This paper concentrates on the general birth-death processes with two different types of catastrophes. The Laplace transform of transition probability function for birth-death processes with two-type catastrophes are is successfully expressed with the Laplace transform of transition probability function of the birth-death processes without catastrophe. The first effective catastrophe occurrence time is considered. The Laplace transform of its probability density function, expectation and variance are obtained.

The regulation of cell death is a fundamental issue in cell biology and continues to be intensely investigated worldwide. The significance of research in this field persists because understanding the determinants of cell lifespan directly impacts the maintenance of multicellular organism homeostasis and, consequently, is crucial for addressing biomedical challenges associated with various diseases. It is recognized that the initiation of cell death can be prompted by both specific signals (such as cytokines or hormones) and nonspecific stimuli, including radiation, temperature increase, or oxidants. When these factors affect a cell, numerous signaling pathways are triggered in the cell, leading to neutralization of the effects of their negative effects or, in case of irreparable damage, to cell elimination. This removal of damaged cells occurs through apoptosis or programmed cell death, a highly regulated process. Numerous signaling molecules participate in orchestrating the apoptotic process, many of which also govern other essential functions within the organism. Physiological factors capable of triggering the apoptotic program in cells include nitric oxide (NO), which serves as one of the key signaling molecules regulating the functions of the cardiovascular, nervous, and immune systems of the organism. The unique chemical nature of NO, along with its numerous intracellular targets and physiologically active redox forms, raises questions about the specific mechanisms through which NO exerts its damaging effects on cells. Utilizing pharmacological preparations- such as sources (donors) of exogenous nitric oxide- represents an approach to investigating the initiation and execution of the apoptotic program in sensitive target cells. Furthermore, this approach holds promise as a direction for discovering new selective drugs.

In this work, we tried to emphasize whole transcriptome expression changes in the Wistar rats brainstem two hours after acute stress. Most of the genes were upregulated. We detected massive shift of neuropeptides Crh, Trh,Cga, Tshb, Uts2b, Tac4, Lep and neuropeptide receptors Hcrtr1, Sstr5, Bdkrb2, Crhr2 signaling, as well as Glutamate Grin3b, Grm2 and GABA Gpr156, Acetylcholine Chrm4,Chrne, Adreno- Adra2b receptors expression uprising. Intensive increase in expression of intermediate filaments Krt83/Krt86/Krt80/Krt84/Krt87/Krt4/Krt76 and motor proteins Myo7a, Klc3 was detected. Remarkably, at this time we also observed signs of microglia activation. Both expression of anti-inflammatory cytokines Il13, Ccl24 and proinflammatory cytokin’s receptors Il9r, Il12rb1, Tnfrsf14, Tnfrsf13c, Tnfrsf25, Tnfrsf1b were increased. In the Wnt signaling pathway, we have seen increased expression of ligands-receptors Wnt1, Wnt11, Ror2, and also negative regulators Notum, Sfrp5, Sost. Also we conducted cDNA libraries normalization with duplex specific nuclease and compared results. On the basis of our RNAseq data, we chose reference genes for RT-qPCR best suitable for experiments with acute stress.

Hydrogen sulfide (H2S) is an environmental toxicant of health concern. The brain is a major target in acute H2S poisoning. This study was to test the hypothesis that acute and subchronic ambient H2S exposures alter the brain metabolome. Male 7-8 week-old C57BL/6J mice were exposed by whole-body inhalation to 1000 ppm H2S for 45 min and euthanized at 5 min or 72 h for acute exposure. For subchronic study, mice were exposed to 5 ppm H2S 2 h/day, 5 days/week for 5 weeks. The brainstem was removed for metabolomic analysis. Enrichment analysis showed the metabolomic profiles in acute and subchronic H2S exposures matched with those of cerebral spinal fluid from patients with seizures or Alzheimer’s disease. Acute H2S exposure decreased excitatory neurotransmitters, aspartate and glutamate, while the inhibitory neurotransmitter, serotonin, was increased, which may explain H2S-induced loss of consciousness. Branched-chain amino acids and glucose were increased by acute H2S exposure. Subchronic H2S exposure within OSHA guideline surprisingly decreased serotonin altering central nervous system. In subchronic H2S exposure, glucose was decreased while polyunsaturated fatty acids, inosine, and hypoxanthine were increased. Collectively, these results provide important mechanistic clues of acute and subchronic ambient H2S poisonings and show that H2S alters brainstem metabolome.

Infective endocarditis is a rare and challenging diagnosis, Q fever endocarditis being a major cause of culture-negative endocarditis (IE). The presence of multiple cerebral microbleeds (CMBs) suggests a particular vascular frailty and could be correlated to potential emergence of a haemorrhagic stroke in IE. We report a case of a 45 years-old patient with Coxiella burnetii endocarditis, with a brainstem hemorrhage and cerebral MRI CMBs resembling those of CAA. However the systemic inflammatory tests, the splenic infarct and kidney pathology could not be explained by a variant of CAA, neither the normal initial cerebral CT scan when the patient had already the brainstem clinical signs without evidencing the hemorrhage. Transthoracic and transesophageal echocardiogram revealed only calcified bicuspid aortic valve with moderate stenosis and regurgitation, without any vegetations and the blood cultures on conventional media were negative. Serology for Coxiella burnetii was positive. Inclusion of CMBs as a new minor imaging criteria for infective endocarditis could upgrade the diagnosis in almost 50% of patients.

Epidemic diseases that arise from infectious RNA viruses, particularly influenza viruses, pose a constant threat to the global economy and public health. Viral evolution has undermined the efficacy of acquired immunity from vaccines and the antiviral effects of FDA-approved drugs. As such, there is an urgent need to develop new antiviral lead agents. Natural compounds, owing to their historical validation of application and safety, have become a promising solution. In this light, a novel marine bacterium, Pseudomonas sp. M20A4R8, has been found to exhibit significant antiviral activity [half maximal inhibitory concentration (IC50) = 1.3 µg/mL, selectivity index (SI) = 919.4] against influenza virus A/Puerto Rico/8/34, surpassing the activity of chloroquine. The antiviral response by M20A4R8 extract was induced during post-entry stages of the influenza virus, indicating suitability for post-application after the establishment of viral infection. Furthermore, post-treatment with M20A4R8 extract protected the host from virus-induced apoptosis, suggesting its potential use in acute respiratory disease complexes resulting from immune effectors' overstimulation and autophagy-mediated self-apoptosis. The extract demonstrated an outstanding therapeutic index against influenza virus A/Wisconsin/15/2009 (IC50 = 8.1 µg/mL, SI = 146.2) and B/Florida/78/2015 Victoria lineage (IC50 = 3.5 µg/mL, SI = 343.8), indicating a broad anti-influenza virus activity with guaranteed safety and effectiveness. This study provides a new perspective on mechanisms for preventing a broad spectrum of viral infections through antiviral agents from novel and natural origins. Future studies on a single or combined compound from the extract hold promise, encouraging its use in preclinical challenge tests with various influenza virus strains.

Covid-19 pandemic has captivated scientists to investigate if this new disease can affect the central nervous system (CNS). The most challenging symptoms of Covid-19 are related to respiratory distress, and most patients admitted in intensive care units cannot breathe by their own. Therefore, a crucial question is if respiratory distress can be partially explained by the CNS affection. SARS-Cov-2 is a beta-coronavirus that shares high similarities with SARS-CoV. The infection of SARS‐CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Those coronaviruses have been able to invade the brainstem via a synapse‐connected route to the medullary respiratory center, where the infected regions included the nucleus of the solitary tract and nucleus ambiguous. The vagal afferent nerves from receptors in the lung communicate with the medulla and pons respiratory control centers to coordinate inspiration and expiration. This suggests that neuroinvasion of SARS‐CoV‐2 might play a role in the acute respiratory failure of Covid-19. Therefore, acute respiratory distress in Covid-19 can be partially explained by brainstem dysfunction, suggesting the needs of more specific and aggressive treatments with the direct participation of neurologists and neurointensivists.

Neuronal cell death in the central nervous system has always been a challenging process to decipher. In physiological condition, neuronal cell death is restricted in the adult brain even as people ages. However, in pathological conditions of various neurodegenerative diseases, the cell death and shrinkage of a specific brain region represent a fundamental pathological feature across different neurodegenerative diseases. In this review, we will briefly go through the general pathways of cell death and describe the evidence of the cell deaths in the context of common neurodegenerative diseases individually, discussing our current understandings of cell death in connecting with the renowned pathogenic proteins, including tau, amyloid-beta, alpha-synuclein, huntingtin, and TDP-43.

Brainstem auditory evoked potentials (BAEPs) testing is very important when microvascular decompression (MVD) is performed with hemifacial spasm (HFS). The reason for this is that the vestibulocochlear nerve is located right next to the facial nerve, so the vestibulocochlear nerve may be affected by manipulation by surgery. The BAEPs test method for detecting vestibulocochlear nerve damage during surgery has been developed a lot and is helping a lot during surgery. In most HFS patients with normal vestibulocochlear nerve, the degree of vestibulocochlear nerve damage caused by surgery is reflected very well in the BAEPs test waveforms. Therefore, a real time test is the best way to minimize the damage to the vestibulocochlear nerve. The purpose of this study was to review the most recently published BAEPs test used in MVD surgery and to find out in detail the relationship between the vestibulocochlear nerve damage and the BAEPs waveforms.

In some species of salmon, reproductive maturity triggers the development of massive pathology resulting from reproductive effort, leading to rapid post-reproductive death. Such reproductive death, which occurs in many semelparous organisms (with a single bout of reproduction), can be prevented by blocking reproductive maturation, and this can increase lifespan dramatically. Reproductive death is often viewed as distinct from senescence in iteroparous organisms (with multiple bouts of reproduction) such as humans. Here we review the evidence that reproductive death occurs in C. elegans and discuss what this means for its use as a model organism to study aging. Inhibiting insulin/IGF-1 signaling and germline removal suppresses reproductive death and greatly extends lifespan in C. elegans, but can also extend lifespan to a small extent in iteroparous organisms. We argue that mechanisms of senescence operative in reproductive death exist in a less catastrophic form in iteroparous organisms, particularly those involving costly resource reallocation, and exhibiting endocrine-regulated plasticity. Thus, mechanisms of senescence in semelparous organisms (including plants) and iteroparous ones form an etiological continuum. Therefore understanding mechanisms of reproductive death in C. elegans can teach us about some mechanisms of senescence that are operative in iteroparous organisms.

