RLF-100 (Aviptadil), a synthetic form of Vasoactive Intestinal Peptide (VIP) is shown to block replication of the SARS-CoV-2 virus and has been granted Fast Track Designation by the US FDA for the treatment of Critical COVID-19 with Respiratory Failure. We describe the clinical course of the first patient treated with this investigational medication in an open label manner -- a 54 year old patient suffering antibody-mediated rejection of his double lung transplant who contracted COVID-19 with respiratory failure refractory to all currently available therapies. He received three infusions of RLF-100 under an FDA-approved emergency use IND. Within 24 hours of the third infusion, substantial improvement in oxygen saturation and radiographic improvement in characteristic COVID-19 pneumonitis was noted. He was discharged from intensive care at that point and scheduled for discharge to home at 1 week on room air. Despite an intervening hospitalization for trauma, he remains alive and free of respiratory failure at 28 days post treatment.

Studies in animal models have suggested that the ketogenic diet may be effective in the treatment of cancer. However, human cohort studies on the ketogenic diet have, thus far, failed to show benefits in cancer survival or in any other hard clinical endpoints of the disease. This paper presents a case report of a patient with glioblastoma multiforme. The patient had initially been treated with standard oncotherapy including surgery, radiotherapy and chemotherapy. Despite standard treatment, the patient experienced a recurrence of the glioblastoma seven months later. Subsequently, the patient refused radiotherapy and chemotherapy and opted to use the paleolithic ketogenic diet (PKD) as a stand-alone therapy. Following the adoption of the PKD, progression of the disease has been completely halted. At the time of writing, the patient has remained in remission for 48 months, is without side-effects and experiences an excellent quality of life without the use of any drugs.

Background: Coronavirus disease 2019 (COVID-19) has emerged as a global threat to human health and disease risk increases with advancing age. The regulation of the ACE2 gene that codes for COVID-19 host receptor ACE2 has been shown to be under epigenetic regulation. Here, we examined whether intensive DNA methylation profiling of the ACE2 gene differed by human host tissue and cell type, gender, and age. Results: Accessing four public datasets, we observed unique human cell-type-specific ACE2 DNA methylation patterns. In human lung tissues, gender differences in DNA methylation at 2 sites related to the ACE2 gene were identified. Further, in freshly isolated airway epithelial cells, DNA methylation near the transcription start site of the ACE2 gene associated with biological age. Conclusion: Epigenetic profiling of host tissue may permit discovery of age and gender-related potential risk factors for COVID-19. How perturbations in ACE2 methylation relate to clinical severity across the ages and gender needs to be determined to guide screening tools and potential epigenetic modification targeting to alleviate COVID-19 morbidity in the elderly.

The current COVID-19 pandemic is one of the most devastating events in recent history. The virus causes relatively minor damage to young, healthy populations, imposing life-threatening danger to the elderly and people with diseases of chronic inflammation. Therefore, if we could reduce the risk for vulnerable populations, it would make the COVID-19 pandemic more similar to other typical outbreaks. Children don’t suffer from COVID-19 as much as their grandparents and have a much higher melatonin level. Bats are nocturnal animals possessing high levels of melatonin, which may contribute to their high anti-viral resistance. Viruses induce an explosion of inflammatory cytokines and reactive oxygen species, and melatonin is the best natural antioxidant that is lost with age. The programmed cell death coronaviruses cause, which can result in significant lung damage, is also inhibited by melatonin. Coronavirus causes inflammation in the lungs which requires inflammasome activity. Melatonin blocks these inflammasomes. General immunity is impaired by anxiety and sleep deprivation. Melatonin improves sleep habits, reduces anxiety and stimulates immunity. Fibrosis may be the most dangerous complication after COVID-19. Melatonin is known to prevent fibrosis. Mechanical ventilation may be necessary but yet imposes risks due to oxidative stress, which can be reduced by melatonin. Thus, by using the safe over-the-counter drug melatonin, we may be immediately able to prevent the development of severe disease symptoms in coronavirus patients, reduce the severity of their symptoms, and/or reduce the immuno-pathology of coronavirus infection on patients’ health after the active phase of the infection is over.

COVID-19 pandemic represents an unprecedented sanitary threat: antiviral and host-directed medications to treat the disease are still urgently needed.A great effort has been paid to find drugs and treatments for hospitalized, severely ill patients. However, medications used for the domiciliary management of initial symptoms, notwithstanding their importance, have not been and are not presently regarded with the same attention. In analogy with other respiratory viral infections, COVID-19 patients in the early phase require specific antivirals (still lacking) and non-etiotropic drugs to lower pain, fever and control inflammation. Non-steroidal antinflammatory drugs (NSAIDs) and paracetamol (PAC) are widely used as non-etiotropic agents in these conditions and hence are both theoretically repurposable for COVID-19. However, a warning from some research reports and National Authorities raised NSAIDs safety concerns because of the supposed induction of ACE2 protein levels (the receptor used by SARS-CoV2 to enter host airways cells), the risk of bacterial superinfections and masking of disease symptoms. As a consequence, the use of NSAIDs was, and is, strongly discouraged while the alternative adoption of paracetamol is still preferred.On the basis of novel data and hypothesis on the possible role of scarce glutathione (GSH) levels in the exacerbation of COVID-19 and of the GSH depleting activity of PAC, this commentary raises the question of whether PAC may produce an oxidative imbalance which could be detrimental in COVID-19 clinical outcomes.

Metabolomic analysis of biological fluids and tissues has become an increasingly routine tool in the biological toolbox. However, challenges remain to be overcome, including developing strategies to maximise coverage of the metabolome without requiring large sample volumes. Here we describe a multimodal strategy that combines data using both LC-MS and GC-MS from a unique vial with a sample of plasma (20µl) or a sample of brain tissue (3mg). Using a split phase extraction the non-aqueous phase was analyzed by reversed phase (RP) LC-MS, whilst the aqueous phase was analyzed using hydrophilic liquid interaction chromatography (HILIC)LC-MS, with both phases also analysed using GC-MS after derivatization of the extract. Analytical performance was assessed in 7 rat cerebellum samples and a pilot study of 40 plasma samples (20 vs. 20: AD vs. healthy controls). The method, which uses four hours of instrument time, measured 20,707 metabolite features in brain samples and 17,266 in plasma samples, from those 44.1% features displayed CV’s below 15% and 75.2% below 30%. The method has potential to resolve subtle biological differences and to correlate metabolite composition directly to clinical outcomes including MMSE, age and ADCS-ADL. This method can acquire in the order of 20K metabolic features when low volumes are available.

COVID-19 is a severe global problem, and AI can play a significant role in preventing losses by monitoring and detecting infected persons in early-stage. This paper aims to propose a high-speed and accurate fully-automated method to detect COVID-19 from the patient's CT scan images. We introduce a new dataset that contains 48260 CT scan images from 282 normal persons and 15589 images from 95 patients with COVID-19 infections. At the first stage, this system runs our proposed image processing algorithm to discard those CT images that inside the lung is not properly visible in them. This action helps to reduce the processing time and false detections. At the next stage, we introduce a novel method for increasing the classification accuracy of convolutional networks. We implemented our method using the ResNet50V2 network and a modified feature pyramid network alongside our designed architecture for classifying the selected CT images into COVID-19 or normal with higher accuracy than other models. After running these two phases, the system determines the condition of the patient using a selected threshold. We are the first to evaluate our system in two different ways. In the single image classification stage, our model achieved 98.49% accuracy on more than 7996 test images. At the patient identification phase, the system correctly identified almost 234 of 245 patients with high speed. We also investigate the classified images with the Grad-CAM algorithm to indicate the area of infections in images and evaluate our model classification correctness.

Efficiently targeted cancer therapy without causing detrimental side effects is necessary for alleviating patient care and improving survival rates. This paper presents observations of morphological changes in H1299 human lung cancer cells following W-band MMW irradiation (75 – 105 GHz) at a non-thermal power density of 0.2 mW/cm², investigated over 14 days of subsequent physiological incubation following exposure. Microscopic analyses of physical parameters measured indicate MMW irradiation induces significant morphological changes characteristic of apoptosis and senescence. The Immediate short-term responses translate into long-term effects, retained over the duration of the experiment(s); reminiscent of the phenomenon of Accelerated Cellular Senescence (ACS) achieving terminal tumorigenic cell growth. Further, results were observed to be treatment-specific in energy (dose) dependent manner and were achieved without the use of chemotherapeutic agents, ionizing radiation or thermal ablation employed in conventional methods; thereby overcoming associated side effects. Adaptation of the experimental parameters of this study for clinical oncology concomitant with current developmental trends of non-invasive medical endoscopy alleviates MMW therapy as an effective treatment procedure for human non-small cell lung cancer (NSCLC).

Currently there is little doubt left on the symbiogenetic nature of eukaryotes - genomes of archaeon and bacterium participated in shaping a genome of last eukaryotic common ancestor in equal albeit asymmetric manner, while a merger event itself indicated the advent of a new domain of life. The “symbiogenetic” framework of interaction of two partners is proposed, outlining similar steps essential for three major advents: the origin of life, the origin of complex life and the origin of humans. Given the immense importance of proper energy source for the evolution of life it seems plausible that for any principal increase in complexity, a partnership with a novel energy donor is required. Moreover, a “language” elaborated in the course of communication of partners might have been a prerequisite for a subsequent increase in complexity. Transitions, which led to RNA-protein world, eukaryotes and human brain, resulted in advent of complex languages via communication onsets between two entities in close partnership. Accordingly this further facilitated formation of first cells, multicellular organisms and human society.

Music has the innate potential to reach all parts of the brain, stimulates certain brain areas which are not achievable through other modalities. Music Therapy (MT) is being used for more than a century to treat individuals who needs personalized care. MT optimizes motor, speech and language responsibilities of the brain and improves cognitive performance. Pervasive developmentdisorder (PDD) is a multifaceted, neuro developmental disorder and autism spectrum disorder (ASD) comes under PDD, which is defined by deficiencies in three principal spheres: social connection with others, communicative and normal movement skills. The conventional imaging studies illustrate reduced brain area connectivity in people with ASD, involving selected parts of the brain cortex. People with ASD express much interest in musical activities which engages the brain network areas and improves communication and social skills.The main objective of this review is to analyze the potential role of MT in treating the neurological conditions, particularly ASD. Evidence based studies have reported the extensive therapeutic application of music on various part of the brain in a nonverbal child with autism through hearing or making music.Hence we hypothesized that MT intervention can improve the communication capacity in people with ASD, than customary neurorestoration therapy alone.

Recent progress in microfabrication technique allowed the rapid development of neural implants. They are getting categorized as effective tools for clinical practice, especially to treat traumatic and neurodegenerative disorders. Microelectrode arrays already have been used in numerous neural interface devices. Basically, almost all neural implants have been developed based on BCI (Brain Computer Interface) system. When BCI system falls under invasive technique, it is referred as BMI or Brain Machine Interface. BMIs hold promises for neurorehabilitation of motor and sensory function, cognitive state evaluation and treatment of neurological chaos. A directed overview of the field of neural implants is discussed in this article. The aim of this review is to give a brief introduction of neural prosthetics as well as their exciting applications in treating neurological disorders and a deep discussion on their functionality are mentioned. BCI system and their different types, their functionality, their pros and cons, how other neural implants developed, and their present status have been covered. Different possibilities and possible future of deep brain stimulation (DBS), Neuralink, motor and sensory neural prosthetics are further discussed.

Chronic eosinophilic pneumonia (CEP) is an idiopathic disorder characterized by an abnormal and marked accumulation of eosinophils in the interstitial and alveolar spaces of the lung. Idiopathic chronic eosinophilic pneumonia is reported to comprise anywhere from 0-2.5% of cases within the registries of interstitial lung disease. Diagnosis is based on the clinical constellation of symptoms, characteristic radiographic findings and peripheral blood or BAL eosinophilia, in the absence of infection or drug-induced eosinophilia. There is no consensus on the dose and duration of treatment, but most authors recommend initial doses of prednisone at 0.5–1 mg/kg/day with gradual tapering of the dose for total treatment duration of 6–12 months.

In the war against the COVID-19 pandemic, the world is experiencing severe resource constraints. Although transmission routes are well understood, we suspect that they cause different disease consequences. We evaluate them in different forms to understand how they affect infection rates and disease severity. In determining how they affect disease outcome, we evaluated target tissue vulnerability, functional role, defense mechanisms, viral concentration, infection vicinity to target vital tissue, and host factors. We found that direct lung infection is the most lethal transmission route followed by bronchi infection. Transmissions by physical contacts, foods, and blood by low viral concentration (as expected in normal human activities) pose lower or much lower risks unless the infection is followed by subsequent lung exposures. After adding transmission route, treatment timings, and improper treatments into the list of known risk factors, we found that death rate and disability rate for young or healthy persons are nearly zero. We show that population based medical model improperly shifts nominal death rate from few vulnerable people to the population resulting in unnecessary population panic, and such panic is responsible for shutting down human activities and the world economy. Finally, we examined limitations in population-based mitigating measures and proposed for governmental and private adoption community guidelines, which are mainly to enable vulnerable people avoid exposures, prevent non-vulnerable people from serving as viral transmitters, get rid of high-risk exposure modes in working environment, improve safety for people in buses, ships and planes, and reduce death and disability rates for infected people.

New research points to a possible link between Autism Spectrum Disorder and the gut microbiota as many autistic children have co-occurring gastrointestinal problems. This review focuses on specific alterations of gut microbiota mostly observed in autistic patients. Particularly, the mechanisms through which such alterations may trigger the production of the bacterial metabolites or leaky gut in autistic people are described. Various altered metabolite levels were observed in autistic children, many of those were of bacterial origin such as short chain fatty acids (SCFAs), indoles and lipopolysaccharides. A less integrative gut-blood-barrier is abundant in autistic individuals. This explains the leakage of bacterial metabolites into the patients triggering new body responses or altered metabolism. Some other co-occurring symptoms such as mitochondrial dysfunction, oxidative stress in the cells, altered tight junctions in the blood brain barrier and structural changes in cortex, hippocampus, amygdala and cerebellum were detected. Moreover, this paper suggests that autism is associated with an unbalanced gut microbiota (dysbiosis). Although the cause-effect relationship between autism and gut microbiota is not yet well established, consumption of specific probiotics may represent a powerful tool to re-establish gut homeostasis and promote gut health. Diagnostic and therapeutic value of new biomarkers leading to the perturbation in the phenylalanine metabolism will be discussed.

