A Neural Mechanism in the Human Orbitofrontal Cortex for Preferring High-Fat Foods Based on Oral Texture.

Although overconsumption of high-fat foods is a major driver of weight gain, the neural mechanisms that link the oral sensory properties of dietary fat to reward valuation and eating behavior remain unclear. Here we combine novel food-engineering approaches with functional neuroimaging to show that the human orbitofrontal cortex (OFC) translates oral sensations evoked by high-fat foods into subjective economic valuations that guide eating behavior. Male and female volunteers sampled and evaluated nutrient-controlled liquid foods that varied in fat and sugar ("milkshakes"). During oral food processing, OFC activity encoded a specific oral-sensory parameter that mediated the influence of the foods' fat content on reward value: the coefficient of sliding friction. Specifically, OFC responses to foods in the mouth reflected the smooth, oily texture (i.e., mouthfeel) produced by fatty liquids on oral surfaces. Distinct activity patterns in OFC encoded the economic values associated with particular foods, which reflected the subjective integration of sliding friction with other food properties (sugar, fat, viscosity). Critically, neural sensitivity of OFC to oral texture predicted individuals' fat preferences in a naturalistic eating test: individuals whose OFC was more sensitive to fat-related oral texture consumed more fat during ad libitum eating. Our findings suggest that reward systems of the human brain sense dietary fat from oral sliding friction, a mechanical food parameter that likely governs our daily eating experiences by mediating interactions between foods and oral surfaces. These findings identify a specific role for the human OFC in evaluating oral food textures to mediate preference for high-fat foods.SIGNIFICANCE STATEMENT Fat and sugar enhance the reward value of food by imparting a sweet taste and rich mouthfeel but also contribute to overeating and obesity. Here we used a novel food-engineering approach to realistically quantify the physical-mechanical properties of high-fat liquid foods on oral surfaces and used functional neuroimaging while volunteers sampled these foods and placed monetary bids to consume them. We found that a specific area of the brain's reward system, the orbitofrontal cortex, detects the smooth texture of fatty foods in the mouth and links these sensory inputs to economic valuations that guide eating behavior. These findings can inform the design of low-calorie fat-replacement foods that mimic the impact of dietary fat on oral surfaces and neural reward systems.

Preferences for nutrients and sensory food qualities identify biological sources of economic values in monkeys.

Value is a foundational concept in reinforcement learning and economic choice theory. In these frameworks, individuals choose by assigning values to objects and learn by updating values with experience. These theories have been instrumental for revealing influences of probability, risk, and delay on choices. However, they do not explain how values are shaped by intrinsic properties of the choice objects themselves. Here, we investigated how economic value derives from the biologically critical components of foods: their nutrients and sensory qualities. When monkeys chose nutrient-defined liquids, they consistently preferred fat and sugar to low-nutrient alternatives. Rather than maximizing energy indiscriminately, they seemed to assign subjective values to specific nutrients, flexibly trading them against offered reward amounts. Nutrient-value functions accurately modeled these preferences, predicted choices across contexts, and accounted for individual differences. The monkeys' preferences shifted their daily nutrient balance away from dietary reference points, contrary to ecological foraging models but resembling human suboptimal eating in free-choice situations. To identify the sensory basis of nutrient values, we developed engineering tools that measured food textures on biological surfaces, mimicking oral conditions. Subjective valuations of two key texture parameters-viscosity and sliding friction-explained the monkeys' fat preferences, suggesting a texture-sensing mechanism for nutrient values. Extended reinforcement learning and choice models identified candidate neuronal mechanisms for nutrient-sensitive decision-making. These findings indicate that nutrients and food textures constitute critical reward components that shape economic values. Our nutrient-choice paradigm represents a promising tool for studying food-reward mechanisms in primates to better understand human-like eating behavior and obesity.

Association of Collagen, Elastin, Glycosaminoglycans, and Macrophages With Tissue Ultimate Material Strength and Stretch in Human Thoracic Aortic Aneurysms: A Uniaxial Tension Study.

