Understanding the effect of density functional choice and van der Waals treatment on predicting the binding configuration, loading, and stability of amine-grafted metal organic frameworks.

Metal organic frameworks (MOFs) are crystalline, three-dimensional structures with high surface areas and tunable porosities. Made from metal nodes connected by organic linkers, the exact properties of a given MOF are determined by node and linker choice. MOFs hold promise for numerous applications, including gas capture and storage. M2(4,4'-dioxidobiphenyl-3,3'-dicarboxylate)-henceforth simply M2(dobpdc), with M = Mg, Mn, Fe, Co, Ni, Cu, or Zn-is regarded as one of the most promising structures for CO2 capture applications. Further modification of the MOF with diamines or tetramines can significantly boost gas species selectivity, a necessity for the ultra-dilute CO2 concentrations in the direct-air capture of CO2. There are countless potential diamines and tetramines, paving the way for a vast number of potential sorbents to be probed for CO2 adsorption properties. The number of amines and their configuration in the MOF pore are key drivers of CO2 adsorption capacity and kinetics, and so a validation of computational prediction of these quantities is required to suitably use computational methods in the discovery and screening of amine-functionalized sorbents. In this work, we study the predictive accuracy of density functional theory and related calculations on amine loading and configuration for one diamine and two tetramines. In particular, we explore the Perdew-Burke-Ernzerhof (PBE) functional and its formulation for solids (PBEsol) with and without the Grimme-D2 and Grimme-D3 pairwise corrections (PBE+D2/3 and PBEsol+D2/3), two revised PBE functionals with the Grimme-D2 and Grimme-D3 pairwise corrections (RPBE+D2/3 and revPBE+D2/3), and the nonlocal van der Waals correlation (vdW-DF2) functional. We also investigate a universal graph deep learning interatomic potential's (M3GNet) predictive accuracy for loading and configuration. These results allow us to identify a useful screening procedure for configuration prediction that has a coarse component for quick evaluation and a higher accuracy component for detailed analysis. Our general observation is that the neural network-based potential can be used as a high-level and rapid screening tool, whereas PBEsol+D3 gives a completely qualitatively predictive picture across all systems studied, and can thus be used for high accuracy motif predictions. We close by briefly exploring the predictions of relative thermal stability for the different functionals and dispersion corrections.

Stratification of chemotherapy-treated stage III colorectal cancer patients using multiplexed imaging and single-cell analysis of T-cell populations.

Colorectal cancer (CRC) has one of the highest cancer incidences and mortality rates. In stage III, postoperative chemotherapy benefits <20% of patients, while more than 50% will develop distant metastases. Biomarkers for identification of patients at increased risk of disease recurrence following adjuvant chemotherapy are currently lacking. In this study, we assessed immune signatures in the tumor and tumor microenvironment (TME) using an in situ multiplexed immunofluorescence imaging and single-cell analysis technology (Cell DIVETM) and evaluated their correlations with patient outcomes. Tissue microarrays (TMAs) with up to three 1 mm diameter cores per patient were prepared from 117 stage III CRC patients treated with adjuvant fluoropyrimidine/oxaliplatin (FOLFOX) chemotherapy. Single sections underwent multiplexed immunofluorescence staining for immune cell markers (CD45, CD3, CD4, CD8, FOXP3, PD1) and tumor/cell segmentation markers (DAPI, pan-cytokeratin, AE1, NaKATPase, and S6). We used annotations and a probabilistic classification algorithm to build statistical models of immune cell types. Images were also qualitatively assessed independently by a Pathologist as 'high', 'moderate' or 'low', for stromal and total immune cell content. Excellent agreement was found between manual assessment and total automated scores (p < 0.0001). Moreover, compared to single markers, a multi-marker classification of regulatory T cells (Tregs: CD3+/CD4+FOXP3+/PD1-) was significantly associated with disease-free survival (DFS) and overall survival (OS) (p = 0.049 and 0.032) of FOLFOX-treated patients. Our results also showed that PD1- Tregs rather than PD1+ Tregs were associated with improved survival. These findings were supported by results from an independent FOLFOX-treated cohort of 191 stage III CRC patients, where higher PD1- Tregs were associated with an increase overall survival (p = 0.015) for CD3+/CD4+/FOXP3+/PD1-. Overall, compared to single markers, multi-marker classification provided more accurate quantitation of immune cell types with stronger correlations with outcomes.