Adenoviruses (Ads) have been extensively manipulated for the development of cancer selective replication, leading to cancer cell death or oncolysis. Clinical studies using E1-modified oncolytic Ads have shown that this therapeutic platform was safe, but with limited efficacy, indicating the necessity of targeting other viral genes for manipulation. To improve the therapeutic efficacy of oncolytic Ads, we treated the entire Ad genome repeatedly with UV-light and have isolated AdUV which efficiently lyses cancer cells as reported previously [1]. In this report, we show that no mutations were observed in the early genes (E1 or E4) of AdUV while several mutations were observed within the Ad late genes which have structural or viral DNA packaging functions. This study also reported the increased release of AdUV from cancer cells. In this study, we found that AdUV inhibits tumor growth following intratumoral injection. These results indicate the potentially significant role of the viral late genes, in particular the DNA packaging genes, to enhance Ad oncolysis.

The paper presents a study of two novel visual motion onset stimulus-based brain–computer interfaces (vmoBCI). Two settings are compared with afferent and efferent to a computer screen center motion patterns. Online vmoBCI experiments are conducted in an oddball event–related potential (ERP) paradigm allowing for “aha–responses” decoding in EEG brainwaves. A subsequent stepwise linear discriminant analysis classification (swLDA) classification accuracy comparison is discussed based on two inter–stimulus–interval (ISI) settings of 700 and 150 ms in two online vmoBCI applications with six and eight command settings. A research hypothesis of classification accuracy non–significant differences with various ISIs is confirmed based on the two settings of 700 ms and 150 ms, as well as with various numbers of ERP response averaging scenarios.The efferent in respect to display center visual motion patterns allowed for a faster interfacing and thus they are recommended as more suitable for the no–eye–movements requiring visual BCIs.

Acute lung injury (ALI) is characterized by inflammation of the lung tissue and oxidative injury caused by excessive accumulation of reactive oxygen species. Studies have suggested that anti-inflammatory or antioxidant agents could be used for the treatment of ALI with a good outcome. Therefore, our study aimed to test whether the mycelium extract of Sanghuangporus sanghuang (SS-1), believed to exhibit antioxidant and anti-inflammatory properties, could be used against the excessive inflammatory response associated with LPS-induced ALI in mice and to investigate its possible mechanism of action. The experimental results showed that the administration of SS-1 could inhibit LPS-induced inflammation. SS-1 could reduce the number of inflammatory cells, inhibit MPO activity, regulate the TLR4/PI3K/Akt/mTOR pathway and the signal transduction of NF-κB and MAPK pathways in the lung tissue, and inhibit HNGB1 activity in BALF. In addition, SS-1 could affect the synthesis of antioxidant enzymes HO-1 and Trx-1 in the lung tissue and regulate signal transduction in the KAP1/Nrf2/Keap1 pathway. Histological results showed that administration of SS-1 prior to induction could inhibit the large-scale LPS-induced neutrophil infiltration of the lung tissue. Therefore, based on all experimental results, we propose that SS-1 exhibits a protective effect against LPS-induced (ALI) in mice. The mycelium of S. sanghuang can potentially be used for the treatment or prevention of inflammation-related diseases

The spread of the infection caused by the new coronavirus SARS-CoV-2 (COVID-19) became pandemic on March 11, 2020. From the time of the first cases (in November 2019, Wuhan, China), to date, a large number of COVID-19 observations have been accumulated in different age groups of patients both in China and abroad. Published scientific data allows us to conclude that children suffer from COVID-19 much less often than adults and tolerate the disease in a milder form, often appear to be asymptomatic. There is currently no final answer why children are less susceptible to this virus; however, scientists are increasingly inclined to consider a complex effect of the immune response and components of the renin-angiotensin system (RAS), which according to recent studies affects not only the cardiovascular system, but is also responsible for the activation of inflammatory reactions. A hypothesis of genetic predisposition to the development of severe forms of COVID-19 has recently been made. We conducted a search for publications in the databases and showed current scientific ideas about COVID-19 pathogenesis and factors influencing the disease development in childhood. Childhood immunity may have several protective features against SARS-CoV-2: immaturity of particular elements of the innate immune response, constitutional lymphocytosis with a shift towards anti-inflammatory Th2-response, as well as "trained" immunity. The influence of renin-angiotensin system reactions in this review is shown from two perspectives: expression of ACE2 receptors and polymorphisms of certain genes of this system. It was established that ACE2 transmembrane protein is not only the entry point for the virus but also plays a regulatory role, turning the pro-inflammatory vasoconstrictor angiotensin II into anti-inflammatory angiotensin (1-7), which has vasodilating properties. Higher ACE2 content in children compared with adults helps maintain balance in the renin-angiotensin system and prevents the development of complications. It was also shown that the presence of certain genetic polymorphisms (AGTR1, AGTR2, ACE2, ACE) could determine the imbalance inside the RAS, leading to more pronounced reactions of alveolocytes, vascular endothelium and smooth muscle fibers in response to SARS-CoV-2 infection due to a shift towards vasoconstrictor, proliferative and profibrotic mechanisms.

Mind and brain/matter interaction is one of the important and controversial issues in Islamic philosophy. In fact, in the resources of Islamic philosophy, one of the basic parts of philosophical discussions is related to mind’s nature and its interaction with the brain. Especially, in Avicenna’s philosophy, there are many articles and books which have addressed the topic of mind and brain and the relation between them. Avicenna was a profound philosopher, an expert physicist and a proficient physician of his time. Because of his experimental proficiency in medicine and surgery and his deep philosophical analysis, his discussion about mind and brain is very interesting for our time, due to recent advances in neuroscience. In this article, we have explained one of Avicenna’s arguments (in his famous opus “al-Isharat”) about the incorporeity of mind (self), which is very close to modern neuroscience and physics literature. In addition, we explain his model of mind and brain interaction. Avicenna described the mechanism of the causal effect of mind on the brain via a third identity, which works as an interface between them (in his main book “al-Shifa”). We try to illustrate his model by the use of some examples, inspired from modern physics. Also, we explore the philosophical constraints which must be considered in any model of mind-matter interaction, within the Islamic philosophy framework. In fact, we propose a new understanding of Avicenna’s philosophy which is in agreement with modern physics and neuroscience.

Brain metastases are highly evolved manifestations of breast cancer arising in a unique microenvironment, giving them exceptional adaptability in the face of new extrinsic pressures. The incidence is rising in line with population ageing, and use of newer therapies that stabilise metastatic disease burden with variable efficacy throughout the body. Historically, there has been a widely held view that brain metastases do not respond to circulating therapeutics because the blood-brain-barrier (BBB) restricts their uptake. However, emerging data are beginning to paint a far more complex picture where the brain acts as a sanctuary for dormant, subclinical proliferations that are initially protected by the BBB, but then exposed to dynamic selection pressures as tumours mature and vascular permeability increases. Here, we review key experimental approaches and landmark studies that have charted the genomic landscape of breast cancer brain metastases. These findings are contextualised with the factors impacting on clonal outgrowth in the brain: intrinsic breast tumour cell capabilities required for brain metastatic fitness, and the neural niche, which is initially hostile to invading cells but then engineered into a tumour-support vehicle by the successful minority. We also discuss how late detection, abnormal vascular perfusion and interstitial fluid dynamics underpin the recalcitrant clinical behaviour of brain metastases, and outline active clinical trials in the context of precision management.

A facilitative transport system exists on the blood brain barrier (BBB) that has been tacitly assumed to be a path for glutamate entry to brain. But glutamate is a non-essential amino acid whose brain content is much greater than plasma, and studies in vivo show that glutamate does not enter brain in material quantities except in those small regions with fenestrated capillaries (circumventricular organs). The situation became understandable when luminal (blood facing) and abluminal (brain facing) membranes were isolated and studied separately. Facilitative transport of glutamate and glutamine exist only on the luminal membranes whereas Na+-dependent transport systems for glutamate, glutamine and some other amino acids are present only on the abluminal membrane. The Na+-dependent cotransporters of the abluminal membrane are in a position to actively transport amino acids from the extracellular fluid (ECF) into the endothelial cells of the BBB. These powerful secondary active transporters couple the energy of the Na+-gradient to move glutamate and glutamine into the ECF whereupon glutamate can exit to blood on the luminal facilitative glutamate transporter. Glutamine may also exit brain on a separate facilitative transport system that exists on the luminal membranes or glutamine can be hydrolyzed to glutamate within the BBB thereby releasing ammonia that is freely diffusible. The γ-glutamyl participate cycle participates indirectly by producing oxoproline (pyroglutamate) that stimulates almost all secondary active transporters yet discovered in the abluminal membranes of the BBB.

1) Introduction: Brain parcellation is an important processing step in the analysis of structural brain MRI. Existing software implementations are optimized for fully developed adult brains, and provide inadequate results when applied to neonatal brain imaging. 2) Methods: We developed a semi-automated pipeline, NeBSS, for extracting 50 discrete brain structures from neonatal brain MRI, using an atlas registration method that leverages the existing ALBERT neonatal atlas 3) Results: We demonstrate a simple linear workflow for neonatal brain parcellation. NeBSS is robust to variation in imaging acquisition protocol and magnet field strength. 4) Conclusion: NeBSS is a robust pipeline capable of parcellating neonatal brain MRIs using a simple processing workflow. NeBSS fills a need in clinical translational research in neonatal imaging, where existing automated or semi-automated implementations are too rigid to be successfully applied to multi-center neuroprotection studies and clinically heterogeneous cohorts. The software is open source and freely available.

Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared with that of normal lung, and high VCAM-1 expression correlated with poor survival of lung cancer patients. VCAM-1 knockdown reduced invasion in A549 human lung cancer cells, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1 (VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1-mediated A549 cell invasion. Next, we developed a human monoclonal antibody specific to human and mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody library using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar affinity for VCAM-1-D6 and that it potently suppressed invasion in A549 and NCI-H1299 lung cancer cell lines. Taken together, these results suggest that VCAM-1-D6 is a novel therapeutic target in VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6 huMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion.

Neuroscience has overwhelmingly and understandably focused on the synaptic modality of signal transmission. There is evidence, however, that from an evolutionary perspective, non-synaptic transmission (NST) preceded synaptic signaling. Moreover, in modern nervous systems, NST coexists and extensively interacts with synaptic transmission modifying neuronal dynamics. In fact, NST remains widespread in complex animals, especially within the interoceptive system where the dearth of insulating barriers such as myelin sheaths and the blood-brain barrier enhances the communication between neural and non-neural tissues mediated by NST. We suggest that this physiological arrangement makes a fundamental contribution to interoception¾the process of sensing visceral states¾which is an essential underpinning of the capacity to feel and the foundation of affective processing.

This work promotes new methods in Mathematical Modeling, consisting in the use of the methods of Non-standard Analysis in Topoi, having as its main purpose, the mathematical definitions of the pseudoparticles from the title, with arguments from Biology/Physiology (Mathematical Neuroscience), Physics (String Theory and Emergent Quantum Mechanics), and Cybernetics (Global Brain, including Natural and Artificial Intelligence). The connections between brain and mind will be scketched via the genetic/epigenetic interplay. The topoi model the intuitionistic logic (multi-valued) and have been used in Quantum Physics while Non-Standard Analysis in SET (= the Category of sets) has been applied in Mathematical Economics; topics from Theory of Categories were also used in the study of Consciousness; however, the combination topoi - non-standard analysis was never used until now in Applied Mathematics. Another important objective is to produce progress in this aria of Pure Mathematics also - the build of non-standard analysis in classes of topoi, already used in Physics. We propose the logic of non-standard extensions in topoi as a model of the human thinking (based on infons/receptons), these theories representing new top and very difficult results in Abstract Mathematics either.

Testing in animals is mandatory in drug testing and the gold standard for evaluation of toxicity. This situation is expected to change in the future because the 3Rs principle, which stands for replacement, reduction and refinement of the use of animals in science, is reinforced by many countries. On the other hand, technologies for alternatives to animals experiments have increased. The necessity to develop and use of alternatives is influenced by the complexity of the research topic and also by the fact, to which extent the currently used animal models can mimic human physiology and/or exposure. Rodent lung morphology and physiology differs markedly for that of humans and inhalation exposure of the animals are challenging. In vitro and in silico methods can assess important aspects of the in vivo action, namely particle deposition, dissolution, action at and permeation across the respiratory barrier and pharmacokinetics. Out of the numerous homemade in vitro and in silico models some are available commercially or open access. This review discusses limitations of animal models and exposure systems and proposes a panel of in vitro and in silico techniques that, in the future, may replace animal experimentation in inhalation testing.

Modularity is arguably one of the most influential theses guiding research on brain and cognitive function since phrenology. This paper considers the following question: is modularity entailed by recent Bayesian models of brain and cognitive function, especially the predictive processing framework? It starts by considering three of the most well-articulated arguments for the view that modularity and predictive processing work well together. It argues that all three kinds of arguments for modularity come up short, albeit for different reasons. The analysis in this paper, although formulated in the context of predictive processing, speaks to broader issues with how to understand the relationship between functional segregation and integration and the reciprocal architecture of the predictive brain. These conclusions have implications for how to study brain and cognitive function. Specifically, when cognitive neuroscience works within an acyclic Markov decision scheme, adopted by most Bayesian models of brain and cognitive function, it may very well be methodologically misguided. This speaks to an increasing tendency within the cognitive neurosciences to emphasise recurrent and reciprocal neuronal processing captured within newly emerging dynamical causal modelling frameworks. The conclusions also suggest that functional integration is an organising principle of brain and cognitive function.