Fiber structures and pathological features, e.g., inflammation and glycosaminoglycan (GAG) deposition, are the primary determinants of aortic mechanical properties which are associated with the development of an aneurysm. This study is designed to quantify the association of tissue ultimate strength and extensibility with the structural percentage of different components, in particular, GAG, and local fiber orientation. Thoracic aortic aneurysm (TAA) tissues from eight patients were collected. Ninety-six tissue strips of thickened intima, media, and adventitia were prepared for uni-extension tests and histopathological examination. Area ratios of collagen, elastin, macrophage and GAG, and collagen fiber dispersion were quantified. Collagen, elastin, and GAG were layer-dependent and the inflammatory burden in all layers was low. The local GAG ratio was negatively associated with the collagen ratio (r2 = 0.173, p < 0.05), but positively with elastin (r2 = 0.037, p < 0.05). Higher GAG deposition resulted in larger local collagen fiber dispersion in the media and adventitia, but not in the intima. The ultimate stretch in both axial and circumferential directions was exclusively associated with elastin ratio (axial: r2 = 0.186, p = 0.04; circumferential: r2 = 0.175, p = 0.04). Multivariate analysis showed that collagen and GAG contents were both associated with ultimate strength in the circumferential direction, but not with the axial direction (collagen: slope = 27.3, GAG: slope = -18.4, r2 = 0.438, p = 0.002). GAG may play important roles in TAA material strength. Their deposition was found to be associated positively with the local collagen fiber dispersion and negatively with ultimate strength in the circumferential direction.

Surgical approach to pediatric mediastinal masses based on imaging characteristics.

BACKGROUND: Pediatric mediastinal masses may be resected using an open or video-assisted thoracoscopic surgery (VATS) approach. We sought to define the preoperative imaging findings predicting amenability to VATS. METHODS: This multicenter retrospective study of pediatric patients undergoing either VATS or open surgical mediastinal mass resection between 2008 and 2018 evaluated the preoperative imaging descriptors associated with VATS. Postoperative endpoints included length of stay (LOS), 30-day readmission, 90-day mortality and complication rates. RESULTS: Mediastinal mass resection was performed in 33 patients. Median tumor size was 6 cm, and 51.5% had anterior mediastinal tumors. The 23 (69.7%) patients who underwent VATS were significantly older (144 months vs 32, P = 0.01) and larger (33.6 kg vs 13.8 P = 0.03). Preoperative imaging characteristics in VATS included "well circumscribed", "smooth margins" and "cystic", while the open surgery group were "heterogeneous" and "coarse calcification". The open group had more germ cell tumors (60.0% vs 13.0%, P = 0.16) but no difference in malignancy. VATS patients had shorter LOS (2 days vs 6.5, P = 0.24). Readmission, complication and mortality rates were similar. CONCLUSIONS: Pediatric patients with apparent malignancy frequently underwent open resection compared with the thoracoscopic group, although final malignant pathology was similar. Equivalent outcomes and shorter LOS should favor a minimally invasive approach. LEVEL OF EVIDENCE: Level III.

Finite Element Model for Hydrocephalus and Idiopathic Intracranial Hypertension.

Hydrocephalus and idiopathic intracranial hypertension (IIH) are neuropathies associated with disturbed cerebrospinal fluid dynamics. Several finite element (FE) brain models were suggested to simulate the pathological changes in hydrocephalus, but with overly simplified assumptions regarding the properties of the brain parenchyma. This study proposes a two-dimensional FE brain model, capable of simulating both hydrocephalus and IIH by incorporating poro-hyperelasticity of the brain and detailed structural information (i.e., sulci).

Quantum mechanics/molecular mechanics studies on the mechanism of action of cofactor pyridoxal 5'-phosphate in ornithine 4,5-aminomutase.

A computational study was performed on the experimentally elusive cyclisation step in the cofactor pyridoxal 5'-phosphate (PLP)-dependent D-ornithine 4,5-aminomutase (OAM)-catalysed reaction. Calculations using both model systems and a combined quantum mechanics/molecular mechanics approach suggest that regulation of the cyclic radical intermediate is achieved through the synergy of the intrinsic catalytic power of cofactor PLP and the active site of the enzyme. The captodative effect of PLP is balanced by an enzyme active site that controls the deprotonation of both the pyridine nitrogen atom (N1) and the Schiff-base nitrogen atom (N2). Furthermore, electrostatic interactions between the terminal carboxylate and amino groups of the substrate and Arg297 and Glu81 impose substantial "strain" energy on the orientation of the cyclic intermediate to control its trajectory. In addition the "strain" energy, which appears to be sensitive to both the number of carbon atoms in the substrate/analogue and the position of the radical intermediates, may play a key role in controlling the transition of the enzyme from the closed to the open state. Our results provide new insights into several aspects of the radical mechanism in aminomutase catalysis and broaden our understanding of cofactor PLP-dependent reactions.

