Protein Dynamics in Complex DNA Lesions.

A single mutagen can generate multiple different types of DNA lesions. How different repair pathways cooperate in complex DNA lesions, however, remains largely unclear. Here we measured, clustered, and modeled the kinetics of recruitment and dissociation of 70 DNA repair proteins to laser-induced DNA damage sites in HeLa cells. The precise timescale of protein recruitment reveals that error-prone translesion polymerases are considerably delayed compared to error-free polymerases. We show that this is ensured by the delayed recruitment of RAD18 to double-strand break sites. The time benefit of error-free polymerases disappears when PARP inhibition significantly delays PCNA recruitment. Moreover, removal of PCNA from complex DNA damage sites correlates with RPA loading during 5'-DNA end resection. Our systematic study of the dynamics of DNA repair proteins in complex DNA lesions reveals the multifaceted coordination between the repair pathways and provides a kinetics-based resource to study genomic instability and anticancer drug impact.

Effect of non-invasive spinal cord stimulation in unmedicated adults with major depressive disorder: a pilot randomized controlled trial and induced current flow pattern.

Converging theoretical frameworks suggest a role and a therapeutic potential for spinal interoceptive pathways in major depressive disorder (MDD). Here, we aimed to evaluate the antidepressant effects and tolerability of transcutaneous spinal direct current stimulation (tsDCS) in MDD. This was a double-blind, randomized, sham-controlled, parallel group, pilot clinical trial in unmedicated adults with moderate MDD. Twenty participants were randomly allocated (1:1 ratio) to receive "active" 2.5 mA or "sham" anodal tsDCS sessions with a thoracic (anode; T10)/right shoulder (cathode) electrode montage 3 times/week for 8 weeks. Change in depression severity (MADRS) scores (prespecified primary outcome) and secondary clinical outcomes were analyzed with ANOVA models. An E-Field model was generated using the active tsDCS parameters. Compared to sham (n = 9), the active tsDCS group (n = 10) showed a greater baseline to endpoint decrease in MADRS score with a large effect size (-14.6 ± 2.5 vs. -21.7 ± 2.3, p = 0.040, d = 0.86). Additionally, compared to sham, active tsDCS induced a greater decrease in MADRS "reported sadness" item (-1.8 ± 0.4 vs. -3.2 ± 0.4, p = 0.012), and a greater cumulative decrease in pre/post tsDCS session diastolic blood pressure change from baseline to endpoint (group difference: 7.9 ± 3.7 mmHg, p = 0.039). Statistical trends in the same direction were observed for MADRS "pessimistic thoughts" item and week-8 CGI-I scores. No group differences were observed in adverse events (AEs) and no serious AEs occurred. The current flow simulation showed electric field at strength within the neuromodulation range (max. ~0.45 V/m) reaching the thoracic spinal gray matter. The results from this pilot study suggest that tsDCS is feasible, well-tolerated, and shows therapeutic potential in MDD. This work also provides the initial framework for the cautious exploration of non-invasive spinal cord neuromodulation in the context of mental health research and therapeutics. The underlying mechanisms warrant further investigation. Clinicaltrials.gov registration: NCT03433339 URL: https://clinicaltrials.gov/ct2/show/NCT03433339 .

Mosquito saliva enhances virus infection through sialokinin-dependent vascular leakage.

Viruses transmitted by Aedes mosquitoes are an increasingly important global cause of disease. Defining common determinants of host susceptibility to this large group of heterogenous pathogens is key for informing the rational design of panviral medicines. Infection of the vertebrate host with these viruses is enhanced by mosquito saliva, a complex mixture of salivary-gland-derived factors and microbiota. We show that the enhancement of infection by saliva was dependent on vascular function and was independent of most antisaliva immune responses, including salivary microbiota. Instead, the Aedes gene product sialokinin mediated the enhancement of virus infection through a rapid reduction in endothelial barrier integrity. Sialokinin is unique within the insect world as having a vertebrate-like tachykinin sequence and is absent from Anopheles mosquitoes, which are incompetent for most arthropod-borne viruses, whose saliva was not proviral and did not induce similar vascular permeability. Therapeutic strategies targeting sialokinin have the potential to limit disease severity following infection with Aedes-mosquito-borne viruses.