We take what we see, hear, smell and feel for the reality. However, as neuroscientists, we know that this reality, that is, our perceptual world, is in fact made up by the brain from the processing of the nerve impulses coming from receptors. Ancient Greeks used to think that this perceptual world, sometimes called our 3D movie (Chalmers), is emitted and has its own physical nature. Given how real the 3D movie looks to us, it is still difficult today to consider that all we would be dealing with would be patterns of brain activity The present study thus aimed at testing whether the perceptual world could have some physical existence in addition to that of the neural patterns responsible for it. To achieve that goal, we tried to see whether brains could be sensitive to the 3D movie of others. This, admittedly unusual, operational hypothesis was based on two assumptions. First, brains are sensitive to the 3D movie, as our experience includes reactions to our perceptual world. Second, the physicality at stake does not differ across individuals. We recorded the event-related brain potentials (ERPs) evoked by stimuli of the international affective picture system in pairs of closely-related participants. Most importantly, they could neither see the stimuli simultaneously presented to their partners nor their reactions to them. As in Bouten et al. (2015), around 400 ms after the onset of the stimuli, ERPs started being more positive in inconsistent conditions. Namely, when the two subjects of each pair were presented with the same stimulus whereas they were told it would be a different one and vice-versa (i.e., different-stimuli expected to be same). ERPs were less positive when the two subjects of a pair were presented with the same stimuli and were told they were the same and conversely (i.e., different-stimuli expected to be different). The same experiment was then run in pairs of strangers. No significant effect of consistency on ERPs was observed even though participants could, this time, see, in the very periphery of their visual field, the reactions of their partner to the stimuli. We thus use the results of both studies to support a new version of the emission theory of consciousness and to suggest that the sensitivity to the perceptual world of others may depend on their prior familiarity with it.

One of the major unsolved mysteries of biological science concerns the question of where and in what form information is stored in the brain. I propose that memory is stored in the brain in a mechanically encoded binary format written into the conformations of proteins found in the cell-extracellular matrix adhesions that organise each and every synapse. The MeshCODE framework outlined here represents a unifying theory of data storage in animals, providing read-write storage of both dynamic and persistent information in a binary format. Mechanosensitive proteins that contain force-dependent switches can store information persistently, which can be written or updated using small changes in mechanical force. These mechanosensitive proteins, such as talin, scaffold each synapse, creating a meshwork of switches that together form a code, the so-called MeshCODE. Large signalling complexes assemble on these scaffolds as a function of the switch patterns and these complexes would both stabilise the patterns and coordinate synaptic regulators to dynamically tune synaptic activity. Synaptic transmission and action potential spike trains would operate the cytoskeletal machinery to write and update the synaptic MeshCODEs, thereby propagating this coding throughout the organism. Based on established biophysical principles, such a mechanical basis for memory would provide a physical location for data storage in the brain, with the binary patterns, encoded in the information-storing mechanosensitive molecules in the synaptic scaffolds, and the complexes that form on them, representing the physical location of engrams. Furthermore, the conversion and storage of sensory and temporal inputs into a binary format would constitute an addressable read-write memory system, supporting the view of the mind as an organic supercomputer.

Lambertianic acid (LA) is a biologically active compound from the leaves of Pinus koraiensis. In the present study, apoptotic mechanisms of LA plus TNF-related apoptosis-inducing ligand (TRAIL) were elucidated in non-small cell lung cancer cells (NSCLCs). Cytotoxicity assay, flow cytometry, immunoprecipitation and Western blotting were performed. Here, combined treatment of LA and TRAIL increased cytotoxicity, sub-G1 population and cleaved poly (ADP-ribose) polymerase (PARP) and caspase3/8/9 in A549 and H1299 cells compared to LA or TRAIL alone. Furthermore, combined treatment of LA and TRAIL significantly decreased anti-apoptotic proteins such as B-cell lymphoma 2 (Bcl-2), Fas-like inhibitor protein (FLIP) and X-linked inhibitor of apoptosis protein (XIAP) and enhanced the activation of pro-apoptotic proteins Bid compared to LA or TRAIL alone. In addition, combined treatment of LA and TRAIL upregulated the expression of Death receptor 4 (DR4) and downregulated phosphorylation of nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-B), inhibitory protein of kB family (p-IB) and FLIP in A549 and H1299 cells along with disrupted binding of XIAP with caspase3 or NF-B. Overall, these findings suggest that lambertianic acid enhances TRAIL-induced apoptosis via inhibition of XIAP/NF-B in TRAIL resistant NSCLCs.

The nature of the interaction between Th17 cells and the blood-brain barrier (BBB) is critical for the development of autoimmune inflammation in the central nervous system (CNS). TNF-a or IL-17 stimulation is known to enhance the adherence of Th17 cells to the brain endothelium. The brain endothelial cells (bEnd.3) express VCAM-1, the receptor responsible for inflammatory cell adhesion, which binds VLA-4 on migrating effector lymphocytes at the early stage of brain inflammation. The present study examines the effect of the pro-inflammatory cytokines TNF-a and IL-17 on the adherence of Th17 cells to bEnd.3 The bEnd.3 cells were found to increase production of CCL2 and CXCL1 after stimulation by pro-inflammatory cytokines, while CCL2, CCL5, CCL20 and IL17 induced Th17 cell migration through a bEnd.3 monolayer. This interaction between Th17 cells and the brain endothelium appears to be mediated by VCAM-1 and some chemotactic cytokines. This observation may suggest potential therapeutic targets for the prevention of autoimmune neuroinflammation development in the CNS.

Social plasticity, defined as the ability to adaptively change the expression of social behavior according to previous experience and to social context, is a key ecological performance trait that should be viewed as crucial for Darwinian fitness. The neural mechanisms for social plasticity are poorly understood, in part due to skewed reliance on rodent models. Fish model organisms are relevant in the field of social plasticity for at least two reasons: first, the diversity of social organization among fish species is staggering, increasing the breadth of evolutionary relevant questions that can be asked. Second, that diversity also suggests translational relevance, since it is more likely that “core” mechanisms of social plasticity are discovered by analyzing a wider variety of social arrangements than relying on a single species. We analyze examples of social plasticity across fish species with different social organizations, concluding that a “core” mechanism is the initiation of behavioral shifts through the modulation of a conserved “social decision-making network”, along with other relevant brain regions, by monoamines, neuropeptides, and steroid hormones. The consolidation of these shifts may be mediated via neurogenomic adjustments and regulation of the expression of plasticity-related molecules (transcription factors, cell cycle regulators, and plasticity products).

Multidisciplinary neurotechnology holds the promise of understanding and non-invasively treating neurodegenerative diseases. In this preclinical trial on Parkinson's disease (PD), we combined neuroscience together with the nascent field of medical virtual reality and generated several important observations. First, we established the Oculus Rift virtual reality system as a potent measurement device for parkinsonian involuntary hand tremors (IHT). Interestingly, we determined changes in rotation were the most sensitive marker of PD IHT. Secondly, we determined parkinsonian tremors can be abolished in VR with algorithms that remove tremors from patients' digital hands. We also found that PD patients were interested in and were readily able to use VR hardware and software. Together these data suggest PD patients can enter VR and be asymptotic of PD IHT. Importantly, VR is an open-medium where patients can perform actions, activities, and functions that positively impact their real lives - for instance, one can sign tax return documents in VR and have them printed on real paper or directly e-sign via internet to government tax agencies. Lastly, we generated a technical framework wherein movements in the real world can be measured side-by-side with those in virtual reality. With this framework, we observed anecdotal evidence of parkinsonian tremors being reduced in real life when our algorithms abolished digital hand tremors in VR.

Fasudil, a potent Rho kinase (ROCK) inhibitor, can ameliorate LPS-induced acute lung injury (ALI) in mice, but the mechanism remains obscure. In this study, a mice model of ALI was established by intra-tracheal instillation of LPS. Histological changes, cytokine levels, lung permeability, and endothelial apoptosis were determined to evaluate the effects of fasudil on lung injury. The cellular and molecular biological mechanisms were explored by culturing human pulmonary microvascular endothelial cells (PMECs). The results showed that fasudil reduced LPS-induced lung inflammation, pulmonary hyperpermeability, and endothelial apoptosis in mice. In cultured human PMECs, fasudil inhibited LPS-induced caspse-3 cleavage and cell apoptosis. It also decreased LPS-induced hyperpermeability of human PMECs monolayer by reversing the down-regulation of intercellular junctions. Moreover, fasudil inhibited LPS-induced overexpression of chemokines and intercellular adhesion molecule (ICAM)-1 in human PMECs, which in turn suppressed neutrophil chemotaxis and neutrophil-endothelial adhesion. Further molecular researches showed fasudil inhibited LPS-induced activation of ROCK, NF-κB, and p38 in human PMECs. Our findings demonstrated that fasudil alleviated LPS-induced ALI by protecting endothelial function via inhibiting endothelial apoptosis, maintaining endothelial barrier integrity, and reducing endothelial inflammation. These effects of fasudil could be attributed to the inhibition of ROCK and its downstream NF-κB and p38 signaling pathways.

Our knowledge on the plastic functions of the serotonin (5-HT) receptor subtype 7 (5-HT7R) in the brain physiology and pathology considerably advanced in the last few years. A wealth of data show that the 5-HT7R is a key player in the establishment and remodeling of neuronal cytoarchitecture during development and in the mature brain, and its dysfunction is linked to neuropsychiatric and neurodevelopmental diseases. The involvement of this receptor in synaptic plasticity is further demonstrated by data showing that its activation allows to rescue long term potentiation (LTP) and long term depression (LTD) deficits in various animal models of neurodevelopmental diseases. In addition, it is becoming clear that the 5-HT7R is involved in inflammatory intestinal diseases, possibly playing a role in the gut-brain axis, and modulates the function of immune cells. In this review, we will mainly focus on recent findings on this receptor’s role in the structural and synaptic plasticity of the mammalian brain, although we will also illustrate novel aspects highlighted in gut and immune system.

Brain development during the prenatal period is rapid and unparalleled by any other time during development. Biological systems undergoing rapid development are at higher risk for disorganizing influences. Therefore, certain prenatal exposures impact brain development, increasing risk for negative neurodevelopmental outcome. While prenatal exposures have been associated with cognitive and behavioral outcomes later in life, the underlying macroscopic brain pathways remain unclear. Here, we review studies investigating the association between prenatal exposures and infant brain development focusing on prenatal exposures via maternal physical health factors, maternal mental health factors, and maternal drug and medication use. Further, we discuss the need for studies to consider multiple prenatal exposures in parallel and suggest future directions for this body of research.

Total 219 countries and territories globally suffering from the recent pandemic COVID-19 is now in its second wave with more brutality, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . It has several symptoms like as persistent fever; respiratory illnesses; cough; fatigue; shortness of breath; loss of appetite; persistent pain or pressure in the chest; dysgeusia; acute respiratory distress syndrome (ARDS) etc., and here the things to worry about is the development of pulmonary fibrosis after COVID-19 in both peoples who had died of due to acute respiratory distress syndrome (ARDS) or those who survived. Due to COVID-19, dysregulated immune response and wound repair mainly in elderly patients causes this secondary pulmonary fibrosis. Thus using anti-fibrotic agents could be meaningful in these circumstances although their efficacy in treating COVID-19 is subject to more detailed laboratory research works. In this review article you will get to know about the lung fibrosis generation due to COVID-19 infection, about anti-fibrotic agents and the currents challenges of this field.

Non-invasive, electroencephalography (EEG)-based brain-computer interfaces (BCIs) on motor imagery movements translate the subject’s motor intention into control signals through classifying the EEG patterns caused by different imagination tasks, e.g. hand movements. This type of BCI has been widely studied and used as an alternative mode of communication and environmental control for disabled patients, such as those suffering from a brainstem stroke or a spinal cord injury (SCI). Notwithstanding the success of traditional machine learning methods in classifying EEG signals, these methods still rely on hand-crafted features. The extraction of such features is a difficult task due to the high non-stationarity of EEG signals, which is a major cause for the stagnating progress in classification performance. Remarkable advances in deep learning methods allow end-to-end learning without any feature engineering, which could benefit BCI motor imagery applications. We developed three deep learning models: 1) a long short-term memory (LSTM); 2) a proposed spectrogram-based convolutional neural network model (pCNN); and 3) a recurrent convolutional neural network (RCNN), for decoding motor imagery movements directly from raw EEG signals without (manual) feature engineering. Results were evaluated on our own, publicly available, EEG data collected from 20 subjects and on an existing dataset known as 2b EEG dataset from "BCI Competition IV". Overall, better classification performance was achieved with deep learning models compared to state-of-the art machine learning techniques, which could chart a route ahead for developing new robust techniques for EEG signal decoding. We underpin this point by demonstrating the successful real-time control of a robotic arm using our CNN based BCI.

Aims TRAIL is a promising anticancer agent that has the potential to sensitize a wide variety of cancer or transformed cells by inducing apoptosis. However, resistance to TRAIL is a growing concern. Current manuscript aimed to employing combination treatment to investigate resveratrol induced TRAIL sensitization in NSCLC. Method A549 and HCC-15 cells were used in experimental design. Cell viability was determined by morphological image, crystal violet staining and MTT assay. Apoptosis was evaluated by LDH assay, Annexin V and DAPI staining. Autophagy and apoptosis indicator protein were examined by western blotting. TEM and puncta assay were carried out to evaluate the autophagy. MTP and ROS activity were evaluated by JC-1 and H₂DCFDA staining. Findings Resveratrol is a polyphenolic compound capable of activation of tumor suppressor p53 and its pro-apoptotic modulator PUMA. Herein, we showed the p53-independent apoptosis by decrease the expression of phosphorylated Akt-mediated suppression of NF-κB that is also substantiated with the downregulation of anti-apoptotic factors Bcl-2 and Bcl-xl in NSCLC, resulting in an attenuation of TRAIL resistance in combined treatment. Furthermore, apoptosis was induced in TRAIL-resistant lung cancer cells with a co-treatment of resveratrol and TRAIL assessed by the loss of MMP, ROS generations which resulting the translocation of cytochrome c from the mitochondria into the cytosol due to mitochondrial dysfunction. Moreover, autophagy flux was not affected by resveratrol-induced TRAIL-mediated apoptosis in NSCLC. Significance Overall, targeting the NF-κB (p65) pathway via resveratrol attenuates TRAIL resistance and induces TRAIL-mediated apoptosis which could be the effective TRAIL-based cancer therapy regimen.