Biomechanical analysis of tendon turnover tenorrhaphy compared to direct repair and Pulvertaft weave.

The aim of the present study was to evaluate biomechanical properties of tendon turnover repair in comparison to direct repair and Pulvertaft weave. A total of 48 sheep flexor tendons were assigned to eight groups comprising single or double tendon turnover repair, tendon turnover segment (without tenorrhaphy), direct repair or Pulvertaft weave. Tensile strength, stiffness and failure mechanisms were evaluated with a 500 N load cell. Turnover repair showed no significant difference in tensile strength to direct repair. Failure in turnover repair occurred largely at the site of tenorrhaphy due to suture pull-through or suture rupture. the increase in cross-sectional area after turnover repair was similar to that after direct repair, but less than after Pulvertaft weave. Tendon turnover offers tensile strength similar to direct repair with no associated increase in bulk. It provides a biomechanically secure and quicker alternative to tendon grafting for reconstructing tendon defects, without secondary donor site morbidity.Level of evidence: V.

Finite Element Analysis for Degenerative Cervical Myelopathy: Scoping Review of the Current Findings and Design Approaches, Including Recommendations on the Choice of Material Properties.

BACKGROUND: Degenerative cervical myelopathy (DCM) is a slow-motion spinal cord injury caused via chronic mechanical loading by spinal degenerative changes. A range of different degenerative changes can occur. Finite element analysis (FEA) can predict the distribution of mechanical stress and strain on the spinal cord to help understand the implications of any mechanical loading. One of the critical assumptions for FEA is the behavior of each anatomical element under loading (ie, its material properties). OBJECTIVE: This scoping review aims to undertake a structured process to select the most appropriate material properties for use in DCM FEA. In doing so, it also provides an overview of existing modeling approaches in spinal cord disease and clinical insights into DCM. METHODS: We conducted a scoping review using qualitative synthesis. Observational studies that discussed the use of FEA models involving the spinal cord in either health or disease (including DCM) were eligible for inclusion in the review. We followed the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. The MEDLINE and Embase databases were searched to September 1, 2021. This was supplemented with citation searching to retrieve the literature used to define material properties. Duplicate title and abstract screening and data extraction were performed. The quality of evidence was appraised using the quality assessment tool we developed, adapted from the Newcastle-Ottawa Scale, and shortlisted with respect to DCM material properties, with a final recommendation provided. A qualitative synthesis of the literature is presented according to the Synthesis Without Meta-Analysis reporting guidelines. RESULTS: A total of 60 papers were included: 41 (68%) "FEA articles" and 19 (32%) "source articles." Most FEA articles (33/41, 80%) modeled the gray matter and white matter separately, with models typically based on tabulated data or, less frequently, a hyperelastic Ogden variant or linear elastic function. Of the 19 source articles, 14 (74%) were identified as describing the material properties of the spinal cord, of which 3 (21%) were considered most relevant to DCM. Of the 41 FEA articles, 15 (37%) focused on DCM, of which 9 (60%) focused on ossification of the posterior longitudinal ligament. Our aggregated results of DCM FEA indicate that spinal cord loading is influenced by the pattern of degenerative changes, with decompression alone (eg, laminectomy) sufficient to address this as opposed to decompression combined with other procedures (eg, laminectomy and fusion). CONCLUSIONS: FEA is a promising technique for exploring the pathobiology of DCM and informing clinical care. This review describes a structured approach to help future investigators deploy FEA for DCM. However, there are limitations to these recommendations and wider uncertainties. It is likely that these will need to be overcome to support the clinical translation of FEA to DCM.

Sound and Noise Sources in Sonotubometry: An Investigation of Eustachian Tube Assessment.

