Regulating Access to Active Sites via Hydrogen Bonding and Cation-Dipole Interactions: A Dual Cofactor Approach to Switchable Catalysis.

Hydrogen bonding networks are ubiquitous in biological systems and play a key role in controlling the conformational dynamics and allosteric interactions of enzymes. Yet in small organometallic catalysts, hydrogen bonding rarely controls ligand binding to the metal center. In this work, a hydrogen bonding network within a well-defined organometallic catalyst works in concert with cation-dipole interactions to gate substrate access to the active site. An ammine ligand acts as one cofactor, templating a hydrogen bonding network within a pendent crown ether and preventing the binding of strong donor ligands, such as nitriles, to the nickel center. Sodium ions are the second cofactor, disrupting hydrogen bonding to enable switchable ligand substitution reactions. Thermodynamic analyses provide insight into the energetic requirements of the different supramolecular interactions that enable substrate gating. The dual cofactor approach enables switchable catalytic hydroamination of crotononitrile. Systematic comparisons of catalysts with varying structural features provide support for the critical role of the dual cofactors in achieving on/off catalysis with substrates containing strongly donating functional groups that might otherwise interfere with switchable catalysts.

Catalyst self-assembly accelerates bimetallic light-driven electrocatalytic H2 evolution in water.

Hydrogen evolution is an important fuel-generating reaction that has been subject to mechanistic debate about the roles of monometallic and bimetallic pathways. The molecular iridium catalysts in this study undergo photoelectrochemical dihydrogen (H2) evolution via a bimolecular mechanism, providing an opportunity to understand the factors that promote bimetallic H-H coupling. Covalently tethered diiridium catalysts evolve H2 from neutral water faster than monometallic catalysts, even at lower overpotential. The unexpected origin of this improvement is non-covalent supramolecular self-assembly into nanoscale aggregates that efficiently harvest light and form H-H bonds. Monometallic catalysts containing long-chain alkane substituents leverage the self-assembly to evolve H2 from neutral water at low overpotential and with rates close to the expected maximum for this light-driven water splitting reaction. Design parameters for holding multiple catalytic sites in close proximity and tuning catalyst microenvironments emerge from this work.

Fever, Rash, and Shortness of Breath in a 69-Year-Old.

A 69-year-old had fever, fatigue, rash, right periorbital swelling, and shortness of breath. Chest computed tomography revealed numerous small, bilateral pulmonary nodules; laboratory testing revealed mean corpuscular volume, 96.1 fL; hemoglobin level, 12.4 mg/dL; and leukopenia. What is the diagnosis and what would you do next?

On the genetic basis of tail-loss evolution in humans and apes.

The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'1-3, with a proposed role in contributing to human bipedalism4-6. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene7-9-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans10. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.

Establishing and maintaining Hox profiles during spinal cord development.

The chromosomally-arrayed Hox gene family plays central roles in embryonic patterning and the specification of cell identities throughout the animal kingdom. In vertebrates, the relatively large number of Hox genes and pervasive expression throughout the body has hindered understanding of their biological roles during differentiation. Studies on the subtype diversification of spinal motor neurons (MNs) have provided a tractable system to explore the function of Hox genes during differentiation, and have provided an entry point to explore how neuronal fate determinants contribute to motor circuit assembly. Recent work, using both in vitro and in vivo models of MN subtype differentiation, have revealed how patterning morphogens and regulation of chromatin structure determine cell-type specific programs of gene expression. These studies have not only shed light on basic mechanisms of rostrocaudal patterning in vertebrates, but also have illuminated mechanistic principles of gene regulation that likely operate in the development and maintenance of terminal fates in other systems.

Nickel-catalyzed ester carbonylation promoted by imidazole-derived carbenes and salts.