Electronic structure and transport properties of N2(AA)-doped armchair and zigzag graphene nanoribbons.

Substitutional doping in graphene nanoribbons (GNRs) promises to enable specific tuning of their electronic properties. Recent work by Lv et al (2012 Nature Sci. Rep. 2 586) on large sheets of nitrogen-doped graphene determined that a highly predominant amount of nitrogen dopants (80%) are present in pairs of neighbouring atoms of the same sublattice A, denoted as N2(AA) dopants, following the notation of Lv et al. Here, we explore the electronic and transport properties of armchair (aGNR) and zigzag (zGNR) graphene nanoribbons under different orientations of the N2(AA) dopants with respect to the ribbon growth direction. For all dopant configurations of zGNRs and aGNRs, we find a substantial decrease in conductance, with new conductance gaps opening in some cases, and spatially localized states induced around the dopant sites. We also provide simulated scanning tunnelling microscopy images that will aid in the experimental identification of the presence of these structures in N-doped GNR samples.

Deep learning-based automated pipeline for blood vessel detection and distribution analysis in multiplexed prostate cancer images.

Introduction: Prostate cancer is a highly heterogeneous disease, presenting varying levels of aggressiveness and response to treatment. Angiogenesis is one of the hallmarks of cancer, providing oxygen and nutrient supply to tumors. Micro vessel density has previously been correlated with higher Gleason score and poor prognosis. Manual segmentation of blood vessels (BVs) In microscopy images is challenging, time consuming and may be prone to inter-rater variabilities. In this study, an automated pipeline is presented for BV detection and distribution analysis in multiplexed prostate cancer images. Methods: A deep learning model was trained to segment BVs by combining CD31, CD34 and collagen IV images. In addition, the trained model was used to analyze the size and distribution patterns of BVs in relation to disease progression in a cohort of prostate cancer patients (N = 215). Results: The model was capable of accurately detecting and segmenting BVs, as compared to ground truth annotations provided by two reviewers. The precision (P), recall (R) and dice similarity coefficient (DSC) were equal to 0.93 (SD 0.04), 0.97 (SD 0.02) and 0.71 (SD 0.07) with respect to reviewer 1, and 0.95 (SD 0.05), 0.94 (SD 0.07) and 0.70 (SD 0.08) with respect to reviewer 2, respectively. BV count was significantly associated with 5-year recurrence (adjusted p = 0.0042), while both count and area of blood vessel were significantly associated with Gleason grade (adjusted p = 0.032 and 0.003 respectively). Discussion: The proposed methodology is anticipated to streamline and standardize BV analysis, offering additional insights into the biology of prostate cancer, with broad applicability to other cancers.

Operating Room Traffic in Total Joint Arthroplasty: One Simple Measure Toward Solving a Complex Problem.

BACKGROUND: Periprosthetic joint infection remains a devastating complication of total joint arthroplasty (TJA). The literature suggests that unnecessary operating room (OR) traffic increases the risk of surgical site infection by increasing bacterial load in the OR. We attempted to determine whether the posting of "restricted access" signs on the outside and inside of OR doors during primary TJA procedures would result in a reduction of OR door openings. METHODS: This prospectively designed, 2-phase study investigated the number of door openings per case for primary TJA. An independent observer collected data for each TJA case; the OR staff were blinded to the data collection to avoid bias. The first phase of this study recorded OR traffic without the use of "restricted access" signs. In the second, interventional phase of the study, OR traffic was monitored with the concomitant application of "restricted access" signs on the doors. The number of openings per case, from the time of incision to the time of dressing application, was collected. RESULTS: The average number of openings per case during the first phase was 75, with 0.59 door openings per minute. The average number of openings per case during the second phase was 40, with 0.28 door openings per minute. Therefore, a 47% reduction in openings per case and a 53% reduction in the number of openings per minute during primary TJA cases were observed. CONCLUSIONS: We demonstrated that the simple addition of "restricted access" signs on the outside and inside of OR doors produced a significant reduction (p < 0.001) in OR traffic during primary TJA. CLINICAL RELEVANCE: Posting signs can decrease door openings, potentially decreasing infection.