Enzyme replacement therapy (ERT) improves the somatic manifestations in mucopolysaccharidoses (MPS))．However, because intravenously administered enzymes cannot cross the blood brain barrier (BBB), ERT is ineffective against the progressive neurodegeneration and resultant severe central nervous system (CNS) symptoms observed in patients with neuronopathic MPS. Attempts to surmount this problem have been made with intrathecal and intracerebroventricular ERT intend to achieve CNS effects, but the burdens on patients are inimical to long-term multiple administrations. However, after pabinafusp alfa, a human iduronate-2-sulfatase fused with a BBB-crossing anti-transferrin receptor antibody, showed both central and peripheral efficacy in mice model, subsequent clinical trials in a total of 62 patients with MPS-II (Hunter syndrome) in Japan and Brazil substantiated this dual efficacy and provided an acceptable safety profile. To date, pabinafusp alfa is the only approved intravenous ERT effective against both the somatic and CNS symptoms of patients with MPS-II. This article summarizes the hitherto obtained preclinical and clinical evidence associated with this drug, and discusses the preclinical, translational and clinical challenges of evaluating, ameliorating and preventing the neurodegeneration in patients with MPS-II.

Drug delivery to the brain represents a challenge especially in the therapy of central nervous system malignancies. Simvastatin (SVT), as other statins, has shown potential anticancer properties that are difficult to exploit in the CNS. In the present work the physico-chemical, mucoadhesive and permeability enhancing properties of simvastatin-loaded poly-ε-caprolactone nanocapsules coated with chitosan for nose-to-brain administration were investigated. Lipid-core nanocapsules coated with different molecular weight (MW) chitosans (LNCchit) prepared by a novel one-pot technique were characterized for particle size, surface charge, particle number density, morphology, drug encapsulation efficiency, interaction between surface nanocapsules with mucin, drug release and permeability across two nasal mucosa models. Results show that all formulations present adequate particle size (below 220 nm), positive surface charge, narrow droplet size distribution (PDI<0.2) and high encapsulation efficiency. Nanocapsules presented controlled drug release and mucoadhesive properties dependent on the MW of the coating chitosan. The results of permeation across RPMI 2650 human nasal cell line evidenced that LNCchit increased the permeation of SVT. In particular, the amount of SVT permeated after 4h for nanocapsules coated with low MW chitosan, high MW chitosan and control SVT was 13.91 ± 0.78 µg, 9.15 ± 1.23 µg and 1.42 ± 0.21 µg respectively. These results were confirmed by the SVT ex vivo permeation across rabbit nasal mucosa. This study highlighted the suitability of LNCchit as promising strategy for the administration of simvastatin for a nose-to-brain approach for the therapy of brain tumors.

The new pandemic coronavirus disease 2019 (COVID-19) is a worldwide threatening health issue. Early progression of this disease starts in the lung airways with an exaggerated inflammation, triggered by the viral infection and characterized by a “cytokine storm” that can lead to lethal lung injuries. In the absence of an effective anti-viral molecule and until the formulation of a successful vaccine, anti-inflammatory drugs might offer a complementary tool for controlling the associated complications and thus decreasing the subsequent fatalities. Drug repurposing for several molecules has emerged as a rapid temporary solution for COVID-19. Among these drugs, Thalidomide, a historically emblematic controversial molecule that harbors an FDA approval for treating Erythema Nodosum Leprosum (ENL) and multiple myeloma (MM). Based on only one-case report of positive outcomes in a patient treated amongst others with Thalidomide, two clinical trials on the efficacy and safety of Thalidomide in treating severe respiratory complications in COVID-19 patients were registered. Conversely, the absence of any substantial, promising evidence on Thalidomide usage in that context along with the discontinued studies on the efficiency of this drug in similar pulmonary diseases might cause a significant obstacle for carrying on clinical studies. In this review, we will discuss the theoretical effectiveness of this drug in attenuating inflammatory complications that are encountered in patients with COVID-19 while pinpointing the lack of evidence that is needed to move forward with this drug.

Brain cancer is the tenth leading cause of death in the U.S. Glioblastoma multiforme (GBM) is the most lethal primary malignant central nervous system tumor in adults. The present study employed samples from 1985-2014 to discover the difference in prognosis among glioblastoma subtypes after the evolution of treatment modalities over the past few years. The current study aims to find the differences between Glioblastoma multiforme (GBM) and giant cell glioblastoma (GCG) in terms of prognosis among adults and elderly patients in the U.S. This study is a historical cohort type of study and is conducted on adults and elderly individuals with GBM or GCG from the years 1985-2014 in the U.S. Data were collected from the Surveillance, Epidemiology, and End Results Program (SEER) database. The study exposure was GBM or GCG and the outcome was mortality. The potential confounders were age, sex, race, ethnicity, year of diagnosis, primary site, and surgery. A chi-square test was used for categorical data. A univariate analysis was used for variables having a p-value < 0.05. Potential confounders were selected and evaluated using multivariate logistic regression models to calculate the odds ratio with stepwise selection. The study sample was 25,117. The incidences of GBM and GCG were not similar in relation to age group. Also, Spanish-Hispanic ethnicity was independently protective of GBM and GCG as compared to Non-Spanish-Hispanic ethnicity patients with GBM have a higher mortality rate than do GCG patients. The mortality rate was higher among patients diagnosed before 2010. In conclusion, GCG was not statistically significant in association to reduced mortality. Non-Spanish-Hispanics with GBM or GCG had a higher mortality rate than did Spanish-Hispanics. Factors such as being female, being age >59, and having a year of diagnosis before 2010 were independently associated with increased mortality.

As the name implies, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a single-stranded RNA virus and a member of the corona virus family, primarily affecting the upper respiratory system and the lungs. Like many other respiratory viruses, SARS-CoV-2 can spread to other organ systems. Apart from causing diarrhea, another most common but debilitating complication caused by the SARS-CoV-2 is neurological symptoms and cognitive difficulties, which occur in up to two thirds of hospitalized covid patients and ranging from shortness of concentration, overall declined cognitive speed to executive or memory function impairment. Neuro-cognitive dysfunction and “brain fog” are frequently present in COVID-19 cases, which can last several months after the infection, leading to disruption of daily life. Cumulative evidence suggests that SARS-CoV-2 affects vasculature in the extra pulmonary systems directly or indirectly, leading to impairment of endothelial function and even multi-organ damage. The post COVID-19 long-lasting neurocognitive impairments have not been studied fully; and the underlying mechanism remains elusive. In this review, we summarize the current understanding of the effects of COVID-19 on vascular dysfunction and how vascular dysfunction leads to cognitive impairment in patients.

Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis (overall survival) in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 72 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival (p=0.014). Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p=0.002) but not in the squamous carcinoma subtype (p=0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.

Without protective and/or therapeutic agents the SARS-CoV-2 infection known as coronavirus disease 2019 (COVID-19) is quickly spreading worldwide. It has surprising transmissibility potential, since it could infect all ages, gender, and human sectors. It attacks respiratory, gastrointestinal, urinary, hepatic, and endovascular systems and can reach the peripheral nervous system (PNS) and central nervous system (CNS) through known and unknown mechanisms. The reports on the neurological manifestations and complications of the SARS-CoV-2 infection are increasing exponentially. Herein, we enumerate seven candidate routes, which the mature or immature SARS-CoV-2 components could use to reach the CNS and PNS, utilizing the within-body crosstalk between organs. The majority of SARS-CoV-2 infected patients suffer from some neurological manifestations (e.g., confusion, anosmia, and ageusia). It seems that although the mature virus did not reach the CNS or PNS of the majority of patients, its unassembled components and/or the accompanying immune-mediated responses may be responsible for the observed neurological symptoms. The viral particles and/or its components have been specifically documented in endothelial cells of lung, kidney, skin, and CNS. This means that the blood-endothelial-barrier may be considered as the main route for SARS-CoV-2 entry into the nervous system, with the barrier disruption being more logical than barrier permeability, as evidenced by postmortem analyses.

Lung cancer is almost the most common cause of cancer death in the world. Clinically, the conventional therapy to eradicate the cancer cells is chemotherapy but a better drug remains required. In this study, the effects of three bufadienolides, kalantuboside B, kalantuboside A and bryotoxin C, isolated from Kalanchoe tubiflora (Harvey) were evaluated and characterized in CL1-5 highly metastatic human lung cancer cells. Contrary to the apoptosis-promoting activity in other cancer cells, these three bufadienolides did not induce apoptosis in CL1-5 cancer cells. Instead, they activated an autophagy pathway, as indicated by the increase of autophagosomes formation. The induction of autophagy by these three bufadienolides was demonstrated to link to down-regulation of p-mTOR as well as up-regulation of LC3-II, ATG5, ATG7, Beclin-1. Moreover, among these three compounds, kalantuboside B in which a monosaccharide is attached at the bufadienolide aglycon, exhibited a better autophagy induction. Our findings revealed an alternative mechanism of drug action by bufadienolides in lung cancer cells and provided evidence for the possibility of treating highly metastatic human lung cancer through an autophagy pathway.

The prevalence of obesity and eating disorders varies by sex, but the extent to which sex influences eating behaviors, especially in childhood, has received less attention. The purpose of this paper is to review the literature on sex differences in eating behavior in children and present new findings supporting the role of sex in child appetitive traits and neural responses to food cues. In children, the literature shows sex differences in basic taste response, food acceptance, eating self-regulation, and appetitive traits. New analyses demonstrate that sex interacts with child weight status to differentially influence appetitive traits and neural responses to food cues. Further, neuroimaging results suggest that obesity in female children is positively related to brain reactivity to higher-energy-dense food cues in regions involved with learning, memory, and object recognition, while the opposite was found in males. In addition to differences in how the brain processes information about food, other factors that may contribute to sex differences include parental feeding practices, societal emphasis on dieting, and peer influences. Future studies are needed to confirm these findings, as they may have implications for the development of effective intervention programs to improve dietary behaviors and prevent obesity.

Pervasive and wide-ranging cognitive deficits are a core feature of schizophrenia and an important determinant of long-term functional outcome. The lack of sufficiently effective treatments for cognitive impairment associated with schizophrenia (CIAS) represents a major unmet need and a central roadblock towards recovery. This is partly due to the current therapeutic focus on clinical symptoms, and the relative neglect of cognitive impairments despite their functionally disabling effects. Furthermore, effective treatment is impeded by our limited knowledge of the complex pathophysiology, which gives rise to perturbed information processing. Here, we review mechanisms and effectiveness of available pharmacological and non-pharmacological treatments for CIAS. Current evidence indicates, that while techniques which broadly enhance neural plasticity show the greatest therapeutic potential, effect sizes are at best moderate. Among other reasons, this is due to a considerable heterogeneity of responses to individual interventions. Furthermore, we discuss how recent conceptual advances in operationalizing cognitive impairments based on cognitive neuroscience have the potential to address these issues and facilitate the development of novel treatment strategies for CIAS. This includes more clearly elucidating pathophysiological mechanisms in both humans and animal models, identifying new treatment targets as well as establishing biomarkers for a better prediction of treatment responses.

The French-Swiss Professor in inductive philosophy Richard Avenarius (1843-1896), the father of empirio-criticism together with Ernst Mach, is one of the most underrated and misunderstood philosophers ever. It mostly depends upon his terminology, which displays an insurmountable difficulty. However, influenced by the most innovative proposals of his times of transition between the idealistic/rationalist legacies and the new Materialism/scientific interpretation of reality – i.e, by cultural evolutionism, linguistics, biomechanics, entropy/energy and, above all, by the newborn experimental psychology-, he produced a complete system of philosophy and innovative methods of investigation of the laws of knowledge. Hints (chunk, scrap, fragments) of his original ideas can be found not only in philosophers of mind after him - such as Gestalt, phenomenalism, behaviourism, functionalism and cybernetics, autopoiesis, dynamical systems theory, embedded/embodied mind, free-energy principle of the brain – but also in recent neuroscientific theories – nervous transduction, electric spikes, cracking of neural code, multisensory integration -. Our aim is to provide the first chronological English summary of his masterpiece, the “Kritik”, to give the possibility to the (almost) totally unaware English speakers to appreciate such a neglected and innovative thinker.

The article describes the rational for inhibition of the angiotensin-converting enzyme 2 (ACE2) pathways as specific targets in patients infected by SARS-CoV-2 in order to prevent the establishment of positive feedback loops triggered by COVID-19 in some predisposed subjects. Making use of a large quantity of published reports in which human/rodent ACE2 pathway inhibitors were administered in vivo, it is hypothesized a possible therapeutic pharmacological intervention through an inhibition strategy of the zinc metalloprotease ACE2 and its downstream pathway for SARS-CoV-2 patients. Of even more interest, metal (zinc) chelators and renin inhibitors (both FDA approved drugs) may also work alone or in combination in inhibiting the positive feedback loops, initially triggered by COVID-19 and subsequently sustained by hypoxia independently on viral trigger, when both arms of renin-angiotensin system (ACE2 and ACE) are upregulated, leading to critical, advanced and untreatable stages of the disease.

