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The Michaelis-Menten (MM) rate law has been a fundamental tool in describing enzyme-catalyzed reactions for over a century. When substrates and enzymes are homogeneously distributed, the validity of the MM rate law can be easily assessed based on relative concentrations: the substrate is in large excess over the enzyme-substrate complex. However, the applicability of this conventional criterion remains unclear when species exhibit spatial heterogeneity, a prevailing scenario in biological systems. Here, we explore the MM rate law's applicability under spatial heterogeneity by using partial differential equations. In this study, molecules diffuse very slowly, allowing them to locally reach quasi-steady states. We find that the conventional criterion for the validity of the MM rate law cannot be readily extended to heterogeneous environments solely through spatial averages of molecular concentrations. That is, even when the conventional criterion for the spatial averages is satisfied, the MM rate law fails to capture the enzyme catalytic rate under spatial heterogeneity. In contrast, a slightly modified form of the MM rate law, based on the total quasi-steady state approximation (tQSSA), is accurate. Specifically, the tQSSA-based modified form, but not the original MM rate law, accurately predicts the drug clearance via cytochrome P450 enzymes and the ultrasensitive phosphorylation in heterogeneous environments. Our findings shed light on how to simplify spatiotemporal models for enzyme-catalyzed reactions in the right context, ensuring accurate conclusions and avoiding misinterpretations in in silico simulations.

Abstract The present study used microdissection, histology, and microcomputed tomography (micro-CT) with the aims of determining the prevalence and patterns of the depressor septi nasi (DSN) and orbicularis oris (OOr) muscles attached to the footplate of the medial crus (fMC) of the major alar cartilage, focusing on their crossing fibers. The DSN and OOr attached to the fMC of the major alar cartilage were investigated in 76 samples from 38 embalmed Korean adult cadavers (20 males, 18 females; mean age 70 years). The DSN, OOr, or both were attached to the fMC. When the DSN ran unilaterally or was absent, some OOr fibers ascended to attach to the fMC instead of the DSN in 20.6% of the samples. Crossing fibers of the DSN or OOr attached to the fMC were found in 82.4% of the samples. Bilateral and unilateral crossing fibers were found in 32.4% and 50.0%, respectively, and no crossing fibers were found in 17.6%. The DSN and OOr that attached to the fMC could be categorized into six types according to presence of the DSN and the crossing patterns of the DSN and OOr. Anatomical findings of the DSN and OOr that attached to the fMC were confirmed in histology and micro-CT images. These findings offer insights on anatomical mechanisms that may underlie the dynamic pulling forces generated by muscles that attach to the fMCs and on evolutionary variation observed in human facial expressions. They can also provide useful information for guiding rhinoplasty of the nasal tip.

Summary: All proteins are translated in the cytoplasm, yet many, including transcription factors, play vital roles in the nucleus. While previous research has concentrated on molecular motors for the transport of these proteins to the nucleus, recent observations reveal perinuclear accumulation even in the absence of an energy source, hinting at alternative mechanisms. Here, we propose that structural properties of the cellular environment, specifically the endoplasmic reticulum (ER), can promote molecular transport to the perinucleus without requiring additional energy expenditure. Specifically, physical interaction between proteins and the ER impedes their diffusion and leads to their accumulation near the nucleus. This result explains why larger proteins, more frequently interacting with the ER membrane, tend to accumulate at the perinucleus. Interestingly, such diffusion in a heterogeneous environment follows Chapman’s law rather than the popular Fick’s law. Our findings suggest a novel protein transport mechanism arising solely from characteristics of the intracellular environment.

Summary: The circadian (∼24h) clock is based on a negative-feedback loop centered around the PERIOD protein (PER), translated in the cytoplasm and then enters the nucleus to repress its own transcription at the right time of day. Such precise nucleus entry is mysterious because thousands of PER molecules transit through crowded cytoplasm and arrive at the perinucleus across several hours. To understand this, we developed a mathematical model describing the complex spatiotemporal dynamics of PER as a single random time delay. We find that the spatially coordinated bistable phosphoswitch of PER, which triggers the phosphorylation of accumulated PER at the perinucleus, leads to the synchronous and precise nuclear entry of PER. This leads to robust circadian rhythms even when PER arrival times are heterogeneous and perturbed due to changes in cell crowdedness, cell size, and transcriptional activator levels. This shows how the circadian clock compensates for spatiotemporal noise.

Abstract This study was conducted to determine the muscular arrangement of the human pyloric sphincter using a comprehensive approach that involved microdissection, histology, and microcomputed tomography (micro‐CT). The stomachs of 80 embalmed Korean adult cadavers were obtained. In all specimens, loose muscular tissue of the innermost aspect of the sphincter wall ran aborally, forming the newly found inner longitudinal muscle bundles, entered the duodenum, and connected with the nearby circular bundles. In all specimens, approximately one-third of the outer longitudinal layer of the sphincter entered its inner circular layer, divided the circular layer into several parts, and finally connected with the circular bundles. Anatomical findings around the sphincter were confirmed in micro-CT images. The sphincter wall comprised three layers: an inner layer of longitudinal bundles, a middle layer of major circular and minor longitudinal bundles, and an outer layer of longitudinal bundles. The stomach outer longitudinal bundles were connected to the sphincter circular bundles. The inner longitudinal bundles of the sphincter were connected to the adjacent circular bundles of the duodenum.