Curcumin, found in the rhizome of turmeric, has extensive therapeutic promises via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown curcumin to be an effective treatment for multiple cancers. These effects are drived by curcumin's ability to induce G2/M cell cycle arrest, induction of autophagy, activation of apoptotic pathways, disruption of molecular signaling, inhibition of invasion and metastasis, and by increasing the efficacy of existing chemotherapeutics. Here we focused on the hormetic behaviour of curcumin. Frequently, low doses of toxins and other stressors not only are harmless but also activate an adaptive stress whereas high dose activates acute responses like autophagy and cell death. This phenomenon is referred to as hormesis. Many molecules that cause cell death elicite an initial autophagic step that is a cytoprotective mechanism relying on elimination of dysfunctional structures intracellular, notably by mitophagy. This phenomenon is considered as a primarily protective mechanism against stressors. At higher doses, cells undergo mitochondrial outer membrane permeabilization due to calcium release from the endoplasmic reticulum and die. Herein, we address the complex crosstalk between the induced mitochondrial biogenesis, mitochondrial destabilization accompanied by mitophagy and cell death that can also be at play.

When a low-salience stimulus of any type of sensory modality—auditory, visual, tactile—shortly precedes an unexpected startle-like stimulus, such as the acoustic startle reflex, the startle motor reaction becomes less pronounced or is even abolished. This phenomenon is known as prepulse inhibition (PPI), and it provides operational measures of information processing by filtering out irrelevant stimuli. Because PPI implies plasticity of a reflex and is related to automatic or attentional processes, depending on the interstimulus intervals, this behavioral paradigm might be considered a potential marker of short- and long-term plasticity. Assessment of PPI is directly related to the examination of neural sensorimotor gating mechanisms, which are plastic adaptive operations for preventing overstimulation and help the brain focus on a specific stimulus among other distracters. Despite their obvious importance in normal brain activity, little is known about the intimate physiology, circuitry, and neurochemistry of sensorimotor gating mechanisms. In this work, we extensively review the current literature focusing on studies that used state-of-the-art techniques to interrogate the neuroanatomy, connectomics, neurotransmitter-receptor functions, and sex-derived differences in the PPI process, and how we can harness it as biological marker in neurological and psychiatric pathology.

To maintain proteostasis, cells must integrate information and activities that supervise protein synthesis, protein folding, conformational stability, and also protein degradation. Extrinsic and intrinsic conditions can both impact on normal proteostasis, causing the appearance of proteotoxic stress. Initially, proteotoxic stress elicits adaptive responses aimed to restore proteostasis, allowing cells to survival the stress condition. However, if the proteostasis restoration fails, a permanent and sustained proteotoxic stress can be deleterious and cell death ensues. Many cancer cells convive with high levels of proteotoxic stress and this condition could be exploited in a therapeutic perspective. Understanding the cell death pathways engaged by proteotoxic stress is instrumental to better hijack the proliferative fate of cancer cells.

Background: By using outcome prediction scores, it is possible to distinguish between good and poor performers with cochlear implants (CI) after CI implantation. The reasons for poor performance, despite good basic conditions, can be manifold. On the one hand, the postoperative fitting may be inadequate; on the other, neurophysiological disease processes may impair speech understanding with a CI. These disease processes are not yet fully understood. In acoustics, it is known that the auditory brainstem responses (ABR) and their latencies and amplitudes allow differential diagnosis based on reference values for normal-hearing individuals. The aim of this study was to provide reference values for electrically evoked brainstem responses (EABRs) in terms of rate-dependent latencies and amplitudes. Methods: 20 experienced adult CI recipients with a predicted and measured good postoperative word recognition score were recruited from the clinic’s patient pool. In the same stimulation mode and intensity we measured latencies and interpeak-latencies of EABRs and electrically evoked compound action potentials (ECAPs). With a defined supra-threshold stimulation intensity above the individual ECAP threshold, we applied stimulation at several rates between 11 and 91 stimuli per second. Results: We found rate dependences for EABR latency t3 and t5 in the order of 0.19 ms and 0.37 ms respectively, while ECAP was not affected by rate. Correspondingly, the interpeak intervalls’ rate dependences for t5-t1, t5-t3 and t3-t1 were of the order of 0.37 ms, 0.18 ms and 0.19 ms. Comparing the EABR amplitudes between the stimulation rates 11/s and 81/s, we found that at 81/s the amplitudes were significantly reduced down: to 73% for A3 and 81% for A5. These rate dependences of latency and amplitude in EABR have characteristics comparable to those of acoustic ABR. Conclusions: These data may serve to provide reference values for EABR and ECAP latencies, interpeak intervals and amplitudes with respect to stimulation rate. Altered response patterns of ECAPs and EABRs to normalised stimulation modes could be used in the future to describe and classify neuropathological processes in a better-differentiated way.

Novel severe acute respiratory syndrome coronavirus 2 infection (SARS-Cov-2) is an acute respiratory and infectious disease. This perspective aims to provide the basic understanding of the inflammation caused by SARS-Cov-2 and relation to trigeminal ganglion (TG). Virus enters through the mucous membranes of orofacial region and reach the TG where it resides and take control of its peptides including Substance P (SP).SP is the main neuropeptide, neuromodulator and neuro-hormone of TG, associated with nociception and inflammation under noxious stimulus. SP release is triggered and consequently, it affects the immune cells, blood vessels to release the mediators for inflammation. Cytokine storming is initiated and cause respiratory distress, bronchoconstriction and death in complicated cases. Neurokinin-1 Receptor (NK-1R) antagonist and glucocorticoids may be used to alleviate the symptoms and treat this infection. SP is the main culprit seem to be involved in the triggering of inflammatory pathways in SARS-Cov-2 infection. It has direct association with cardiorespiratory rhythm, sleep-wake cycle, nociception, ventilator responses and regulates many important physiological and pathological roles. Its over-secretion should be blocked by NK-1R antagonist. However, experimental work leading to clinical trials are mandatory for further confirmation.

Aneuploidy describes the gain or loss of entire chromosomes or chromosome arms. Already more than 100 years ago, aneuploidy was described to be featured in cancer and it is known today to be present in 68-90 % of cancers, depending on tumour entity. Aneuploidy is implicated to affect cancer growth, therapy response and frequently affects prognosis. Chromosomal instability (CIN) is recognized as the main cause of aneuploidy and is characterised as the fluent process of gaining or losing chromosomes. Chromosomally instable cells need to be kept in check, or cleared, to prohibit the sampling of aneuploid karyotypes able to drive tumorigenesis. Of note, even aneuploid cancer cells often show CIN, a feature that promotes therapy related drug-resistance. Here, we review how CIN can be prevented or limited to spread by the induction of cell death and the relevance of different p53 responses triggered in response to mitotic perturbations to prohibit the formation of cancer driving aneuploidies.

Extracellular vesicles (EVs) have been identified as novel mediators of intercellular communication. They work via delivering the sequestered cargo to cells in close vicinity as well as distant sites in the body, regulating pathophysiological processes. Cell death and inflammation are biologically crucial processes in both normal physiology and pathology. These processes are indistinguishably linked with their effectors modulating the other process. For instance, during an unresolvable infection, the upregulation of specific immune mediators leads to inflammation causing cell death and tissue damage. EVs have gained considerable interest as mediators of both cell death and inflammation during conditions such as sepsis. This review summarizes the types of extracellular vesicles known to date and their roles in mediating immune responses leading to cell death and inflammation with specific focus on sepsis and lung inflammation.

The main features of the instrumental global mean surface temperature (GMST) are reasonably well described by a simple linear response model driven by anthropogenic, volcanic and solar forcing. This model acts as a linear long-memory filter of the forcing signal. The physical interpretation of this filtering is the delayed response due to the thermal inertia of the ocean. This description is considerably more accurate if El Ni\~{n}o Southern Oscillation (ENSO) and the Atlantic Multi-decadal Oscillation (AMO) are regarded as additional forcing of the global temperature and hence subject to the same filtering as the other forcing components. By considering these as predictors in a linear regression scheme, more than 92\% of the variance in the instrumental GMST over the period 1870-2017 is explained by this model, and in particular all features of the 1998 -- 2015 hiatus, including its death. While the more prominent pauses during 1870 -- 1915 and 1940 -- 1970 can be attributed to clustering in time of strong volcanic eruptions, the recent hiatus is an unremarkable phenomenon that is attributed to ENSO and a small contribution from solar activity.

To date, no scientific study has found evidence of an afterlife, and the mechanism of consciousness is two of the most challenging questions. Here, I show a hypothesis for consciousness and the probability of an afterlife through three simple thought experiments and theoretical evidence. More studies are needed to understand the mechanism precisely. I found that consciousness can be discussed based on a new theory. Here, I hypothesize that when a person or animal dies, the selection of a new nervous system's characteristic of a new life might depend on the characteristics of the final evolved yet unknown particle. Here, I suggest that the positive or adverse evolution of the said particle depends on the natural evolution of the materialistic brain's cognition, including intelligence. The fittest intellectuals, those who have a higher potential scan mind virus, may survive happier and help more for others to improve psychological well-being. Here, I suggest that when a brain dies, the two microparticles might emit at infinite speed from the dead brain and simultaneously bond with a naturally select suitable zygote or early nervous system somewhere in the universe/s, forming a new life with the impact of new nurture.

Super-Resolution Microscopy enables non-invasive, molecule-specific imaging of the internal structure and dynamics of cells with sub-diffraction limit spatial resolution. One of its major limitations is the requirement for high-intensity illumination, generating considerable cellular phototoxicity. This factor considerably limits the capacity for live-cell observations, particularly for extended periods of time. Here, we overview new developments in hardware, software and probe chemistry aiming to reduce phototoxicity. Additionally, we discuss how the choice of biological model and sample environment impacts the capacity for live-cell observations.

Host immunological pathways have been proposed including TH1, TH2, TH3, TH9, TH17, TH22, TH1-like, and THαβ immune reactions. Besides TH2 and TH9 immune responses which are against multicellular parasites, host immunological pathways against viruses, intracellular micro-organisms (bacteria, protozoa, and fungi), and extracellular micro-organisms can use programmed cell death pathways to trigger immune reactions or to execute effective strategies to eliminate these pathogens. These programmed cell deaths include apoptosis, autophagic death, pyroptosis, ferroptosis, necroptosis, and NETosis. Apoptosis is related to host anti-virus eradicable THαβ immunity. Autophagic death is related to host anti-virus tolerable TH3 immunity. Pyroptosis is related to host anti-intracellular micro-organism eradicable TH1 immunity. Ferroptosis is related to host anti-intracellular micro-organism tolerable TH1-like immunity. Necroptosis is related to host anti-extracellular micro-organism eradicable TH22 immunity. NETosis is related to host anti-extracellular micro-organism tolerable TH17 immunity.