Modeling brain dynamics to better understand and control complex behaviors underlying various cognitive brain functions are of interests to engineers, mathematicians, and physicists from the last several decades. With a motivation of developing computationally efficient models of brain dynamics to use in designing control-theoretic neurostimulation strategies, we have developed a novel data-driven approach in a long short-term memory (LSTM) neural network architecture to predict the temporal dynamics of complex systems over an extended long time-horizon in future. In contrast to recent LSTM-based dynamical modeling approaches that make use of multi-layer perceptrons or linear combination layers as output layers, our architecture uses a single fully connected output layer and reversed-order sequence-to-sequence mapping to improve short time-horizon prediction accuracy and to make multi-timestep predictions of dynamical behaviors. We demonstrate the efficacy of our approach in reconstructing the regular spiking to bursting dynamics exhibited by an experimentally-validated 9-dimensional Hodgkin-Huxley model of hippocampal CA1 pyramidal neurons. Through simulations, we show that our LSTM neural network can predict the multi-time scale temporal dynamics underlying various spiking patterns with reasonable accuracy. Moreover, our results show that the predictions improve with increasing predictive time-horizon in the multi-timestep deep LSTM neural network.

Importance: The COVID-19 pandemic is currently accelerating. Patients with locally advanced non-small cell lung cancer (LA-NSCLC) may require treatment in locations where resources are limited and the prevalence of infection is high. Patients with LA-NSCLC frequently present with comorbidities that increase the risk for severe morbidity and mortality from COVID-19. These risks may be further increased by treatments for LA-NSCLC. Observation: We present expert thoracic oncology multidisciplinary (radiation oncology, medical oncology, surgical oncology) consensus of alternative strategies for the treatment of LA-NSCLC during a pandemic. The overarching goals of these approaches are to reduce the number of visits to a healthcare facility, reduce the risk of SARS-CoV-2 exposure, and attenuate the immunocompromising effects of lung cancer therapies. Patients with resectable disease can be treated with definitive non-operative management if surgical resources are limited or the risks of perioperative care are high. Non-operative options include chemotherapy, chemoimmunotherapy, and radiation therapy with sequential schedules. The order of treatments may be based on patient factors and clinical resources. Whenever radiation therapy is delivered without concurrent chemotherapy, hypofractionated schedules are appropriate. For patients who are confirmed to have COVID-19, usually cancer therapies may be withheld until symptoms have resolved with negative viral test results. Conclusions and Relevance: The risk of severe treatment-related morbidity and mortality is significantly elevated for patients undergoing treatment for LA-NSCLC during the COVID-19 pandemic. Adapting alternative treatment strategies as quickly as possible may save lives and should be implemented through communication with the multidisciplinary cancer team.

This study investigated the risk of lung and bladder cancers in people residing in proximity of a coal-oil-fired thermal power plant in an area of north-eastern Italy, covered by a population-based cancer registry. Incidence rate ratios (IRR) by sex, age, and histology were computed according to tertiles of residential exposure to benzene, nitrogen dioxide (NO2), particular matter, and sulfur dioxide (SO2) among 1076 incident cases of lung and 650 cases of bladder cancers. In men of all ages and in women under 75 years of age, no significant associations were observed. Conversely, in women aged >75 years significantly increased risks of lung and bladder cancers were related to high exposure to benzene (IRR for highest vs. lowest tertile: 2.00 for lung cancer and 1.94 for bladder cancer) and NO2 (IRR: 1.72 for lung cancer; and 1.94 for bladder cancer). In these women, a 1.71-fold higher risk of lung cancer was also related to a high exposure to SO2. The findings of this descriptive study indicated that air pollution may have a role with regard to the risk of lung and bladder cancers, limited to women aged ≥ 75 years. Such increased risk warrants further analytical investigations.

To understand lung damage caused by COVID-19, we deduced two-phase lung damage mechanisms. After the lungs are infected with SARS-CoV-2 virus, the affected lung tissue swells and surface properties of pulmonary capillaries change, resulting in an increased flow resistance of affected capillaries. If a sufficient number of capillaries are affected by the infection, the swelling and increased cell wall adhesion collectively raise pulmonary vascular resistance. The increased vascular resistance further increases the dwell times of WBCs in affected capillaries and nearly capillaries. When pulmonary pressure is sufficiently higher, WBCs are forced to squeeze into interstitial spaces or alveolar spaces when local pressures are higher than what the capillaries can withstand. When more and more WBCs are dynamically retained, the flow resistance of more capillaries rises, pulmonary vascular resistance rises, and pulmonary pressure rises. The rise in the pulmonary pressure in turn results in elevated capillary pressures. When capillary pressures around the alveoli are sufficiently high, they cause interstitial pressures to change from normally negative values to positive values. The positive pressures cause fluid leakage to the alveolar space and thus degrade lung function. Tissue swelling, and occupation of WBCs in interstitial spaces and alveolar spaces further reduce compressible volume, and thus cause further rise in the pulmonary vascular resistance and pulmonary pressure. When the pulmonary pressure has reached a critical point as in the second phase, the blood breaks capillary walls and squeezes through interstitial spaces to reach alveolar spaces, resulting in irreversible lung damages. The available free volume in the thorax cage, organ usable capacities, temperature and humid are expected to have great impacts on degree of lung damages. The free volume in the thorax cage, lung usable surplus capacity, and other organ usable capacities determine the arrival time of last-phase irreversible damage. The mechanisms imply that the top priority for protecting lungs is maintaining pulmonary micro-circulation and preserving organ functions in the entire disease course while controlling viral reproduction should be stressed in the earliest time possible. The mechanisms also explain leukecytes are recruited and migrated into inflamed tissues by increasing their dwell times caused by increased local flow resistance.

Both lung adenocarcinoma and SARS-CoV-2 infection could cause pulmonary inflammation. Angiotensin-converting enzyme 2, not only as the functional receptor of SARS-CoV-2 but also play key role in lung adenocarcinoma. To study the risk of SARS-CoV-2 infection in lung adenocarcinoma patients, mRNA and miRNA profiles were obtained from TCGA and GEO databases followed by bioinformatics analysis. A regulatory network which regards angiotensin-converting enzyme 2 as the center would be structured. In addition, via immunological analysis about key factors in lung adenocarcinoma patients, to explore the essential reasons for the susceptibility of SARS-CoV-2. Compared with normal tissue, angiotensin-converting enzyme 2 was increased in lung adenocarcinoma patients. Furthermore, a total of 7 differently expressed correlated mRNAs (ACE2, CXCL9, MMP12, IL6, AZU1, FCN3, HYAL1 and IRAK3) and 5 differently expressed correlated miRNAs (miR-125b-5p, miR-9-5p, miR-130b-5p, miR-381-3p and miR-421) were screened followed by enrichment analysis. Interestingly, toll-like receptor signaling pathway with the most frequent occurrence was enriched by mRNA (IL6) and miRNA (miR-125b-5p) sets simultaneously. Finally through comprehensive analysis, it was assumed that miR-125b-5p-ACE2-IL6 axis in the structured regulatory network could alter risk of SARS-CoV-2 infection in lung adenocarcinoma patients.

The incidence of lung cancer has increased in recent years and causes major mortalities across the globe. Besides, the availability of the several chemotherapeutics modalities in the management, there is still a challenge to find out an efficient remedy with lesser or no toxic effects. Hence, there is a necessity to employ complementary research to establish effective management for lung cancer. In this study, we have implemented a novel herbal informatics model to find out the alternative remedy in the treatment of lung cancer. This model utilizes five major steps of the bioprospection process based on the classical surge followed by the binary index and rationale-based selection of herbal products targeting the cancer-causing factors which are explained in detail in the methodology section of this model. This study revealed 07 herbals such as Withania somnifera (Ws), Berberis vulgaris(Bv), Glycyrrhiza glabra(Gg), Andrographis paniculate(Ap), Azadirachta indica(Ai), Cinnamomum Verum(Cv), Piper longum(Pl) based on the fuzzy set optimization scoring(0.6-1) that could be further studied in vitro and in vivo level for utilization in the management of lung cancer.

To understand great disparities in disease outcomes between CIVID-19 patients, we explore infection and host responses in kinetics. From existing data, we deduced a model that the lungs are damaged by rapidly rising flow resistance as a result of retaining white blood cells in lung tissues. The retention of white blood cells is initially triggered by viral infection but aggravated by injuries caused by low temperature. Lungs are initially damaged by fluid leakage, rapidly followed by extruding blood into alveolar spaces. The step of blood extruding is predicted to take place in a very short time. Our simulations show that as little as 0.1% retention of white blood cells in the lungs can lead to their failure in 5 to 10 days. The small degrees of imbalance implies that this imbalance could be corrected by a large number of factors that are known to reduce flow resistance. The model implies that the top priority is maintaining blood micro-circulation and preserving organ functions in the entire disease course, especially after the virus has spread the whole lungs. From exploring a large number of hypothetical infection modes, we propose preventive, mitigating and treatment strategies for ultimately ending the pandemic. The first strategy is avoiding exposures that could result in widespread damages to lungs and taking post exposure mitigating measures that would reduce disease severity. The second strategy is reducing death rate and disability rate from the current levels to one tenth for infected patients by using multiple factors health optimization method. The double reduction strategies are expected to generate a series of chain reactions that favor mitigating or ending the pandemic. Some reactions include a big reduction of the amount of viral discharges from infected patients into the air, the avoidance of panic, chronic stress and emotional distress, and cross-infections which are expected in quarantines. The double reductions would have a final effect of ending the pandemic.

Omega-3 polyunsaturated fatty acids (ω3-PUFAs), including docosahexaenoic acid (DHA), have been shown to exert anticancer effects by inducing apoptotic cell death. However, the mechanism for DHA-induced cell death in lung cancer is not fully understood. Here, we show that DHA induces apoptosis in two human EGFR mutant non-small cell lung cancer (NSCLC) cell lines, and that DHA-induced cell death is accompanied by SIRT6 activation and attenuated Hedgehog (Hh) signaling. Knockdown of SIRT6 using siRNAs inhibited DHA-induced apoptosis, whereas SIRT6 overexpression increased apoptotic cell death. DHA-induced SIRT6 activation was associated with downregulation of Hh signaling, and knockdown of SIRT6 resulted in augmentation of Hh signaling. Pretreatment of NSCLC cells with a Smoothened agonist prevented DHA-induced decreases in the levels of Hh signaling proteins and increases in cleaved PARP levels. Moreover, endogenous production of ω3-PUFAs in PC9 cells via fat-1 expression resulted in elevated SIRT6 levels and reduced levels of Hh signaling molecules, including Gli, following DHA treatment. Overall, these results implicate that ω3-PUFAs induce apoptosis by downregulating Hh signaling via SIRT6 activation in human EGFR mutant NSCLC cells. These findings suggest that ω3-PUFAs potentially represent an effective therapy for the chemoprevention and treatment of NSCLC.

This review focuses on the evidence for neurotherapeutics for Attention Deficit Hyperactivity Disorder (ADHD). EEG-Neurofeedback has been tested for about 45 years with latest meta-analyses of randomised controlled trials (RCT) showing small/medium effects compared to non-active controls only. Three small studies piloted neurofeedback of frontal activations in ADHD using functional magnetic resonance imaging or near-infrared spectroscopy, finding no superior effects over control conditions. Brain stimulation has been applied to ADHD using mostly repetitive transcranial magnetic and direct current stimulation (rTMS/tDCS). rTMS has shown mostly negative findings on improving cognition or symptoms. Meta-analyses of tDCS studies targeting mostly dorsolateral prefrontal cortex show small effects on cognitive improvements with only two out of three studies showing clinical improvements. Trigeminal nerve stimulation has shown to improve ADHD symptoms with medium effect in one RCT. Modern neurotherapeutics are attractive due to their relative safety and potential neuroplastic effects. However, they need to be thoroughly tested for clinical and cognitive efficacy across settings and beyond core symptoms and for their potential for individualised treatment.

Background: Lung CT provides an effective modality to evaluate patients with suspected COVID-19. However, overlapping imaging findings with cardiogenic pulmonary oedema have been reported. Reports comparing lung CT features of these diseases have not been elaborated. Thus, we aimed to investigate these gaps in the knowledge regarding low-dose lung CT features of patients with COVID-19 pneumonia with those with acute heart failure (HF). Methods: This retrospective analysis enrolled hospitalized patients with COVID-19 (n=10) and acute heart failure (n=9) that exclusively underwent low-dose lung CT scans within 24-hours of admission. Clinical and lung CT characteristics were collected and analysed. Results: Ground-glass-opacities (GGO) appearance has been recorded in all subjects in HF and COVID-19 group. There was no significant statistical difference between the two groups for rounded morphology, consolidation, crazy paving pattern, lesion distribution, parenchymal band (P> 0.05). However, diffuse lesions were more frequent in HF cases (55.6% vs. 0%) than in COVID-19 pneumonia, which had predominantly multifocal pattern. Notably, CT images in HF patients were more likely to have signs of interstitial tissue thickening such as the interlobular septums, fissures and peribronchovascular interstitium (55.6% vs 0%, 88.9% vs 20% and 44.4% vs 0%,respectively), as well as cardiomegaly (77.8% vs 0%), increased artery to bronchus ratio (55.6% vs 0%), and pleural effusions (77.8% vs 0%). Conclusions: Major overlaps of lung CT imaging features existed between COVID-19 pneumonia and acute HF cases. However, signs of fluid redistribution are clues that favour HF over COVID-19 pneumonia.