Muscarinic acetylcholine receptor status in Alzheimer's disease assessed using (R, R) 123I-QNB SPECT.

BACKGROUND: One of the most characteristic changes in Alzheimer's disease (AD) is a deficit in cortical cholinergic neurotransmission and associated receptor changes. OBJECTIVE: To investigate differences in the distribution of M1/M4 receptors using (R, R) (123)I-iodo-quinuclidinyl-benzilate (QNB) and single photon emission computed tomography (SPECT) in patients with mild/moderate AD and age-matched controls. Also, to compare (123)I-QNB uptake to the corresponding changes in regional cerebral blood flow (rCBF) in the same subjects. METHODS: Forty two subjects (18 AD and 24 healthy elderly controls) underwent (123)IQNB and perfusion (99m)Tc-exametazime SPECT scanning. Image analysis was performed using statistical parametric mapping (SPM99) following intensity normalisation of each image to its corresponding mean whole brain uptake. Group differences and correlations were assessed using two sample t-tests and linear regression respectively. RESULTS: Significant reductions in (123)I-QNB uptake were observed in regions of the frontal rectal gyrus, right parahippocampal gyrus, left hippocampus and areas of the left temporal lobe in AD compared to controls (height threshold of p < or = 0.001 uncorrected). Such regions were also associated with marked deficits in rCBF. No significant correlations were identified between imaging data and clinical variables. CONCLUSION: Functional impairment as measured by rCBF is more widespread than changes in M1/M4 receptor density in mild/moderate AD, where there was little or no selective loss of M1/M4 receptors in these patients that was greater than the general functional deficits shown on rCBF scans.

Expression of cyclooxygenase and lipoxygenase enzymes in nasal polyps of aspirin-sensitive and aspirin-tolerant patients.

OBJECTIVE: To evaluate the expression of cyclooxygenase (COX) and lipoxygenase (LO) enzymes in nasal polyp specimens from aspirin-sensitive (AS) and aspirin-tolerant (AT) patients. DESIGN: Immunohistochemical staining of archived tissue. Subjects Specimens from 26 patients (11 AS and 15 AT) with nasal polyps were analyzed; specimens from 4 patients were used as controls. INTERVENTIONS: Immunohistochemical techniques were used to evaluate the expression of the enzymes COX-1, COX-2, 5-LO, 12-LO, and 15-LO in nasal polyp tissue specimens from AS and AT patients. The results were compared with those of a control group of patients without a history of nasal polyposis or rhinosinusitis. RESULTS: Characteristic staining patterns of epithelium and submucosal glands were noted for each enzyme. Statistically significant (P<.05) differences in staining of columnar epithelium were noted for COX-1 (basal cell layer cytoplasm), COX-2 (apical cell layer cytoplasm), and 12-LO (full-thickness cytoplasm and nucleus). Increased 15-LO (full-thickness cytoplasm) expression in columnar epithelium was noted only in the AT group. Significant differences in the staining of submucosal glands were noted for COX-2 (plasma membrane and cytoplasm), 12-LO (cytoplasm), and 15-LO (cytoplasm) between control and AS patients as well as between control and AT patients (P<.05). The only significant difference noted between the AS and AT groups was cytoplasm staining for 5-LO in submucosal glands, which was greater in the AS group. No epithelial staining differences were noted between AT and AS patients. CONCLUSIONS: There were significant differences in the expression of COX and LO enzymes between patients with nasal polyps and controls, irrespective of aspirin sensitivity. With 1 exception, there were no significant differences between AS and AT groups.