Millions of tons of acetyl derivatives such as acetic acid and acetic anhydride are produced each year. These building blocks of chemical industry are elaborated into esters, amides, and eventually polymer materials, pharmaceuticals, and other consumer products. Most acetyls are produced industrially using homogeneous precious metal catalysts, principally rhodium and iridium complexes. We report here that abundant nickel can be paired with imidazole-derived carbenes or the corresponding salts to catalyze methyl ester carbonylation with turnover frequency (TOF) exceeding 150 hour-1 and turnover number (TON) exceeding 1600, benchmarks that invite comparisons to state-of-the-art rhodium-based systems and considerably surpass known triphenylphosphine-based nickel catalysts, which operate with TOF ~7 hour-1 and TON ~100 under the same conditions.

Synthesis and bonding analysis of pentagonal bipyramidal rhenium carboxamide oxo complexes.

Seven-coordinate rhenium oxo complexes supported by a tetradentate bipyridine carboxamide/carboxamidate ligand are reported. The neutral dicarboxamide H2Phbpy-da ligand initially coordinates in an L4 (ONNO) fashion to an octahedral rhenium oxo precursor, yielding a seven-coordinate rhenium oxo complex. Subsequent deprotonation generates a new oxo complex featuring the dianionic (L2X2) carboxamidate (NNNN) form of the ligand. Computational studies provide insight into the relative stability of possible linkage isomers upon deprotonation. Structural studies and molecular orbital theory are employed to rationalize the relative isomer stability and provide insight into the rhenium-oxo bond order.

Ultrafast X-Ray Scattering Reveals Composite Amplitude Collective Mode in the Weyl Charge Density Wave Material (TaSe_{4})_{2}I.

We report ultrafast x-ray scattering experiments of the quasi-1D charge density wave (CDW) material (TaSe_{4})_{2}I following ultrafast infrared photoexcitation. From the time-dependent diffraction signal at the CDW sidebands we identify a 0.11 THz amplitude mode derived primarily from a transverse acoustic mode of the high-symmetry structure. From our measurements we determine that this mode interacts with the valence charge indirectly through another collective mode, and that the CDW system in (TaSe_{4})_{2}I has a composite nature supporting multiple dynamically active structural degrees of freedom.

Making ends meet - relating a self-reported indicator of financial hardship to health status.

BACKGROUND: Area-based index of multiple deprivation (IMD) indicators of financial hardship lack individual specificity and sensitivity. This study compared self-reports of hardship with area measures in relation to health status. METHODS: Interviews in one London Borough, reported financial hardship and health status. Associations of health status with most and least deprived quintiles of the IMD 2015 were compared with self-reported hardship; always or sometimes 'having difficulty making ends meet at the end of the month' in relation to never. RESULTS: 1024 interviews reported hardship status in 1001 (98%). 392 people (39%) reported they 'always' or 'sometimes' had hardship. In multivariate analysis, self-reported hardship was more strongly associated with smoking; odds ratio = 5.4 (95% CI: 2.8-10.4) compared with IMD, odds ratio = 1.9 (95% CI: 1.2-3.2). Health impairment was also more likely with self-reported hardship, odds ratio = 11.1 (95% CI: 4.9-25.4) compared with IMD; odds ratio = 2.7 (95% CI: 1.4-5.3). Depression was similarly related; odds ratio = 2.4 (95% CI: 1.0-5.6) and 2.7 (95% CI: 1.2-6.6), respectively. CONCLUSIONS: Self-reported hardship was more strongly related to health status than area-based indicators. Validity and implementation in routine health care settings remains to be established.

Closure of a distal splenorenal shunt as a therapy for refractory hyperammonaemia in setting of neuropsychiatric symptoms.

