Systematic analysis of electronic barrier heights and widths for concerted proton transfer in cyclic hydrogen bonded clusters: (HF)n, (HCl)n and (H2O)n where n = 3, 4, 5.

The MP2 and CCSD(T) methods are paired with correlation consistent basis sets as large as aug-cc-pVQZ to optimize the structures of the cyclic minima for (HF)n, (HCl)n and (H2O)n where n = 3-5, as well as the corresponding transition states (TSs) for concerted proton transfer (CPT). MP2 and CCSD(T) harmonic vibrational frequencies confirm the nature of each minimum and TS. Both conventional and explicitly correlated CCSD(T) computations are employed to assess the electronic dissociation energies and barrier heights for CPT near the complete basis (CBS) limit for all 9 clusters. Results for (HF)n are consistent with prior studies identifying Cnh and Dnh point group symmetry for the minima and TSs, respectively. Our computations also confirm that CPT proceeds through Cs TS structures for the C1 minima of (H2O)3 and (H2O)5, whereas the process goes through a TS with D2d symmetry for the S4 global minimum of (H2O)4. This work corroborates earlier findings that the minima for (HCl)3, (HCl)4 and (HCl)5 have C3h, S4 and C1 point group symmetry, respectively, and that the Cnh structures are not minima for n = 4 and 5. Moreover, our computations show the TSs for CPT in (HCl)3, (HCl)4 and (HCl)5 have D3h, D2d, and C2 point group symmetry, respectively. At the CCSD(T) CBS limit, (HF)4 and (HF)5 have the smallest electronic barrier heights for CPT (≈15 kcal mol-1 for both), followed by the HF trimer (≈21 kcal mol-1). The barriers are appreciably higher for the other clusters (around 27 kcal mol-1 for (H2O)4 and (HCl)3; roughly 30 kcal mol-1 for (H2O)3, (H2O)5 and (HCl)4; up to 38 kcal mol-1 for (HCl)5). At the CBS limit, MP2 significantly underestimates the CCSD(T) barrier heights (e.g., by ca. 2, 4 and 7 kcal mol-1 for the pentamers of HF, H2O and HCl, respectively), whereas CCSD overestimates these barriers by roughly the same magnitude. Scaling the barrier heights and dissociation energies by the number of fragments in the cluster reveals strong linear relationships between the two quantities and with the magnitudes of the imaginary vibrational frequency for the TSs.

Spinal magnetic stimulation to treat chronic back pain: a feasibility study in veterans.

Aim: Chronic low back pain represents a significant societal problem leading to increased healthcare costs and quality of life. This study was designed to evaluate the feasibility and effectiveness of non-invasive spinal electromagnetic simulation (SEMS) to treat nonspecific chronic low back pain (CLBP). Methods: A single-site prospective study was conducted to evaluate SEMS in reducing pain and improving disability. A total of 17 patients received SEMS two to three sessions a week. The Numeric Rating Scale and the Modified Oswestry Disability Questionnaire were used to assess pain and disability. Results: Participants receiving SEMS exhibited statistically significant reductions in pain and disability. Conclusion: Current results suggest that non-invasive SEMS can be an effective treatment in reducing pain and improving disability associated with CLBP.

Patient outcomes associated with subcutaneous C1INH prophylaxis for hereditary angioedema: a retrospective analysis.

BACKGROUND: Real-world data on subcutaneous C1INH (C1INH[SC]) usage and patient-level impacts on hereditary angioedema (HAE)-related outcomes and quality of life (QoL) are both lacking and challenging to generate using conventional study methodologies. Using a hybrid study design involving patient interviews supplemented by retrospective medical chart data review, we conducted a real-world assessment of the impact of C1INH(SC) prophylaxis on HAE attack patterns, QoL, and on-demand medication use. METHODS: The study was conducted at seven US sites and included 36 adults with HAE who had been treated with C1INH(SC) long-term prophylaxis following ≥ 12 months of on-demand management only. Patients underwent 30-min interviews, facilitated and analyzed by a trained qualitative research specialist. Medical records were reviewed for 12 months before (pre-index) and after (post-index) initiation of C1INH(SC). Using interview data with descriptive terms converted to numerical values, we compared pre- versus post-index attack frequency, severity, and rescue medication usage. RESULTS: Mean (SD) annualized attack frequency per patient decreased 82.0%, from 38.8 (38.8) attacks/year pre-index to 7.0 (15.3) attacks/year (P < 0.001); the median number of attacks decreased by 97.0% (30 pre-index to 1 post-index). For 20 patients, the annualized attack rate after starting C1INH(SC) prophylaxis was ≤ 1 attack/year; 12 of these patients reported 0 attacks. Mean (SD) attack severity (scale: 0 = none/mild to 4 = very severe) decreased from 2.3 (0.7) pre-index to 0.9 (0.9) post-index (P < 0.001). Mean/median rescue medication use decreased by 77.2%/96.3%. Improved QoL was narratively described for many domains. CONCLUSIONS: These real-world findings indicate that long-term prophylaxis with C1INH(SC) markedly improves important factors that contribute to the goal of achieving total disease control and normalization of patients' lives, including fewer and less severe attacks, less rescue medication usage, and improved QoL.