Assessment of 123I-FIAU imaging of herpes simplex viral gene expression in the treatment of glioma.

BACKGROUND: Herpes simplex virus 1716 (HSV1716), a selectively replication competent mutant of HSV1, is under investigation as an oncolytic viral therapy in human malignant glioma. As with similar therapies, a technique for measurement of viral replication and distribution over time following virus administration is required. Imaging expression of the HSV-thymidine kinase (HSV-tk) gene offers an opportunity for non-invasive assessment of viral distribution in living subjects. This is the first study to explore the use of HSV-tk as a reporter gene and radiolabelled thymidine analogue 5-[(123)I]iodo-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) uracil ((123)I-FIAU) as a marker substrate to non-invasively monitor HSV1716 replication in humans during treatment of high-grade glioma. METHODS: I-FIAU brain SPECT imaging was undertaken in eight patients receiving intra-tumoural injection of HSV1716, before and after administration of the virus. Baseline images were acquired 3 days prior to virus administration and between 1 and 5 days following virus administration. Region of interest analysis was used to investigate whether there was an increase in (123)I-FIAU concentration following virus administration due to HSV-tk expression. RESULT: Increased (123)I-FIAU accumulation due to HSV-tk expression was not detected in this study. The possible explanations for this finding are explored and design options for future studies are discussed.

Future directions in the treatment of oral cancer.

Future developments in the realms of nanotechnology and directed therapeutics will alter the diagnosis and treatment of oral cancer relative to contemporary treatment modalities. Continued experience and investigation will determine the clinical usefulness of the various technologies that have been described in this article.

Soft tissue implants and fillers.

The number and variety of soft tissue implants and fillers at the clinician's disposal continues to increase rapidly as new materials and bioengineering techniques evolve. The ideal implant for all purposes does not yet exist, so the clinician must be familiar with a wide variety of products for each application. Continued advances in synthetic, allogeneic, and autologous products and experience with existing products will further augment the surgeon's armamentarium in the coming years.

Improved all-carbon spintronic device design.

The discovery of magnetism in carbon structures containing zigzag edges has stimulated new directions in the development and design of spintronic devices. However, many of the proposed structures are designed without incorporating a key phenomenon known as topological frustration, which leads to localized non-bonding states (free radicals), increasing chemical reactivity and instability. By applying graph theory, we demonstrate that topological frustrations can be avoided while simultaneously preserving spin ordering, thus providing alternative spintronic designs. Using tight-binding calculations, we show that all original functionality is not only maintained but also enhanced, resulting in the theoretically highest performing devices in the literature today. Furthermore, it is shown that eliminating armchair regions between zigzag edges significantly improves spintronic properties such as magnetic coupling.

Temperature-dependent and bistable current-voltage measurements in zinc porphyrin molecular junctions.

We report bistability in current-voltage curves from di(PEP)PorZn in an electromigrated molecular junction. Bistability was observed at ±0.3 V at 300 K but did not occur at 4 K. No bistability was identified at 300 K for another porphyrin molecule (di(Xyl)PorZn), where the phenyl-ethnyl-phenyl (PEP) side groups were replaced with a flexible p-xylene. Molecular dynamics simulations show that bistability may be due to conformation changes related to the fluctuation of the dihedral angle surrounding the zinc and/or the rotation of the porphyrin central plane of the molecule. Results suggest that other mechanisms may play a role in the current-voltage characteristics observed.

Muscarinic receptors in basal ganglia in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease.