This research aims to enhance the understanding of the acoustic processes occurring during sonotubometry, a method used to assess the Eustachian tube (ET) function. Recent advancements in digital signal processing enable a more comprehensive data analysis. In this project, a silicone model of the ET was developed to systematically study the existing noise and sound sources. These measurements were then compared with recordings from human subjects. Three distinct 'noise sources' were identified, which can influence the assessment of the ET opening using transmission measurements of the imposed signal: sound leakage from the speaker, a clicking noise at the initiation of ET opening, and rumbling/swallowing noise. Through spectral analysis, it was also possible to ascertain the spectral and temporal occurrence of these sound and noise types. The silicone model exhibited remarkable similarity to the healthy human ET, making it a robust experimental model for investigating the acoustics of sonotubometry. The findings underscore the significance of delving deeper into the analysed sound, as the noise occurring during sonotubometry can be easily misconstrued as an actual ET opening. Particularly, careful consideration is warranted when evaluating data involving clicking and swallowing noise.

Brief training in ultrasound equips novice clinicians to accurately and reliably measure jugular venous pressure in obese patients.

Introduction/Purpose: Measurement of jugular venous pressure (JVP) by novice clinicians can be unreliable, particularly when evaluating obese patients. Measurement of JVP using ultrasound (uJVP) is simple to perform and provides accurate measurements. This study evaluated whether students and residents inexperienced with ultrasound could rapidly be taught to measure JVP using ultrasound in obese patients with the same accuracy as cardiologists measuring JVP via physical examination. Additionally, this study also evaluated the correlation between qualitative and quantitative JVP assessment. Methods: This prospective, blinded study compared uJVP measurements performed by novice clinicians after brief training to JVP measurements performed by cardiologists (cJVP) on physical examination. Association between uJVP and cJVP was assessed using linear correlation, agreement and bias were assessed using the Bland-Altman analysis and inter-rater reliability of uJVP was assessed using intraclass correlation coefficient (ICC). The association between qualitative and quantitative JVP assessment was assessed using linear correlation. Results: Novice clinicians (n = 16) obtained 34 measurements from 26 patients (mean BMI 35.5) and reported moderate-to-high confidence in all measurements. uJVP correlated well with cJVP (r = 0.73) with an average error of 0.06 cm. The estimated uJVP ICC was 0.83 (95% CI = 0.44, 0.96). Qualitative uJVP had only a moderate correlation (r = 0.63) to quantitative uJVP. Discussion: Novice clinicians often have difficulty assessing JVP on physical examination, particularly in obese patients. Our findings show a high degree of correlation between JVP measurements performed by novice clinicians using ultrasound compared with JVP measurements made by experienced cardiologists on physical examination. Furthermore, novice clinicians were able to be trained quickly, their measurements were determined to be accurate and precise and they expressed moderate-to-high confidence in their results. Conclusions: After brief training, novice clinicians were able to accurately assess JVP in obese patients as compared to measurements made by experienced cardiologists on physical examination. Results suggest that ultrasound may greatly improve novice clinicians' JVP assessment accuracy, particularly in obese patients.

Could spinal cord oscillation contribute to spinal cord injury in degenerative cervical myelopathy?

Introduction: Degenerative Cervical Myelopathy [DCM] is a slow-motion spinal cord injury. Compression and dynamic compression have been considered disease hallmarks. However, this is likely an oversimplification, as compression is more commonly incidental and has only modest correlation to disease severity. MRI studies have recently suggested spinal cord oscillation could play a role. Research question: To determine if spinal cord oscillation could contribute to spinal cord injury in degenerative cervical myelopathy. Material and methods: A computational model of an oscillating spinal cord was developed from imaging of a healthy volunteer. Using finite element analysis, the observed implications of stress and strain, were measured in the context of a simulated disc herniation. The significance was bench marked by comparison to a more recognised dynamic injury mechanism; a flexion extension model of dynamic compression. Results: Spinal cord oscillation altered both compressive and shear strain on the spinal cord. Following initial compression, compressive strain moves from within the spinal cord to the spinal cord surface, whilst shear strain is magnified by 0.1-0.2, depending on the amplitude of oscillation. These orders of magnitude are equivalent to a dynamic compression model. Discussion and conclusion: Spinal cord oscillation could significantly contribute to spinal cord damage across DCM. Its repeated occurrence with every heartbeat, draws parallels to the concept of fatigue damage, which could reconcile differing theories on the origins of DCM. This remains hypothetical at this stage, and further investigations are required.