High-grade gliomas are the most common and aggressive adult primary brain tumors with a median survival of only 12-15 months. Current standard therapy consists of maximal safe surgical resection followed by DNA-damaging agents, such as irradiation and chemotherapy that can delay but not prevent inevitable recurrence. Some have interpreted glioma recurrence as evidence of glioma stem cells which persist in a relatively quiescent state after irradiation and chemotherapy, before the ultimate cell cycle re-entry and glioma recurrence. Conversely, latent cancer cells with a therapy-induced senescent phenotype have been shown to escape senescence, giving rise to more aggressive stem-like tumor cells than those present in the original tumor. Therefore, approaches are needed to either eliminate or keep these glioma-initiating cells in a senescent state for a longer time to prolong survival. In our current study, we demonstrate that the radiation-induced cell cycle inhibitor P21 can provide a powerful route to induce cell death in short-term explants of PDXs derived from three molecularly diverse human gliomas. Additionally, cells not killed by P21 overexpression were maintained in a stable senescent state for longer than control cells. Collectively, these data suggest that P21 activation may provide an attractive therapeutic target to improve therapeutic outcomes.

Hox genes represent an important gene family that is involved in the segmentation pattern and identity of the segments during the formation of the body plan in metazoans. For many years, several studies have sought to establish a correlation between the evolution of these genes and the evolution of large groups of metazoans. Here, we use publicly available sequences of Hox gene clusters to reconstruct the evolutionary history of anterior Hox genes. We show that information harbored by these genes, in part, reflects the evolution and diversification of most animal archetypes, but in many cases, there were conflicts between the evolutionary history of some genes and the history of large groups, these cases may have occurred due to specific and similar selective pressures in relatively distant groups, which may have led to evolutionary convergences. Our findings also reveal that the evolution of Hox genes (and clusters) as a multigene family is consistent to a birth-and-death model constrained by development, where there is a trade-off between a relatively fast gene turnover and their central developmental roles

Eukaryotic plasma membrane (PM) transporters face critical challenges that are not widely present in prokaryotes. The two most important issues are proper subcellular traffic and targeting to the PM, and regulated endocytosis in response to physiological, developmental or stress signals. Sorting of transporters from their site of synthesis, the Endoplasmic Reticulum (ER), to the PM has been long thought, but not formally shown, to occur via the conventional Golgi-dependent vesicular secretory pathway. Endocytosis of specific eukaryotic transporters has been studied more systematically and shown to involve ubiquitination, internalization, and sorting to early endosomes, followed by turnover in the MVB/lysosomes/vacuole system. In specific cases internalized transporters have been shown to recycle back to the PM. However, the mechanisms of transporter forward trafficking and turnover have been overturned recently through systematic work in the model fungus Aspergillus nidulans. In this review we present evidence that shows that transporter traffic to the PM takes place through Golgi-bypass and transporter endocytosis operates via a mechanism that is distinct from that of recycling membrane cargoes essential for fungal growth. We discuss these findings in relation to adaptation to challenges imposed by cell polarity in fungi as well as in other eukaryotes and provide a rationale why transporters and possibly other housekeeping membrane proteins ‘avoid’ routes of polar trafficking.

The fate of a viral infection in the host begins with various types of cellular responses, such as abortive, productive, latent, and destructive infections. Apoptosis, necroptosis, and pyroptosis are the three major types of regulated cell death mechanisms that play critical roles in viral infection response. Cell shrinkage, nuclear condensation, bleb formation, and retained membrane integrity are all signs of osmotic imbalance-driven cytoplasmic swelling and early membrane damage in necroptosis and pyroptosis. Caspase-driven apoptotic cell demise is considered in many circum-stances as an anti-inflammatory, and some pathogens hijack the cell death signaling routes to initiate a targeted attack against the host. In this review, we selected mechanisms by which viruses interfere with cell death are discussed in-depth and are used to illustrate the general principles and cellular signaling mechanisms of virus-host specific molecule interactions.

Background: New controversies have raised on brain death (BD) diagnosis when lesions are localized in the posterior fossa. Objective: To discuss the particularities of diagnosis BD in patients with posterior fossa lesions. Material and Methods. The author made a systematic review of literature on this topic. Results and Conclusions: A supratentorial brain lesion usually produces a rostrocaudal transtentorial brain herniation, resulting in forebrain and brainstem loss of function. In secondary brain lesions [i.e., cerebral hypoxia], the brainstem is also affected like the forebrain. Nevertheless, some cases complaining posterior fossa lesions [i.e., basilar artery thrombotic infarcts, or hemorrhages of the brainstem and/or cerebellum] may retain intracranial blood flow and EEG activity. In this article I discuss that if a posterior fossa lesion does not produce an enormous increment of intracranial pressure, a complete intracranial circulatory arrest does not occur, explaining the preservation of EEG activity, evoked potentials, and autonomic function. I also address Jahi McMath, who was declared braindead, but ancillary tests, performed 9 months after initial brain insult, showed conservation of intracranial structures, EEG activity, and autonomic reactivity to “Mother Talks” stimulus, rejecting the diagnosis of BD. Jahi McMath’s MRI study demonstrated a huge lesion in the pons. Some authors have argued that in patients with primary brainstem lesions it might be possible to find a in some cases partial recover of consciousness, even fulfilling clinical BD criteria. This was the case in Jahi McMath.

Receptor-interacting protein kinase 1 (RIPK1) plays a crucial role in controlling inflammation and cell death. Its function is tightly controlled through post-translational modifications, enabling its dynamic switch between promoting cell survival and triggering cell death. Phosphorylation of RIPK1 at various sites serves as a critical mechanism for regulating its activity, exerting either activating or inhibitory effects. Perturbations in RIPK1 phosphorylation status have profound implications for the development of severe inflammatory diseases in humans. This review explores the intricate regulation of RIPK1 phosphorylation and dephosphorylation and highlights the potential of targeting RIPK1 phosphorylation as a promising therapeutic strategy for mitigating human diseases.

The currently available anti-cancer therapies, such as gamma-radiation and chemotherapeutic agents, induce cell death and cellular senescence not only in cancer cells but also in the adjacent normal tissue. New anti-tumor approaches focus on limiting the side effects on normal cells. In this frame, the potential anti-tumor properties of Pulsed Electromagnetic Fields (PEMFs) through irradiation of breast cancer epithelial cells (MCF-7 and MDA-MB-231) and normal fibroblasts (FF95) were investigated. PEMFs had a frequency of 8 Hz, full-square wave type, magnetic flux density of 0.011 T and applied twice daily for 5 days. Data collected showcases that PEMF application decreases the proliferation rate and viability of breast cancer cells while having the opposite effect on normal fibroblasts. Moreover, PEMF irradiation induced cell death and cellular senescence only in breast cancer cells without any effect in the non-cancerous cells. These findings suggest PEMF irradiation as a novel, non-invasive anti-cancer strategy in combination with senolytic drugs, to eliminate both cancer and the remaining senescent cells while simultaneously avoiding the side effects of the current treatments.

According to Swiss-American Doctor of Sciences and Agricultural Engineer Jean-Pierre Jost, "plants communicate with each other by the quality of light emitted by their leaves or by means of stress hormones and other volatile chemicals. They also make use of cocktails of chemicals, pheromones, shape and colors to attract pollinators whereas other signals repel unwanted organisms. Insects are able to decode such messages and respond accordingly. Plants are apparently also communicating by sounds and electric signals." (1) How do plants do these things? Of course, it's easy to imagine it's all purely mechanical. But at the risk of sounding like a mysticism fanatic, I wonder if plants' activities are part of a spectrum of consciousness that pervades the entire universe. This spectrum would result from everything in the universe having the BITS or BInary digiTS of electronics as their ultimate composition. As explained in this hypothesis, something I call vector-tensor-scalar geometry is essential to my hypothesis. VTS geometry produces the particles of chemicals and pheromones, and refers to communication via electric signals when it speaks of electromagnetic-gravitational interaction. There's another consequence if everything in the universe is ultimately composed of electronic BITS and the cosmos is a spectrum of consciousness/artificial intelligence. It's impossible for an absence of consciousness to exist, either after death or before conception.

Objective: We aim to assess the reporting discrepancy and the difference between confirmed and unreported COVID-19-like death counts.Study Design: The study is based on time-series data.Methods: We used publicly available data to explore the differences between confirmed death counts and deaths with Codiv-19 symptoms between March 8, 2020, and July 11, 2020, in Bangladesh.Results: During the week ending May 9, 2020, the unreported COVID-19-like death count was higher than the confirmed COVID-19 death count; however, it was lower in the following weeks. On average, unreported COVID-19-like death counts were similar to the confirmed COVID-19 death counts during the same period. However, the reporting authority neither considers these deaths nor adjusts for potential seasonal influenza or other related deaths, which might produce incomplete COVID-19 data and respective mortality rates. Conclusions: Documenting unreported deaths with COVID-19 symptoms needs to be included in provisional death counts because it is essential to estimate a robust COVID-19 mortality rate and to offer data-driven pandemic response strategies. An urgent initiative is needed to prepare an acceptable guideline for COVID-19 death reporting.

Silicified ostracods from the Lower Carboniferous (Lower Tin Mountain Limestone; Kinderhookian-early Osagean; 350-358.9 Ma) of Lost Burro Gap, Death Valley region, Inyo County, California, USA augment the diversity of Paleozoic ostracods of western North America. Acid maceration of pelmatozoan, micritic and silicate clay-rich micritic marine limestones yielded the following palaeocopid and podocopid ostracods: Acratia spp., Bairdia quasilecta Bushmina, 1975, Bairdia sp. cf. B. orientalis, Ceratobairdia sp., Kirkbya panamintensis sp. nov., Rectobairdia sp. cf. R. legumen, and Silenites sp. This is the first report of Ceratobairdia and Silenites from the Tin Mountain Limestone. These ostracods occupied a Panthalassan carbonate ramp environment, and represent part of a fauna that was widespread in shallow marine waters of Panthalassa.

COVID-19 is a potentially fatal viral infection. This study investigates geography, demography, socioeconomics, health conditions, hospital characteristics, and politics as potential explanatory variables for death rates at the state and county levels. Data from the Centers for Disease Control and Prevention, the Census Bureau, Centers for Medicare and Medicaid, Definitive Healthcare, and USAfacts.org were used to evaluate regression models. Yearly pneumonia and flu death rates (state level, 2014-2018) were evaluated as a function of the governors’ political party using repeated measures analysis. At the state and county level, spatial regression models were evaluated. At the county level, we discovered a statistically significant model that included geography, population density, racial and ethnic status, three health status variables along with a political factor. State level analysis identified health status, minority status, and the interaction between governors’ parties and health status as important variables. The political factor, however, did not appear in a subsequent analysis of 2014-2018 pneumonia and flu death rates. The pathogenesis of COVID-19 has greater and disproportionate effect within racial and ethnic minority groups, and the political influence on the reporting of COVID-19 mortality was statistically relevant at the county level and as an interaction term only at the state level.

