Physiological Connections Research Articles

Index of microvascular resistance (IMR) and fractional flow reserve (FFR) relationship in patients with angina and non-obstructive coronary artery (ANOCA) disease

Abstract Background Despite the plausible physiological connection between the index of microvascular resistance (IMR) and fractional flow reserve (FFR), a comprehensive understanding of their correlation is lacking. Purpose This study aims to elucidate the association between IMR and FFR in patients presenting with angina and non-obstructive coronary artery disease, employing various IMR threshold values. Methods Consecutively enrolled patients with angina and non-obstructive coronary artery disease underwent a thorough functional assessment encompassing both epicardial (Pd/Pa, FFR) and microvascular (coronary flow reserve, CFR; IMR) domains by the thermodilution technique. The hyperemic response to adenosine (Δ) was quantified as the disparity between Pd/Pa and FFR. Correlations between FFR and IMR, as well as between Δ and IMR, were examined globally and categorized based on the presence of coronary microvascular dysfunction (CMD, CFR<2). Subsequently, patients were stratified into three groups based on IMR values: Group 1 (IMR<25), Group 2 (25≤IMR<40), and Group 3 (IMR ≥ 40). Further analyses of adenosine hyperemic response, IMR, and FFR correlations were conducted within each group. Results A total of 116 patients and lesions were evaluated, with 71 in Group 1, 32 in Group 2, and 13 in Group 3. Globally, FFR showed no correlation with IMR (r = 0.025, p = 0.788), regardless of CMD presence (CMD, r = 0.210, p = 0.325; no CMD r = -0.051, p = 0.631). Same results were observed for the relationship of hyperemic response to adenosine and IMR (r = -0.0398, p = 0.673). However, upon stratification by IMR values, only patients in Group 3 exhibited a positive correlation between FFR and IMR (r = 0.580, p = 0.037), with a notable reduction in the hyperemic response to adenosine as IMR values increased (r = -0.5485, p = 0.052). After adjusting for potential confounding factors, a significant increase of 0.01 in FFR values was observed for every 10-unit rise in IMR (p = 0.045) in this Group. Conclusions FFR appears to be particularly influenced by elevated IMR values (≥40). Prudent interpretation of FFR values in such instances is imperative, especially in cases of functionally borderline epicardial stenosis.

Origin of division of labor is decoupled from polymorphism in colonial animals.

Division of labor, the specialization of sometimes phenotypically divergent cell types or group members, is often associated with ecological success in eukaryotic colonial organisms. Despite its many independent evolutionary origins, how division of labor emerges remains unclear. Conventional hypotheses tend toward an "economic" model, so that biological division of labor may reflect a partitioning of preexisting tasks and morphologies into specialized colony members. Here, we present an alternative model of the origin of division of labor, which can explain the evolution of new functions within a colony. We show that in colonies of the Cretaceous aged (103-96 Ma) fossil bryozoan of the genus Wilbertopora, the first cheilostome bryozoan to evolve polymorphism, preexisting morphologies were not simply partitioned among new members, but instead expanded into novel morphospace as they lost functions, specifically feeding. This expansion occurred primarily during two pulses of heightened morphological disparity, suggesting that the evolution of polymorphism corresponded to relaxed constraints on morphology and perhaps to the exploration of novel functions. Using a simple model of physiological connections, we show that regardless of the functionality of these new colony members, all nonfeeding members could have been supported by neighboring feeding members. This suggests that geometric constraints and physiological connectedness could be prerequisites for evolving both polymorphism and division of labor in modular organisms, and that a classic partitioning model of specialization cannot be broadly applied to biological systems.

