Geometry relaxation-mediated localization and delocalization of excitons in organic semiconductors: A quantum chemical study.

Photo-induced relaxation processes leading to excimer formations or other traps are in the focus of many investigations of optoelectronic materials because they severely affect the efficiencies of corresponding devices. Such relaxation effects comprise inter-monomer distortions in which the orientations of the monomer change with respect to each other, whereas intra-monomer distortions are variations in the geometry of single monomers. Such distortions are generally neglected in quantum chemical investigations of organic dye aggregates due to the accompanied high computational costs. In the present study, we investigate their relevance using perylene-bisimide dimers and diindenoperylene tetramers as model systems. Our calculations underline the importance of intra-monomer distortions on the shape of the potential energy surfaces as a function of the coupling between the monomers. The latter is shown to depend strongly on the electronic state under consideration. In particular, it differs between the first and second excited state of the aggregate. Additionally, the magnitude of the geometrical relaxation decreases if the exciton is delocalized over an increasing number of monomers. For the interpretation of the vibronic coupling model, pseudo-Jahn-Teller or Marcus theory can be employed. In the first part of this paper, we establish the accuracy of density functional theory-based approaches for the prediction of vibrationally resolved absorption spectra of organic semiconductors. These investigations underline the accuracy of those approaches although shortcomings become obvious as well. These calculations also indicate the strength of intra-monomer relaxation effects.

The feasibility of prostate-specific membrane antigen positron emission tomography(PSMA PET/CT)-guided radiotherapy in oligometastatic prostate cancer patients

Background. To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC (68Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively. Methods. A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients. Results. A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1-29.0 ng/mL). A median dose of 43.5 Gy (range 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range 2-17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8-83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p < 0.01). One patient experienced grade 2 acute gastrointestinal toxicity. Grade 3 or more toxicity events were not observed. Conclusions. By providing optimal LC, low toxicity and a promising PFS in CS patients, the current retrospective study illustrated that 68Ga PSMA PET-CT-guided RT may be an attractive treatment strategy in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited (AU)

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The ortho-benzyne cation is not planar.

A recent review on the photoionisation of the C6H4 isomer ortho-benzyne suggests that bands reported in earlier photoelectron spectra might be due to side products or contaminations, while computations raise doubts, whether the cation has a planar geometry. We therefore reinvestigate the photoionisation of ortho-benzyne, generated by pyrolysis from benzocyclobutenedione, by photoion mass-selected threshold photoelectron (ms-TPE) spectroscopy using synchrotron radiation. The experiments are accompanied by a theoretical study that investigates the structure of the ortho-benzyne cation systematically as a function of the computational method, up to CASPT2(11,14) ab initio computations. Our study leads to a re-evaluation of the ionisation energy of ortho-benzyne. It reveals that the ortho-benzyne cation has indeed a twisted C2 geometry rather than a C2v structure. A vertical ionisation energy IEvert of 9.77 eV and an adiabatic ionisation energy of IEad = 9.56 eV are computed for ortho-benzyne. A Franck-Condon simulation of the photoelectron spectrum based on the CASPT2 results and including three electronic states of the cation is in agreement with the experiment and yields IEad = 9.51 eV (+50 meV/-100 meV). Since this value is in contrast with previous work, the ionisation energy has to be revised based on our study. Computational methods based on density functional theory give a reasonable description of the cationic ground state, but fail for the corresponding excited electronic states that are indispensible for a proper assignment of the photoelectron spectrum.

The feasibility of prostate-specific membrane antigen positron emission tomography(PSMA PET/CT)-guided radiotherapy in oligometastatic prostate cancer patients.