Synthesis and Characterization of Stimuli-Responsive Polymer Brushes in Nanofluidic Channels.

Nanochannels with controllable gating behavior are attractive features in a wide range of nanofluidic applications including viral detection, particle sorting, and flow regulation. Here, we use selective sidewall functionalization of nanochannels with a polyelectrolyte brush to investigate the channel gating response to variations in solution pH and ionic strength. The conformational and structural changes of the interfacial brush layer within the channels are interrogated by specular and off-specular neutron reflectometry. Simultaneous fits of the specular and off-specular signals, using a dynamical theory model and a fitting optimization protocol, enable detailed characterization of the brush conformations and corresponding channel geometry under different solution conditions. Our results indicate a collapsed brush state under basic pH, equivalent to an open gate, and an expanded brush state representing a partially closed gate upon decreasing the pH and salt concentration. These findings open new possibilities in noninvasive in situ characterization of tunable nanofluidics and lab-on-chip devices with advanced designs and improved functionality.

Using Data Analytics to Improve Nursing Home Quality.

BACKGROUND: There exists an array of quality performance measures for nursing homes. They can confuse consumers, administrators, and government regulators. Our methodology provides a unified multidimensional evaluation. OBJECTIVE: To present a methodology to perform a multidimensional assessment of each nursing home within any specified group of nursing homes to aid policy makers, administrators, and consumers with a clear, easy-to-interpret evaluation of a nursing home quality performance. METHODS: We use data envelopment analysis (DEA) to integrate several quality measures into a comprehensive benchmarking model. We present statewide results comparing DEA performance scores with the Five-Star rating using data from New York State (NYS) Department of Health. RESULTS: In total, 212 of the 526 nursing homes performed as well as possible. Public nursing homes are most likely to lie on the frontier and have the highest average performance scores. The relationship between the DEA-based performance scores and the NYS Five-Star quality ratings is very weak. CONCLUSION: DEA is a comprehensive methodology for measuring nursing home quality. The DEA factor performance scores provide detailed information for individual nursing homes, enabling administrators to benchmark their facility's quality performance and to focus quality improvement efforts more effectively.

The histone variant macroH2A1.1 regulates RNA polymerase II-paused genes within defined chromatin interaction landscapes.

The histone variant macroH2A1.1 plays a role in cancer development and metastasis. To determine the underlying molecular mechanisms, we mapped the genome-wide localization of endogenous macroH2A1.1 in the human breast cancer cell line MDA-MB-231. We demonstrate that macroH2A1.1 specifically binds to active promoters and enhancers in addition to facultative heterochromatin. Selective knock down of macroH2A1.1 deregulates the expression of hundreds of highly active genes. Depending on the chromatin landscape, macroH2A1.1 acts through two distinct molecular mechanisms. The first mitigates excessive transcription by binding over domains including the promoter and the gene body. The second stimulates expression of RNA polymerase II (Pol II)-paused genes, including genes regulating mammary tumor cell migration. In contrast to the first mechanism, macroH2A1.1 specifically associates with the transcription start site of Pol II-paused genes. These processes occur in a predefined local 3D genome landscape, but do not require rewiring of enhancer-promoter contacts. We thus propose that macroH2A1.1 serves as a transcriptional modulator with a potential role in assisting the conversion of promoter-locked Pol II into a productive, elongating Pol II.

Concurrent CDX2 cis-deregulation and UBTF::ATXN7L3 fusion define a novel high-risk subtype of B-cell ALL.