Before the widespread use of the transjugular intrahepatic portosystemic shunt, portal hypertension was addressed by the creation of an operative distal splenorenal shunt (DSRS). DSRS was largely regarded as a safe and effective therapy, though it did have a risk of precipitating hyperammonaemia and hepatic encephalopathy.A woman suffered a gunshot wound to the abdomen. This trauma led to portal vein thrombosis, cavernous transformation of the vein and eventually bleeding oesophageal varices from portal hypertension. A DSRS was created to decrease portal hypertension. Years later, she had profound depression with psychomotor slowing in the setting of hyperammonaemia. To reduce hepatic encephalopathy as a contributor to her neuropsychiatric condition, her shunt was closed. The hyperammonaemia resolved and neuropsychiatric symptoms improved.This case highlights several interesting clinical features, including portal hypertension due to chronic portal vein occlusion, cavernous transformation, a surgical DSRS causing hyperammonaemia and hepatic encephalopathy manifesting as neuropsychiatric symptoms.

Recruitment of grid-like responses in human entorhinal and piriform cortices by odor landmark-based navigation.

Olfactory navigation is universal across the animal kingdom. Humans, however, have rarely been considered in this context. Here, we combined olfactometry techniques, virtual reality (VR) software, and neuroimaging methods to investigate whether humans can navigate an olfactory landscape by learning the spatial relationships among discrete odor cues and integrating this knowledge into a spatial map. Our data show that over time, participants improved their performance on the odor navigation task by taking more direct paths toward targets and completing more trials within a given time period. This suggests that humans can successfully navigate a complex odorous environment, reinforcing the notion of human olfactory navigation. fMRI data collected during the olfactory navigation task revealed the emergence of grid-like responses in entorhinal and piriform cortices that were attuned to the same grid orientation. This result implies the existence of a specialized olfactory grid network tasked with guiding spatial navigation based on odor landmarks.

Semi-Empirical Satellite-to-Ground Quantum Key Distribution Model for Realistic Receivers.

Satellite-based link analysis is valuable for efficient and secure quantum communication, despite seasonal limits and restrictions on transmission times. A semi-empirical quantum key distribution model for satellite-based systems was proposed that simplifies simulations of communication links. Unlike other theoretical models, our approach was based on the experimentally-determined atmospheric extinction coefficient typical for mid-latitude ground stations. The parameter was measured for both clear and foggy conditions, and it was validated using published experimental data from the Micius satellite. Using this model, we simulated secure QKD between the Micius satellite and ground stations with 300 mm and 600 mm aperture telescopes.

Non-randomized evaluation of hospitalization after a prescription for nirmatrelvir/ritonavir versus molnupiravir in high-risk COVID-19 outpatients.

OBJECTIVES: To assess and compare subsequent hospital admissions within 30 days for patients after receiving a prescription for either oral nirmatrelvir/ritonavir or oral molnupiravir. METHODS: We conducted a retrospective review of 3207 high-risk, non-hospitalized adult COVID-19 patients who received a prescription for molnupiravir (n = 209) or nirmatrelvir/ritonavir (n = 2998) at an academic medical centre in New York City from April to December 2022. Variables including age, vaccination status, high-risk conditions and demographic factors were pulled from the electronic medical record. We used multivariable logistic regression to adjust for potential confounding variables. RESULTS: All-cause 30 day hospitalization was not significantly different between patients who received nirmatrelvir/ritonavir compared with molnupiravir (1.4% versus 1.9%, P value = 0.55). The association between COVID-related hospitalization and medication was also not significant (0.7%versus 0.5%, P value = 0.99). Patients who received molnupiravir were more likely to have more underlying high-risk conditions. After adjusting for potential confounders, the odds of all-cause hospitalizations were not significantly different between patients who received nirmatrelvir/ritonavir compared with molnupiravir (OR = 1.16, 95% CI: 0.4-3.3, P value = 0.79). CONCLUSIONS: These data provide additional evidence to support molnupiravir as a suitable alternative when other COVID-19 antivirals cannot be given.

Catalytic reduction of dinitrogen to ammonia using molybdenum porphyrin complexes.