Temperature-dependent study reveals that dynamics of hydrophobic residues plays an important functional role in the mitochondrial Tim9-Tim10 complex.

Protein-protein interaction is a fundamental process in all major biological processes. The hexameric Tim9-Tim10 (translocase of inner membrane) complex of the mitochondrial intermembrane space plays an essential chaperone-like role during import of mitochondrial membrane proteins. However, little is known about the functional mechanism of the complex because the interaction is weak and transient. This study investigates how electrostatic and hydrophobic interactions affect the conformation and function of the complex at physiological temperatures, using both experimental and computational methods. The results suggest that, first, different complex conformational states exist at equilibrium, and the major difference between these states is the degree of hydrophobic interactions. Second, the conformational change mimics the biological activity of the complex as measured by substrate binding at the same temperatures. Finally, molecular dynamics simulation and detailed energy decomposition analysis provided supporting evidence at the atomic level for the presence of an excited state of the complex, the formation of which is largely driven by the disruption of hydrophobic interactions. Taken together, this study indicates that the dynamics of the hydrophobic residues plays an important role in regulating the function of the Tim9-Tim10 complex.

Large-scale domain conformational change is coupled to the activation of the Co-C bond in the B12-dependent enzyme ornithine 4,5-aminomutase: a computational study.

We present here an energetic and atomistic description of how D-ornithine 4,5-aminomutase (OAM), an adenosylcobalamin (AdoCbl; coenzyme B(12))-dependent isomerase, employs a large-scale protein domain conformational change to orchestrate the homolytic rupture of the Co-C bond. Our results suggest that in going from the open form (catalytically inactive) to the closed form (catalytically active), the Rossmann domain of OAM effectively approaches the active site as a rigid body. It undergoes a combination of a ~52° rotation and a ~14 Å translation to bring AdoCbl-initially positioned ~25 Å away-into the active-site cavity. This process is coupled to repositioning of the Ado moiety of AdoCbl from the eastern conformation to the northern conformation. Combined quantum mechanics and molecular mechanics calculations further indicate that in the open form, the protein environment does not impact significantly on the Co-C bond homolytic rupture, rendering it unusually stable, and thus catalytically inactive. Upon formation of the closed form, the Co-C bond is activated through the synergy of steric and electrostatic effects arising from tighter interactions with the surrounding enzyme. The more pronounced effect of the protein in the closed form gives rise to an elongated Co-C bond (by 0.03 Å), puckering of the ribose and increased "strain" energy on the Ado group and to a lesser extent the corrin ring. Our computational studies reveal novel strategies employed by AdoCbl-dependent enzymes in the control of radical catalysis.

Pressure effects on enzyme-catalyzed quantum tunneling events arise from protein-specific structural and dynamic changes.

The rate and kinetic isotope effect (KIE) on proton transfer during the aromatic amine dehydrogenase-catalyzed reaction with phenylethylamine shows complex pressure and temperature dependences. We are able to rationalize these effects within an environmentally coupled tunneling model based on constant pressure molecular dynamics (MD) simulations. As pressure appears to act anisotropically on the enzyme, perturbation of the reaction coordinate (donor-acceptor compression) is, in this case, marginal. Therefore, while we have previously demonstrated that pressure and temperature dependences can be used to infer H-tunneling and the involvement of promoting vibrations, these effects should not be used in the absence of atomistic insight, as they can vary greatly for different enzymes. We show that a pressure-dependent KIE is not a definitive hallmark of quantum mechanical H-tunneling during an enzyme-catalyzed reaction and that pressure-independent KIEs cannot be used to exclude tunneling contributions or a role for promoting vibrations in the enzyme-catalyzed reaction. We conclude that coupling of MD calculations with experimental rate and KIE studies is required to provide atomistic understanding of pressure effects in enzyme-catalyzed reactions.

Mechanical and histological characteristics of aortic dissection tissues.