BACKGROUND: To investigate the efficacy and toxicity of 68Ga-PSMA-HBED-CC (68Ga-PSMA) PET-CT-guided RT in the treatment of oligometastatic prostate cancer retrospectively. METHODS: A total of 23 prostate cancer patients with biochemical relapse, of which 13 were castration sensitive (CS) and 10 castration resistant (CR), were treated with intensity-modulated and image-guided RT (IMRT-IGRT) on ≤3 metastases detected by 68Ga PSMA PET-CT. Androgen deprivation therapy was continued in CR patients. RESULTS: A total of 38 metastases were treated. The involved sites were pelvic bone (n = 16), pelvic lymph nodes (n = 11), paraaortic lymph nodes (n = 6), ribs (n = 3) and vertebral body (n = 2). The median PSA prior to RT was 1.1 ng/mL (range 0.1-29.0 ng/mL). A median dose of 43.5 Gy (range 30-64 Gy) was delivered by IMRT-IGRT in 12-27 fractions. At a median follow-up of 7 months (range 2-17 months), 19 patients (83%) were in remission. Four patients (17%) developed distant recurrences. The actuarial 1-year LC, PFS and OS rates were 100, 51 (95% CI 8-83%) and 100%. Univariate analysis demonstrated a statistically significantly better PFS in CS patients as compared to CR patients (1-year PFS 67 vs. 0%, p < 0.01). One patient experienced grade 2 acute gastrointestinal toxicity. Grade 3 or more toxicity events were not observed. CONCLUSIONS: By providing optimal LC, low toxicity and a promising PFS in CS patients, the current retrospective study illustrated that 68Ga PSMA PET-CT-guided RT may be an attractive treatment strategy in patients with oligometastatic prostate cancer. Validation by randomized trials is eagerly awaited.

New Algorithms for Global Optimization and Reaction Path Determination.

We present new schemes to improve the convergence of an important global optimization problem and to determine reaction pathways (RPs) between identified minima. Those methods have been implemented into the CAST program (Conformational Analysis and Search Tool). The first part of this chapter shows how to improve convergence of the Monte Carlo with minimization (MCM, also known as Basin Hopping) method when applied to optimize water clusters or aqueous solvation shells using a simple model. Since the random movement on the potential energy surface (PES) is an integral part of MCM, we propose to employ a hydrogen bonding-based algorithm for its improvement. We show comparisons of the results obtained for random dihedral and for the proposed random, rigid-body water molecule movement, giving evidence that a specific adaption of the distortion process greatly improves the convergence of the method. The second part is about the determination of RPs in clusters between conformational arrangements and for reactions. Besides standard approaches like the nudged elastic band method, we want to focus on a new algorithm developed especially for global reaction path search called Pathopt. We started with argon clusters, a typical benchmark system, which possess a flat PES, then stepwise increase the magnitude and directionality of interactions. Therefore, we calculated pathways for a water cluster and characterize them by frequency calculations. Within our calculations, we were able to show that beneath local pathways also additional pathways can be found which possess additional features.

Anisotropy of singlet exciton diffusion in organic semiconductor crystals from ab initio approaches.

Due to its importance for the function of organic optoelectronic devices, accurate simulations of the singlet exciton diffusion are crucial to predict the performance of new materials. We present a protocol which allows for the efficient directional analysis of exciton transport with high-level ab initio methods. It is based on an alternative to the frequently employed rate equation since the latter was found to be erroneous in some cases. The new approach can be used in combination with the master equation which is considerably faster than the corresponding Monte Carlo approach. The long-range character of the singlet exciton coupling is taken into account by an extrapolation scheme. The approach is applied to singlet exciton diffusion in those substances where these quantities are experimentally best established: naphthalene and anthracene. The high quality of the crystals, furthermore, diminish uncertainties arising from the geometrical structures used in the computations. For those systems, our new approach provides exciton diffusion lengths L for naphthalene and anthracene crystals which show an excellent agreement with their experimental counterparts. For anthracene, for example, the computed L value in a direction is computed to 58 nm while the experimental value is 60 ± 10 nm.

Stereotactic radiotherapy for oligometastatic cancer: a prognostic model for survival.