What is the axillary arch (of Langer)?

We read with great interest the article by Weninger et al. (2023) on the presence of the axillary arch (AA) (of Langer) found during anatomical dissections-"Axillary arch (of Langer): A large-scale dissection and simulation study based on unembalmed cadavers of body donors." The authors performed their study using 400 axillae from 200 unembalmed cadavers; they identified this variant muscle in 27 axillae of 18 cadavers. Weninger et al. (2023) described the muscular AA in 15 cases; AA was composed of connective tissue in six cases, and AA comprised muscular and connective tissue in six cadavers. Moreover, these authors indicated that after passive abduction and lateral rotation of the arm, 17 arches (63%) came into contact with the neurovascular axillary bundle, which is of clinical importance. In our opinion, this is the most precise and detailed AA muscle study in the literature, illustrated with excellent photographs and schemes. Such studies expand the existing data in the literature and are of real help to clinicians. However, we want to present our modest comments about the title of the article and would like to pose the question, "What is the axillary arch (of Langer)?" Weninger et al. (2023) stated that connective or muscular tissue crossing the axilla is termed the AA (of Langer). This structure splits from the latissimus dorsi muscle, crosses the axilla, and joins the anterior part of the upper limb. The first detailed description of this variation was published in 1846 by Karl Langer Ritter von Edenberg (Langer, 1846). Nowadays, a significant number of articles term all muscular and fibromuscular connections between the latissimus dorsi muscle and the anterior part of the upper limb as "Langers AA" (Markou et al., 2023; Sang et al., 2019; Scrimgeour et al., 2020; Taterra et al., 2019). What Langer described in his work "Zur anatomie des musculus latissimus dorsi" was a fibrous thickening of the medial edge of the axillary fascia between the borders of the pectoralis major and the latissimus dorsi muscles, a structure he termed "Achselbogen." In a sequel of this article, Langer investigated muscular fibers inserting at or encircling the connective tissue "Achselbogen" (Langer, 1846). Therefore, in our opinion, in the study of Weninger et al. (2023), the term AA (of Langer) should only be used to describe the cases presenting solely with a connective tissue "arch" or these comprised of both, muscular and connective tissue. Weninger et al. (2023) noted that muscle fibers could not be excluded in these cases. Of course, to answer this question accurately, a histological study of these cases would be necessary.

Physical Exercise-Induced DNA Methylation in Disease-Related Genes in Healthy Adults-A Systematic Review With Bioinformatic Analysis.

ABSTRACT: Vasileva, F, Hristovski, R, Font-Lladó, R, Georgiev, G, Sacot, A, López-Ros, V, Calleja-González, J, Barretina-Ginesta, J, López-Bermejo, A, and Prats-Puig, A. Physical exercise-induced DNA methylation in disease-related genes in healthy adults-A systematic review with bioinformatic analysis. J Strength Cond Res 38(2): 384-393, 2024-This study aimed to systematically review the existing literature regarding physical exercise (PE) and DNA methylation (DNAm) in healthy adults. Specific goals were to (a) identify differently methylated genes (DMGs) after PE intervention, their imprinting status, chromosome and genomic location, function, and related diseases; and (b) to screen for core genes and identify methylation changes of the core genes that can be modified by PE intervention. Our search identified 2,869 articles from which 8 were finally included. We identified 1851 DMGs ( p < 0.05) after PE intervention, although 45 of them were imprinted. Aerobic exercise (AE) seems to induce more DNA hypermethylation rather than hypomethylation, whereas anaerobic exercise (AN) seems to induce more DNA hypomethylation rather than hypermethylation. Aerobic exercise induced highest % of methylation changes on chromosome 6, whereas AN and mixed type (MT) on chromosome 1. Mixed type induced higher % of methylation changes close to transcription start site in comparison to AE and AN. After PE intervention, DMGs were mainly involved in fat metabolism, cell growth, and neuronal differentiation, whereas diseases regulated by those genes were mainly chronic diseases (metabolic, cardiovascular, neurodegenerative). Finally, 19 core genes were identified among DMGs, all related to protein metabolism. In conclusion, our findings may shed some light on the mechanisms explaining PE-induced health benefits such as the potential role that PE-induced DNAm may have in disease prevention and disease treatment.