The aim of this study was to determine how the depressor supercilii (DS) connects to the levator labii superioris alaeque nasi (LLSAN) and inferior fibers of the orbicularis oculi (OOc INF) in the human midface. While grimacing, contraction of the DS with fibers connecting to the LLSAN and OOc INF can assist in pulling the medial eyebrow downward more than when these connecting fibers are not present. Contraction of these distinct connecting fibers between the DS and the LLSAN can also slightly elevate the nasal ala and upper lip. The DS was examined in 44 specimens of embalmed adult Korean cadavers. We found that the DS connected to the LLSAN or the OOc INF by muscle fibers or thin aponeuroses in 33 (75.0%) of the 44 specimens. The DS was connected to both the LLSAN and OOc INF by muscle fibers or aponeuroses and had no connection to either in 5 (11.4%) and 11 (25.0%) specimens, respectively. The DS was connected to the LLSAN by the muscle fibers and thin aponeuroses in 6 (13.6%) and 4 (9.1%) specimens, respectively. The DS was connected to the OOc INF by the muscle fibers and thin aponeuroses in 5 (11.4%) and 23 (52.3%) specimens, respectively. Our findings regarding the anatomical connections of the glabellar region DS to the midface LLSAN and OOc INF provide insights on the dynamic balance between the brow depressors such as the DS and brow-elevating muscle and contribute to understanding the anatomical origins of individual variation in facial expressions. These results can also improve the safety, predictability, and aesthetics of treatments for the glabellar region with botulinum toxin type A and can be helpful when performing electromyography.

In this study, a literature survey was conducted of research into the development and use of wearable devices and sensors in patients with depression. We collected 18 studies that had investigated wearable devices for assessment, monitoring, or prediction of depression. In this report, we examine the sensors of the various types of wearable devices (e.g., actigraphy units, wristbands, fitness trackers, and smartwatches) and parameters measured through sensors in people with depression. In addition, we discuss future trends, referring to research in other areas employing wearable devices, and suggest the challenges of using wearable devices in the field of depression. Real-time objective monitoring of symptoms and novel approaches for diagnosis and treatment using wearable devices will lead to changes in management of patients with depression. During the process, it is necessary to overcome several issues, including limited types of collected data, reliability, user adherence, and privacy concerns.

A minute thrombus can pass through a small type of interatrial communication, which can result in a stroke or transient ischemic attack and several associated symptoms. This study sought to investigate a new type of interatrial communication. Thirty-one hearts from embalmed adult cadavers were investigated. Each interatrial channels (IACs) was classified as either an open or obstructed channel according to the connection of each hole on the right and left surfaces of the interatrial septum. Open channels were found in two specimens (6.5%). Both open and obstructed IACs followed tortuous courses through the interatrial septum. On the right surface of the interatrial septum, the hole was usually found adjacent to the left border of the interatrial septum between the opening of the superior vena cava into the right atrium and the superior margin of the fossa ovalis. Conversely, holes on the left surface of the interatrial septum were usually found in the upper and middle parts adjacent to the left border of the interatrial septum. This novel finding is expected to support our understanding of the onset of possible symptoms such as stroke in the absence of classical atrial septal defects.

The aim of this study was to clarify the heights and spatial relationships of the facial muscles acting on the nasolabial fold (NLF) by dissection and three-dimensional microcomputed tomography for use in aesthetic treatments. This study used 56 specimens from 34 embalmed adult Korean. A reference line (RF) was set to imitate the NLF after removing the skin, from the superior point of the alar facial crease to the lateral point of the orbicularis oris muscle at the level of the corner of the mouth. The heights and spatial relationships of the facial muscles along the RF could be categorized into five main patterns. The dominant pattern was that the levator labii superioris alaeque nasi muscle (LLSAN), levator labii superioris muscle (LLS), zygomaticus minor muscle (Zmi), and zygomaticus major muscle (Zmj) were on the medial third, medial half, middle third, and lateral third of the RF, respectively. In micro-CT imaging, beneath the skin of the medial half of the NLF, the LLSAN and Zmi fibers inserted into the dermis of the NLF and adjacent to the NLF. Beneath the skin of the middle third of the NLF, the Zmi fibers were found before the muscle inserted into the dermis of the NLF and adjacent to the NLF. Beneath the skin of the lateral third of the NLF, the lateral margin of the orbicularis oris muscle and some Zmj fibers were found at the location of the NLF. The present study utilized dissections and micro-CT to reveal the general pattern and variations of heights and spatial relationships of the facial muscles passing beneath the NLF. These findings will be useful for understanding which muscles affect specific parts of NLFs with various contours, for reducing the NLF in aesthetic treatments, and for reconstructing the NLF in cases of facial paralysis.

Objective: To assess the association between the healthcare system’s efficiency and policy factors (the types of healthcare systems and various health policy indicators). Methods: In this study, a data envelopment analysis (DEA) with bootstrapping was applied to the healthcare system’s efficiency to correct the bias of efficiency scores and to rank countries appropriately. We analyzed data mainly from the OECD (Organization for Economic Co-operation and Development) Health Data from 2014. After obtaining the efficiency score result, we analyzed which policy factor caused the inefficiency of the healthcare system by Tobit Regression. Results: Based on five types of healthcare system classification, the result suggested that the social health insurance (e.g., Austria, Germany, Switzerland) showed the lowest efficiency score on average when compared to other types of systems, but evidence of a statistically significant difference in healthcare efficiency among four types of healthcare systems was not found. It was shown that the pure technological efficiency of the healthcare system was negatively influenced by two main factors: user choice for basic insurance coverage and degree of decentralization to sub-national governments. Conclusions: Our findings suggest that countries with relatively low healthcare system efficiency may learn from countries that implement policies related to a low level of user choice and a high level of centralization to achieve more economical allocation of their healthcare resources.