Agmatine modulation of gut-brain axis alleviates dysbiosis-induced depression-like behavior in rats

Depression is a global health concern affecting nearly 280 million individuals. It not only imposes a significant burden on economies and healthcare systems but also manifests complex physiological connections and consequences. Agmatine, a putative neuromodulator derived primarily from beneficial gut microbes specially Lactobacillus, has emerged as a potential therapeutic agent for mental health. The microbiota-gut-brain axis is involved in the development of depression through the peripheral nervous system, endocrine system, and immune system and may be a key factor in the effect of agmatine. Therefore, this study aimed to investigate the potential mechanism of agmatine in antibiotic-induced dysbiosis and depression-like behavior in rats, focusing on its modulation of the gut-brain axis. Depression-like behavior associated with dysbiosis was induced through a seven-day regimen of the broad-spectrum antibiotic, comprising ampicillin and metronidazole and validated through microbial, biochemical, and behavioral alterations. On day 8, antibiotic-treated rats exhibited loose fecal consistency, altered fecal microbiota, and depression-like behavior in forced swim test. Pro-inflammatory cytokines were elevated, while agmatine and monoamine levels decreased in the hippocampus and prefrontal cortex. Antibiotic administration disrupted tight junction proteins in the ileum, affecting gut architecture. Oral administration of agmatine alone or combined with probiotics significantly reversed antibiotic-induced dysbiosis, restoring gut microbiota and mitigating depression-like behaviors. This intervention also restored neuro-inflammatory markers, increased agmatine and monoamine levels, and preserved gut integrity. The study highlights the regulatory role of endogenous agmatine in the gut-brain axis in broad-spectrum antibiotic induced dysbiosis and associated depression-like behavior.

Skin inflammatory signatures, as measured by disordered spatial redness patterns, predict current and future skin ageing attributes.

Facial skin redness can be an indicator of skin inflammation, however the physiological connection between facial redness and inflammatory status, as well as its role in age-related skin changes, remains poorly understood. This study aims to investigate the association between the pattern of facial skin redness and biological inflammatory status, as well as age-related changes occurring in the skin. Four studies were conducted recruiting healthy Northern Asian females. Disordered spatial patterns of facial skin redness signals were assessed using image analysis, i.e., the a* gradient algorithm, which quantifies the disordered shape and pattern of localized redness signals on facial skin. This redness pattern was compared with (1) inflammatory protein markers (IL-1Ra/ IL-1α and IL-8) measured from stripped corneocyte samples, (2) gene expression profiles obtained through transcriptome analysis using skin biopsy samples, and (3) the distribution pattern of blood vessel measured using a photoacoustic microscope. The association between the skin redness pattern and current and future ageing-related skin changes was examined through a longitudinal study tracking the same subjects for 10 years. A significant correlation was observed between the a* gradient and the levels of inflammatory cytokines (IL-1Ra/IL-1α and IL-8). Transcriptome analysis revealed upregulation of genes related to acute inflammation, chronic inflammation, cellular senescence, and angiogenesis in subjects with higher a* gradients. The high a* gradient group exhibited an extension of blood vessel diameter and increased blood vessel density, while the medium a* gradient group only exhibited blood vessel extension. Lastly, the 10-year longitudinal study demonstrated that the a* gradient was associated with current and future skin ageing-related attributes, such as increased skin texture and wrinkle formation. The spatial pattern of localized redness on the skin reflects the biological inflammatory status, and this inflammatory condition helps predict current and future age-related skin changes.

Eye-brain connections revealed by multimodal retinal and brain imaging genetics

The retina, an anatomical extension of the brain, forms physiological connections with the visual cortex of the brain. Although retinal structures offer a unique opportunity to assess brain disorders, their relationship to brain structure and function is not well understood. In this study, we conducted a systematic cross-organ genetic architecture analysis of eye-brain connections using retinal and brain imaging endophenotypes. We identified novel phenotypic and genetic links between retinal imaging biomarkers and brain structure and function measures from multimodal magnetic resonance imaging (MRI), with many associations involving the primary visual cortex and visual pathways. Retinal imaging biomarkers shared genetic influences with brain diseases and complex traits in 65 genomic regions, with 18 showing genetic overlap with brain MRI traits. Mendelian randomization suggests bidirectional genetic causal links between retinal structures and neurological and neuropsychiatric disorders, such as Alzheimer’s disease. Overall, our findings reveal the genetic basis for eye-brain connections, suggesting that retinal images can help uncover genetic risk factors for brain disorders and disease-related changes in intracranial structure and function.