AIMS: This study investigated the association between the macroscopic mechanical response of aortic dissection (AoD) flap, its fibre features, and patient physiological features and clinical presentations. METHODS: Uniaxial test was performed with tissue strips in both circumferential and longitudinal directions from 35 patients with (AoD:CC) and without (AoD:w/oCC) cerebral/coronary complications, and 19 patients with rheumatic or valve-related heart diseases (RH). A Bayesian inference framework was used to estimate the expectation of material constants (C1, D1, and D2) of the modified Mooney-Rivlin strain energy density function. Histological examination was used to visualise the elastin and collagen in the tissue strips and image processing was performed to quantify their area percentages, fibre misalignment and waviness. RESULTS: The elastin area percentage was negatively associated with age (p = 0.008), while collagen increased about 6% from age 40 to 70 (p = 0.03). Elastin fibre was less dispersed and wavier in old patients and no significant association was found between patient age and collagen fibre dispersion or waviness. Features of fibrous microstructures, either elastin or collagen, were comparable between AoD:CC and AoD:w/oCC group. Elastin and collagen area percentages were positively correlated with C1 and D2, respectively, while the elastin and collagen waviness were negatively correlated with C1 and D2, respectively. Elastin dispersion was negatively correlated to D2. Multivariate analysis showed that D2 was an effective parameter which could differentiate patient groups with different age and clinical presentations, as well as the direction of tissue strip. CONCLUSION: Fibre dispersion and waviness in the aortic dissection flap changed with patient age and clinical presentations, and these can be captured by the material constants in the strain energy density function. STATEMENT OF SIGNIFICANCE: Aortic dissection (AoD) is a severe cardiovascular disease. Understanding the mechanical property of intimal flap is essential for its risk evaluation. In this study, mechanical testing and histology examination were combined to quantify the relationship between mechanical presentations and microstructure features. A Bayesian inference framework was employed to estimate the expectation of the material constants in the modified Mooney-Rivlin constitutive equation. It was found that fibre dispersion and waviness in the AoD flap changed with patient age and clinical presentations, and these could be captured by the material constants. This study firstly demonstrated that the expectation of material constants can be used to characterise tissue microstructures and differentiate patients with different clinical presentations.

In-silico characterization of the effects of phosphorylated tyrosines 86 and 106 on structure and binding of MAL: insight into hyperinflammatory response to infection by the human malaria parasites.

The innate immune system uses inflammation to respond to infection of humans by various parasitic organisms and in some individuals can produce a hyperinflammatory response to infection by the human malaria parasites Plasmodium falciparum and vivax, leading to a more severe form of the disease-cerebral malaria (CM). Toll-like receptors (TLRs) 2 and 4 and members of its signaling pathway, including myeloid differentiation primary response protein (MyD88), MyD88 adapter-like protein (MAL) and suppressor of cytokine signaling 1 (SOCS1), are involved in this inflammatory response. A number of studies have suggested a possible role for MAL in developing CM and that modulating the behavior of MAL may prevent such complications. Mutagenesis studies have suggested that MAL becomes active after phosphorylation of tyrosines and the computational studies presented here characterize the possible roles of two tyrosines-Tyr86 and Tyr106-in MAL activity. The effects of phosphorylation on the structure of MAL and on its binding with two binding partners MyD88 and SOCS1 are studied here. The results suggest that phosphorylation of Tyr86 leads to conformational changes in the BB loop of MAL, and this conformational switch forms the interface for binding with MyD88. Similarly, our results suggest that phosphorylation of Tyr106 contributes to the stability of MAL-MyD88 dimer formation, and may form a possible binding site for SOCS1. Thus, our study supports roles for tyrosines 86 and 106 in signaling pathways involving MAL, and hence as potential drug targets against hyperinflammatory response to infection by Plasmodium falciparum and vivax.

Epitendinous suture techniques in extensor tendon repairs--an experimental evaluation.

