment algorithm and proposing treatment end points will hopefully spur comparative research that will ultimately lead to a better understanding of this challenging condition.
We report a manganese porphyrin mediated aliphatic C−H bond chlorination using sodium hypochlorite as the chlorine source. In the presence of catalytic amounts of phase transfer catalyst and ...manganese porphyrin Mn(TPP)Cl 1, reaction of sodium hypochlorite with different unactivated alkanes afforded alkyl chlorides as the major products with only trace amounts of oxygenation products. Substrates with strong C−H bonds, such as neopentane (BDE =∼100 kcal/mol) can be also chlorinated with moderate yield. Chlorination of a diagnostic substrate, norcarane, afforded rearranged products indicating a long-lived carbon radical intermediate. Moreover, regioselective chlorination was achieved by using a hindered catalyst, Mn(TMP)Cl, 2. Chlorination of trans-decalin with 2 provided 95% selectivity for methylene-chlorinated products as well as a preference for the C2 position. This novel chlorination system was also applied to complex substrates. With 5α-cholestane as the substrate, we observed chlorination only at the C2 and C3 positions in a net 55% yield, corresponding to the least sterically hindered methylene positions in the A-ring. Similarly, chlorination of sclareolide afforded the equatorial C2 chloride in a 42% isolated yield. Regarding the mechanism, reaction of sodium hypochlorite with the MnIII porphyrin is expected to afford a reactive MnVO complex that abstracts a hydrogen atom from the substrate, resulting in a free alkyl radical and a MnIVOH complex. We suggest that this carbon radical then reacts with a MnIVOCl species, providing the alkyl chloride and regenerating the reactive MnVO complex. The regioselectivity and the preference for CH2 groups can be attributed to nonbonded interactions between the alkyl groups on the substrates and the aryl groups of the manganese porphyrin. The results are indicative of a bent MnvO---H---C geometry due to the CH approach to the MnvO (dπ−pπ)* frontier orbital.
The first multiphysical invisible sensor is theoretically and experimentally presented. An ultrathin, homogeneous, and isotropic shell is designed to simultaneously manipulate heat flux and DC ...current and eliminate the multiphysical perturbation, while maintaining the receiving and transmitting properties of the sensor.
Since the introduction of serum prostate-specific antigen (PSA) screening 25 years ago, prostate cancer diagnosis and management have been guided by this biomarker. Yet, PSA has proven controversial ...as a screening assay owing to several inherent limitations. The next wave of prostate cancer biomarkers has emerged, introducing new assays in serum and urine that may supplement or, in time, replace PSA because of their higher cancer specificity. This expanding universe of biomarkers has been facilitated, in large part, by new genomic technologies that have enabled an unbiased look at cancer biology. Such efforts have produced several notable success stories that involve rapidly moving biomarkers from the bench to the clinic. However, biomarker research has centered on disease diagnostics, rather than prognosis and prediction, which would address disease management. The development of biomarkers to stratify risk of prostate cancer aggressiveness at the time of screening remains the greatest unmet clinical need in prostate cancer. We review the current state of prostate cancer biomarker research, including the PSA revolution, its impact on early cancer detection, the recent advances in biomarker discovery, and the future efforts that promise to improve clinical management of this disease.
Lower urinary tract symptoms affect more than half of older men. Options for bothersome symptoms include α-adrenergic-receptor blockers, 5α-reductase inhibitors, phosphodiesterase-5 inhibitor ...therapy, and antimuscarinic therapy.
Foreword
This
Journal
feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines, when they exist. The article ends with the authors' clinical recommendations.
Stage
A 59-year-old man with a history of benign prostatic hyperplasia and lower urinary tract symptoms comes for care. He has been receiving doxazosin at a dose of 4 mg daily (his only medication) for the past 2 years, with minimal improvement. He continues to have nocturia, a weak urinary stream, and urinary frequency (voiding eight times per day). How would you manage this case?
The Clinical Problem
Benign prostatic hyperplasia, a histologic diagnosis, is a condition that occurs with aging; the prevalence increases from 25% among men 40 to 49 years of age to more than 80% among men . . .
Neuromodulatory systems exert profound influences on brain function. Understanding how these systems modify the operating mode of target circuits requires spatiotemporally precise measurement of ...neuromodulator release. We developed dLight1, an intensity-based genetically encoded dopamine indicator, to enable optical recording of dopamine dynamics with high spatiotemporal resolution in behaving mice. We demonstrated the utility of dLight1 by imaging dopamine dynamics simultaneously with pharmacological manipulation, electrophysiological or optogenetic stimulation, and calcium imaging of local neuronal activity. dLight1 enabled chronic tracking of learning-induced changes in millisecond dopamine transients in mouse striatum. Further, we used dLight1 to image spatially distinct, functionally heterogeneous dopamine transients relevant to learning and motor control in mouse cortex. We also validated our sensor design platform for developing norepinephrine, serotonin, melatonin, and opioid neuropeptide indicators.
Small cell lung cancer (SCLC) is a recalcitrant, aggressive neuroendocrine-type cancer for which little change to first-line standard-of-care treatment has occurred within the last few decades. ...Unlike nonsmall cell lung cancer (NSCLC), SCLC harbors few actionable mutations for therapeutic intervention. Lysine-specific histone demethylase 1A (LSD1 also known as KDM1A) inhibitors were previously shown to have selective activity in SCLC models, but the underlying mechanism was elusive. Here, we found that exposure to the selective LSD1 inhibitor ORY-1001 activated the NOTCH pathway, resulting in the suppression of the transcription factor ASCL1 and the repression of SCLC tumorigenesis. Our analyses revealed that LSD1 bound to the
locus, thereby suppressing NOTCH1 expression and downstream signaling. Reactivation of NOTCH signaling with the LSD1 inhibitor reduced the expression of ASCL1 and neuroendocrine cell lineage genes. Knockdown studies confirmed the pharmacological inhibitor-based results. In vivo, sensitivity to LSD1 inhibition in SCLC patient-derived xenograft (PDX) models correlated with the extent of consequential NOTCH pathway activation and repression of a neuroendocrine phenotype. Complete and durable tumor regression occurred with ORY-1001-induced NOTCH activation in a chemoresistant PDX model. Our findings reveal how LSD1 inhibitors function in this tumor and support their potential as a new and targeted therapy for SCLC.
PDF