Motion reconstruction and finite element analysis of the temporomandibular joint during swallowing in healthy adults

There is a close physiological connection between swallowing and the temporomandibular joint (TMJ). However, a shortage of quantitative research on the biomechanical behavior of the TMJ during swallowing exists. The purpose of this study was to reconstruct the movement of the temporomandibular joint (TMJ) based on in vivo experiment and analyze the biomechanical responses during swallowing in healthy adults to investigate the role of the TMJ in swallowing. Motion capture of swallowing, computed tomography (CT), and magnet resonance images (MRI) were performed on six healthy subjects. The movements of the TMJ during swallowing were reconstructed from the motion capture data. The three-dimensional finite element model was constructed. The dynamic finite element analysis of the swallowing process was performed based on the motion data. The range of condylar displacement was within 1 mm in all subjects. The left and right condyle movements were asymmetrical in two-thirds of the subjects. The peak stresses of the discs were relatively low, with a maximum of 0.11 MPa. During swallowing, the condylar displacement showed two trends: slow retraction and slow extension. The tendency to extend could lead to a gradual increase in stress on the disc.

Inpatient mortality outcomes of patients with hepatocellular carcinoma with congestive heart failure: A nationwide retrospective cohort study.

e16256 Background: Chronic conditions create challenges in improving outcomes and treatment strategies for cancer patients. In the general population, for example, congestive heart failure (CHF) has been associated with poor cardiovascular health and thus increased mortality. However, its prognostic implications in patients with hepatocellular carcinoma (HCC) are less clear despite the physiological connection of the cardiohepatic system. This study aims to elucidate the relationship between CHF and mortality among HCC patients, offering insights that could inform clinical management strategies and improve care. Methods: The 2017 – 2019 versions of the National Inpatient Sample (NIS) database from the Healthcare Cost and Utilization Project (HCUP) were used to acquire the sample population. ICD-10 codes were used to identify diagnoses and procedures. The main sample population consisted of all patients diagnosed with HCC. A multivariate regression model was used (adjusted for age, sex, race, median household income based on patient ZIP code, Charleston Comorbidity Index score, hospital region, hospital teaching status based on rural/urban setting) to calculate the adjusted odds ratio (aOR) for outcomes. First, the association between CHF and inpatient outcomes was examined. Then mortality was calculated for HCC patients receiving therapeutic interventions (chemoradiation, liver transplant, radiation, or immunotherapy) based on CHF status. Results: There were 29,396 patients with HCC. Of this amount, 3,810 patients (13%) had CHF diagnoses. For inpatient procedures, 1,120 patients (3.8%) underwent a liver transplant, 265 (0.9%) received chemotherapy, 2 (0.01%) received immunotherapy, and 5 (0.02%) received radiation therapy. The cohort of CHF patients was found to be older than non-CHF patients (70.2 ± 0.3 years and 64.3 ± 0.2 years, respectively, with p < 0.001). The multivariate regression analysis for the entire sample showed that the adjusted odds of mortality for HCC patients with CHF was 0.92 times that of not having CHF but not significant (95% CI 0.8 – 1.07, p = 0.3). The analysis was then applied to HCC patients receiving one of the four treatments during their hospitalization. Results showed that the CHF cohorts had increased odds of mortality if they received a liver transplant (aOR 20.3, 95% CI 2.5 – 165.7; p = 0.005) or chemotherapy (aOR 338.4, 95% CI 10.0 – 11428.9; p = 0.001). Conclusions: Having CHF is not a significant predictor of mortality in patients with HCC. However, when considering HCC patients undergoing liver transplantation, having comorbid CHF significantly carried about a 20-fold odds in mortality. In addition, HCC patients receiving chemotherapy had a 338-fold odds of death if they have CHF. Thus, careful consideration and planning must be taken into account to optimize patients’ cardiac status when considering treatment options.

Cardiorespiratory Effects of Yogic Versus Slow Breathing in Individuals with a Spinal Cord Injury: An Exploratory Cohort Study.