PURPOSE: The tension-band principle might be relevant to extensor tendon repairs, and a dorsal-only Silfverskiöld epitendinous repair is stronger and stiffer than more conventional techniques in vitro. We aimed to evaluate the strength and stiffness of the strongest epitendinous sutures described, using an in vitro model that subjects the repair to angular force over a pulley, thereby creating a tension-band model. METHODS: Silfverskiöld dorsal-only epitendinous extensor tendon repairs in porcine foot tendons (n = 8) were compared to reverse (buried) Silfverskiöld (n = 8), Halsted (n = 8), and interrupted horizontal mattress (IHM) repairs (n = 6) in vitro with a tensiometer around a 45° pulley. Thirty tendons total were tested to assess the force required for 2-mm gapping and ultimate tensile strength. RESULTS: The IHM repair had a significantly higher ultimate tensile strength (43 N; SD, 10 N) than the other repairs, which had strengths between 27 N (SD, 4 N) and 31 N (SD, 7 N). The IHM was also significantly more resistant to gapping than the Silfverskiöld and Halsted repairs. CONCLUSIONS: Interlocking horizontal mattress, dorsal-only extensor tendon repairs were significantly stronger and more resistant to gapping than Silfverskiöld and Halsted repairs. Other repairs were still strong and resistant to gapping in comparison to previously published data for conventional repairs. CLINICAL RELEVANCE: The IHM is a relatively difficult technique to perform, and it remains to be seen whether the additional strength translates to clinical benefits over the easier Silfverskiöld technique.

3D printed biomimetic cochleae and machine learning co-modelling provides clinical informatics for cochlear implant patients.

Cochlear implants restore hearing in patients with severe to profound deafness by delivering electrical stimuli inside the cochlea. Understanding stimulus current spread, and how it correlates to patient-dependent factors, is hampered by the poor accessibility of the inner ear and by the lack of clinically-relevant in vitro, in vivo or in silico models. Here, we present 3D printing-neural network co-modelling for interpreting electric field imaging profiles of cochlear implant patients. With tuneable electro-anatomy, the 3D printed cochleae can replicate clinical scenarios of electric field imaging profiles at the off-stimuli positions. The co-modelling framework demonstrated autonomous and robust predictions of patient profiles or cochlear geometry, unfolded the electro-anatomical factors causing current spread, assisted on-demand printing for implant testing, and inferred patients' in vivo cochlear tissue resistivity (estimated mean = 6.6 kΩcm). We anticipate our framework will facilitate physical modelling and digital twin innovations for neuromodulation implants.

Barrier compression and its contribution to both classical and quantum mechanical aspects of enzyme catalysis.

It is generally accepted that enzymes catalyze reactions by lowering the apparent activation energy by transition state stabilization or through destabilization of ground states. A more controversial proposal is that enzymes can also accelerate reactions through barrier compression-an idea that has emerged from studies of H-tunneling reactions in enzyme systems. The effects of barrier compression on classical (over-the-barrier) reactions, and the partitioning between tunneling and classical reaction paths, have largely been ignored. We performed theoretical and computational studies on the effects of barrier compression on the shape of potential energy surfaces/reaction barriers for model (malonaldehyde and methane/methyl radical anion) and enzymatic (aromatic amine dehydrogenase) proton transfer systems. In all cases, we find that barrier compression is associated with an approximately linear decrease in the activation energy. For partially nonadiabatic proton transfers, we show that barrier compression enhances, to similar extents, the rate of classical and proton tunneling reactions. Our analysis suggests that barrier compression-through fast promoting vibrations, or other means-could be a general mechanism for enhancing the rate of not only tunneling, but also classical, proton transfers in enzyme catalysis.

Direct analysis of donor-acceptor distance and relationship to isotope effects and the force constant for barrier compression in enzymatic H-tunneling reactions.

The role of dynamical effects in enzyme catalysis is both complex and widely debated. Understanding how dynamics can influence the barrier to an enzyme catalyzed reaction requires the development of new methodologies and tools. In particular compressive dynamics-the focus of this study-may decrease both the height and width of a reaction barrier. By making targeted mutations in the active site of morphinone reductase we are able to alter the equilibrium of conformational states for the reactive complex in turn altering the donor-acceptor (D-A) distance for H-transfer. The sub-A changes which we induce are monitored using novel spectroscopic and kinetic "rulers". This new way of detecting variation in D-A distance allows us to analyze trends between D-A distance and the force constant of a compressive dynamical mode. We find that as the D-A distance decreases, the force constant for a compressive mode increases. Further, we demonstrate that-contrary to current dogma-compression may not always cause the magnitude of the primary kinetic isotope effect to decrease.