Oncogenic alterations underlying B-cell acute lymphoblastic leukemia (B-ALL) in adults remain incompletely elucidated. To uncover novel oncogenic drivers, we performed RNA sequencing and whole-genome analyses in a large cohort of unresolved B-ALL. We identified a novel subtype characterized by a distinct gene expression signature and the unique association of 2 genomic microdeletions. The 17q21.31 microdeletion resulted in a UBTF::ATXN7L3 fusion transcript encoding a chimeric protein. The 13q12.2 deletion resulted in monoallelic ectopic expression of the homeobox transcription factor CDX2, located 138 kb in cis from the deletion. Using 4C-sequencing and CRISPR interference experiments, we elucidated the mechanism of CDX2 cis-deregulation, involving PAN3 enhancer hijacking. CDX2/UBTF ALL (n = 26) harbored a distinct pattern of additional alterations including 1q gain and CXCR4 activating mutations. Within adult patients with Ph- B-ALL enrolled in GRAALL trials, patients with CDX2/UBTF ALL (n = 17/723, 2.4%) were young (median age, 31 years) and dramatically enriched in females (male/female ratio, 0.2, P = .002). They commonly presented with a pro-B phenotype ALL and moderate blast cell infiltration. They had poor response to treatment including a higher risk of failure to first induction course (19% vs 3%, P = .017) and higher post-induction minimal residual disease (MRD) levels (MRD ≥ 10-4, 93% vs 46%, P < .001). This early resistance to treatment translated into a significantly higher cumulative incidence of relapse (75.0% vs 32.4%, P = .004) in univariate and multivariate analyses. In conclusion, we discovered a novel B-ALL entity defined by the unique combination of CDX2 cis-deregulation and UBTF::ATXN7L3 fusion, representing a high-risk disease in young adults.

A Novel Approach to Evaluating Cardiac Surgery Providers: An Alternative to the RAMR.

OBJECTIVE: We propose an alternative to the Risk Adjusted Mortality Rate (RAMR), about which we identify four serious concerns. We apply our method to cardiac surgery. DESIGN: We present a methodology that uses the upper and lower tail probabilities (UTP/LTP) of the binomial distribution to screen for poor/high performing providers. STUDY SETTING: The New York State Department of Health (NYS DOH) publicly releases data on all cardiac surgery patients in the state. We download cardiac surgery data from the NYS DOH website for the years 2011 through 2013. The state's objective is to identify poorly performing hospitals and surgeons and thereby reduce deaths. NYS employs the RAMR. RESULTS: The UTP/LTP approach agrees with the RAMR in its classification of all 132 surgeons and all 40 hospitals. However, performance is a continuous construct and strict categorization can lead to failure to identify marginal providers. CONCLUSIONS: Our methodology addresses all four concerns regarding the RAMR. The UTP/LTP approach avoids inappropriate hypothesis testing and is consistent with standard statistical theory and practice in its approach to case volume. It does not require confidence intervals and it applies to all providers regardless of case volume.

Predicting photosynthetic capacity in tobacco using shortwave infrared spectral reflectance.

Plateauing yield and stressful environmental conditions necessitate selecting crops for superior physiological traits with untapped potential to enhance crop performance. Plant productivity is often limited by carbon fixation rates that could be improved by increasing maximum photosynthetic carboxylation capacity (Vcmax). However, Vcmax measurements using gas exchange and biochemical assays are slow and laborious, prohibiting selection in breeding programs. Rapid hyperspectral reflectance measurements show potential for predicting Vcmax using regression models. While several hyperspectral models have been developed, contributions from different spectral regions to predictions of Vcmax have not been clearly identified or linked to biochemical variation contributing to Vcmax. In this study, hyperspectral reflectance data from 350-2500 nm were used to build partial least squares regression models predicting in vivo and in vitro Vcmax. Wild-type and transgenic tobacco plants with antisense reductions in Rubisco content were used to alter Vcmax independent from chlorophyll, carbon, and nitrogen content. Different spectral regions were used to independently build partial least squares regression models and identify key regions linked to Vcmax and other leaf traits. The greatest Vcmax prediction accuracy used a portion of the shortwave infrared region from 2070 nm to 2470 nm, where the inclusion of fewer spectral regions resulted in more accurate models.

Leaf temperature impacts canopy water use efficiency independent of changes in leaf level water use efficiency.