The enigmatic os supratrochleare anterius: from rarity to recognition in elbow pathology-case report and review of literature.

Accessory bones around the elbow are scarce, with a reported mean incidence rate of 0.77%. The rarest one is the os supratrochleare anterius, with only a handful of documented cases in the literature. Despite their scarcity, various types of ossicles have been documented, posing diagnostic challenges and potential misinterpretation on X-rays. Herein, we report a case of an accidentally found os supratrochleare anterius in a 43-year-old pig farmer presenting with symptoms of tennis elbow. After conservative treatment with nonsteroidal anti-inflammatory drugs and physiotherapy, he made a full recovery within 2 weeks. This report emphasizes the rarity of the ossupra trochleare anterius, the importance of accurate diagnosis, and the need for continued research and awareness of this anatomical variation.

The coracobrachialis muscle: typical morphology, accessory forms, and the issues with terminology.

The coracobrachialis muscle (CB) represents one of the anterior arm compartment muscles. It has been defined by classic anatomy textbooks and old papers, as a muscle of one belly arising from the coracoid process tip and partially from the tendon of the biceps brachii short head, and inserted into the humeral shaft, above the bone's midpoint. However, recent cadaveric studies have confirmed that in the majority of cases, the CB is a two-headed muscle consisting of a superficial and a deep head. This finding has caused confusion regarding the terminology of CB's morphology. Typical CB morphology, according to recent data should not be considered the muscle of one belly, but the two-headed muscle. In particular, the musculocutaneous nerve's (MCN) course plays an important role in defining the CB morphological characteristics. If the MCN courses medially to the CB, with no signs of penetration after dissection, it can be concluded, that the CB is composed of one head; otherwise, if the muscle is composed of two or more heads, the MCN will courses between the CB bellies. In conclusion, it is of paramount importance to adopt common-universal terminology. Hence, considering recent findings, if the CB origin and/or the insertion differs from the typical anatomy, an "atypical CB" is the proper definition of the muscle, while if this "atypical CB" coexists with a typical CB, the terminology "accessory CB" may be used.

A bilateral four-headed brachialis muscle with a variant innervation: a cadaveric report with possible clinical implications.

PURPOSE: Anterior compartment muscles of the arm present high morphological variability, with possible clinical significance. The current cadaveric report aims to describe a bilateral four-headed brachialis muscle (BM) with aberrant innervation. Emphasis on the embryological background and possible clinical significance are also provided. METHODS: Classical upper limb dissection was performed on an 84-year-old donated male cadaver. The cadaver was donated to the Anatomy Department of the National and Kapodistrian University of Athens. RESULTS: On the left upper limb, the four-headed BM was supplied by the musculocutaneous and the median nerves after their interconnection. On the right upper limb, the four-headed BM received its innervation from the median nerve due to the musculocutaneous nerve absence. A bilateral muscular tunnel for the radial nerve passage was identified, between the BM accessory heads and the brachioradialis muscle. CONCLUSION: BM has clinical significance, due to its proximity to important neurovascular structures and frequent surgeries at the humerus. Hence, knowledge of these variants should keep orthopedic surgeons alert when intervening in this area. Further dissection studies with a standardized protocol are needed to elucidate the prevalence of BM aberrations and concomitant variants.

Thermodynamics 2.0: Bridging the natural and social sciences.

Thermodynamics is a universal science. The language of thermodynamics is energy and its derivatives such as entropy and power. The physical theory of thermodynamics reigns across a full spectrum of non-living objects as well as living beings. In the traditions of the past, the dichotomy between matter and life resulted in the natural sciences studying matter while the social sciences focused on living beings. As the state of human knowledge continues to evolve, anticipating the sciences of matter (natural science) and of life (social science) becoming unified under a single overarching theory is not unnatural. This article is part of the theme issue 'Thermodynamics 2.0: Bridging the natural and social sciences (Part 1)'.

Nerve to subclavius for neurotization procedures: an anatomical feasibility study.