Background: An intricate physiological and pathophysiological connection exists between the heart and lungs, which is especially important in individuals with spinal cord injury (SCI). While an exercise intervention may seem the best approach to leverage this relationship, the prior work has shown that, despite numerous health benefits, regular exercise training does not improve cardiorespiratory control in individuals with SCI. Breath training presents an alternative intervention that is uniquely accessible, with yogic breathing directly engaging linked fluctuations in respiration and cardiovascular control. In addition, there is evidence across a range of populations that regular yogic breathing reduces cardiovascular disease risk. It is possible that the chronic decrease in breathing frequency associated with regular yogic breathing, rather than the specific yogic breathing techniques themselves, is the primary contributor to the observed risk reduction. Methods: Therefore, in 12 individuals with traumatic SCI from C4 to T8, the authors compared Unpaced and conventional 0.083 Hz (Slow) paced breathing with various yogic breathing techniques including: (1) inspiratory-expiratory breath holds (i.e., Kumbhaka or "Box Breathing"), (2) extended exhalation (1:2 duty cycle), and (3) expiratory resistance via throat constriction (i.e., Ujjayi). Beat-to-beat heart rate and blood pressure were measured as well as end-tidal CO2 and O2 saturation were measured. Statistical analysis was performed using a one-way repeated-measures analysis of variance with post hoc pairwise t tests corrected for multiple comparisons. Results: As expected, all slow breathing patterns markedly increased respiratory sinus arrhythmia (RSA) compared with Unpaced in all (n = 12) individuals. More importantly, Ujjayi breathing appeared to improve ventilatory efficiency over Unpaced breathing in individuals with SCI by increasing O2 saturation (97.6% vs. 96.1%; p = 0.042) and tended to decrease end-tidal CO2 (32 mmHg vs. 35 mmHg; p = 0.08). While other slow breathing patterns demonstrated similar effects, only Ujjayi improved RSA while increasing heart rate and improving ventilatory efficiency. Conclusions: Hence, slow breathing per se can result in important cardiorespiratory changes, but the yogic breathing practice of Ujjayi, with glottic throat resistance, may hold the greatest promise for improving cardiorespiratory control in individuals with SCI (CTR ID No. NCT05480618).

Stress and insomnia – A vicious circle

Insomnia is experiencing unsatisfactory sleep, typically characterised by difficulties initiating or maintaining sleep. Individuals with insomnia are dissatisfied with their sleep quality and perceive it as hindering their ability to perform well in work, school and social settings. The common symptoms of insomnia include fatigue, decreased mood, irritability, general discomfort and cognitive difficulties. On the other hand, stress results from emotional or physical tension triggered by various events that can make a person feel frustrated, angry or anxious. Stress is the body’s response to a challenge or demand, accompanied by the release of hormones. The specific physiological response to stress depends on factors such as the type of stress, the individual’s characteristics, their neuroendocrine system and the combination of these elements, collectively determining how the brain and body react to a particular stressor. The activation of the hypothalamic–pituitary–adrenal axis is a response mechanism triggered by stress. Disturbed sleep, particularly insomnia, is a common side effect of stress, varying in intensity. Sleep plays a crucial role in maintaining both physical and mental well-being, making the physiological connections between sleep and stress vital in understanding the development of stress-induced pathophysiology. Current treatments for insomnia include cognitive behavioural therapy, improving sleep hygiene and employing psychological and pharmacological interventions. However, these approaches aim to improve insomnia symptoms rather than address its underlying cause. In the context of homoeopathy, the concept of constitution refers to an individual’s unique structure, composition, nature and physical makeup, influenced by both inherited qualities and environmental factors. Therefore, it is essential to individualise each case and administer a simillimum remedy, the remedy most likely to restore health, and achieve complete healing according to homoeopathic principles. This review explores the physiological and neuroendocrine changes that occur due to the interplay between stress and the development of insomnia.

Research progress in brain-targeted nasal drug delivery.

The unique anatomical and physiological connections between the nasal cavity and brain provide a pathway for bypassing the blood-brain barrier to allow for direct brain-targeted drug delivery through nasal administration. There are several advantages of nasal administration compared with other routes; for example, the first-pass effect that leads to the metabolism of orally administered drugs can be bypassed, and the poor compliance associated with injections can be minimized. Nasal administration can also help maximize brain-targeted drug delivery, allowing for high pharmacological activity at lower drug dosages, thereby minimizing the likelihood of adverse effects and providing a highly promising drug delivery pathway for the treatment of central nervous system diseases. The aim of this review article was to briefly describe the physiological structures of the nasal cavity and brain, the pathways through which drugs can enter the brain through the nose, the factors affecting brain-targeted nasal drug delivery, methods to improve brain-targeted nasal drug delivery systems through the application of related biomaterials, common experimental methods used in intranasal drug delivery research, and the current limitations of such approaches, providing a solid foundation for further in-depth research on intranasal brain-targeted drug delivery systems (see Graphical Abstract).