Hereditary Parkinson’s disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response. We demonstrated the combination of PINK1-knockout with overexpression of SNCAA53T in double mutant (DM) mice to exacerbate locomotor deficits and to reduce lifespan. To survey posttranslational modifications of proteins underlying the pathology, brain hemispheres of old DM mice underwent quantitative label-free global proteomic mass spectrometry, focused on Ser/Thr-phosphorylations. As exceptionally strong effect, we detected >300-fold reductions of phosphoThr1928 in MAP1B, a microtubule-associated protein, and a similar reduction of phosphoSer3781 in ANK2, an interactor of microtubules. MAP1B depletion is known to trigger perturbations of microtubular mitochondria trafficking, neurite extension and synaptic function, so it was noteworthy that relevantly decreased phosphorylation was detected also for other microtubule and microfilament factors, namely MAP2S1801, MARK1S394, MAP1AT1794, KIF1AS1537, 4.1NS541, 4.1GS86 and ADD2S528. While the MAP1B heavy chain supports regeneration and growth cones, its light-chain assists DAPK1-mediated autophagy. Interestingly, relevant phosphorylation decreases of DAPK2S299, VPS13DS2429 and VPS13CS2480 in the DM brain affected regulators of autophagy, which are implicated in PD. Overall, significant downregulations were enriched for PFAM C2 domains, other kinases, and synaptic transmission factors upon automated bioinformatics, while upregulations were not enriched for selective motifs or pathways. Validation experiments confirmed the change of LC3 processing as reflection of excessive autophagy in DM brain, and dependence of ANK2/MAP1B expression on PINK1 levels. Our new data provide independent confirmation in a mouse model with combined PARK1/PARK4/PARK6 pathology that MAP1B/ANK2 phosphorylation events are implicated in Parkinsonian neurodegeneration. These findings expand on previous observations in D. melanogaster that the MAP1B ortholog futsch in the presynapse is a primary target of the PARK8 protein LRRK2, and on a report that MAP1B is a component of the pathological Lewy body aggregates in PD patient brains. Similarly, ANK2 gene locus variants are associated with the risk of PD, ANK2 interacts with PINK1/Parkin-target proteins such as MIRO1 or ATP1A2, and ANK2-derived peptides are potent inhibitors of autophagy.

Although several plant-derived drug groups (vinca alkaloids, taxanes, podophyllotoxin derivatives and camptothecins) continue to be widely used in cancer therapy, the anticancer potential of the Plant Kingdom remains largely unexplored. In this work, we have carried out a random screening for selective anticancer activity of 57 extracts from 45 plants collected in Grazalema Natural Park, an area in the South of Spain of high plant diversity and endemism. Using lung cancer cells (A549) and lung non-malignant cells (MRC-5), we found that several extracts were more cytotoxic and selective against the cancer cell line than the standard anticancer agent cisplatin. Five active extracts were further tested in cancer and normal cell lines from other tissues, including three skin cell lines with increasing degree of malignancy. An extract from the leaves of Daphne laureola L. (Thymelaeaceae) showed a striking potency and selectivity on lung cancer cells and leukemia cells; the IC₅₀ values against these cancer cells were approximately 10000-fold lower than against the normal cells. Daphnane-type diterpene orthoesters may be responsible for this highly selective anticancer activity.

A frequent co-morbidity of cerebrovascular pathology and Alzheimer's disease pathology has been observed over past decades. Accordingly, much evidence has been reported which indicates that microvascular endothelial dysfunction, due to cerebrovascular risk factors (e.g., atherosclerosis, obesity, diabetes, smoking, hypertension, aging), precedes cognitive decline in Alzheimer's disease and contributes to its pathogenesis. By incorporating appropriate drug(s) into biomimetic (lipid cubic phase) nanocarriers, one obtains a multitasking combination therapeutic which targets certain cell-surface scavenger receptors, mainly class B type I (i.e., SR-BI), and crosses the blood-brain barrier (BBB). Such targeting allows for various Alzheimer's-related cell types to be simultaneously searched out, in vivo, for localized drug treatment. This in vivo targeting advantage may be particularly important for repurposing an FDA-approved drug, especially one which has shown the added ability to restore some cognitive functions in certain animal models of Alzheimer's disease (e.g., the anticancer drug bexarotene); this (candidate repurposing) drug up to now, by itself (i.e, without nanocarrier), displayed poor CNS penetration in human subjects.

Neural microprobes represent an important component of neural prosthetic systems where implanted microprobes record the electro-potentials generated by specific thoughts in the brain and convey the signals to algorithms trained to interpret these thoughts. Here, we present novel elongated multi-site neural probe that can reach depths greater than 10mm. We hypothesize that reaching such depth allows the recording of cognitive signals required to drive cognitive prosthetics. The impedance of the recording sites on the probes was on the order of 500 kΩ at 1 kHz, which is consistent with probes used for neurophysiological recordings. The probes were made porous using Xenon Difluoride (XeF₂) dry etching to improve the biocompatibility and their adherence to the surrounding neural tissue. Numerical studies were performed to determine the reliability of the porous probes. We implanted the elongated probe in rats and show that the elongated probes are capable of simultaneously recording both spikes and local field potentials (LFPs) from various recording sites.

Type 2 diabetes mellitus (T2DM) and late-onset Alzheimer’s disease-dementia (LOAD) are increasing in global prevalence and current predictions indicate they will only increase over the coming decades. These increases may be a result of the concurrent increases of obesity and aging. T2DM is associated with cognitive impairments associated with metabolic factors and increases the cellular vulnerability to develop the age-related increased risk of LOAD. This review addresses possible mechanisms due to obesity, aging, multiple intersections between T2DM and LOAD and mechanisms for the continuum of progression. Multiple ultrastructural images in female diabetic db/db models are utilized to demonstrate marked cellular remodeling changes of mural and glia cells and provide for the discussion of functional changes in T2DM. Throughout this review multiple endeavors to demonstrate how T2DM increases the vulnerability of the brain’s neurovascular unit (NVU), neuroglia and neurons are presented. Five major intersecting links are considered: i. aging (chronic age-related diseases); ii. metabolic (hyperglycemia - advanced glycation end-products and its receptor (AGE/RAGE) interactions and hyperinsulinemia – insulin resistance (a linking linchpin); iii. oxidative stress (reactive oxygen-nitrogen species); iv. inflammation (peripheral macrophage and central brain microglia); v. vascular (macrovascular accelerated atherosclerosis - vascular stiffening and microvascular NVU/neuroglial remodeling) with resulting impaired cerebral blood flow.

In Kenya, millions of children have limited access to nurturing care. With the COVID-19 pandemic, it is anticipated that vulnerable children will bear the biggest brunt of the direct and indirect impacts of the pandemic. This review aimed to deepen understanding of the effects of COVID-19 on nurturing care from conception to four years of age, a period where the care of children is often delivered through caregivers or other informal platforms. The review has drawn upon the empirical evidence from previous pandemics and epidemics, and anecdotal and emerging evidence from the ongoing COVID-19 crisis. Multifactorial impacts fall into five key domains: direct health; health and nutrition systems, economic, social and child protection, and child development and early learning. The review proposes program and policy strategies to guide the re-orientation of nurturing care, prevent the detrimental effects associated with deteriorating nurturing care environments, and support the optimal development of the youngest and most vulnerable children. These include the provision of cash transfers and essential supplies for vulnerable households, and strengthening of community-based platforms for nurturing care. Further research on COVID-19 and the ability of children’s ecology to provide nurturing care is needed, as is further testing of new ideas.

Background: Post-traumatic stress disorder (PTSD) is a common debilitating psychiatric condition for which pharmacological therapy is not always solvable. Various treatments have been suggested for these patients. Deep brain stimulation (DBS) is currently under investigation for patients affected by PTSD. 2) Methods: We review the neurocircuitry and up to date clinical concepts that may be of relevance for the implementation of DBS in posttraumatic stress disorder (PTSD). 3) Results: The role of DBS in treatment-refractory PTSD patients has been investigated relying on both preclinical and clinical studies. 4) Conclusions: DBS for PTSD is in its preliminary phases and likely to provide hope to patients with medical refractory PTSD following the results of randomized controlled studies.

Cachexia is a complex metabolic syndrome characterized by loss of skeletal muscle, leading to a significant weight loss that impacts patient morbidity and mortality. Given the complexity of gene regulatory networks that control gene expression, our objective was to perform an integrative mRNA and miRNA profiling to identify genetic programs that capture essential mechanistic details that promote muscle atrophy in cancer cachexia. Here, we used RNA sequencing to analyze miRNAs and mRNAs expression profiles in tibialis anterior (TA) muscles of the Lewis lung carcinoma model of cancer cachexia. In addition, we compared these findings with RNA-Seq data from C2C12 myotubes treated in vitro with the cachectic factors tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). Extracellular matrix (ECM) alterations were validated by picrosirius staining, western blot, and fractal dimension analyses. We found 1,008 mRNAs and 18 miRNAs differentially expressed in cachectic mice. This set of genes was associated with the ECM, proteolysis, and inflammatory response. Enrichment analysis of transcriptional factor binding sites revealed activation of the atrophy-related transcriptional factors: NF-κB, Stat3, AP-1, and FoxO. Furthermore, the integration of mRNA and miRNA expression profiles identified post-transcriptional regulation by miRNAs of genes involved in ECM organization, cell migration, transcription factors binding, ion transport, and FoxO signaling pathway. C2C12 myotubes treated with TNF-α and IFN-γ similarly down-regulate subsets of ECM genes, including collagens. Our integrative analysis of miRNA-mRNA co-profiles comprehensive characterized regulatory relationships of molecular pathways and revealed miRNAs targeting ECM-associated genes in cancer cachexia. We also confirmed in C2C12 myotubes that changes in ECM-associated genes are dependent on inflammatory signaling of the cytokines TNF-α and IFN-γ.

Recent research has revealed surprisingly important connections between animals’ microbiome and social behaviour. Social interactions can affect the composition and function of the microbiome; conversely, the microbiome affects social communication by influencing the hosts’ central nervous system and peripheral chemical communication. These discoveries set the stage for novel research venues focusing on the evolution and physiology of animal social behaviour in relation to microbial transmission strategies. Here, we discuss the emerging roles of teleost fish model candidates and their key potential for advancing research fields linked to sociality and microbial regulation. We argue that fish models, such as the zebrafish, sticklebacks, guppies and cleaner-client dyads, will provide valuable insights into the roles of microbiome in shaping social behaviour and vice versa, while also being of direct relevance to the food and ornamental fish trades.

The CCAAT/enhancer-binding protein β (C/EBPβ) is a transcription factor that regulates cellular proliferation, differentiation, apoptosis and tumorigenesis. Although the pro-oncogenic roles of C/EBPβ have been implicated in various human cancers, how it contributes to tumorigenesis or tumor progression has not been determined. Immunohistochemistry with human non-small cell lung cancer (NSCLC) tissues revealed that higher levels of C/EBPβ protein are expressed compared to normal lung tissues. Knockdown of C/EBPβ by siRNA reduced the proliferative capacity of NSCLC cells by delaying G₂/M transition of the cell cycle. In C/EBPβ-knockdown cells, a prolonged increase in phosphorylation of cyclin dependent kinase 1 at tyrosine 15 (Y15-pCDK1) was displayed with increased Wee1 and decreased Cdc25B expression, simultaneously. ChIP analysis showed that C/EBPβ bound to distal promoter regions of WEE1 and repressed WEE1 transcription through the interaction with histone deacetylase 2. Treatment of C/EBPβ-knockdown cells with a Wee1 inhibitor induced a decrease in Y15-pCDK1 and recovered cells from G₂/M arrest. In the xenograft tumors, the depletion of C/EBPβ significantly reduced tumor growth. Taken together, these results indicate that Wee1 is a novel transcription target of C/EBPβ that is required for the G₂/M phase of cell cycle progression, ultimately regulating proliferation of NSCLC cells.

How can neuroscience help everyone to live and care for our confined brains? Understanding and studying human behaviour allows us to measure the impact of such confinement on each of us and to identify those who need help. The challenges are to understand the psychological repercussions following confinement and to understand how neuroscience and neurotechnology can be very interesting tools for dealing with the health crisis. Neuroscience is changing our traditional philosophical and ethical views by providing information about the biological basis of our moral behaviour. The exception of the brain is at the heart of neuroethical thinking and discourse. Neuroethics is an interdisciplinary discipline placed at the intersection between the human sciences and the neurosciences, and aims to help understand how knowledge and research in neurosciences and neurotechnologies will affect the future of society, their impact on humans, relationships, daily life, the labour market ... but also how they can help and provide solutions and answers to the questions of citizens in a health crisis. But it's a double-edged sword, collecting and analyzing brain data in real time seems to be increasingly simple and within everyone's reach, without having the hindsight of the real meaning of these data, allowing one day to read people's thoughts, control them and manipulate them. It is becoming clear that the boundaries between medical and non-medical uses of neuroscience and neurotechnology are becoming very porous, inviting us to reflect on neuroethical issues in order to put safeguards on these uses.

In the last years evidence has emerged that neurodegenerative diseases (NDs) are strongly associated with the microbiome composition in the gut. Parkinson’s disease (PD) is the most intensively studied neurodegenerative disease in this context. In this review, we performed a systematic evaluation of published literature comparing changes in colonic microbiome in PD to the ones observed in other NDs including Alzheimer’s Disease (AD), Multiple system atrophy (MSA), Multiple sclerosis (MS), Neuromyelitis optica (NMO) and Amyotrophic lateral sclerosis (ALS). To warrant comparability of different studies, only human case-control studies were included. Several studies showed an increase of Lactobacillus, Bifidobacterium, Verrucomicrobiaceae and Akkermansia in PD. A decrease in PD was observed of Faecalibacterium spp., Coprococcus spp., Blautia spp., Prevotella spp. and Prevotellaceae. On low taxonomic resolution, like phylum level, the changes are not disease specific and inconsistent. However, on higher taxonomic resolution like genus or species level, a minor overlap was observed between PD and MSA, both alpha synucleinopathies. We show that a methodical standardization of sample collection and analysis is necessary for ensuring the reproducibility and comparability of data. We also provide the evidence, that assessing the microbiota composition at high taxonomic resolution, reveals changes in relative abundance, that may be specific or characteristic for one disease, or a disease-group and might evolve discriminative power. The interactions between bacterial species and strains and moreover the co-abundances must be more deeply investigated before assumptions of the effects of specific bacteria on the host can be made with certainty.

Here, we review findings and trends in sleep research in 2020-2021 demonstrating how COVID-19 and sleep disorders can induce the BBB leakage via neuroinflammation, which might contribute to the 'coronasomnia' phenomenon. The new studies suggest that the controlling of sleep hygiene and quality should be incorporated into the rehabilitation of COVID-19 patients. We also discuss perspective strategies for prevention of COVID-19-related BBB disorders. We demonstrate that sleep might be a novel biomarker of the BBB leakage and the analysis of sleep EEG patterns can be a breakthrough non-invasive technology for diagnosis of the COVID-19-caused BBB disruption.