Injuries to the inferior trunk of the brachial plexus and its components can be debilitating. As such injuries are prioritized by surgeons during repair, an additional nerve transfer is considered herein. In the supine position, 13 adult cadavers (26 sides) underwent dissection of the nerve to subclavius and the proximal brachial plexus in the supraclavicular region. Once the nerve was located and isolated from origin to termination, measurements of its length and diameter were made. Next, the C8 and T1 roots and inferior trunk were identified. The distal end of the nerve to subclavius was transected and swung to these roots and the inferior trunk. Once the nerves to subclavius were transposed and in a tension-free manner, the length of excess nerve following being brought to each of these nerves was measured. A nerve to subclavius was identified on all sides. The nerve originated from the superior trunk and traveled anterior to the middle and inferior trunks on all sides. The mean diameter of the nerve to subclavius was 0.8 mm, and the mean length was 57 mm. After cutting the nerve to subclavius at its entrance into the subclavius muscle, the distal nerve could be transferred tension free to the inferior trunk of the brachial plexus and T1 ventral ramus on all sides. The distal nerve to subclavius reached the T1 ventral ramus with an average of 18 mm of additional length and to the C8 ventral ramus with an average of 19 mm. The nerve also could be transferred to the inferior trunk of the brachial plexus with an average of 20 mm of additional length. The nerve to subclavius was found to have approximately 3000 axons. To our knowledge, use of the nerve to subclavius has previously not been used for nerve transfer procedures. Based on our cadaveric study, this often-overlooked nerve can be easily transposed to other regional nerves such as the inferior trunk of the brachial plexus.

Accessory extensor pollicis longus from the extensor digitorum: a rare case report and review of the literature.

PURPOSE: Variations of the extensor pollicis longus are rare. When present, these include a separate extensor pollicis longus muscle, tendon or an intertendinous connection with nearby tendons within the deep extensor compartment of the forearm. Here, we report an extremely rare variation of an accessory extensor pollicis longus originating from the extensor digitorum. METHODS: An unusual muscle was found during the routine dissection forearm of a 71 year-old at death male cadaver. RESULTS: This variant muscle originated from part of the extensor digitorum muscle belly that supplies the index finger. It became tendinous and entered the third extensor compartment of the wrist before joining the ulnar side of the extensor pollicis longus tendon. Traction on the muscle belly resulted in simultaneous extension of both the thumb and the index finger. CONCLUSION: This study documents an extremely rare extensor tendon to the thumb originating from the extensor digitorum, with a unique attachment to the normal extensor pollicis tendon. There have been minimal accounts of this variation, and the present report adds to the limited literature. Furthermore, the report suggests a new subtype, 1f, be included in the existing classification system. Surgeons should be aware of this rare variant for proper evaluation, diagnosis and surgical treatment. Further anatomical studies are needed to study the prevalence of this variant.

Lacritin proteoforms prevent tear film collapse and maintain epithelial homeostasis.

Lipids in complex, protein-enriched films at air/liquid interfaces reduce surface tension. In the absence of this benefit, the light refracting and immunoprotective tear film on eyes would collapse. Premature collapse, coupled with chronic inflammation compromising visual acuity, is a hallmark of dry eye disease affecting 7 to 10% of individuals worldwide. Although collapse seems independent of mutation (unlike newborn lung alveoli), selective proteome and possible lipidome changes have been noted. These include elevated tissue transglutaminase and consequent inactivation through C-terminal cross-linking of the tear mitogen lacritin, leading to significant loss of lacritin monomer. Lacritin monomer restores homeostasis via autophagy and mitochondrial fusion and promotes basal tearing. Here, we discover that lacritin monomer C-terminal processing, inclusive of cysteine, serine, and metalloproteinase activity, generates cationic amphipathic α-helical proteoforms. Such proteoforms (using synthetic peptide surrogates) act like alveolar surfactant proteins to rapidly bind and stabilize the tear lipid layer. Immunodepletion of C- but not N-terminal proteoforms nor intact lacritin, from normal human tears promotes loss of stability akin to human dry eye tears. Stability of these and dry eye tears is rescuable with C- but not N-terminal proteoforms. Repeated topical application in rabbits reveals a proteoform turnover time of 7 to 33 h with gradual loss from human tear lipid that retains bioactivity without further processing. Thus, the processed C-terminus of lacritin that is deficient or absent in dry eye tears appears to play a key role in preventing tear film collapse and as a natural slow release mechanism that restores epithelial homeostasis.