Canopy water use efficiency (above-ground biomass over lifetime water loss, WUEcanopy) can influence yield in wheat and other crops. Breeding for WUEcanopy is difficult because it is influenced by many component traits. For example, intrinsic water use efficiency (WUEi), the ratio of net carbon assimilation (Anet) over stomatal conductance, contributes to WUEcanopy and can be estimated from carbon isotope discrimination (Δ). However, Δ is not sensitive to differences in the water vapor pressure deficit between the air and leaf (VPDleaf). Alternatively, measurements of instantaneous leaf water use efficiency (WUEleaf) are defined as Anet over transpiration and can be determined with gas exchange, but the dynamic nature of field conditions are not represented. Specifically, fluctuations in canopy temperature lead to changes in VPDleaf that impact transpiration but not Anet. This alters WUEleaf and in turn affects WUEcanopy. To test this relationship, WUEcanopy was measured in conjunction with WUEi, WUEcanopy, and canopy temperature under well-watered and water-limited conditions in two drought-tolerant wheat cultivars that differ in canopy architecture. In this experiment, boundary layer conductance was low and significant changes in leaf temperature occurred between cultivars and treatments that correlated with WUEcanopy likely because of the effect of canopy temperature on VPDleaf driving T. However, deviations between WUEi, WUEleaf, and WUEcanopy were present because measurements made at the leaf level do not account for variations in leaf temperature. This uncoupled the relationship of measured WUEleaf and WUEi from WUEcanopy and emphasizes the importance of canopy temperature on carbon uptake and transpired water loss.

Age-related and disease locus-specific mechanisms contribute to early remodelling of chromatin structure in Huntington's disease mice.

Temporal dynamics and mechanisms underlying epigenetic changes in Huntington's disease (HD), a neurodegenerative disease primarily affecting the striatum, remain unclear. Using a slowly progressing knockin mouse model, we profile the HD striatal chromatin landscape at two early disease stages. Data integration with cell type-specific striatal enhancer and transcriptomic databases demonstrates acceleration of age-related epigenetic remodelling and transcriptional changes at neuronal- and glial-specific genes from prodromal stage, before the onset of motor deficits. We also find that 3D chromatin architecture, while generally preserved at neuronal enhancers, is altered at the disease locus. Specifically, we find that the HD mutation, a CAG expansion in the Htt gene, locally impairs the spatial chromatin organization and proximal gene regulation. Thus, our data provide evidence for two early and distinct mechanisms underlying chromatin structure changes in the HD striatum, correlating with transcriptional changes: the HD mutation globally accelerates age-dependent epigenetic and transcriptional reprogramming of brain cell identities, and locally affects 3D chromatin organization.

Alternative Enhancer Usage and Targeted Polycomb Marking Hallmark Promoter Choice during T Cell Differentiation.

During thymic development and upon peripheral activation, T cells undergo extensive phenotypic and functional changes coordinated by lineage-specific developmental programs. To characterize the regulatory landscape controlling T cell identity, we perform a wide epigenomic and transcriptional analysis of mouse thymocytes and naive CD4 differentiated T helper cells. Our investigations reveal a dynamic putative enhancer landscape, and we could validate many of the enhancers using the high-throughput CapStarr sequencing (CapStarr-seq) approach. We find that genes using multiple promoters display increased enhancer usage, suggesting that apparent "enhancer redundancy" might relate to isoform selection. Furthermore, we can show that two Runx3 promoters display long-range interactions with specific enhancers. Finally, our analyses suggest a novel function for the PRC2 complex in the control of alternative promoter usage. Altogether, our study has allowed for the mapping of an exhaustive set of active enhancers and provides new insights into their function and that of PRC2 in controlling promoter choice during T cell differentiation.

Using Data Analytics to Improve Hospital Quality Performance.