Derivatives of the muscarinic antagonist 3-quinuclidinyl-4-iodobenzilate (QNB), particularly [123I]-(R,R)-I-QNB, are currently being assessed as in vivo ligands to monitor muscarinic receptors in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB), relating changes to disease symptoms and to treatment response with cholinergic medication. To assist in the evaluation of in vivo binding, muscarinic receptor density in post-mortem human brain was measured by autoradiography with [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB and compared to M1 ([3H]pirenzepine) and M2 and M4 ([3H]AF-DX 384) receptor binding. Binding was calculated in tissue containing striatum, globus pallidus (GPe), claustrum, and cingulate and insula cortex, in cases of AD, DLB, Parkinson's disease (PD) and normal elderly controls. Pirenzepine, AF-DX 384 and (R,S)-I-QNB binding in the striatum correlated positively with increased Alzheimer-type pathology, and AF-DX 384 and (R,R)-I-QNB cortical binding correlated positively with increased Lewy body (LB) pathology; however, striatal pirenzepine binding correlated negatively with cortical LB pathology. M1 receptors were significantly reduced in striatum in DLB compared to AD, PD, and controls and there was a significant correlation between M1 and dopamine D2 receptor densities. [3H]AF-DX 384 binding was higher in the striatum and GPe in AD. Binding of [125I]-(R,R)-I-QNB, which may reflect increased muscarinic M4 receptors, was higher in cortex and claustrum in DLB and AD. [125I]-(R,S)-I-QNB binding was higher in the GPe in AD. Low M1 and D2 receptors in DLB imply altered regulation of the striatal projection neurons which express these receptors. Low density of striatal M1 receptors may relate to the extent of movement disorder in DLB, and to a reduced risk of parkinsonism with acetylcholinesterase inhibition.

Comparative distribution of binding of the muscarinic receptor ligands pirenzepine, AF-DX 384, (R,R)-I-QNB and (R,S)-I-QNB to human brain.

Quinuclidinyl benzilate (QNB) and its derivatives are being developed to investigate muscarinic receptor changes in vivo in Alzheimer's disease and dementia with Lewy bodies. This is the first study of [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB binding in vitro in human brain. We have compared the in vitro binding of the muscarinic ligands [3H]pirenzepine and [3H]AF-DX 384, which have selectivity for the M1 and M2/M4 receptor subtypes, respectively, to the binding of [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB. This will provide a guide to the interpretation of in vivo SPET images generated with [123I]-(R,R)-I-QNB and [123I]-(R,S)-I-QNB. Binding was investigated in striatum, globus pallidus, thalamus and cerebellum, and cingulate, insula, temporal and occipital cortical areas, which show different proportions of muscarinic receptor subtypes, in post-mortem brain from normal individuals. M1 receptors are of high density in cortex and striatum and are relatively low in the thalamus and cerebellum, while M4 receptors are mainly expressed in the striatum, and M2 receptors are most evident in the cerebellum and thalamus. [125I]-(R,R)-I-QNB and [125I]-(R,S)-I-QNB density distribution patterns were consistent with binding to both M1 and M4 receptors, with [125I]-(R,R)-I-QNB additionally binding to a non-cholinergic site not displaceable by atropine. This distribution can be exploited by in vivo imaging, developing ligands for both SPET and PET, to reveal muscarinic receptor changes in Alzheimer's disease and dementia with Lewy bodies during the disease process and following cholinergic therapy.

A bolus/infusion paradigm for the novel NMDA receptor SPET tracer [123I]CNS 1261.

We have previously performed quantitative kinetic modeling of [(123)I]CNS 1261, a new SPET ligand for the MK801 intrachannel site of the NMDA receptor. We now report a bolus-infusion protocol, which eliminates the need for arterial blood sampling. Dynamic SPET scanning and venous blood sampling were performed in 7 healthy volunteers. Good agreement was obtained between kinetic and equilibrium analysis. SPET scanning with a bolus-infusion protocol is a valid method to estimate the total volume of distribution for [(123)I]CNS 1261 in clinical populations.

Kinetic modelling of [123I]CNS 1261--a potential SPET tracer for the NMDA receptor.

N-(1-napthyl)-N'-(3-[(123)I]-iodophenyl)-N-methylguanidine ([(123)I]CNS 1261) is a novel SPET ligand developed for imaging the NMDA receptor intra-channel MK 801/PCP/ketamine site. Data was acquired in 7 healthy volunteers after bolus injection of [(123)I]CNS 1261. Kinetic modeling showed reversible tracer binding. Arterial and venous time-activity curves overlapped after 90 min. The rank order of binding was: Thalamus > striatum > cortical regions > white matter. This distribution concurs with [(11)C]-ketamine and [(18)F]-memantine PET studies. These data provide a methodological basis for further direct in vivo challenge studies.