Near-IR & Mid-IR Silicon Photonics Modulators.

As the silicon photonics field matures and a data-hungry future looms ahead, new technologies are required to keep up pace with the increase in capacity demand. In this paper, we review current developments in the near-IR and mid-IR group IV photonic modulators that show promising performance. We analyse recent trends in optical and electrical co-integration of modulators and drivers enabling modulation data rates of 112 GBaud in the near infrared. We then describe new developments in short wave infrared spectrum modulators such as employing more spectrally efficient PAM-4 coding schemes for modulations up to 40 GBaud. Finally, we review recent results at the mid infrared spectrum and application of the thermo-optic effect for modulation as well as the emergence of new platforms based on germanium to tackle the challenges of modulating light in the long wave infrared spectrum up to 10.7 µm with data rates of 225 MBaud.

Surface Chemistry Study of the Interactions of Sesame Oil with Meibomian Films.

A possible approach for the treatment of meibomian gland disease (MGD) can be the supplementation of meibomian gland secretion (MGS) with nonpolar lipids (NPL) rich plant oils. Sesame oil (SO), approximately equal in monounsaturated fat (oleic acid, 40% of total) and polyunsaturated fat (linoleic acid, 42% of total), has shown multiple health benefits due to its anti-inflammatory and antioxidant effects. Thus, the interactions between SO and MGS in surface layers deserve further study. Therefore, pseudobinary films were formed with controlled MGS/SO molar ratios (0%, 10%, 30%, 50%, and 100% SO) at the air/water surface of the Langmuir trough over phosphate buffered saline (pH 7.4) subphase. Surface pressure (π)-area (A) isotherms and Brewster angle microscopy observations showed nonideal interactions where SO aggregates with MGS and complements the NPL stratum of the meibomian layers. The analysis of stress relaxation transients with Kohlrausch-Williams-Watts equation revealed that the supplementation of fixed amount of MGS with excess lipids via SO altered the dilatational elasticity of the films as reflected by the increase of the exponent ß. Thus, SO with its unique combination of high oxidative stability and abundance of long polyunsaturated acyl chains might be a useful supplement to MGS layers.

Common trunk of the internal thoracic artery, inferior thyroid artery and thyrocervical trunk from the subclavian artery: a rare arterial variant.

PURPOSE: In this article, we describe a complex and rare variant of the common trunk arising as a branch of the subclavian artery. This description highlights the clinical relevance of such a variation for medical practice. METHODS: A routine dissection was carried out on an adult 74-year-old female cadaver. After identification and preparation of the common trunk, measurements and photographs were taken. RESULTS: The dissection revealed a common trunk arising from the first part of the left subclavian artery. It divided into the left internal thoracic artery, the inferior thyroid artery, and the thyrocervical trunk. Further on, the branches of the thyrocervical trunk supplied blood to the trapezius muscle, the longus colli muscle and the supraspinatus muscle. CONCLUSION: For the first time, we report the specific appearance of a common trunk from the left subclavian artery that includes the origin of the left internal thoracic artery, inferior thyroid artery, and thyrocervical trunk. Knowledge of the different variations of subclavian branches is essential because of the high frequency with which this region is involved in diagnostic and surgical procedures. LEVEL OF EVIDENCE: II Basic Science Research.

A new variety of chondrocoracoideus muscle, or an additional head of pectoralis major muscle.

The pectoralis major and pectoralis minor muscles are located in the anterior chest wall. This region is characterized by high morphological variability. During dissection an additional muscle was found, originating from the lateral border of the pectoralis major muscle. After fusion it passed into the tendinous part coursing under the insertion of the pectoralis major muscle, then formed a common junction with the short head of the biceps brachii muscle, the distal attachment of which is on the coracoid process. Such an accessory structure could lead to neurovascular compression and cause thoracic outlet syndrome, of which pain is usually the first symptom. This muscle has not been described in the literature so far and for that reason we can name the present case as an unique structure.