Lewis et al. published an important and timely necessary article about the determination of death by neurological criteria, revising the Uniform Determination of Death.The acceptance of brain death (BD) has been progressively accepted beginning at the late 1950s. Nonetheless, contentious brain-death cases have recently raised new controversies about the diagnosis of BD, such as the Jahi McMath case, extensively covered by the US and international press. Jahi McMath meant a terrible tragedy for her and her family. But further than this gloomy story, the case has also raised confusion and challenging qualms about a fundamental query: how we confirm whether a person is dead or alive? Since 1981, the Uniform Determination of Death Act (UDDA) has served as the legal foundation for the medical practice of determining death. But, although death by neurologic criteria is considered legal death throughout the United States, several recent lawsuits have quizzed the rightfulness the authority of the UDDA to declare death by neurological criteria. This issue explains the importance of Lewis’s et al. paper. In this article I want to present the historical procedure for issuing a law in Cuba for the determination and certification of death. Of course, it is impossible to compare our country with USA. Cuba is a small and developing country, in which a law encompasses a national scenery, in contrast with USA, a multistate nation.

Jamoytius kerwoodi, is a primitive, eel-like jawless vertebrate found uniquely in an Early Silurian (Llandovery epoch; 444-433 Ma) horizon near Lesmahagow, Scotland. This species is a rare component of a low-diversity dominantly nektonic detritus and herbivorous fauna living over an anoxic bottom and is found at the transition from a marine-influenced, probably brackish-water, deep-water basin to a shallower-water, less saline and likely freshwater basin. In the absence of true teeth, Jamoytius was probably a detritivore or herbivore feeding on Ceratiocaris. Jamoytius may be a direct ancestor of living lampreys, especially as their ectoparasitic mode of life might have evolved from ancestral microphagous filterers or herbivores.

Apoptosis, necroptosis, and autophagy are cellular mechanisms by which cells are programmed to die under a wide range of physiological and developmental stimuli. A multitude of protein mediators of programmed cell death have been identified and apoptosis, necroptosis, and autophagy signals have been found to utilize common pathways elucidating the proteins involved. This narrative review focuses on caspase-dependent and caspase-independent programmed cell death systems. Included studies of caspase-dependent programmed cell death include extrinsic pathway apoptotic mechanisms including phosphatidylserine (PS), FAS (APO-1/CD95), Tumor Necrosis Factor (TNF) Receptor type 1 (TNF-R1) and TNF-Related Apoptosis-Inducing Ligand (TRAIL) and intrinsic or mitochondrial pathway such as Cytochrome C, the Bcl-2 family of proteins and Smac/Diablo. The Bcl-2 family has apoptotic mediators Bcl-2-associated X protein (Bax) and Bcl-2 homologous antagonist/killer (Bak), Bcl-2-Interacting Protein BIM (Bim), Bcl-2 agonist of cell death (Bad), Bid, Bcl-2 adenovirus E1B 19kDa-interacting protein 1 NIP3 (Bnip3), BMF, HRK, Noxa and PUMA and anti-apoptotic proteins such as Bcl-2 itself, Mcl-1, Bcl-w, A1, and Bcl-XL. Moreover, caspase-independent programmed cell death pathways include the mitochondrial pathway with the protein mediators Apoptosis Inducing Factor (AIF), and Endonuclease G, the pathways Necroptosis, and Autophagy. Understanding programmed cell death from those reported in this review could shed substantial light on the processes of biological homeostasis. In addition, identifying specific proteins involved in these processes is mandatory to identify molecular biomarkers as well as therapeutic targets. This knowledge could provide the ability to modulate the programmed cell death response and could lead to new therapeutic interventions in a wide range of diseases.

Prostate cancer (PCa) is a complex disease and the cause of one of the highest cancer-related mortalities in men worldwide. Annually, more than 1.2 million new cases are diagnosed globally, accounting for 7% of newly diagnosed cancers in men. Programmed cell death (PCD) plays an essential role in removing infected, functionally dispensable or potentially neoplastic cells. Apoptosis is the canonical form of PCD with no inflammatory responses elicited, and the close relationship between apoptosis and PCa has been well studied. Necroptosis and pyroptosis are two lytic forms of PCD resulting in the release of intracellular contents, which induces inflammatory responses. An increasing number of studies have confirmed that necroptosis and pyroptosis are also closely related to the occurrence and progression of PCa. Recently, a novel form of PCD named PANoptosis, which is a combination of apoptosis, necroptosis, and pyroptosis, revealed the attached connection among them and may be a promising target for PCa. Apoptosis, necroptosis, pyroptosis and PANoptosis are good examples to better understand the mechanism underlying PCD in PCa. This review aims to summarize the emerging roles and therapeutic potential of apoptosis, necroptosis, pyroptosis and PANoptosis in PCa.

ABSTRACT Two years after first patients approached the emergency rooms of hospitals in Wuhan becouse of respiratory distress,thousend of SARS-CoV-2 infected persons continue to die every day worldwide.SARS-CoV-2-infected patients undergo a process of dehydration and malnutrition before they develop respiratory problems and approach the emergency room of a hospital.This is,in many cases, the consequence of high fever which causes massive loss of fluids. In addition loss of appetite, is responsible for the deficit of protein intake.Most of the virus-infected patients admitted to the emergency room are therefore hypovolemic and hypoproteinemic and suffer of respiratory distress accompanied by ground grass opacities at CT-scan of the lungs.Critically ill patients are treated following the guidelines for treatment of septic shock but with „conservative“ fluid replacement and administration of diuretics to assure sufficient hourly urine production. The combination of conservative fluid administration with reduced protein content in the enterally administered diet, together with administration of diuretics, has severe hemodynamic consequenses in mostly aged,dehydrated,critically ill patients. Many of them will develop acute kidney injury in the next 24 hours.In most of the cases, patients continue to loose weight by loosing skeletal muscle mass. Ischemic damage in the lung capillaries is responsible for the acute respiratory distreass syndrome (ARDS) and for the hallmark of autoptic findings,diffuse alveolar damage (DAD) characterized by hyaline membrane formation,fluid invasion of the alveoli recruitment of some inflammatory cells and progressive arrest of blood flow in the pulmonary vessels.The consequence is progressive congestion , increase of lung weight and progressive hypoxia (progressive severity of ARDS).Sequestration of blood in the lungs worsen hypovolemia and ischemia in different organs.This is most probably responsible for recruitment of inflammatory cells and for persistance of elevated serum levels of positive acute-phase markers and of hypoalbuminemia. Autoptic studies have been performed mostly in patients who died in the ICU after SARS-CoV-2-infection because of progessive ARDS.In those patients, tubulus epithelium necrosis in the kidney is a frequent finding as it has been the case in the first SARS-CoV-1 pandemic.In the death certification charts, many times weeks after first symptoms have started ,cardiac arrest is the cause of death after respitatory insufficiency.Replacement therapy with sufficient amount of fluid and albumin should be part of the early individualized life-saving supportive measures avoiding mechanical ventilation.

Abstract. The COVID-19 has turned in to a global human tragedy and economic devastation. Governments have implemented lockdown measures, blocked international travel, and enforced other public containment measures to mitigate the virus morbidity and mortality. As of today, no drug has the power to fight the infection and bring normalcy to the utter chaos. This leaves us with only one choice namely an effective and safe vaccine that shall be manufactured as soon as possible and available to all countries and populations affected by the pandemic at an affordable price. There has been an unprecedented fast track path taken in R&D by the World community for developing an effective and safe vaccine. Platform technology has been exploited to develop candidate vaccines in a matter of days to weeks and as of now, 108 such vaccines are available. Six of these vaccines have entered clinical trials. As clinical trials are ‘rate-limiting’ and ‘time-consuming’, many innovative methods are in practice for a fast track. These include parallel phase I-II trials and obtaining efficacy data from phase IIb trials. Human ‘challenge experiments’ to confirm efficacy in humans is under serious consideration. The availability of the COVID-19 vaccine has become a race against time in the middle of death and devastation. There is an atmosphere of tremendous hype around the COVID-19 vaccine and developers are using every moment to make claims, which remain unverified. However, concerns are raised about a rush to deploy a COVID-19 vaccine. Applying ‘Quick fix’ and ‘short cuts’ can lead to errors with disastrous consequences.

Abstract. The remarks by the Supreme Leader of the Islamic Revolution on the toll of the famines that afflicted occupied Iran in World War I and World War II indicate a desire to incorporate these calamities in Iran’s national narrative and collective memory. His criticism of famine historiography and stated toll numbers, and the unfolding catastrophic famine in Gaza, justify and necessitate a fresh look at each famine’s historiography and toll. This article re-estimates the toll of each famine by including many overlooked and neglected primary sources and in ways not previously done. It builds a trajectory of Iran’s demographic development from 1810 to 1944, and derives the toll of each famine. The World War II famine and typhus epidemics had claimed 5.5 million. World War I famine was also more deadly, though the 1869-73 famine was not far behind. At least 15.5 million Iranians died in the two world wars, a fact nowhere reflected in the history of the conflicts. Iran’s 1944 population of 12 million was unchanged from that of 1850 and a century of population growth obliterated

Excessive activation of frog eggs, so called overactivation, can be initiated by strong oxidative stress, leading to expedited calcium-dependent non-apoptotic cell death. Overactivation also occurs spontaneously, albeit with a low frequency, in natural populations of spawned frog eggs. Currently, cytological and biochemical events of the spontaneous process are not characterized. In the present study, we demonstrate that spontaneous overactivation of Xenopus frog eggs, similarly to oxidative stress- and mechanical stress-induced overactivation, is characterized by the fast and irreversible contraction of the egg’s cortical layer, increase in the egg size, depletion of intracellular ATP, drastic increase in the intracellular ADP/ATP ratio, and degradation of M phase-specific cyclin B2. These events manifest in eggs in the absence of caspase activation within just one hour of triggering overactivation. Importantly, large amounts of ATP and ADP leak from the overactivated eggs, indicating that plasma membrane integrity is compromised in these cells. The rapture of the plasma membrane and acute depletion of intracellular ATP define explicitly necrotic cell death. Finally, we report that egg overactivation can occur in the frog’s genital tract. Our data argue that mechanical stress may be a key factor promoting egg overactivation during natural spawning in frogs.