Porphyrin complexes are well-known in O2 and CO2 reduction, but their application to N2 reduction is less developed. Here, we show that oxo and nitrido complexes of molybdenum supported by tetramesitylporphyrin (TMP) are effective precatalysts for catalytic N2 reduction to ammonia, verified by 15N2 labeling studies and other control experiments. Spectroscopic and electrochemical studies illuminate some relevant thermodynamic parameters, including the N-H bond dissociation free energy of (TMP)MoNH (43 ± 2 kcal mol-1). We place these results in the context of other work on homogeneous N2 reduction catalysis.

Using wearable technology to prevent pressure injuries: An integrative review.

BACKGROUND: Hospital-acquired pressure injuries (HAPIs) are a significant problem for hospitals worldwide, negatively affecting patients and organizations by decreasing quality of life and increasing organizational cost of care and workload. A common pressure injury prevention intervention is frequent turning, though compliance can be low. As a newer technology, wearable sensors have emerged as an intervention to increase turn compliance. AIMS: The aim of this integrative review was to determine the clinical outcomes of using wearable sensors as a HAPI prevention intervention. METHODS: This integrative review was appraised by two independent reviewers using the Johns Hopkins Nursing Evidence-Based Practice Research Appraisal Tool. RESULTS: Eleven articles were included. The use of wearable sensors increases compliance with frequent turn protocols while decreasing HAPIs and reducing organizational costs. Despite this, the use of such technology was not found to increase the quality of turns. Although staff who used this technology reported positive feedback, technological training is needed to ensure proper use of the sensors. LINKING ACTION TO PRACTICE: This innovation has the potential to transform how nursing staff prevent pressure injuries, but more research is needed to definitively state whether wearable sensors will be efficacious as a pressure injury prevention intervention.

Tunable and Switchable Catalysis Enabled by Cation-Controlled Gating with Crown Ether Ligands.

ConspectusCatalysis has become an essential tool in science and technology, impacting the discovery of pharmaceuticals, the manufacture of commodity chemicals and plastics, the production of fuels, and much more. In most cases, a particular catalyst is optimized to mediate a particular reaction, continually producing a desired product at a given rate. There is enormous opportunity in developing catalysts that are dynamic, capable of responding to a change in the environment to alter structure and function. Controlled catalysis, in which the activity or selectivity of a catalytic reaction can be adjusted through an external stimulus, offers opportunities for innovation in catalysis. Catalyst discovery could be simplified if a single thoughtfully designed complex could work synergistically with additives to optimize performance rather than trying a multitude of different metal/ligand combinations. Temporal control could be gained to facilitate the execution of multiple reactions in the same flask, for example, by activating one catalyst and deactivating another to avoid incompatibilities. Selectivity switching could enable copolymer synthesis with well-defined chemical and material properties. These applications might sound futuristic for synthetic catalysts, but in nature, such a degree of controlled catalysis is commonplace. For example, allosteric interactions and/or feedback loops modulate enzymatic activity to enable complex small-molecule synthesis and sequence-defined polymerization reactions in complex mixtures containing many catalytic sites. In many cases, regulation is achieved by "gating" substrate access to the active site. Fundamental advances in catalyst design are needed to better understand the factors that enable controlled catalysis in the arena of synthetic chemistry, particularly in achieving substrate gating outside of macromolecular environments. In this Account, the development of design principles for achieving cation-controlled catalysis is described. The guiding hypothesis was that gating substrate access to a catalyst site could be achieved by controlling the dynamics of a hemilabile ligand through secondary Lewis acid/base and/or cation-dipole interactions. To enforce such interactions, catalysts sitting at the interface of organometallic catalysis and supramolecular chemistry were designed. A macrocyclic crown ether was incorporated into a robust organometallic pincer ligand, and these "pincer-crown ether" ligands have been explored in catalysis. Complementary studies of controlled catalysis and detailed mechanistic analysis guided the development of iridium, nickel, and palladium pincer-crown ether catalysts capable of substrate gating. Toggling the gate between open and closed states leads to switchable catalysis, where cation addition/removal changes the turnover frequency or the product selectivity. Varying the degree of gating leads to tunable catalysis, where the activity can be tuned based on the identity and amount of salt added. Research has focused on reactions of alkenes, particularly isomerization reactions, which has in turn led to design principles for cation-controlled catalysts.