Interplay between Vitamin D and Sphingolipids in Cardiometabolic Diseases

Sphingolipids (SLs) are structural, bioactive molecules with several key cellular roles, whereas 1,25-dihydroxyvitamin D (1,25(OH)D), the active form of vitamin D, is considered the major regulator of calcium homeostasis, although it also exerts other extraskeletal effects. Many studies reported the physiological connection between vitamin D and SLs, highlighting not only the effects of vitamin D on SL metabolism and signaling but also the influence of SLs on vitamin D levels and function, thus strongly suggesting a crosstalk between these molecules. After a brief description of 1,25(OH)D and SL metabolism, this review aims to discuss the preclinical and clinical evidence on the crosstalk between SLs and 1,25(OH)D, with a special focus on cardiometabolic diseases.

КЛИНИЧЕСКИЕ ПРОЯВЛЕНИЯ ЖЕЛЧНОКАМЕННОЙ БОЛЕЗНИ У СЕЛЬСКИХ ЖИТЕЛЕЙ РЕСПУБЛИКИ САХА (ЯКУТИЯ)

In recent years, cholelithiasis has been significantly increasing not only in elderly people, but in middle and young people of the most working age. We are the first to analyze in-depth comprehensive studies of rural residents of Western Yakutia. The entire adult population of two villages was invited to the survey, from which those who completely filled out the questionnaire were selected for the study. The search criteria were previously diagnosed cholelithiasis and ultrasound data of the abdominal organs. Gallstone disease is generally asymptomatic. Persons with cholelithiasis are significantly more likely to have poor tolerance to fatty and fried foods. The appearance of pain in the epigastric region, in the right hypochondrium in persons with cholelithiasis was noted after an error in food, consumption of fatty, fried and spicy foods. People after cholecystectomy tolerate fatty foods better, but more often report pain in the left hypochondrium and girdle pain compared to the general population, which may be associated with the development of biliary pancreatitis, due to the close anatomical and physiological connection with the pancreas. Painful and dyspeptic symptoms were reliably often noted by persons after cholecystectomy. The severity of pain and dyspeptic complaints in people after cholecystectomy is probably associated with a violation of the usual diet with limited fat and simple carbohydrates after surgical treatment. People with cholelithiasis significantly more often than the general population experience stool disorders in the form of diarrhea and constipation. Some risk factors for cholelithiasis in rural residents are modifiable, which requires preventive and therapeutic measures among the population.

Train vs. Play: Evaluating the Effects of Gamified and Non-Gamified Wheelchair Skills Training Using Virtual Reality.

This study compares the influence of a gamified and a non-gamified virtual reality (VR) environment on wheelchair skills training. In specific, the study explores the integration of gamification elements and their influence on wheelchair driving performance in VR-based training. Twenty-two non-disabled participants volunteered for the study, of whom eleven undertook the gamified VR training, and eleven engaged in the non-gamified VR training. To measure the efficacy of the VR-based wheelchair skills training, we captured the heart rate (HR), number of joystick movements, completion time, and number of collisions. In addition, an adapted version of the Wheelchair Skills Training Program Questionnaire (WSTP-Q), the Igroup Presence Questionnaire (IPQ), and the Simulator Sickness Questionnaire (SSQ) questionnaires were administered after the VR training. The results showed no differences in wheelchair driving performance, the level of involvement, or the ratings of presence between the two environments. In contrast, the perceived cybersickness was statistically higher for the group of participants who trained in the non-gamified VR environment. Remarkably, heightened cybersickness symptoms aligned with increased HR, suggesting physiological connections. As such, while direct gamification effects on the efficacy of VR-based wheelchair skills training were not statistically significant, its potential to amplify user engagement and reduce cybersickness is evident.

Biomimetic Connection of Transcutaneous Implants with Skin.