Background: Pulmonary emboli (PE) is a life threatening condition that is discovered in many patients only "post mortem". Adequate and timely detection of PE is crucial, because of the high mortality and morbidity and the sudden unexpected hemodynamic collapse that may occur in patients with PE. Objectives: To assess the ability to predict clinical outcome of patients with acute PE, using a non-gated computed tomography pulmonary angiography (CTPA), based on the dimensions of the right ventricle. Methods: A retrospective study that analyzed CTPA images of patients admitted with acute PE during the years 2012-2017 in Baruch Padeh Medical Center. The cohort study included 300 patients with documented acute PE, among them 255 were hospitalized in medical (non-intensive care unit) wards, and 45 were patients were hospitalized in an intensive care unit (ICU). Results: Among the 45 patients admitted to the ICU, 8% died. Larger RV diameters predicted mortality (OR=10.14, 95% CI [1.09-93.86]) as well as lower systolic and diastolic blood pressure measurements (p=0.001 and 0.01). Among the 255 patients that were admitted in the Internal Medicine Ward 7% died. Older age (p=0.028), sepsis and cancer (both p<0.001), high WBCs count (p<0.001), and renal failure (p<0.001) predicted death. Overall, of all 300 patients that were admitted, lower blood pressure (systolic and diastolic) (p<0.001, 0.008), older age (p<0.007), sepsis (p<0.001), cancer (p=0.006), higher WBCs count (p<0.001), and impaired renal function (p<0.001) predicted death among patients admitted with confirmed acute PE. Conclusions: Clinical parameters and hematological parameters could predict the outcome of patients admitted with acute PE. RV diameter, measured by the non-ECG gated CTPA had an additive predictive value for patients who were hemodynamically unstable on admission and were hospitalized in the ICU.

Fire-related deaths are issues for forensic pathologists particularly in ascertaining if death occurred before or during fire. The authors highlight a unique bronchiolar epithelial cytological clue (nuclear heat-induced elongation) determined by active inhalation of hot gases and fumes, not yet described in the literature at distal small airways level.

Dysfunction and selective loss of retinal ganglion cells (RGCs) is a known cause of vision loss in glaucoma and other neuropathies where ocular hypertension (OHT) is the major risk factor. We investigated the impact of transient non-ischemic OHT spikes (spOHT) on RGC function and viability in vivo to identify cellular pathways linking low-grade repetitive mechanical stress to RGC pathology. We found that repetitive spOHT had an unexpectedly high impact on intraocular homeostasis and RGC viability, while exposure to steady OHT (stOHT) of similar intensity and duration failed to induce pathology. The repetitive spOHT induced a rapid activation of the inflammasome, marked by the upregulation of NLRP1, NLRP3, AIM2, caspases -1, -3/7, -8, gasdermin D (GsdmD) and the release of interleukin-1β (IL-1β) and other cytokines into the vitreous. Similar effects were also detected after 5 weeks of exposure to chronic OHT in an induced glaucoma model. The onset of these immune responses in both spOHT and glaucoma models preceded a 50% deficit in pattern electroretinograms (PERG) amplitude, and significant loss of RGCs at 7 days post-injury. Inactivation of inflammasome complexes in NLRP1-/- , Casp1-/- and GsdmD-/- knockout animals, significantly suppressed the spOHT induced inflammatory response and protected RGCs. Our results demonstrate that mechanical stress produced by acute repetitive spOHT or chronic OHT is mechanistically linked to inflammasome activation, which leads to RGC dysfunction and death.

Acute chemical ablation of lateral line hair cells is an important tool to understand lateral line-mediated behaviors in free-swimming fish larvae and adults. However, lateral line-mediated behaviors have not been described in fish larvae prior to swim bladder inflation, possibly because single doses of ototoxin do not effectively silence lateral line function at early developmental stages. To determine if ototoxins can effectively silence the lateral line during early development, we repeatedly expose zebrafish larvae to the ototoxin neomycin during a 36-hour period from 3-4 days post-fertilization (dpf). We use simultaneous transgenic and vital dye labeling of hair cells to compare 6- hour and 12-hour repeated treatment timelines and neomycin concentrations between 0–400 µM in terms of larval survival, hair cell death, regeneration, and functional recovery. Following exposure to neomycin, we find that the emergence of newly functional hair cells outpaces cellular regeneration, likely due to the maturation of ototoxin-resistant hair cells that survive treatment. Furthermore, hair cells of 4 dpf larvae exhibit faster recovery compared to 3 dpf larvae. Our data suggest that the rapid functional maturation of ototoxin-resistant hair cells limits the effectiveness of chemical-based methods to disrupt lateral line function. Furthermore, we show that repeated neomycin treatments can continually ablate lateral line hair cells between 3–4 dpf in larval zebrafish.

Background Recent studies indicate that donor innate immune responses participate in initiating and accelerating innate responses and allorecognition in the recipient. These immune responses negatively affect recipient outcomes and predispose recipients to allograft coronary artery vasculopathy (CAV). We hypothesized that donor cause of death (COD) associated with higher levels of innate immune response would predispose recipients to more adverse outcomes post-transplant, including CAV. Methods We performed a single-institution retrospective analysis comparing donor characteristics and COD to recipient adverse cardiovascular outcomes. We analyzed the medical records of local adult donors (age 18-64) in a database of donors where adequate data was available. We linked donor characteristics and COD to recipient adverse cardiac outcomes after transplant, including cardiovascular (CV) death and incidence of significant antibody-mediated rejection (pAMR) after transplant (>2 episodes of pAMR within 90 days post-transplant). The data were analyzed using logistic regression, log-rank test of differences, and Tukey Contrast. Results Donor advanced age, female sex, and CODs of motor vehicle accident and intracranial hemorrhage were significantly associated with a higher incidence of recipient CV death and early pAMR compared to other donor characteristics and CODs. Conclusions In this single institution study, we found that recipients with hearts from donors over 40 years, donors who were female, or donors who died with a COD of motor vehicle accidents or intracranial hemorrhage had a higher frequency of CV related deaths and early pAMR. Donor monitoring and potential treatment of innate immune activation may decrease subsequent recipient innate responses and allorecognition stimulated by donor derived inflammatory signaling which lead to adverse outcomes.

Toxoplasmosis is a zoonotic disease caused by the apicomplexa protozoan parasite Toxoplasma gondii. This disease is a health burden, mainly in pregnant women and immunocompromised individuals. Dehydroepiandrosterone (DHEA) has proved to be an important molecule that could drive resistance against a variety of infections, including intracellular parasites such as Plasmodium falciparum and Trypanozoma cruzi, among others. However, to date it has not been explored the role of DHEA on T. gondii. In here, we demonstrated for the first time the toxoplasmicidal effect of DHEA on extracellular tachyzoites. Ultrastructural analysis of treated parasites showed that DHEA alters the cytoskeleton structures, leading to the loss of the organelle structure and organization, as well as the loss of the cellular shape. In vitro treatment with DHEA reduces the viability of extracellular tachyzoites and passive invasion process. 2D SDS-PAGE analysis revealed that in the presence of the hormone a progesterone receptor membrane component (PGRMC) with a cytochrome b5 family heme/steroid binding domain-containing protein was expressed, while the expression of proteins that are essential for motility and virulence was highly reduced. Finally, in vivo DHEA treatment induced a reduction of parasitic load in male, but not in female mice.

The coronavirus disease pandemic 2019 (COVID-19) has emerged in Wuhan province, China in December 2019 and has spread over all countries. The current study was carried out to predict active, death and cured rate of COVID 19 in Algeria for a future period of 35 days using FB prophet model. Results shoed that the active rate and the death rate decrease for the next days while the cured rate increase. The active, cured and death rates are estimated at 19.7% 78.85% and 2.55% respectively. These results highlight the importance of FB prophet model in COVID-19 prediction which could help national authorities in adopting the best preventive measures.

Standard evolutionary theory, supported by mathematical modelling of outbred, dispersed populations predicts that ageing is not an adaptation. We recently argued that in clonal, viscous populations, programmed organismal death could promote fitness through social benefits and has, in some organisms (e.g. Caenorhabditis elegans), evolved to shorten lifespan. Here we review previous adaptive death theory, including consumer sacrifice, biomass sacrifice, and defensive sacrifice types of altruistic adaptive death. In addition we discuss possible adaptive death in semelparous fish, coevolution of reproductive and adaptive death, and adaptive reproductive senescence in C. elegans. We also describe findings from recent tests for the existence of adaptive death in C. elegans using computer modelling. Such models have provided new insights into how trade-offs between fitness at the individual and colony levels mean that senescent changes can be selected traits. Exploring further the relationship between adaptive death and social interactions, we consider examples where adaptive death results more from action of kin than from self-destructive mechanisms and, to describe this, introduce the term adaptive killing of kin.

Our report presents the findings from a treatment program that involved plant-based diets (PBDs) and supplements for 1,750 elderly cardiology patients diagnosed with COVID-19 between April 2020 and June 2023. At the start of the program, there was no published data supporting the use of PBDs for COVID-19 patients. However, after 18 months, studies were released that indicated the effectiveness of PBDs in decreasing the incidence and severity of COVID-19. Our treatment protocol differed from these studies in several ways. We carefully controlled the quality, quantity, and processing method of the foods we provided, opting for raw instead of cooked vegetables. Additionally, we incorporated supplementation that complemented the nutrients lacking in a PBD and enhanced the anti-viral, anti-inflammatory, antioxidant, antithrombotic, and immunomodulatory properties of a PBD. Our patients recovered faster (12±1.4 days vs. 20.9±4.3 days), with lower severity (2% vs. 10-20%), hospitalizations (0 vs. 5-10%), and deaths (0 vs. 15-17%) compared to the general population. These favorable outcomes are particularly noteworthy given Indonesia's high COVID-19 morbidity and mortality rates, among the highest in Asia. The findings of this report provide valuable insights for practitioners in managing high-risk elderly COVID-19 patients, particularly in avoiding severity and mortality.

Risk stratification for malignant ventricular arrhythmias and sudden cardiac death is a daunting task for physicians in daily practice. Multiparametric mapping sequences obtained via cardio-vascular magnetic resonance imaging can improve the risk for malignant ventricular arrhythmias by unveiling the presence of pathophysiological pro-arrhythmogenic processes. However, their employment in clinical practice is still restricted. The present review explores the current evidence supporting the association between mapping abnormalities and the risk of ventricular arrhyth-mias in several cardiovascular diseases. The key message is that further clinical studies are needed to test the additional value of mapping techniques beyond conventional cardiovascular magnetic resonance imaging for selecting patients eligible for an implantable cardioverter defibrillator.