Lewis Structures and the Bonding Classification of End-on Bridging Dinitrogen Transition Metal Complexes.

The activation of dinitrogen by coordination to transition metal ions is a widely used and promising approach to the utilization of Earth's most abundant nitrogen source for chemical synthesis. End-on bridging N2 complexes (µ-η1:η1-N2) are key species in nitrogen fixation chemistry, but a lack of consensus on the seemingly simple task of assigning a Lewis structure for such complexes has prevented application of valence electron counting and other tools for understanding and predicting reactivity trends. The Lewis structures of bridging N2 complexes have traditionally been determined by comparing the experimentally observed NN distance to the bond lengths of free N2, diazene, and hydrazine. We introduce an alternative approach here and argue that the Lewis structure should be assigned based on the total π-bond order in the MNNM core (number of π-bonds), which derives from the character (bonding or antibonding) and occupancy of the delocalized π-symmetry molecular orbitals (π-MOs) in MNNM. To illustrate this approach, the complexes cis,cis-[(iPr4PONOP)MCl2]2(µ-N2) (M = W, Re, and Os) are examined in detail. Each complex is shown to have a different number of nitrogen-nitrogen and metal-nitrogen π-bonds, indicated as, respectively: W≡N-N≡W, Re═N═N═Re, and Os-N≡N-Os. It follows that each of these Lewis structures represents a distinct class of complexes (diazanyl, diazenyl, and dinitrogen, respectively), in which the µ-N2 ligand has a different electron donor number (total of 8e-, 6e-, or 4e-, respectively). We show how this classification can greatly aid in understanding and predicting the properties and reactivity patterns of µ-N2 complexes.

Oxidative Addition of a Phosphinite P-O Bond at Nickel.

Oxidative addition is an essential elementary reaction in organometallic chemistry and catalysis. While a diverse array of oxidative addition reactions has been reported to date, examples of P-O bond activation are surprisingly rare. Herein, we report the ligand-templated oxidative addition of a phosphinite P-O bond in the diphosphinito aniline compound HN(2-OPiPr2-3,5-tBu-C6H2)2 [H(P2ONO)] at Ni0 to form (PONO)Ni(HPiPr2) after proton rearrangement. Notably, the P-O cleavage occurs selectively over an amine N-H bond activation. Additionally, the ligand cannibalization is reversible, as addition of XPR2 (X = Cl, Br; R = iPr, Cy) to (PONO)Ni(HPiPr2) readily produces either symmetric or unsymmetric (P2ONO)NiX species and free HPiPr2. Finally, the mechanisms of both the initial P-O bond cleavage and its subsequent reconstruction are investigated to provide further insight into how to target P-O bond activation.

Optimization and Validation of a Virtual Reality Orientation and Mobility Test for Inherited Retinal Degenerations.