EXECUTIVE SUMMARY: The objective of this study was to build a unified quality performance model for hospitals using publicly available data. We obtained data from the New York State Department of Health's Statewide Planning and Research Cooperative System database for our model, which had three outcome measures that we wished to make smaller (deaths, readmissions, average length of stay). Because this was a performance model rather than an economic efficiency model, we excluded costs, which are affected significantly by local economic conditions. We included four site characteristics. With our data envelopment analysis model structure, we used logistic regression to analyze the output. We extracted data for 2,233,214 discharges in 2014 from 183 hospitals in the state. We found that 20.8% of the facilities were on the quality performance frontier-20.6% of the not-for-profit facilities and 21.4% of the other facilities. Hospitals with more discharges performed better with respect to mortality, readmission, and average length of stay. We found no difference in performance between not-for-profit hospitals and others. We concluded that 79.2% of hospitals could improve their quality of care. As an upper bound, if all hospitals increased each quality factor performance to 100%, there would have been 11,722 (24.8%) fewer deaths, 17,840 (15.8%) fewer readmissions, and the statewide average length of stay would have been 0.71 days (13.5%) less.

Global chromatin conformation differences in the Drosophila dosage compensated chromosome X.

In Drosophila melanogaster the single male chromosome X undergoes an average twofold transcriptional upregulation for balancing the transcriptional output between sexes. Previous literature hypothesised that a global change in chromosome structure may accompany this process. However, recent studies based on Hi-C failed to detect these differences. Here we show that global conformational differences are specifically present in the male chromosome X and detectable using Hi-C data on sex-sorted embryos, as well as male and female cell lines, by leveraging custom data analysis solutions. We find the male chromosome X has more mid-/long-range interactions. We also identify differences at structural domain boundaries containing BEAF-32 in conjunction with CP190 or Chromator. Weakening of these domain boundaries in male chromosome X co-localizes with the binding of the dosage compensation complex and its co-factor CLAMP, reported to enhance chromatin accessibility. Together, our data strongly indicate that chromosome X dosage compensation affects global chromosome structure.

Communication: Gas phase vibrational spectroscopy of the azide-water complex.

The vibrational spectra of the azide-water complex, N3 -(H2O), and its fully deuterated isotopologue are studied using infrared photodissociation (IRPD) spectroscopy (800-3800 cm-1) and high-level ab initio computations. The IRPD spectrum of the H2-tagged complex exhibits four fundamental transitions at 3705, 3084, 2003, and 1660 cm-1, which are assigned to the free OH stretching, the hydrogen-bonded O-H stretching, the antisymmetric N3 stretching, and the water bending mode, respectively. The IRPD spectrum is consistent with a planar, singly hydrogen-bonded structure according to an MP2 and CCSD(T) anharmonic analysis via generalized second-order vibrational perturbation theory. The red-shift of the hydrogen-bonded OH stretching fundamental of 623 cm-1 associated with this structure is computed within 6 cm-1 (or 1%) and is used to estimate the proton affinity of azide (1410 kJ mol-1). Born-Oppenheimer molecular dynamics simulations show that large amplitude motions are responsible for the observed band broadening at cryogenic temperature. Temperature-dependent (6-300 K) IR multiphoton dissociation spectra of the untagged complex are also presented and discussed in the context of spectral diffusion observed in the condensed phase.

Measuring Hospital Performance Using Mortality Rates: An Alternative to the RAMR.

BACKGROUND: The risk-adjusted mortality rate (RAMR) is used widely by healthcare agencies to evaluate hospital performance. The RAMR is insensitive to case volume and requires a confidence interval for proper interpretation, which results in a hypothesis testing framework. Unfamiliarity with hypothesis testing can lead to erroneous interpretations by the public and other stakeholders. We argue that screening, rather than hypothesis testing, is more defensible. We propose an alternative to the RAMR that is based on sound statistical methodology, easier to understand and can be used in large-scale screening with no additional data requirements. METHODS: We use an upper-tail probability to screen for hospitals performing poorly and a lower-tail probability to screen for hospitals performing well. Confidence intervals and hypothesis tests are not needed to compute or interpret our measures. Moreover, unlike the RAMR, our measures are sensitive to the number of cases treated. RESULTS: To demonstrate our proposed methodology, we obtained data from the New York State Department of Health for 10 Inpatient Quality Indicators (IQIs) for the years 2009-2013. We find strong agreement between the upper tail probability (UTP) and the RAMR, supporting our contention that the UTP is a viable alternative to the RAMR. CONCLUSION: We show that our method is simpler to implement than the RAMR and, with no need for a confidence interval, it is easier to interpret. Moreover, it will be available for all hospitals and all diseases/conditions regardless of patient volume.

Dissociation Energy of the H2O···HF Dimer.