Bacterial infection is a crucial complication in implant restoration, in particular in permanent skin-penetrating implants. Therein, the resulting gap between transcutaneous implant and skin represents a permanent infection risk, limiting the field of application and the duration of application. To overcome this limitation, a tight physiological connection is required to achieve a biological and mechanical welding for a long-term stable closure including self-healing probabilities. This study describes a new approach, wherein the implant is connected covalently to a highly porous electrospun fleece featuring physiological dermal integration potential. The integrative potential of the scaffold is shown in vitro and confirmed in vivo, further demonstrating tissue integration by neovascularization, extracellular matrix formation, and prevention of encapsulation. To achieve a covalent connection between fleece and implant surface, self-initiated photografting and photopolymerization of hydroxyethylmethacrylate is combined with a new crosslinker (methacrylic acid coordinated titanium-oxo clusters) on proton-abstractable implant surfaces. For implant modification, the attached fleece is directed perpendicular from the implant surface into the surrounding dermal tissue. First in vitro skin implantations demonstrate the implants' dermal integration capability as well as wound closure potential on top of the fleece by epithelialization, establishing a bacteria-proof and self-healing connection of skin and transcutaneous implant.

Molecular therapy of cardiac ischemia-reperfusion injury based on mitochondria and ferroptosis.

Excessive death of myocardial cells can lead to various cardiovascular diseases and even develop into heart failure, so developing ideal treatment plans based on pathogenesis is of great significance for cardiopathy. After the heart undergoes ischemia‒reperfusion (I/R), myocardial cells accumulate a large amount of peroxides, leading to mitochondrial dysfunction and inducing ferroptosis. Ferroptosis is a form of iron-dependent regulatory cell death (RCD) caused by imbalanced redox and iron metabolism that leads to severe cell damage through the accumulation of peroxides. The mechanism of ferroptosis is highly correlated with mitochondrial metabolism. Myocardial cells are rich in a large number of mitochondria, which serve as energy supply centers and are prone to producing reactive oxygen species (ROS), providing opportunities for oxidative stress caused by ferroptosis. Ferroptosis is related to various cardiovascular diseases, and potential treatment methods designed around ferroptosis may alter the pathological progression of cardiovascular diseases. Therefore, this review investigates the regulatory mechanisms of ferroptosis, exploring the close pathological and physiological connections between ferroptosis and mitochondrial and cardiac I/R injury. Targeting ferroptosis and mitochondria for intervention may be an effective plan for preventing and treating cardiac I/R injury.

Mitochondrial Neurodegenerative Diseases: Three Mitochondrial Ribosomal Proteins as Intermediate Stage in the Pathway That Associates Damaged Genes with Alzheimer's and Parkinson's.

Currently, numerous research endeavors are dedicated to unraveling the intricate nature of neurodegenerative diseases. These conditions are characterized by the gradual and progressive impairment of specific neuronal systems that exhibit anatomical or physiological connections. In particular, in the last twenty years, remarkable efforts have been made to elucidate neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. However, despite extensive research endeavors, no cure or effective treatment has been discovered thus far. With the emergence of studies shedding light on the contribution of mitochondria to the onset and advancement of mitochondrial neurodegenerative disorders, researchers are now directing their investigations toward the development of therapies. These therapies include molecules designed to protect mitochondria and neurons from the detrimental effects of aging, as well as mutant proteins. Our objective is to discuss and evaluate the recent discovery of three mitochondrial ribosomal proteins linked to Alzheimer's and Parkinson's diseases. These proteins represent an intermediate stage in the pathway connecting damaged genes to the two mitochondrial neurological pathologies. This discovery potentially could open new avenues for the production of medicinal substances with curative potential for the treatment of these diseases.

Impact of Pesticide Residues on the Gut-Microbiota-Blood-Brain Barrier Axis: A Narrative Review.