BACKGROUND: Stereotactic radiotherapy (SRT) is a safe and locally effective treatment for patients with inoperable oligometastases. The challenge remains identifying subsets of patients that benefit in terms of overall survival (OS). PATIENTS AND METHODS: Between 2005 and 2011, 309 patients with ≤5 metastases were treated by stereotactic body radiotherapy (n=209) and/or by intracranial single or fractionated stereotactic radiotherapy (n=107). We analyzed OS and carried out a risk factor analysis. RESULTS: The median survival of all patients was 24 months. The 3-, 4- and 5-year OS rates were 32%, 25% and 19%, respectively. The following four risk factors were independently associated with impaired OS: nonadenocarcinoma histology (P<0.01), intracranial metastases (P<0.01), synchronous oligometastatic disease (P<0.01) and male gender (P=0.02). Patients with 0, 1 and 2 risk factors displayed a median survival (95% CI) of 40 (24-63), 29 (23-35) and 23 (16-29) months, respectively, and are defined as patients with good prognosis. Patients with 3 and 4 risk factors had a median survival of 9 (6-11) and 4 (1-7) months only and are defined as bad prognostic patients. CONCLUSIONS: We identified subsets of oligometastatic cancer patients with good prognosis after SRT. These patients are candidates for inclusion in prospective randomized trials for defining the role of SRT in the management of oligometastases.

Design of T-cell receptor libraries with diverse binding properties to examine adoptive T-cell responses.

Adoptive T-cell therapies have shown significant promise in the treatment of cancer and viral diseases. One approach, which introduces antigen-specific T-cell receptors (TCRs) into ex vivo activated T cells, is designed to overcome central tolerance mechanisms that prevent responses by endogenous T-cell repertoires. Studies have suggested that use of higher-affinity TCRs against class I major histocompatibility complex antigens could drive the activity of both CD4(+) and CD8(+) T cells, but the rules that govern the TCR binding optimal for in vivo activity are unknown. Here, we describe a high-throughput platform of 'reverse biochemistry' whereby a library of TCRs with a wide range of binding properties to the same antigen is introduced into T cells and adoptively transferred into mice with antigen-positive tumors. Extraction of RNA from tumor-infiltrating lymphocytes (TILs) or lymphoid organs allowed high-throughput sequencing to determine which TCRs were selected in vivo. The results showed that CD8(+) T cells expressing the highest-affinity TCR variants were deleted in both the TIL population and in peripheral lymphoid tissues. In contrast, these same high-affinity TCR variants were preferentially expressed within CD4(+) T cells in the tumor, suggesting they had a role in antigen-specific tumor control. The findings thus revealed that the affinity of the transduced TCRs controlled the survival and tumor infiltration of the transferred T cells. Accordingly, the TCR library strategy enables rapid assessment of TCR-binding properties that promote peripheral T-cell survival and tumor elimination.

Single-chain VαVß T-cell receptors function without mispairing with endogenous TCR chains.

Transduction of exogenous T-cell receptor (TCR) genes into patients' activated peripheral blood T cells is a potent strategy to generate large numbers of specific T cells for adoptive therapy of cancer and viral diseases. However, the remarkable clinical promise of this powerful approach is still being overshadowed by a serious potential consequence: mispairing of the exogenous TCR chains with endogenous TCR chains. These 'mixed' heterodimers can generate new specificities that result in graft-versus-host reactions. Engineering TCR constant regions of the exogenous chains with a cysteine promotes proper pairing and reduces the mispairing, but, as we show here, does not eliminate the formation of mixed heterodimers. By contrast, deletion of the constant regions, through use of a stabilized Vα/Vß single-chain TCR (scTv), avoided mispairing completely. By linking a high-affinity scTv to intracellular signaling domains, such as Lck and CD28, the scTv was capable of activating functional T-cell responses in the absence of either the CD3 subunits or the co-receptors, and circumvented mispairing with endogenous TCRs. Such transduced T cells can respond to the targeted antigen independent of CD3 subunits via the introduced scTv, without the transduced T cells acquiring any new undefined and potentially dangerous specificities.

Phase II study of helical tomotherapy for oligometastatic colorectal cancer.

BACKGROUND: To evaluate the efficacy and toxicity of helical tomotherapy in the treatment of oligometastatic colorectal cancer (CRC) patients who were not amenable for metastasectomy and/or (further) systemic treatment. PATIENTS AND METHODS: CRC patients with five or less metastases were enrolled. No limitations concerning dimension or localization of the metastases were imposed. Patients were treated with intensity-modulated and image-guided radiotherapy using helical tomotherapy, delivering a total dose of 40 Gy in fractions of 4 Gy. Positron emission tomography-computed tomography (PET-CT) was carried out at baseline and 3 months after the initiation of radiotherapy to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST) version 1.0. Side-effects were scored using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTC AE) version 3.0. RESULTS: Twenty-three patients were enrolled. A total of 52 metastases were treated. One patient (4%) experienced grade 3 vomiting; two patients (9%) grade 2 diarrhea and dysphagia, respectively. Twenty-two patients were evaluated by post-treatment PET-CT. Five (23%) and seven patients (32%) achieved a complete and partial metabolic response, respectively, resulting in an overall metabolic response rate of 55%. The actuarial 1-year local control, progression-free survival, and overall survival were 54%, 25% and 86%, respectively. CONCLUSION: The use of helical tomotherapy in oligometastatic CRC patients resulted in a promising metabolic response rate of 55%.