Purpose: To optimize a virtual reality (VR) orientation and mobility (O&M) test of functional vision in patients with inherited retinal degenerations (IRDs). Methods: We developed an O&M test using commercially available VR hardware and custom-generated software. Normally sighted subjects (n = 20, ages = 14-67 years) and patients with IRDs (n = 29, ages = 15-63 years) participated. Individuals followed a dim red arrow path to a "course exit," while trying to identify nine obstacles adjacent to, or directly in their path. Dark-adapted subjects completed 35 randomly selected VR courses at increasing luminances, twice per luminance step, binocularly, and uni-ocularly. Performance was graded automatically by the software. Patients with IRD completed a modified Visual Function Questionnaire (VFQ). Results: Normally sighted subjects identified approximately 50% of the obstacles at the dimmest course luminance. Except for two patients with IRD with poor vision, all patients were able to complete the test, although they required brighter (by >2 log units) luminances to identify 50% of the obstacles. In a single-luminance screening test in which normal subjects detected at least eight of nine objects, most patients with IRD underperformed; their performance related to disease severity, as measured by visual acuity, kinetic visual field extent, and VFQ scores. Test-retest differences in object detection were similar to the differences between the two eyes (±2 SD = ±2 objects). Conclusions: This VR-O&M test was able to distinguish subjects with IRDs from normal subjects reliably and reproducibly. Translational Relevance: This easily implemented, flexible, and objectively scored VR-O&M test promises to become a useful tool to assess the impact that IRDs and their treatments have on functional vision.

The feminine and the transgender sinthome: clinical and theoretical issues / Feminino e sintoma transgênero: questões clínicas e teóricas / Féminin et sinthome transgenre: enjeux cliniques et théoriques / Feminino y síntoma transgénero: cuestiones clínicas y teóricas

In some contemporary psychoanalytic theories, a thesis has emerged according to which gender transition can constitute a sinthome. But gender remains a much-discussed notion in Lacanian psychoanalysis, especially in France. This article contributes to the debate by questioning the notion of femininity since it seems to be an essential point in how gender studies and Lacanian sexuation theory diverge. First, we clarify the Lacanian notion of femininity and its conceptual link to the notion of sinthome. Then, we discuss the clinical case of a transgender woman for whom the question of femininity was central during her transition. Finally, we argue how gender transition might function as a sinthome and the limits to such an understanding.

Em algumas teorias psicanalíticas contemporâneas, surgiu a tese de que a transição de gênero pode constituir um sinthoma. Mas gênero continua sendo uma noção muito discutida na psicanálise lacaniana, especialmente na França. Este artigo contribui para o debate ao questionar a noção de feminilidade, pois parece ser um ponto essencial na divergência entre os estudos de gênero e a teoria lacaniana da sexuação. Primeiramente, esclarecemos a noção lacaniana de feminilidade e seu vínculo conceitual com a noção de sinthoma. Em seguida, discutimos o caso clínico de uma mulher transgênero para quem a questão da feminilidade foi central durante sua transição. Por fim, discutimos como a transição de gênero pode funcionar como um sinthoma e os limites para tal compreensão.

Dans certaines théories psychanalytiques contemporaines, une thèse a émergé selon laquelle la transition de genre peut constituer un sinthome. Mais le genre reste une notion très discutée dans la psychanalyse lacanienne, notamment en France. Cet article contribue au débat en interrogeant la notion de féminité puisqu'elle semble être un point sur lequel divergent les études de genre et la théorie lacanienne de la sexuation. Pour ce faire, nous clarifions la notion lacanienne de féminité et son lien conceptuel avec la notion de sinthome. Ensuite, nous étudions le cas clinique d'une femme transgenre pour qui la question de la féminité a été centrale lors de sa transition. Enfin, nous discutons de la manière dont la transition de genre peut fonctionner comme un sinthome et des limites de cette thèse.

En algunas teorías psicoanalíticas contemporáneas ha surgido la tesis de que la transición de género puede constituir un sinthome. Pero el género sigue siendo una noción muy discutida en el psicoanálisis lacaniano, especialmente en Francia. Este artículo contribuye al debate cuestionando la noción de feminidad ya que parece ser un punto esencial en la divergencia entre los estudios de género y la teoría lacaniana de la sexuación. Primero, aclaramos la noción lacaniana de feminidad y su vínculo conceptual con la noción de sinthome. Luego, discutimos el caso clínico de una mujer transgénero para quien la cuestión de la feminidad fue central durante su transición. Finalmente, argumentamos cómo la transición de género podría funcionar como un sinthome y los límites de tal comprensión.