The role of postoperative adjuvant radiation therapy in the treatment of mucosal melanomas of the head and neck region.

BACKGROUND: Mucosal melanoma of the head and neck is uncommon, and has a poor prognosis due to locoregional and distant failure. The optimal treatment paradigm for patients with this disease has yet to be determined. OBJECTIVE: To compare the outcomes of patients treated with various commonly used protocols for mucosal melanoma of the head and neck. DESIGN: Retrospective study. SETTING: Academic tertiary referral center. PATIENTS: The medical records of 48 consecutive patients treated at a single institution from January 1, 1985, to December 31, 1998, were reviewed. INTERVENTIONS: Patients were treated with surgery alone, surgery and adjuvant radiotherapy, or surgery and biochemotherapy, with or without adjuvant radiotherapy. MAIN OUTCOME MEASURES: The outcomes of disease recurrence and survival were correlated with the treatment received. RESULTS: Twenty patients received surgical treatment alone; in 9 patients (45%), this treatment failed locoregionally, and 10 (50%) of the patients developed distant metastases. The 5-year survival rate was 45% (9 of 20 patients). Twenty-four patients received postoperative adjuvant radiotherapy; in 4 patients (17%), this treatment failed locally, and 11 (46%) of the patients developed distant metastases. The 5-year survival rate was 29% (7 of 24 patients). CONCLUSION: The addition of radiotherapy tended to decrease the rate of local failure (P =.13), but did not significantly improve survival (P =.73), because of the high rate of distant metastatic disease.

Self-organized and cu-coordinated surface linear polymerization.

We demonstrate a controllable surface-coordinated linear polymerization of long-chain poly(phenylacetylenyl)s that are self-organized into a "circuit-board" pattern on a Cu(100) surface. Scanning tunneling microscopy/spectroscopy (STM/S) corroborated by ab initio calculations, reveals the atomistic details of the molecular structure, and provides a clear signature of electronic and vibrational properties of the poly(phenylacetylene)s chains. Notably, the polymerization reaction is confined epitaxially to the copper lattice, despite a large strain along the polymerized chain that subsequently renders it metallic. Polymerization and depolymerization reactions can be controlled locally at the nanoscale by using a charged metal tip. This control demonstrates the possibility of precisely accessing and controlling conjugated chain-growth polymerization at low temperature. This finding may lead to the bottom-up design and realization of sophisticated architectures for molecular nano-devices.

North Carolina internists' and endocrinologists' knowledge, opinions, and behaviors regarding periodontal disease and diabetes: need and opportunity for interprofessional education.

The aim of this study was to determine the knowledge and practice behaviors of one state's internists and endocrinologists who treat patients with any type of diabetes. A thirty-five-item questionnaire was mailed to 1,000 internists and 115 endocrinologists in North Carolina. Questions were open and closed ended and Likert-scaled. Descriptive statistics and bivariate analysis were utilized. The response rate was 34 percent (N=378). The overall usable response rate was 23 percent (N=254). Over half of the respondents (66 percent) were males. Internists' and endocrinologists' knowledge about periodontal disease was high. The majority of the respondents agreed that physicians should be taught about periodontal disease (88 percent) and should be trained to screen for periodontal disease in their patients (78 percent). However, when asked if they are confident in providing an oral health screening for their patients, the responses were evenly distributed from strongly agree to strongly disagree. This study suggests that internists and endocrinologists have some knowledge about oral health and believe that there is a link between periodontal disease and diabetes mellitus; however, the majority do not have sufficient familiarity with the studies that link periodontal disease and diabetes mellitus. They agree with the idea of collaboration with dental professionals to reduce the number of patients at risk for developing periodontal disease. Perhaps the time is conducive to promote interprofessional education and collaboration between medical and dental health care providers to prepare for the future increase in patient and treatment needs.