Accumulating evidence indicates that chronic exposure to a low level of pesticides found in diet affects the human gut-microbiota-blood-brain barrier (BBB) axis. This axis describes the physiological and bidirectional connection between the microbiota, the intestinal barrier (IB), and the BBB. Preclinical observations reported a gut microbial alteration induced by pesticides, also known as dysbiosis, a condition associated not only with gastrointestinal disorders but also with diseases affecting other distal organs, such as the BBB. However, the interplay between pesticides, microbiota, the IB, and the BBB is still not fully explored. In this review, we first consider the similarities/differences between these two physiological barriers and the different pathways that link the gut microbiota and the BBB to better understand the dialogue between bacteria and the brain. We then discuss the effects of chronic oral pesticide exposure on the gut-microbiota-BBB axis and raise awareness of the danger of chronic exposure, especially during the perinatal period (pregnant women and offspring).

Transient interactions drive the lateral clustering of cadherin-23 on membrane

Cis and trans-interactions among cadherins secure multicellularity. While the molecular structure of trans-interactions of cadherins is well understood, work to identify the molecular cues that spread the cis-interactions two-dimensionally is still ongoing. Here, we report that transient, weak, yet multivalent, and spatially distributed hydrophobic interactions that are involved in liquid-liquid phase separations of biomolecules in solution, alone can drive the lateral-clustering of cadherin-23 on a membrane. No specific cis-dimer interactions are required for the lateral clustering. In cells, the cis-clustering accelerates cell-cell adhesion and, thus, contributes to cell-adhesion kinetics along with strengthening the junction. Although the physiological connection of cis-clustering with rapid adhesion is yet to be explored, we speculate that the over-expression of cadherin-23 in M2-macrophages may facilitate faster attachments to circulatory tumor cells during metastasis.

Cortico-thalamic development and disease: From cells, to circuits, to schizophrenia.

The human brain is the most complex structure generated during development. Unveiling the ontogenesis and the intrinsic organization of specific neural networks may represent a key to understanding the physio-pathological aspects of different brain areas. The cortico-thalamic and thalamo-cortical (CT-TC) circuits process and modulate essential tasks such as wakefulness, sleep and memory, and their alterations may result in neurodevelopmental and psychiatric disorders. These pathologies are reported to affect specific neural populations but may also broadly alter physiological connections and thus dysregulate brain network generation, communication, and function. More specifically, the CT-TC system is reported to be severely affected in disorders impacting superior brain functions, such as schizophrenia (SCZ), bipolar disorder, autism spectrum disorders or epilepsy. In this review, the focus will be on CT development, and the models exploited to uncover and comprehend its molecular and cellular mechanisms. In parallel to animal models, still fundamental to unveil human neural network establishment, advanced in vitro platforms, such as brain organoids derived from human pluripotent stem cells, will be discussed. Indeed, organoids and assembloids represent unique tools to study and accelerate fundamental research in CT development and its dysfunctions. We will then discuss recent cutting-edge contributions, including in silico approaches, concerning ontogenesis, specification, and function of the CT-TC circuitry that generates connectivity maps in physiological and pathological conditions.

The UBE2C/CDH1/DEPTOR axis is an oncogene and tumor suppressor cascade in lung cancer cells.

Ubiquitin-conjugating enzyme E2C (UBE2C) mediates ubiquitylation chain formation via the K11 linkage. While previous in vitro studies showed that UBE2C plays a growth-promoting role in cancer cell lines, the underlying mechanism remains elusive. Still unknown is whether and how UBE2C plays a promoting role in vivo. Here we report that UBE2C was indeed essential for growth and survival of lung cancer cells harboring Kras mutations, and UBE2C was required for KrasG12D-induced lung tumorigenesis, since Ube2c deletion significantly inhibited tumor formation and extended the lifespan of mice. Mechanistically, KrasG12D induced expression of UBE2C, which coupled with APC/CCDH1 E3 ligase to promote ubiquitylation and degradation of DEPTOR, leading to activation of mTORC signaling. Importantly, DEPTOR levels fluctuated during cell cycle progression in a manner dependent on UBE2C and CDH1, indicating their physiological connection. Finally, Deptor deletion fully rescued the tumor inhibitory effect of Ube2c deletion in the KrasG12D lung tumor model, indicating a causal role of Deptor. Taken together, our study shows that the UBE2C/CDH1/DEPTOR axis forms an oncogene and tumor suppressor cascade that regulates cell cycle progression and autophagy and validates UBE2C an attractive target for lung cancer associated with Kras mutations.