Interactions of Meibum and Tears with Mucomimetic Polymers: A Hint towards the Interplay between the Layers of the Tear Film.

Recent clinical findings suggest that mucomimetic polymers (MMP) can alter not only the texture of the aqueous tear but also the spreading and structure of the tear film (TF) lipid layer, thereby allowing for their synchronized performance in vivo. Thus, we aimed to evaluate in vitro (i) the capability of pharmaceutically applicable MMP to ensure the formation of post-evaporative ferning patterns (a characteristic feature of the "healthy" tear colloid) and (ii) the MMP interactions with human meibum films accessed in the course of blink-like deformations via Langmuir surface balance and Brewster angle microscopy (BAM). Four MMP were used- hyaluronic acid (HA), cross-linked hyaluronic acid (CHA), carboxymethyl cellulose (CMC) and gellan gum (GG)- at the concentrations of 0.0001%, 0.001%, 0.01%, 0.05% and 0.1%. Significant differences were observed in the MMP fern formation capability: CHA (≥0.001%) > HA (≥0.01%) = CMC (≥0.01%) > GG (≥0.05%). All MMP affected the spreading of meibum, with BAM micrographs revealing thickening of the films. CHA was particularly efficient, showing concentration-dependent enhancement of tear ferning and of meibomian layer structure, surfactant properties and viscoelasticity. Thus, endogenous and exogenous MMP may play key roles for the concerted action of the TF layers at the ocular surface, revealing novel routes for TF-oriented therapeutic applications.

The co-occurrence of a four-headed coracobrachialis muscle, split coracoid process and tunnel for the median and musculocutaneous nerves: the potential clinical relevance of a very rare variation.

The coracobrachialis muscle (CBM) originates from the apex of the coracoid process, in common with the short head of the biceps brachii muscle, and from the intermuscular septum. Both the proximal and distal attachment of the CBM, as well as its relationship with the musculocutaneus nerve demonstrate morphological variability, some of which can lead to many diseases. The present case study presents a new description of a complex origin type (four-headed CBM), as well as the fusion of both the short biceps brachii head, brachialis muscle and medial head of the triceps brachii. In addition, the first and second heads formed a tunnel for the musculocutaneus and median nerves. This case report has clear clinical value due to the split mature of the coracoid process, and is a significant indicator of the development of interest in this overlooked muscle.

The clinical anatomy of variations of the pectoralis minor.

Shoulder pathology is a very common medical presentation and can be due to anatomical variations. Therefore, knowledge of variants is important for the clinician treating patients with such complaints so that misdiagnosis is minimized and iatrogenic injury prevented. A review of the literature was performed of the variant anatomy of the pectoralis minor muscle. The aim of this review is to better inform clinicians who might treat patients with shoulder pathology so that if identified, variants of the pectoralis minor muscle are better appreciated.

Improving Stability of Tear Film Lipid Layer via Concerted Action of Two Drug Molecules: A Biophysical View.

The tear film at the ocular surface is covered by a thin layer of lipids. This oily phase stabilizes the film by decreasing its surface tension and improving its viscoelastic properties. Clinically, destabilization and rupture of the tear film are related to dry eye disease and are accompanied by changes in the quality and quantity of tear film lipids. In dry eye, eye drops containing oil-in-water emulsions are used for the supplementation of lipids and surface-active components to the tear film. We explore in detail the biophysical aspects of interactions of specific surface-active compounds, cetalkonium chloride and poloxamer 188, which are present in oil-in-water emulsions, with tear lipids. The aim is to better understand the macroscopically observed eye drops-tear film interactions by rationalizing them at the molecular level. To this end, we employ a multi-scale approach combining experiments on human meibomian lipid extracts, measurements using synthetic lipid films, and in silico molecular dynamics simulations. By combining these methods, we demonstrate that the studied compounds specifically interact with the tear lipid film enhancing its structure, surfactant properties, and elasticity. The observed effects are cooperative and can be further modulated by material packing at the tear-air interface.