Analgesics, sedatives and neuromuscular blockers as part of end-of-life decisions in Dutch NICUs.

BACKGROUND: Clinicians frequently administer analgesics and sedatives at the time of withholding or withdrawal of life-sustaining treatment in newborns. This practice might be regarded as intentionally hastening of death. OBJECTIVE: To describe type, doses and reasons for administering medications as part of end-of-life decisions in the Dutch neonatal intensive care units. DESIGN AND SETTING: We reviewed the medical files of 340 newborn deaths with a preceding end-of-life decision over a 12-month period to describe the use of analgesics, sedatives and/or neuromuscular blockers. The neonatologists of 147 of the 150 newborns with a preceding end-of-life decision based on the infant's poor prognosis were interviewed to obtain additional details about the use of medication. RESULTS: Analgesics and sedatives were administered to 224 of 340 newborns before the end-of-life decision and to 292 newborns after the decision. The medication was increased in 94 of 289 newborns whose death was imminent and in 110 of 150 newborns with a poor prognosis. Reasons for the increase were treatment of pain and suffering, and in 4% of cases hastening of death. Reasons were undocumented in 55% of deaths. Neuromuscular blockers were administered in 16% of patients because they already received these agents or to stop or prevent gasping. CONCLUSIONS: Analgesics and sedatives are generally increased after the end-of-life decision to treat pain and suffering and rarely to hasten death. Neuromuscular blockers were administered in 16% of deaths. Medical files provide insufficient documentation of considerations leading to the increase of medication, which hinders (external) review.

Principles and effects of microRNA-mediated post-transcriptional gene regulation.

MicroRNAs (miRNAs) are abundant regulatory RNAs involved in the regulation of many key biological processes. Recent advances in understanding the mechanism of RNA interference and miRNA-mediated mechanisms shed light on major principals of the formation of the regulatory complex and provide models to explain how these small regulatory RNA species interfere with gene expression and how they influence the translational status of the transcriptome.

S=N versus S+-N-: an experimental and theoretical charge density study.

To elucidate the bonding situation in the widely discussed hypervalent sulfur nitrogen species, the charge density distributions rho(r) and related properties of four representative compounds, methyl(diimido)sulfinic acid H(NtBu)(2)SMe (1), methylene-bis(triimido)sulfonic acid H(2)C[S(NtBu)(2) (NHtBu)](2) (2), sulfurdiimide S(NtBu)(2) (3), and sulfurtriimide S(NtBu)(3) (4), were determined experimentally by high-resolution low-temperature X-ray diffraction experiments (T = 100 K). This set of molecules represents an ideal frame of reference for the comparison of SN bonding modes, because they contain short formal S=N double bonds as well as long S-N single bonds, some of them influenced by inter- or intramolecular hydrogen bonds. For comparison, the gas-phase ab initio calculations of the four model compounds, H(NMe)(2)SMe, H(2)C[S(NMe)(2)(NHMe)](2), S(NMe)(2), and S(NMe)(3), were performed. The topological features were found to be not particularly sensitive with respect to different substituents R (R = H, Me, tBu). In this paper, it is documented that theory and experiment differ in the eigenvalues of the Hessian matrix because of systematically differing positions of the bond critical points but agree very well concerning the spatial Laplacian distribution and the distinct polarization of all investigated sulfur-nitrogen bonds. Both recommend the S(+)-N(-) formulation of sulfur nitrogen bonds in 1 and 2 since all nitrogen atoms are found to be sp(3) hybridized. The planar SNx (x = 2, 3) units in the diimide 3 and the triimide 4 reveal characteristics of m-center-n-electron systems. For none of the investigated S-N bonds, a classical double bond formulation can be supported. This is further substantiated by the NBO/NRT approach. Valence expansion to more than eight electrons at the sulfur atom can definitely be excluded to explain the bonding.