This paper presents a comprehensive analysis of the SEIRS COVID-19 pandemic model with saturated incidence rate. By modifying the existing model and proposing a new simplified version, we investigate the dynamics of disease transmission, including the impact of saturation terms on disease spread. Through stability analysis at disease-free and endemic equilibria, we aim to enhance understanding of the spread of COVID-19 and inform effective control strategies. Drawing on mathematical models and epidemiological insights, this study contributes to the ongoing efforts to combat the global pandemic.

Ferroptosis is an iron-dependent cell death pathway that involves depletion of intracellular glutathione (GSH) levels and iron-mediated lipid peroxidation. Ferroptosis is experimentally caused by inhibition of the cystine/glutamate antiporter xCT, which depletes cells of GSH, or by inhibition of Glutathione peroxidase 4 (GPx4), a key regulator of lipid peroxidation. The events that occur between GPx4 inhibition and the execution of ferroptotic cell death are currently a matter of active research. Previous work has shown that calcium release from the endoplasmic reticulum (ER) mediated by ryanodine receptor (RyR) channels contributes to ferroptosis-induced cell death in primary hippocampal neurons. Here, we used SH-SY5Y neuroblastoma cells, which do not express RyR channels, to test if calcium release mediated by the inositol 1,4,5-trisphosphate receptor (IP3R) channel plays a role in this process. We show that inhibition of GPx4 by RAS Selective Lethal Compound 3 (RSL3) generated an increase in reactive oxygen species (ROS), increased cytoplasmic and mitochondrial calcium levels, increased lipid peroxidation and caused cell death. The RSL3-induced calcium signals were inhibited by Xestospongin B, an inhibitor of the ER-resident IP3R calcium channel, by decreasing IP3R levels with carbachol and by IP3R1 knock-down. The intracellular calcium chelator BAPTA-AM inhibited RSL3-induced calcium signals, which were not affected by extracellular calcium depletion. We propose that GPx4 inhibition activates IP3R-mediated calcium release in SH-SY5Y cells, leading to increased cytoplasmic and mitochondrial calcium levels, which in turn stimulate the production of ROS and induce lipid peroxidation and ferroptotic cell death in a noxious positive feedback cycle.

Ceramide is a lipid that regulates cell death including apoptosis and necroptosis and acts as a powerful tumor suppressor. These characteristics have supported the development of ceramide-based cancer therapeutics. In the present study, ceramide mimetics (RT-25, RT-71 and YM-07) were designed and chemically synthesized, and their potential as necroptosis-inducing chemotherapeutic reagents was examined. RT-71 and YM-07, but not RT-25, potently decreased cell viability in multiple cancer cell lines. The ranges of IC50 values for RT-71 and YM-07 were 8.4–40.8 µM and 4.4–23.7 µM, respectively. Cleavage of PARP, an apoptosis marker, was not observed in MCF-7 cells treated with the mimetics. To determine the effects on necroptotic cell death, we used siRNAs specific to mixed lineage kinase domain-like protein (MLKL). MLKL knockdown significantly suppressed the cell death induced by YM-07 but not RT-71. These results suggest that YM-07 exhibits pro-necroptotic activity. Taken together, these findings indicate ceramide mimetic YM-07 as a lead compound for developing MLKL-activating necroptotic reagents. Our results help establish a foundation for pro-necroptotic therapy for cancer.

Sudden unexpected death (SUD) is a fatal event that occurs in an apparently healthy subject so that such an abrupt outcome could have not been predicted. SUD - including sudden intrauterine unexplained death (SIUD), sudden neonatal unexpected death (SNUD), sudden infant death syndrome (SIDS), sudden unexpected death of the young (SUDY), sudden unexpected death in the adult (SUDA) - occurs as the first manifestation of an unknown underlying disease or within a few hours of presentation of a disease. SUD is a major unsolved, shocking form of death that occurs frequently and can happen at any time without warning. For each case of SUD, a review of clinical history data and performance of a complete autopsy, particularly focused on the study of the cardiac conduction system were carried out according to the necropsy protocol devised by the Lino Rossi Research Center, Università degli Studi di Milano, Italy. Research cases are represented by 75 SUD victims, subdivided into 15 SIUD, 15 SNUD, 15 SUDY, and 15 SUDA victims, collected and selected for this study. After the routine autopsy and clinical history analysis, the death remained unexplained and hence a diagnosis of SUD was assigned to the 75. subjects, which included45 females (60%) and 30 (40%) males, ranging in age from 27 gestational weeks to 76 years. Serial sections of the cardiac conduction system disclosed frequent congenital alterations, of the cardiac conduction system in fetuses and infants. An age-related significant difference in distribution among the 5 age-related groups was detected for the following anomalies of the conduction system: central fibrous body (CFB) islands of conduction tissue, fetal dispersion, resorptive degeneration, Mahaim fiber, CFB cartilaginous meta-hyperplasia, His bundle septation, sino-atrial node (SAN) artery fibromuscular thickening, atrio-ventricular junction hypoplasia, intramural right bundle branch, and SAN hypoplasia. The results data are useful to understand the cause of death for all SUD cases that were unexpected and would have otherwise remained unexplained, so to motivate medical examiners and pathologists to perform more in-depth studies.

Background: Due to the importance of brain death (BD) diagnostic do not mistake, reliable confirmatory exams should be performed to enhance its security. This study aims to evaluate the intracranial pressure (ICP) pulse morphology behavior in brain-dead patients through a noninvasive monitoring system. Methods: A pilot case-control study was conducted in adults that met the BD national protocol criteria. Quantitative data from the ICP waveforms were extracted and analyzed comparing BD patients and health subjects. Results: Fifteen patients were included. ICP waveforms presented substantial differences amidst BD patients when compared to the control group. Moreover, pulse amplitude and time to peak variables values in the case group were also statistically significant. Conclusions: In this exploratory study, noninvasive ICP waveforms have shown potential as a screening method in patients with suspected brain death. Future studies should be carried out in a larger population.

Text fields in electronic medical records (EMR) contain information on important factors that influence health outcomes, however, they are underutilized in clinical decision making due to their unstructured nature. We analyzed 6,497 inpatient surgical cases with 719,308 free text notes from Le Bonheur Children’s Hospital EMR. We used a text mining approach on preoperative notes to obtain the text-based risk score algorithm as predictive of death within 30 days of surgery. We studied the additional performance obtained by including text-based risk score as a predictor of death along with other structured data based clinical risk factors. The C-statistic of a logistic regression model with 5-fold cross-validation significantly improved from 0.76 to 0.92 when text-based risk scores were included in addition to structured data. We conclude that preoperative free text notes in EMR include significant information that can predict adverse surgery outcomes.

Cosmetic surgery is the subfield of plastic surgery that enhances appearance mainly for aesthetic reasons. Currently, cosmetic surgery interventions are highly considered appealing and popular all around the world. Several factors have contributed in this rapidly evolving field such as scientific and economic development, breaking down barriers and cultural norms, globalization, social media and mental disorders. Nowadays, the morality of cosmetic surgery is facing many dilemmas due to its benefits and drawbacks. It is proven that the advantages of cosmetic surgery include improved body confidence, mental health, and function. Additionally, aesthetic corrections can upscale the quality of life and create career opportunities for special targeted groups. Also, cosmetic surgery has a major impact in gender affirmation procedures. Although, herein we also describe the disadvantages of this widely developing field such as minor and major medical complications, potential postoperative risks and addiction in plastic surgeries associated with damaging economic issues. Lack in self-confidence, altered mental health status and ethical crisis consist another negative aspects of aesthetic surgery’s impact.

Oral cancer ranks sixth among Taiwan's top 10 cancers, and most patients with poor prognosis acquire metastases. The essential fatty acid alpha-linolenic acid (ALA) has been found to diminish many cancer properties. However, the anti-cancer activity of ALA in oral cancer has yet to be determined. Migration and invasion assays confirmed OSCC cells' EMT capabilities, whereas flow cytometry and Western blotting identified the molecular pathways. ALA dramatically reduced cell growth in a concentration dependent manner, according to the findings. Low concentrations of ALA (100 or 200 μM) inhibit colony formation, expression of Twist and EMT-related proteins, expression of MMP2/-9 proteins and enzyme activity, as well as cell migration and invasion. Treatment with high concentrations of ALA (200 or 400 μM) greatly increases JNK phosphorylation and c-jun nuclear accumulation, then upregulates the FasL/caspase8/caspase3 and Bid/cytochrome c/caspase9/caspase3 pathways, leading to cell death. Low concentrations of ALA inhibit SAS and GNM cell migration and invasion by suppressing Twist and downregulating EMT-related proteins, or by decreasing the protein expression and enzyme activity of MMP-2/-9, whereas high concentrations of ALA promote apoptosis by activating the JNK/FasL/caspase 8/caspase 3-extrinsic pathway and the Bid/cytochrome c/caspase 9 pathway. ALA demonstrates potential as a treatment for OSCC patients.

Production of biofuel from lignocellulosic biomass is relatively low due to the limited knowledge about natural cell wall loosening and cellulolytic processes in plants. Industrial separation of cellulose fiber mass from lignin, its saccharification and alcoholic fermentation is still cost-ineffective and environmental unfriendly. Assuming that the green transformation is inevitable and that the new sources of raw materials for biofuels are needed, we decided to study cell death - a natural process occurring in plants in a context of reducing the recalcitrance of lignocellulose for production of second generation bioethanol. “members of the enzyme families responsible for lysigenous aerenchyma formation were identified during the root hypoxia stress in Arabidopsis thaliana cell death mutants. The cell death regulatory genes, LESION SIMULATING DISEASE 1 (LSD1), PHYTOALEXIN DEFICIENT 4 (PAD4) and ENHANCED DISEASE SUSCEPTIBILITY 1 (EDS1) conditionally regulate the cell wall when suppressed in transgenic aspen. During four years of growth in the field the following effects were observed: lignin content was reduced, the cellulose fiber polymerization degree increased and the growth itself was unaffected. The wood of transgenic trees was more efficient as a substrate for saccharification, alcoholic fermentation and bioethanol production. The presented results may trigger the development of novel biotechnologies in the biofuel industry.

Phototherapy is an efficient strategy to respond to oxidative stress and has been in the spotlight in various therapeutic fields through its biological effect, but the exact molecular mechanism has not yet been established. As a result of irradiating RAW264.7 cells with a 630 nm or 850 nm LED with an energy intensity of 0.01J/cm2, cell viability was increased depend on the irradiation time. After H2O2 was added, 630 nm or 850 nm LEDs were irradiated for 10 min or 40 min to increase cell viability by about 1.7- or 1.6-fold, respectively. In addition, 630nm or 850nm LED irradiation showed a significant ROS scavenging effect and significantly reduced TUNEL-positive cells by 45.7% and 37.8%, respectively, compared to cells treated only with H2O2. In the result of flow cytometry, the number of cells in the late apoptosis stage was about 2.3- and 1.8-fold lower than that of the cells treated with H2O2 only, but there was no significance. The Bax/Bcl-2 ratio of cells irradiated with 630 nm or 850 nm LED was significantly lower than that of cells treated with H2O2 only, and the expression of procaspase-3 and cleaved PARP was also significantly expressed in the direction of suppressing cell death. In conclusion, the ROS scavenging activity by 630 nm or 850 nm LED irradiation, leading the expression of cell death pathway proteins in the direction of inhibiting cell death.