Computers and artificial intelligence affect every field of life nowadays. In medical image interpretation automatic decision making using algorithms are used increasingly in every sub-field and computer aided diagnosis (CAD) is one of the main tools available to medical science today. CAD systems are used as an augmented option for both the medical practitioner and the patients, with image analysis and interpretation being of primary importance. In particular, spatial relations are used in knowledge representation, and these relations can be used for effective medical image interpretation. In this paper, we put forth an algorithm for defining non-small cells lungs cancer (NSCLC) stages in lungs images interpretation using topological spatial relations. We show an application case study in event motion predictions for lung cancer staging scoring - tumor, nodes and metastasis (TNM) - with combined topological and directional relations.

Intranasal (i.n.) administration became an alternative strategy to bypass the blood-brain barrier and improve drug bioavailability in the brain. The main goal of this work was to preliminarily study the biodistribution of mixed amphiphilic mucoadhesive nanoparticles made of chitosan-g-poly(methyl methacrylate) and poly(vinyl alcohol)-g-poly(methyl methacrylate) and ionotropically crosslinked with sodium tripolyphosphate in the brain after intravenous (i.v.) and i.n. administration to Hsd:ICR mice. After i.v. administration, the highest nanoparticle accumulation was detected in the liver, among other peripheral organs. After i.n. administration of a 10-times smaller nanoparticle dose, the accumulation of the nanoparticles in off-target organs was much lower than after i.v. injection. In particular, the accumulation of the nanoparticles in the liver was 20 times lower than by i.v. When brains were analyzed separately, intravenously administered nanoparticles accumulated mainly in the “top” brain, reaching a maximum after 1h. Conversely, in i.n. administration, nanoparticles were detected in the “bottom” brain and the head (maximum reached after 2 h) owing to their retention in the nasal mucosa and could serve as a reservoir from which the drug is released and transported to the brain over time. Overall results indicate that i.n. nanoparticles reach similar brain bioavailability, though with a 10-fold smaller dose, and accumulate in off-target organs to a more limited extent and only after redistribution through the systemic circulation. At the same time, both administration routes seem to lead to differential accumulation in brain regions and thus, they could be beneficial in the treatment of different medical conditions.

Lung cancer is one of the most important health risks worldwide for human. Non-small cell lung cancer (NSCLC) is the most common cause of premature death from malignant disease. This study provides in-depth insights from systems biology analyses to identify molecular to inform systemic drug targeting in NSCLC. Gene expression profiles from non small cell lung cancer were analyzed with genome-scale biomolecular networks (I,e., protein-protein interaction, transcriptional and post transcriptional regulatory networks). The aim of the study was to determine the pathways and expression profile of the genes to discover molecular signature at RNA and protein levels which could serve as potential drug targets for therapeutics innovation and the identification of novel targets. Eight proteins, six TFs and seven miRNAs came into prominence as potential drug targets. The differential expression profiles of these reporter biomolecules were cross-validated by independent RNA-Seq and miRNA-Seq. Risk discrimination performance of the reporter biomolecules NPR3, JUN, PPARG, TP53, CKMT1A, SP3 and TFAP2A were also evaluated. Total 213 drugs and 7 proteins were found for non small cell lung cancer through dgidb. Among these identified drugs seven drugs such as- Gemcitabine, Carboplatin, paclitaxel, Docetaxel, Crizotinib, Bevacizumab and Gemcitabine is used for NSCLC which is approved by National Cancer Institute. The molecular signatures and repurposed drugs presented here permit further attention for experimental studies which are offer significant potential as biomarkers and candidate therapeutics for precision medicine approaches to clinical management of NSCLC.

During mechanical ventilation, a disparity between flow, pressure or volume demands of the patient and the assistance delivered by the mechanical ventilator often occurs. Asynchrony effect and ventilator performance are frequently studied from ICU datasets or using commercially available lung simulators and test lungs. This paper introduces an alternative approach of simulating and evaluating patient-ventilator interactions with high fidelity using the electro-mechanical lung simulator xPULM™ under selected conditions. The xPULM™ approximates respiratory activities of a patient during alternating phases of spontaneous breathing and apnoea intervals while connected to a mechanical ventilator. Focusing on different triggering events, volume assist-controlled (V/A-C) and pressure support ventilation (PSV) modes were chosen to test patient-ventilator interactions. In V/A-C mode a double-triggering was detected every third breathing cycle leading to an asynchrony index of 16.67%, being classified as severe. This asynchrony causes a major increase of Peak Inspiratory Pressure PIP = 12.80 ± 1.39 cmH2O and Peak Expiratory Flow PEF = -18.33 ± 1.13 L/min when compared to synchronous phases of the breathing simulation. Additionally, events of premature cycling were observed during PSV mode. In this mode, the peak delivered volume during simulated spontaneous breathing phases almost doubles compared to apnoea phases. The presented approach demonstrates the possibility of simulating and evaluating disparities in fundamental ventilation characteristics caused by double-triggering and premature cycling under V/A-C and PSV ventilation modes. Various dynamic clinical situations can be approximated and could help to identify undesired patient-ventilation interactions in the future. Rapidly manufactured ventilator systems could also be tested using this approach.

We discuss what we believe could be an improvement in future discussions of the ever-changing brain. We do so by distinguishing different types of brain variability and outlining methods suitable to analyse them. We argue that, when studying brain and behaviour data, classical methods such as regression analysis and more advanced approaches both aim to decompose the total variance into sensible variance components. In parallel, we argue that a distinction needs to be made between innate and acquired brain variability. For varying high-dimensional brain data, we present methods useful to extract their low-dimensional representations. Finally, to trace potential causes and predict plausible consequences of brain variability, we discuss how to combine statistical principles and neurobiological insights to make associative, explanatory, predictive, and causal enquires; but cautions are needed to raise association- or prediction-based neurobiological findings to causal claims.

A growing area in neurosciences is focused on the modeling and analysis the complex system of connections in neural systems, i.e. the connectome. Here we focus on the representation of connectomes by using graph theory formalisms. The human brain connectomes are usually derived from neuroimages; the analyzed brains are co-registered in the image domain and brought to a common anatomical space. An atlas is then applied in order to define anatomically meaningful regions that will serve as the nodes of the network - this process is referred to as parcellation. Recently, it has been proposed to perform atlas-free random brain parcellation into nodes and align brains in the network space instead of the anatomical image space to define network nodes of individual brain networks. In the network domain, the question of comparison of the structure of networks arises. Such question is tackled by modeling the comparison of brain network as a network alignment (NA) problem. In this paper, we first defined the NA problem formally, then we applied three existing state of the art of multiple alignment algorithms (MNA) on diffusion MRI-derived brain networks and we compared the performances. The results confirm that MNA algorithms may be applied in cases of atlas-free parcellation for a fully network-driven comparison of connectomes.

Blood-brain-barrier is a major obstacle in treating brain-related disorders as it does not allow to deliver drugs in the brain. In order to facilitate delivery of drugs in brain, we developed a method for predicting blood-brain-barrier penetrating peptides. These blood-brain barriers penetrating peptides (B3PPs) can act as therapeutic as well as drug delivery agents. We trained, tested, and evaluated our models on blood-brain-barrier peptides obtained from the B3Pdb database. First, we compute a wide range of peptide features then we select relevant peptide features. Finally, we developed numerous machine learning-based models for predicting blood-brain-barrier peptides using selected features. Our model based on random forest performed best on the top 80 selected features and achieved a maximum 85.08% accuracy with 0.93 AUROC. We also developed a web server, B3pred that implements our best models. It has three major modules that allow users to; i) predict B3PPs, ii) scanning B3PPs in a protein sequence, and iii) designing B3PPs using analogs. Our web server and standalone software is freely available at https://webs.iiitd.edu.in/raghava/b3pred/.

Traumatic brain injury (TBI) can result in persistent sensorimotor and cognitive deficits, which occur through a cascade of deleterious pathophysiological events over time. In this study, we investigated the hypothesis that neurodegeneration caused by TBI leads to impairments in sensorimotor function. TBI induces the activation of the caspase-3 enzyme, which triggers cell apoptosis in an in vivo model of fluid percussion injury (FPI). We analyzed caspase-3 mediated apoptosis by TUNEL staining and PARP and annexin V western blotting. We correlated the neurodegeneration with sensorimotor deficits by conducting the animal behavioral tests including grid walk, balance beam, inverted screen test, and climb test. Our study demonstrated that the excess cell death or neurodegeneration correlated with the neuronal dysfunction and sensorimotor impairments associated with TBI.

Cancer cell lines are widely used as in vitro models of tumorigenesis, facilitating fundamental discoveries in cancer biology and translational medicine. Currently, there are few options for glioblastoma (GBM) treatment and limited in vitro models with accurate genomic and transcriptomic characterization. Here, a detailed characterization of a new GBM cell line, namely AHOL1, was conducted in order to fully characterize its molecular composition based on its copy number alteration (CNA) and transcriptome profiling, followed by the validation of key elements associated with GBM tumorigenesis. Large numbers of CNAs and differentially expressed genes (DEGs) were identified. CNAs were distributed throughout the genome, including gains at Xq11.1-q28, Xp22.33-p11.1, Xq21.1-q21.33, 4p15.1-p14, 8q23.2-q23.3 and losses at Yq11.21-q12, Yp11.31-p11.2 and 12p13.31 positions. Nine druggable genes were identified, including HCRTR2, ETV1, PTPRD, PRKX, STS, RPS6KA6, ZFY, USP9Y and KDM5D. By integrating DEGs and CNAs, we identified 57 overlapping genes enriched in fourteen pathways. Altered expression of several cancer-related candidates found in the DEGs-CNA dataset was confirmed by RT-qPCR. Taken together, this first comprehensive genomic and transcriptomic landscape of AHOL1 provides unique resources for further studies and identifies several druggable targets that may be useful for therapeutics and biologic and molecular investigation of GBM.

This paper proposes several LabVIEW applications to accomplish the data acquisition, processing, features extraction and real-time classification of the electroencephalographic (EEG) signal detected by the embedded sensor of the NeuroSky Mindwave Mobile headset. The LabVIEW applications are aimed at the implementation of a Brain-Computer Interface system, which is necessary to people with neuromotor disabilities. It is analyzed a novel approach regarding the preparation and automatic generation of the EEG dataset by identifying the most relevant multiple mixtures between selected EEG rhythms (both time and frequency domains of raw signal, delta, theta, alpha, beta, gamma) and extracted statistical features (mean, median, standard deviation, route mean square, Kurtosis coefficient and others). The acquired raw EEG signal is processed and segmented into temporal sequences corresponding to the detection of the multiple voluntary eye-blinks EEG patterns. The main LabVIEW application accomplished the optimal real-time artificial neural networks techniques for the classification of the EEG temporal sequences corresponding to the four states: 0 - No Eye-Blink Detected; 1 - One Eye-Blink Detected; 2 – Two Eye-Blinks Detected and 3 – Three Eye-Blinks Detected. Nevertheless, the application can be used to classify other EEG patterns corresponding to different cognitive tasks, since the whole functionality and working principle could estimate the labels associated with various classes.

The risk of lung cancer continues to elevate for both smokers and never-smokers. With the increasing morbidities and mortalities related to lung cancer, there is much interest on establishing other confounding factors that lead to lung cancer, other than smoking which is the most common cause. Some of the environmental factors have been identified as potential lung cancer causes. Therefore, the aim of this systematic review is to assess the relationship of environmental factors and lung cancer incidences by investigating various carcinogenic risks exposures that predispose an individual to lung cancer. The objective of this systematic review is thus to assess the evidence of relationship between environmental carcinogens and lung cancer incidence by systematically reviewing relevant studies. A standard criterion for the review methodology was formulated to guide the review process and data extraction. Online databases like PubMed, MEDLINE, Scopus (EMBASE), Google Scholar, Web of Science, and CINAHL were systematically searched for articles published between 2000 and 2021 that explored potential environmental carcinogens that were believed to expose occupational workers and individuals within the environment with lung cancer risks. 25 studies were eligible based on the selection criteria, and were finally included in the systematic review among which four were case-control studies, seven were cohorts, five was prospective, four were previous systematic reviews and four were systematic analysis. Chemical exposures like pesticides were analyzed for their carcinogenesis. Air pollution was also discussed with particulate and coal being the core of evidence of association with lung cancer. Second hand smoke, Asbestos, metal compounds like copper, PVC dust particles and ionizing radiations also provided evidence of environmental carcinogenesis associating to lung cancer cases.

In the field of nasal delivery, one of the most fascinating applications is the delivery of drugs directly to the central nervous system bypassing the blood brain barrier. This approach would provide a series of benefits, such as dose lowering and direct targeting of potent drugs, ultimately reducing their systemic side effects. Recently, clinical trials have explored the nasal administration of insulin for the treatment of Alzheimer’s disease, with promising results. The use of nanomedicines could provide further options for making nose-to-brain delivery reality. In particular, apart from the selection of devices able to deposit the formulation in the upper part of the nose, surface modification of these nanomedicines appears the key strategy to optimize the delivery of drugs from the nasal cavity to the brain. In this review, nanomedicines delivery approaches based on surface electrostatic charges, mucoadhesive polymers, as well as chemical moieties targeting nasal epithelium, will be discussed and critically evaluated for nose-to-brain delivery.

The latest research cumulates staggering information about the correlation between the microbiota-gut-brain axis and neurodevelopmental disorders. This review aims to shed light on the potential influence of the microbiome on the development of the most prevalent neurodevelopmental disease, attention-deficit-hyperactive disorder (ADHD). As the etiology and pathophysiology of ADHD are still unclear, finding viable biomarkers and effective treatment still represent a challenge. Therefore, we focused on factors that have been associated with a higher risk of developing ADHD while simultaneously influencing the microbial composition. We reviewed the effect of a differing microbial composition on neurotransmitter concentrations important in the pathophysiology of ADHD. Additionally, we deduced factors that correlate with a high prevalence of ADHD while simultaneously affecting the gut microbiome such as emergency c-sections, and premature birth as the former leads to a decrease of the gut microbial diversity and the latter causes neuroprotective Lactobacillus levels to be reduced. Also, we assessed nutritional influences such as breastfeeding, ingestion of short-chain fatty acids (SCFAs) and polyunsaturated fatty acids (PUFAs) on the host’s microbiome and development of ADHD. Finally, we discussed the potential significance of Bifidobacterium as a biomarker for ADHD, the importance of preventing premature birth as prophylaxis and nutrition as a prospective therapeutic measurement against ADHD.