Even though (H2O)2 and (HF)2 are arguably the most thoroughly characterized prototypes for hydrogen bonding, their heterogeneous analogue H2O···HF has received relatively little attention. Here we report that the experimental dissociation energy ( D0) of this important paradigm for heterogeneous hydrogen bonding is too large by 2 kcal mol-1 or 30% relative to our computed value of 6.3 kcal mol-1. For reference, computational procedures similar to those employed here to compute D0 (large basis set CCSD(T) computations with anharmonic corrections from second-order vibrational perturbation theory) provide results within 0.1 kcal mol-1 of the experimental values for (H2O)2 and (HF)2. Near the CCSD(T) complete basis set limit, the electronic dissociation energy for H2O···HF is ∼4 kcal mol-1 larger than those for (H2O)2 and (HF)2 (∼9 kcal mol-1 for the heterogeneous dimer vs ∼5 kcal mol-1 for the homogeneous dimers). Results reported here from symmetry-adapted perturbation theory computations suggest that this large difference is primarily due to the induction contribution to the interaction energy.

Single-cell absolute contact probability detection reveals chromosomes are organized by multiple low-frequency yet specific interactions.

At the kilo- to megabase pair scales, eukaryotic genomes are partitioned into self-interacting modules or topologically associated domains (TADs) that associate to form nuclear compartments. Here, we combine high-content super-resolution microscopies with state-of-the-art DNA-labeling methods to reveal the variability in the multiscale organization of the Drosophila genome. We find that association frequencies within TADs and between TAD borders are below ~10%, independently of TAD size, epigenetic state, or cell type. Critically, despite this large heterogeneity, we are able to visualize nanometer-sized epigenetic domains at the single-cell level. In addition, absolute contact frequencies within and between TADs are to a large extent defined by genomic distance, higher-order chromosome architecture, and epigenetic identity. We propose that TADs and compartments are organized by multiple, small-frequency, yet specific interactions that are regulated by epigenetics and transcriptional state.

A Reaction Valley Investigation of the Cycloaddition of 1,3-Dipoles with the Dipolarophiles Ethene and Acetylene: Solution of a Mechanistic Puzzle.

The reaction mechanism of the cycloaddition of 10 1,3-dipoles with the two dipolarphiles ethene and acetylene is investigated and compared using the Unified Reaction Valley Approach in a new form, which is based on a dual-level strategy, an accurate description of the reaction valley far out into the van der Waals region, and a comparative analysis of the electronic properties of the reaction complex. A detailed one-to-one comparison of 20 different 1,3-dipolar cycloadditions is performed, and unknown mechanistic features are revealed. There are significant differences in the reaction mechanisms for the two dipolarophiles that result from the van der Waals complex formation in the entrance channel of the cycloadditions. Hydrogen bonding between the 1,3-dipoles and acetylene is generally stronger, which leads to higher reaction barriers in the acetylene case, but which also facilitates to overcome the problem of a reduced charge transfer from 1,3-dipole to acetylene. Mechanistic differences are found in the prechemical and chemical reaction regions with regard to reactant orientation, preparation for the reaction, charge transfer, charge polarization, rehybridization, and bond formation. It is shown that similarities in the reaction barriers as determined by CCSD(T)-F12/aug-cc-pVTZ calculations result from a fortuitous cancellation of different electronic effects. In general, a caveat must be made with regard to oversimplified descriptions of the reaction mechanism based on orbital theory or energy decomposition schemes.

A New Method for Describing the Mechanism of a Chemical Reaction Based on the Unified Reaction Valley Approach.

The unified reaction valley approach (URVA) used for a detailed mechanistic analysis of chemical reactions is improved in three different ways: (i) Direction and curvature of path are analyzed in terms of internal coordinate components that no longer depend on local vibrational modes. In this way, the path analysis is no longer sensitive to path instabilities associated with the occurrences of imaginary frequencies. (ii) The use of third order terms of the energy for a local description of the reaction valley allows an extension of the URVA analysis into the pre- and postchemical regions of the reaction path, which are typically characterized by flat energy regions. (iii) Configurational and conformational processes of the reaction complex are made transparent even in cases where these imply energy changes far less than a kcal/mol by exploiting the topology of the potential energy surface. As examples, the rhodium-catalyzed methanol carbonization, the Diels-Alder reaction between 1,3-butadiene and ethene, and the rearrangement of HCN to CNH are discussed.