Gossypol is a complex plant polyphenol reported to be cytotoxic and anti-inflammatory, but little was known about its effect on gene expression in macrophages. The objective was to explore gossypol’s toxicity and its effect on gene expression involved in inflammatory responses, glucose transport and insulin signaling pathway in mouse macrophages. Mouse RAW264.7 macrophages were treated with multiple concentrations of gossypol for 2-24 h. Gossypol toxicity was estimated by MTT assay and soluble protein content. qPCR analyzed the expression of anti-inflammatory tristetraprolin family (TTP/ZFP36), proinflammatory cytokine, glucose transporter (GLUT) and insulin signaling genes. Cell viability was greatly reduced by gossypol, accompanied with dra-matic reduction of soluble protein content in the cells. Gossypol treatment resulted in an increase of TTP mRNA level 6-20 fold and increased ZFP36L1, ZFP36L2 and ZFP36L3 mRNA levels by 26-69 fold. Gossypol increased proinflammatory cytokine TNF, COX2, GM-CSF, INFγ and IL12b mRNA levels up to 39-458 fold. Gossypol treatment upregulated mRNA levels of GLUT1, GLUT3 and GLUT4 genes as well as INSR, AKT1, PIK3R1 and LEPR but not APP genes. This study demonstrated that gossypol induced macrophage death and reduced soluble protein content that was accom-panied with massive stimulation of anti-inflammatory TTP family and proinflammatory cytokine gene expression as well as elevation of gene expression involved in glucose transport and insulin signaling pathway in mouse macrophages.

This study investigated the trends of registered Death and Birth in Nigeria using Generalized Linear Models. Annual data on Death and Birth was collected from National Population Commission for the period of 2004 to 2017. The Natural increase calculated revealed a positive trend in the natural increase in Nigeria from 2004 to 2017. Evidence from summary statistics revealed some level of over dispersion (variance > mean). This study explored Poisson Regression Models and Negative Binomial Regression Models using two links (identity and log). The results revealed a positive increase in registration of birth and death rates in Nigeria and among the competing the models, Negative Binomial regression model with identity link emerged as the best model for modeling birth and death rates registration in Nigeria. Data on numbers of deaths and causes of death are essential if countries are to determine priorities, formulate and monitor policies for public health care as well as other government policies that may be based on such data

The work proposes a backtesting analysis in comparison between the Lee-Carter and the Cairns-Blake-Dowd mortality models, employing Italian data. The mortality data come from the Italian National Statistics Institute (ISTAT) database and span the period 1975-2014, over which we computed back-projections evaluating the performances of the models in comparisons with real data. We propose three different backtest approaches, evaluating the goodness of short-run forecast versus medium-length ones. We find that both models were not able to capture the improving shock on the mortality observed for the male population on the analyzed period. Moreover, the results suggest that CBD forecast are reliable prevalently for ages above 75, and that LC forecast are basically more accurate for this data.

Background: Laparoscopic cholecystectomy has gained popularity. The goal of this study was to evaluate outcome differences between open vs laparoscopic cholecystectomy. Method: Using a large NIS database and ICD-9 coding for open vs laparoscopic cholecystectomy, we compared inpatient outcomes for these two procedures regarding the occurrence of myocardial infarctions and mortality using uni- and multivariate analysis by studying 5 years of data from 2010 to 2015. Results: Open cholecystectomy was inferior to laparoscopic procedure with a higher occurrence of non-ST-elevation myocardial infarction (Non-STEMI), ST-elevation myocardial infarction (STEMI), and mortality in comparison to laparoscopic cholecystectomy. For example, using 2010 database, the occurrence of STEMI was 0.2 vs 0% (OR 3.1, CI 1.7-5.5, p<0.001), for Non-STEMI 1 vs 0.4% (OR 2.5 CI 2.0-3.0, p<0001) and for mortality 0.4 vs 0.4% (OR 9.2, CI 7.9-10.6, p<0001). After adjustment for age, obesity, diabetes, and hypertension, the occurrence of STEMI, Non-STEMI, and mortality remained higher in the open cholecystectomy cohort (mortality multivariate OR 6.4, CI 5.5-7.4, p<0001). Conclusion: Open cholecystectomy is associated with a higher rate of STEMI, Non-STEMI, and a markedly higher rate of mortality in comparison to the laparoscopic approach. Our study suggests that laparoscopic cholecystectomy should remain the first choice for patients needing gallbladder surgery.

(1) Background: In patients suffering from heart failure, the main causes of death are either he-modynamic failure, or ventricular arrhythmias. The only tool to significantly reduce arrhythmic sudden death is the implantable cardioverter defibrillator (ICD), but not all patients benefit to the same extend of these devices. (2) Methods: The primary outcome of this single center study was defined as cardiovascular death in patients with ischemic and non-ischemic heart failure who have benefited from ICD therapy. The secondary outcomes were death from any cause, sudden cardiac death, ICD-related therapies (appropriate antitachycardia pacing or shock therapy for ventricular tachycardia or fi-brillation) and recurrences of ventricular tachyarrhythmias. (3) Results: A total of 403 consecutive ICD recipients – symptomatic heart failure patients with ICD for the primary prevention of sudden cardiac death – were included retrospectively: 59% is-chemic cardiomyopathy (ICMP) and 41% non-ischemic cardiomyopathy (NICMP). Within a median follow-up period of 36 months, the incidence of cardiovascular mortality was not signif-icantly different in patients with NICMP and ICMP: the primary outcome had occurred in 9 pa-tients (5.4%) in the NICMP group and in 14 patients (5.9%) in the ICMP group (hazard ratio 1; 95%confidence interval [CI] 0.45 to 2.28; p =0.97). All-cause mortality occurred in 14 of 166 pa-tients (8.4%) in NICMP group and 18 of 237 patients (7.6%) in ICMP group. Sudden cardiac death occurred in 2 patients (1.2%) in the NICMP group and in 4 patients (1.7%) in the ICMP group (hazard ratio 0.71; 95% CI, 0.13 to 3.88; P=0.69). The rate of appropriate device therapies was comparable in both groups. (4) Conclusion: In this study, ICD implantation for primary prevention of sudden cardiac death in patients with symptomatic systolic heart failure was associated with similar rates of cardiovas-cular and all-cause mortality in patients with ischemic heart disease, and in patients with heart failure from other causes. NICMP and ICMP showed comparable rates of recurrent ventricular tachyarrhythmias and appropriate ICD therapies.

Essential oils (EO) are a great antimicrobial resource against bacterial resistance in public health. Math models are useful describing the growth, survival, and inactivation of microorganisms against antimicrobials. We evaluated the antimicrobial activity of M. armillaris EO obtained from plants placed in the province of Buenos Aires (Argentina) against Staphylococcus aureus. Minimum Inhibitory and Bactericidal Concentrations were close and decreased slightly acidifying the medium from pH 7.4 to 6.5 and 5.0. This result was also evidenced by applying a sigmoid model, where the time and EO concentration necessaries to achieve 50% of the maximum effect decreased when medium was acidified. Moreover, at pH 7.4, applying the Gompertz model, we found that subinhibitory concentrations of EO decreased the growth rate and the maximum population density, and increased the latency period respect to the control. Additionally, we established physicochemical parameters for quality control and standardization of M. armillaris EO. Mathematical modelling allowed us to estimate key parameters in the behavior of S. aureus and Melaleuca armillaris EO at different pHs. This is interesting in situations where the pH changes are relevant, such as the control of intracellular infections in public health or the development of preservatives for food industry.

Background: Oenothera biennis (evening primrose) produces bioactive substances with a diverse range of pharmacological functions. However, it is currently unknown whether extract prepared from the aerial parts of O. biennis (APOB) can protect the skin against oxidative stress. To investigate the protective effects of APOB against oxidative stress-induced damage in human skin keratinocytes (HaCaT) and elucidate the underlying mechanisms. Methods: We pretreated HaCaT cells with various concentrations of APOB or the antioxidant N-acetyl-L-cysteine before applying H2O2. We then compared the cell viability, intracellular reactive oxygen species (ROS) production, and DNA and mitochondrial damage between pretreated and untreated control cells using a range of assays, flow cytometry, and Western blot analysis and also examined the reducing power and DPPH free radical-scavenging activity of APOB. Results: APOB pretreatment significantly increased cell viability, effectively attenuated H2O2-induced comet tail formation, and inhibited H2O2-induced phosphorylation of the histone γH2AX, as well as the number of apoptotic bodies and Annexin V-positive cells. APOB was found to have a high reducing power and DPPH radical-scavenging activity and also exhibited scavenging activity against intracellular ROS accumulation and restored the loss of mitochondrial membrane potential caused by H2O2. APOB pretreatment almost totally reversed the enhanced cleavage of caspase-3, the degradation of poly (ADP-ribose)-polymerase (PARP), DNA fragmentation that usually occurs in the presence of H2O2 and increased the levels of heme oxygenase-1 (HO-1), a potent antioxidant enzyme that is associated with the induction of nuclear factor-erythroid 2-related factor 2 (Nrf2). Conclusions: APOB can protect HaCaT cells from H2O2-induced DNA damage and cell death by blocking cellular damage related to oxidative stress via a mechanism that affects ROS elimination and by activating the Nrf2/HO-1 signaling pathway.

Sword-duels are interesting, from a game-theoretical perspective, as they correspond to sudden-death interactions between players (i.e., defeat means removal from the game), and where victory/defeat depend on not just skill, but also luck. Analyzing probabilities of victory streaks, given a certain level of self and others' skill, is thus relevant for any application domain that can be modeled in the same way. This paper takes inspiration from Miyamoto Musashi, famously undefeated for 61 duels, and implements a Markov-chain Monte-Carlo simulation approach to evaluate this scenario. Results suggest that a 61 victory streak can be probabilistically observed when skill level is roughly 6.5 times that of the average duelist, and with 95\% confidence when skill level is roughly 1000 times that of the average duelist. More generally, this paper provides a method for determining chances of victory streaks in game-theoretical sudden-death encounters, when both "skill" and "luck" contribute to the outcome of the encounter. Specific scenarios can be modeled by modifying the utilized Markov chain and adjusting sampled distributions as required.