Scientific theories on the functioning and dysfunction of the human brain require a good understanding of both its development — before and after birth, and through maturation to adulthood — and its evolution from the ancestral primate brain. Adopting a complex-systems approach, here we propose that the apparent uniqueness of humans’ cognitive capacities might best be understood as emerging from multiple nested “virtuous cycles.” In particular, we propose that the intimate link that exists between oxygen metabolic loops, cortical expansion, and ultimately cognitive and social demands is a key driver of genetic developmental programs for the human brain. Overall, our proposed evolutionary model makes explicit mechanistic links between metabolism, molecular and cellular brain heterogeneity, and behaviour that may in time provide a clearer understanding of brain developmental trajectories and their disorders.

Head injury is among the most devastating types of injury, specifically called Traumatic Brain Injury (TBI). There is need to diminish the morbidity related with TBI and to improve the outcome of patients suffering TBI. Among the improvements on the treatment of TBI, neuroprotection is one of the upcoming improvements. Citicoline has been used in the management of brain ischemia related disorders, such as TBI. Citicoline has biochemical, pharmacological, and pharmacokinetic characteristics that make it a potentially useful neuroprotective drug for the management of TBI. A short review of these characteristics is included in this paper. Also, a narrative review of almost all the published or communicated studies performed with this drug in the management of patients with head injury is included. Based on the results obtained in these clinical studies, it is possible to conclude that citicoline was able to accelerate recovery of consciousness and to improve the outcome of this kind of patients, with an excellent safety profile. Thus, citicoline could have a potential role in the management of TBI.

Recent biotechnological innovations make feasible the new paradigm of creating biological neural circuits de novo. With advances in protein, cell and tissue engineering techniques, as well as cellular reprogramming methods, we are entering an era where the construction of neural circuits can open completely new ways for studying nervous systems and for treating nervous system disorders. I explore here three technologies, namely cellular engraftment, neuronal reprogramming and transsynaptic molecule engineering, and delineate how they are being used in a variety of basic research and translational medicine contexts. In basic neuroscience, neural circuit construction methods are enabling ways to study causality in neural development (e.g. neural precursor differentiation and migration) and circuit function (e.g. excitation/inhibition balance, neural population dynamics). In translational neuroscience, they are providing opportunities for the targeted correction of circuit malfunction in brain disorders, both psychiatric (e.g. schizophrenia) and neurological (e.g. Parkinson’s, Huntington’s and Alzheimer’s disease, as well as epilepsy). I discuss the challenges that these methods currently face, such as targeting specificity and cell survival, and outline future paths and opportunities to realize the full potential of technologies for creating new biological neural circuits.

The tumor microenvironment is known to have increased levels of cytokines and metabolites, such as glutamate, due to their release from the surrounding cells. A normal cell around the tumor that responds to the inflammatory environment is likely to be subsequently altered. We will discuss how these abnormalities will support tumor survival via the actions of gap junctions (GJs) and hemichannels (HCs) which are composed of hexamer of connexin 43 (Cx43) protein. In particular, we will discuss how GJ intercellular communication (GJIC) in glioma cells, the primary brain tumor, is a regulatory factor and its attenuation leads to tumor invasion. In contrast, the astrocytes, which are normal cells around the glioma, are "hijacked" by tumor cells, either by receiving the transmission of malignant substances from the cancer cells via GJIC, or perhaps via astrocytic HC activity through the paracrine signaling which enable the delivery of these substances to the distal astrocytes. This astrocytic signaling would promote tumor expansion in the brain. In addition, brain metastasis from peripheral tissues has also been known to be facilitated by GJs formed between cerebral vascular endothelial cells and cancer cells. Astrocytes and microglia are generally thought to eliminate cancer cells at the blood brain barrier. In contrast, some reports suggest they facilitate tumor progression as tumor cells take advantage of the normal functions of astrocytes that support the survival of the neurons by exchanging nutrients and metabolites. In summary, GJIC is essential for the normal physiological function of growth and allowing the diffusion of physiological substances. Therefore, whether GJIC is cancer promoting or suppressing may be dependent by what permeates through GJs, when it is active, and to which cells. The nature of GJs, which has been ambiguous in brain tumor progression, will need to be re-visited and understood together with new findings on Cx proteins and HC activities.

Conclusions: Meningiomas with histopathological CNS invasion show a higher proliferative activity.

In the last three decades, the robust scientific data emerged, demonstrating that the immune-inflammatory response is a fundamental component of the pathophysiology of major depressive disorder (MDD). Psychological stress and various inflammatory comorbidities contribute to such immune activation. Still, this is not uncommon that patients with depression do not have defined inflammatory comorbidities, and alternative mechanisms of immune activation need to take place. The gastrointestinal (GI) tract, along with gut-associated lymphoid tissue (GALT), constitutes the largest lymphatic organ in the human body and forms the biggest surface of contact with the external environment. It is also the most significant source of bacterial and food-derived antigenic material. There is a broad range of reciprocal interactions between the GI tract, intestinal microbiota, increased intestinal permeability, activation of immune-inflammatory response, and the CNS that has crucial implications in brain function and mental health. This intercommunication takes place within the microbiota-gut-immune-glia (MGIG) axis, and glial cells are the main orchestrator of this communication. A broad range of factors, including psychological stress, inflammation, dysbiosis and other, may compromise the permeability of this barrier. This leads to excessive bacterial translocation and the excessive influx of food-derived antigenic material that contributes to activation of the immune-inflammatory response and depressive psychopathology. This chapter summarizes the role of increased intestinal permeability in MDD and mechanisms of how the "leaky gut" may contribute to immune-inflammatory response in this disorder.

The physics of the human brain has two components – basic physics common to all mammals and the physics of thinking inherent only in man. The development of the mental component of the structural and functional organization of the brain in phylogeny was associated with the chiral factor of the external environment, and in ontogenesis - with the social factor. The sensitivity of the brain to these factors was based on the single-connected nature of its aqueous basis, the mechanism of electromagnetic induction, and the features of the thermodynamics of the brain in a state of night sleep. In order to unify the description of the mechanism of electromagnetic processes in the brain, the concept of a quasiphoton has been introduced, combining all forms of excitation of electronic and molecular-cellular structures of the brain. Equivalent schemes of vibrational contours of neural network elements and macrostructures of the brain are proposed. Estimates of the kinetic parameters (activation energy, velocity) of the physical processes underlying the energy-information exchange of the brain with the external environment are made. Mechanisms of operative (physical) and permanent (chemical) memory of the brain, including a model of nonlocal quantum correlations, are discussed.

We conducted many model simulations to understand the causes of the damages of coronavirus (COVID-19) to lung tissue and constructed a diagram showing apparent viral reproduction, immune response and damage accumulation curves. We found that lung damages include virus-caused damage, tissue damage caused by immune responses and tissue damage caused by accumulated wastes. The virus-caused damage is proportional to the phase lag between the viral reproduction curve and the delayed adaptive immune response curve, while waste-induced damage is attributed to imbalance in removing viral, cellular and metabolic by-products. We found that treatment strategies should slow down viral reproduction and speed up immune response, and improve blood micro-circulation in the lungs. Consistent with the strategies, measures are taken to void direct lung infection, strengthen innate responses, promote immune responses, dilute viral concentration in lung tissue, maintain waste removal balance, protect heart and kidneys, control other infections, avoid allergic reactions and other inflammation, etc. We show that medical, dietary, emotional, lifestyle, environmental, mechanical factors, etc. may be simultaneously used to mitigate lung damages and prove that multiple factor health optimization method is magnitudes more powerful than a single factor treatment. Such a method does not depend on molecular specificity and can be used in parallel to antiviral drugs.

In quantum approaches to consciousness, the authors try to propose a model and mechanism for the mind-brain interaction using modern physics and some quantum concepts which do not exist in the classical physics. The independent effect of mind on the brain has been one of the challenging issues in the history of science and philosophy. In some recent mind-brain interaction models, the direct influence of mind on matter is either not accepted (as in Stapp’s model) or not clear, and there have not been any clear mechanism for it (as in Penrose-Hameroff’s model or in Eccles’s model). In this manuscript we propose a model and mechanism for mind’s effect on the matter using an extended Bohmian quantum mechanics and Avicenna’s ideas. We show that mind and mental states can affect brain’s activity without any violation of physical laws. This is a mathematical and descriptive model which shows the possibility of providing a causal model for mind’s effect on matter. It is shown that this model guarantees the realistic philosophical constraints and respects the laws of nature. In addition, it is shown that it is in agreement with the Libet style experimental results and parapsychological data. To propose this model, we obtained a modified (non-unitary) Schrödinger equation via second quantization method which affects the particle through a modified quantum potential and a new term in the continuity equation. At the second quantized level, which is equivalent to quantum field theory level (QFT), we can use the path integral formalism of Feynman. We show that there are three methods to extend Bohmian QM via path integral formalism, which has different interpretations. By numerical simulation of trajectories in the two-slits experiment, we show their differences and choose one of these methods for our mind-brain model which can be the basis for explaining some phenomena which are not possible to explain in the standard Bohmian QM.

In our continuous search for selective anticancer treatments, we have screened 65 extracts from 45 plants collected in several areas of Western Andalusia (Spain) for cytotoxic activity against lung cancer cells and lung normal cells. Active extracts were also tested against 11 cell lines from other tissues. An extract from the leaves of Tetraclinis articulata (Vahl) Mast. (Cupressaceae) showed a marked cytotoxicity (IC₅₀ = 0.37 ± 0.03 µg/mL) and selectivity (selectivity index = 378.3) against the lung cancer cells; cisplatin, 5-fluorouracil and an extract from the leaves of Taxus baccata L. (Taxaceae) were less cytotoxic and selective.

The introduction of anti-amyloid monoclonal antibodies against Alzheimer’s disease (AD) is of high importance. However, even though treated patients show very little amyloid pathology, there is only a modest effect on the rate of cognitive decline. Although this effect possibly can increase over time, there is still a need for alternative treatments that will improve the cognitive function in patients with AD. Therefore, the purpose of this study was to characterize the triazinetrione ACD856, a novel pan-Trk positive allosteric modulator, in multiple models to address its neuroprotective and potential disease modifying effects. The pharmacological effect of ACD856 was tested in recombinant cell lines, primary cortical neurons or animals. We demonstrate that ACD856 enhanced NGF-induced neurite outgrowth, increased the levels of the pre-synaptic protein SNAP25 in PC12 cells and increased the degree of phosphorylated TrkB in SH-SY5Y cells. In primary cortical neurons, ACD856 led to increased levels of phospho-ERK1/2, showed neuroprotective effect against amyloid-beta or energy-deprivation induced neurotoxicity, and increased the levels of brain derived neurotrophic factor (BDNF). Consequently, administration of ACD856 resulted in a significant increase of BDNF in the brains of 21-months old mice. Furthermore, repeated administration of ACD856 resulted in a sustained anti-depressant effect which lasted up to seven days, suggesting effects that go beyond merely symptomatic effects. In conclusion, the results confirm ACD856 as a cognitive enhancer, but more importantly, they provide substantial in vitro and in vivo evidence of neuroprotective and long-term effects that contribute to neurotrophic support and increased neuroplasticity. Presumably, the described effects of ACD856 may improve cognition, increase resilience, and promote neurorestorative processes, thereby leading to a healthier brain in patients with AD.

The importance of diet and the gut-brain axis for brain health and cognitive function is increasingly acknowledged. Dietary interventions are tested for their potential to prevent and/or treat brain disorders. Intermittent fasting (IF), the abstinence or strong limitation of calories for 12 to 48 hours, alternated with periods of regular food intake, has shown promising results on neurobiological health in animal models. In this review article, we discuss the potential benefits of IF on cognitive function and the possible effects on the prevention and progress of brain-related disorders in animals and humans. We do so by summarizing the effects of IF which - through metabolic, cellular and circadian mechanisms - lead to anatomical and functional changes in the brain. Our review shows that there is no clear evidence of a positive short-term effect of IF on cognition in healthy subjects. Clinical studies show benefits of IF for epilepsy, Alzheimer’s disease and multiple sclerosis on disease symptoms and progress. Findings from animal studies show mechanisms by which Parkinson’s disease, ischaemic stroke, autism spectrum disorder and mood- and anxiety disorders could benefit from IF. Future research should disentangle whether positive effects of IF hold true regardless of age or the presence of obesity. Also, variations in fasting patterns, total caloric intake and intake of specific nutrients may be relevant components of IF success. Longitudinal studies and Randomized Clinical Trials (RCTs) will provide a window into the long-term effects of IF on the development and progress of brain-related diseases.

The anti-inflammatory effect of ginsenoside Rh2 (GRh2) is one of the most important ginsenosides. The purpose of this study is to identify the anti-inflammatory and antioxidant effects of GRh2 after LPS challenge lung injury animal model. GRh2 reduced LPS-induced NO, TNF-α, IL-1, IL-4, IL-6 and IL-10 productions in lung tissues. GRh2 treatment decreased the histological alterations in the lung tissues and BALF protein content and total cells number also diminished in LPS-induced lung injury mice. Moreover, GRh2 blocked iNOS, COX-2, the phosphorylation of IκB-α, ERK, JNK, p38, Raf-1 and MEK protein expression which is corresponded to the growth of HO-1, Nrf-2, catalase, SOD and GPx expressions in LPS-induce lung injury. An experimental study has suggested that GRh2 has provided with anti-inflammatory effects in vivo, and its potential therapeutic efficacy in major anterior segment lung diseases.