Metal partitioning in a sulfidic canal sediment: metal solubility as a function of pH combined with EDTA extraction in anoxic conditions.

The chemical forms of low concentrations of metals (Zn, Pb, Cu, Cd, Co and Mn) and main components (Fe and Ca) were determined under the original reducing conditions of a sulfide-rich sediment from the Gent-Terneuzen Canal (Belgium). Therefore, dissolution experiments as a function of pH were made in a salt solution mimicking the canal water. The centrifugates remaining after the dissolution vs. pH experiments were subsequently further extracted with 0.1 M EDTA/0.5 M NaAc (pH 4.65) to determine eventually readsorbed and/or reprecipitated metal ions. The experimental dissolution vs. pH edge of calcium, iron, manganese and cobalt had a lower slope than theoretically expected on the basis of the solubility of, respectively, calcium carbonate, iron sulfide/iron carbonate, manganese sulfide/manganese carbonate and cobalt sulfide and was explained by the combination of (a) the solubilities of the various minerals and (b) metal readsorption onto clay minerals and organic matter. Higher metal recoveries were measured in the 0.1 M EDTA/0.5 M NaAc mixture and proved that in addition coprecipitate formation with iron sulfide/iron carbonate minerals may occur. The solubility of zinc, lead, cadmium and copper was very low in the mimicking salt solution even at very low pH values (up to pH 1) in agreement with the theoretical solubility of their discrete metal sulfides. However, by using an additional 0.1 M EDTA/0.5 M NaAc extraction on the centrifugates remaining after the dissolution vs. pH experiments, it was qualitatively shown that zinc and lead were partly associated with iron sulfide/iron carbonate phases in the real sediment (in addition to their presence in discrete metal sulfides). Cadmium was present solely in discrete cadmium sulfide phases. It was not possible to verify whether copper was present in discrete copper sulfide phases and/or in mixed coprecipitates with iron sulfide/iron carbonate minerals.

UBM-guided chamber angle surgery for glaucoma management: an experimental study.

PURPOSE: The aim of this experimental study was to investigate the potential of ultrasound bimicroscopy (UBM)-guided chamber angle surgery as an alternative or supplement to gonioscopy and intraocular microendoscopy for intraoperative control. METHODS: In 15 porcine cadaver eyes, mechanical goniopuncture or punctual Er:YAG laser trabecular ablation was performed without operating microscope or gonioscopy, but with real-life ultrasound biomicroscopy monitoring with a 50 MHz transducer. Intraoperative localization of the microsurgical instruments and tissue-instrument contact were qualitatively evaluated. RESULTS: The instruments could be clearly visualized within the chamber angle and disturbing artefacts were only minimal when using mechanically fixed instruments in slow motion. Topographic localization, tissue contact, and penetration depth of the instruments entering the scleral were well illustrated as far as the technical resolution limits of UBM would allow. CONCLUSIONS: UBM can be used intraoperatively to monitor the correct manoeuvring of microsurgical instruments in selected ab interno procedures. Some adaptations and further modifications of the technique presented here will be necessary before UBM-guided surgery can be considered for clinical use in humans.

Ultrasound biomicroscopy and its value in predicting the long term outcome of viscocanalostomy.

AIMS: To examine whether the early postoperative morphology at the site of sclerectomy, as visualised by ultrasound biomicroscopy (UBM), is an indicator of the mechanisms that lower intraocular pressure (IOP) and/or predictors of the long term outcome of viscocanalostomy. METHODS: 15 eyes of 14 patients with medically uncontrolled open angle glaucoma and no history of surgery underwent viscocanalostomy according to Stegmann's technique. Ultrasound biomicroscopy was performed during the first month after surgery. The following parameters were assessed: dimensions of the intrascleral "lake," presence of a filtering bleb, presence of a subconjunctival cavity or a suprachoroidal hypoechoic area, and the thickness of the residual trabeculocorneal membrane. A complete ophthalmological examination was performed the day before and the day after surgery. Follow up visits were scheduled 1 week, 4 weeks, 6 months, and 12 months after surgery. RESULTS: At 1 year successful control of IOP (<20 mm Hg) was achieved without further manipulation or medication in six of 15 eyes. The size of the intrascleral "lake" (average 0.62 mm(3)) did not correlate with later IOP; however, a visible route under the scleral flap and accidental perforation of the trabeculocorneal membrane were associated with long term lowering of IOP. Normal thickness of the trabeculocorneal membrane (0.10-0.15 mm) was indicative of IOP control with and without medication. When UBM showed an early collapse of the intrascleral cavity, control of IOP was not achieved. Other UBM findings did not predict long term function. CONCLUSION: In accordance with previous studies, the authors found that UBM examination is a useful method to evaluate outflow mechanisms after glaucoma surgery. This study shows that UBM imaging of external filtration during the early postoperative period can be used to predict the success of viscocanalostomy. However, to establish conclusively what parameters of UBM predict successful viscocanalostomy a larger number of patients must be studied.

Multiple transcripts generated by the DCAMKL gene are expressed in the rat hippocampus.

We have recently cloned a novel Doublecortin CaMK-like kinase (rDCAMKL) cDNA, and a related cDNA called CaMK-related peptide (CARP) from the rat hippocampus. These genes are structurally highly similar to the human DCAMKL-1 gene and doublecortin, a gene associated with X-linked lissencephaly and subcortical band heterotopia. Here we report on the genomic organization of the murine DCAMKL gene and its products. Our results show that DCAMKL and CARP are alternative splice products of the same gene. The DCAMKL gene also generates three alternatively-spliced rDCAMKL transcripts of which we have cloned the corresponding cDNAs and which potentially generate different DCAMKL proteins. In situ hybridization experiments show that the different rDCAMKL transcripts are all expressed in the adult rat hippocampus. We conclude that alternative splicing of the DCAMKL gene may generate different but similar proteins in the adult rat hippocampus thereby regulating different but overlapping aspects of DCAMKL controlled neuronal plasticity.

The suitability of the ultrasound biomicroscope for establishing texture in giant cell arteritis.

AIM: To establish whether ultrasound biomicroscope (UBM) is a helpful tool in locating the arterial segment responsible in patients with segmental attacks in giant cell arteritis METHODS: The superficial temporal arteries of 19 patients with suspected giant cell arteritis were examined with the UBM before biopsy. RESULTS: 20 specimens provided the histological proof of giant cell arteritis in five patients. Side differences, a dark perivascular halo, and high reflexivity of the intra-arterial space were found. CONCLUSION: it is assumed that there are two types of arteritic inflammation: (1) the occlusion of intra-arterial space due to intimal fibrosis (UBM: high reflexive "filling"), and (2) inflammation of the perivascular zone with oedematous thickening and infiltration of the media (UBM: dark halo) and its combination. UBM is helpful in obtaining an indication of the side and segment for biopsy.

An experimental and computational study on the reactivity and regioselectivity for the nitrosoarene ene reaction: comparison with triazolinedione and singlet oxygen.

The regioselectivities and the reactivities (relative rates) for the ene reaction of the enophile 4-nitronitrosobenzene (ArNO) with an extensive set of regiochemically defined acyclic and cyclic olefins have been determined. These experimental data establish that the ArNO enophile attacks the olefinic substrate along the novel skew trajectory, with preferred hydrogen abstraction at the corner (twix regioselectivity). This is in contrast to the isoelectronic species singlet oxygen ((1)O(2)), which abstracts at the higher substituted side of the double-bond (cis effect), and triazolindione (TAD), which undergoes the ene reaction at the more crowded end (gem effect). Ab initio computations (B3LYP/6-31+g) for the ene reaction of the ArNO with 2-methyl-2-butene reveal that the steric effects between the aryl group of the enophile and the substituents of the olefin dictate the skew trajectory. These computations identify the aziridine N-oxide (AI) as a bona fide intermediate in this ene reaction, whose formation is usually rate-determining and, thus, irreversible along the skew trajectory (twix selectivity). The reversible generation of the AI becomes feasible when conformational constraints outweigh steric effects, as manifested by enhanced twin regioselectivity.