A retrospective study was conducted on pathologically diagnosed arrhythmogenic cardiomyopathy (ACM) from consecutive cases over the past 34 years (n = 1,109). The cardiac conduction system (CCS) was removed in two blocks, containing the following structures: Sino-atrial node (SAN), atrio-ventricular junction (AVJ) including the atrio-ventricular node (AVN), the His bundle (HB), the bifurcation (BIF), the left bundle branch (LBB) and the right bundle branch (RBB). The ACM cases (2.07% of the total cases) consisted of 20 (86.96%) sudden unexpected cardiac death (SUCD) and 3 (13.04%) native explanted hearts; 16 (69.56%) were males and 7 (30.44%) were females, ranging in age from 5 to 65 (mean age ± SD, 36.13 ± 16.06) years. The following anomalies of the CCS, displayed as percentages of ACM SUCD cases, have been detected: Hypoplasia of SAN (80%) and/or AVJ (86.67%) due to fatty-fibrous involvement, AVJ dispersion and/or septation (46.67%), central fibrous body (CFB) hypoplasia (33.33%), fibromuscular dysplasia of SAN (20%) and/or AVN (26.67%) arteries, hemorrhage and infarct-like lesions of CCS (13.33%), islands of conduction tissue in CFB (13.33%), Mahaim fibers (13.33%), LBB block by fibrosis (13.33%), AVN tongue (13.33%), HB duplicity (6.67%%), CFB cartilaginous meta-hyperplasia (6.67%), and right sided HB (6.67%). Arrhythmias are the hallmark of ACM, not only from the fatty-fibrous disruption of the ventricular myocardium that accounts for reentrant ventricular tachycardia, but also from the fatty-fibrous involvement of CCS itself. The careful examination of the cardiac conduction system on serial sections was crucial in documenting the fatty-fibrous infiltration of CCS in ACM.

Caspase-3, onto which there is a convergence of the intrinsic and extrinsic apoptotic pathways, is the main executioner of apoptosis. We here review the current literature on the intervention of the protease in the execution of naturally occurring neuronal death (NOND) during cerebellar development. We will consider data on the most common altricial species (rat, mouse and rabbit), as well as humans. Among the different types of neurons and glia in cerebellum, there is ample evidence for an intervention of caspase-3 in the regulation of NOND of the post-mitotic cerebellar granule cells (CGCs) and Purkinje neurons as a consequence of failure to establish proper synaptic contacts with target (secondary cell death). It seems possible that also the GABAergic interneurons undergo a similar type of secondary cell death, but the intervention of caspase-3 in this case still remains to be clarified in full. Remarkably, CGCs also undergo primary cell death at the precursor/pre-migratory stage of differentiation, in this case without the intervention of caspase-3. Glial cells as well undergo a process of regulated cell death, but it seems possible that expression of caspase-3, at least in the Bergmann glia, is related to differentiation rather than death.

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.

Background: Methadone is a centrally-acting synthetic opioid analgesic widely used in the methadone maintenance therapy (MMT) programs throughout the world. Considering its neurotoxic effects particularly on the cerebellum, this study aims to address the behavioral and histological alterations in the cerebellar cortex associated with methadone administration. Materials and Methods: Twenty-four adult male albino rats were randomized into two groups of control and methadone treatment. Methadone was subcutaneously administered (2.5–10 mg/kg) once a day for two consecutive weeks. The functional and structural changes in the cerebellum were compared to the control group. Results: Our data revealed that treating rats with methadone not only induced cerebellar atrophy, but also prompted the actuation of microgliosis, astrogliosis, and apoptotic biomarkers. We further demonstrated that treating rats with methadone increased complexity of astrocyte processes and decreased complexity of microglia processes. Our result showed that methadone impaired motor coordination and locomotor performance and neuromuscular activity. Additionally, relative gene expression of TNF-α, caspase-3 and RIPK3 increased significantly due to methadone. Conclusions: Our findings suggest that methadone administration has a neurodegenerative effect on the cerebellar cortex via dysregulation of microgliosis, astrogliosis, apoptosis, and neuro-inflammation.

Neuronal cell fate is predominantly controlled by the effects of growth factors, such as neurotrophins, and the activation of a variety of signaling pathways acting through neurotrophin receptors, namely Trk and p75 (p75NTR). Despite their beneficial effects on brain function, their therapeutic use is compromised, due to their polypeptidic nature and blood–brain-barrier impermeability. To overcome these limitations, our previous studies have proven that DHEA-derived synthetic analogs can act like neurotrophins, lacking endocrine side effects. The present study focuses on the biological characterization of a newly synthesized analog, ENT-A044, and its role on inducing cell specific functions of p75NTR. We show that ENT-A044 can induce cell death and phosphorylation of JNK protein by activating p75NTR. Additionally, ENT-A044 can induce the phosphorylation of TrkB receptor, indicating that our molecule can activate both neurotrophin receptors, leading towards the protection of neuronal populations that express both receptors. Furthermore, the present study demonstrates for the first time the expression of p75NTR in human induced Pluripotent Stem Cells - derived Neural Progenitor Cells (hiPSCs - derived NPCs) and receptor-dependent cell death induced by ENT-A044 treatment. In conclusion, ENT-A044 could be proven a lead molecule for the development of novel pharmacological agents, aiming on new therapeutic approaches and research tools, by controlling p75NTR actions.

Estimating age at death is essential to establish a biological profile from human skeletal remains in both forensic and archeological settings. Imaging studies of skeletal age changes in adults have described metamorphosis of trabecular bone structure and bone loss in the proximal femur , as well as changes in morphology during different stages of life. This study aims to assess the utility of a digital representation of conventional X-ray films of the proximal femur for the estimation of age at death in a sample of 91 adult individuals (47 females and 44 males) of the Coimbra Identified Skeletal Collection. The proposed approach showed a root mean squared error (RMSE) of 17.32 years (and mean absolute error of 13.47 years) for females and an RMSE of 14.06 years (mean absolute error of 11.08 years) for males. The main advantage of this approach is the consistency in the feature detection and extraction, as X-ray images projected on the femora space will always produce the same set features to be analyzed for age estimation while more traditional methods rely heavily on operator experience which can lead to inconsistent age estimates among experts.

Introduction: Intrauterine fetal death (IFD) is death of fetus after the 20th week of gestation. Despite regular monitoring, the incidence of IFD remains high. This study aims to assess the incidence and risk factors for IFD in term pregnancies for better prevention and reduction of neonatal morbidity and mortality. Materials and Methods: A retrospective cohort study was conducted with term pregnant women diagnosed with IFD. The analysis included the number of deliveries, live births, and stillbirths. Statistical analysis involves descriptive and analytical statistical methods. Results: Average age was 30 years. Most patients had intermediate and high education, and one-third of patients had regular pregnancy monitoring. 53.33% were primiparous, and pregnancies occurred spontaneously. IFD mainly occurred in the 39th week of gestation. The average birth weight was approximately 3000g. 38.3% had one to two associated diseases, 5% more than three, and 56.7% were healthy. Recurrence of IFD was reported by 10% of patients, while 8.33% had a history of spontaneous abortion. Over 80% of placental histopathological findings indicated some pathology (infarction, infections, abruptio placenta). Conclusion: The most significant risk factors were pregnancy-induced hypertensive disorders, obesity, and diabetes, followed by hypothyroidism, maternal tachycardia, and anemia.

Excessive activation of frog eggs (overactivation) is a pathological process that renders eggs unfertilizable. Its physiological inducers are unknown. Previously, oxidative stress was shown to cause time- and dose-dependent overactivation of Xenopus laevis frog eggs [1]. Here, we demonstrate that the oxidative stress-induced egg overactivation is a calcium-dependent phe-nomenon which can be attenuated in the presence of the selective calcium chelator BAPTA. Degradation of cyclin B2, which is known to be initiated by calcium transient in fertilized or parthenogenetically activated eggs, can also be observed in the overactivated eggs. Decline in mitochondrial membrane potential, ATP depletion and termination of protein synthesis manifest in the eggs within one hour of triggering overactivation. These intracellular events occur in the absence of caspase activation. Furthermore, plasma membrane integrity is compromised in the overactivated eggs, as evidenced by ATP leakage and egg swelling. In sum, our data demonstrate that oxidative stress-induced overactivation of frog eggs causes fast and dramatic disruption of cellular homeostasis, resulting in robust and expedited cell death by a calcium-dependent non-apoptotic mechanism.

Cell death resistance is a key feature of tumor cells. One of the main anti-cancer therapies is increasing the susceptibility of cells to death. Cancer cells have developed a capability of tumor immune escape. Hence, restoring the immunogenicity of cancer cells can be suggested as an effective approach against cancer. Accumulating evidence proposes that several anticancer agents provoke the release of danger-associated molecular patterns (DAMPs) that are determinants of immunogenicity and stimulate immunogenic cell death (ICD). It has been suggested that ICD inducers are two different types according to their various activities. Here, we review the well-characterized DAMPs and focus on the different types of ICD inducers and recent combination therapies that can augment the immunogenicity of cancer cells.

Zika virus (ZIKV) is an emerging human mosquito-transmitted pathogen of global concern, known to be associated with complications such as congenital defects and neurological disorders in adults. ZIKV infection is associated with induction of cell death. However, previous studies suggest that the virally-induced apoptosis occurs at a slower rate compared to the course of viral production. In this present study, we investigated the capacity of ZIKV to delay host cell apoptosis. We provide evidence that ZIKV has the ability to interfere with apoptosis whether it is intrinsically or extrinsically induced. In cells expressing viral replicon-type constructions, we show that this control is achieved through replication. Finally, our work highlights an important role for anti-apoptotic Bcl-2 family protein in the ability of ZIKV to control apoptotic pathways, avoiding premature cell death and thereby promoting virus replication in the host-cell.

Here we show how a recently-introduced method from algebraic topology, namely proximal planar vortex 1-cycles, might be helpful in detecting hidden features of the shapes and holes in images, therefore contributing to the solution of both cold and fresh forensic cases. In particular, we test the efficacy of this technique by assessing one of the most puzzling cases of recent history, i.e., Aldo Moro’s death. Terrorists of the Red Brigades claimed that they killed Moro when he was placed inside the trunk of a car,shooting him with a barrage of bullets. We demonstrate, based on the analysis of the photographs taken during the autoptic procedure, that the terrorist’s account does not hold true. Our results, showing different series of shots, point towards a three-step execution, with the first phasestaking place outside the car. In conclusion, the novel forensic analysis method introduced in this paper permits the evaluation of a collection of vortex cycles/nerves equipped with a connectedness proximity, which makes it possible to assess unexpected spatial clusters in photographs.

The high interest in N-heterocyclic platinum carbene complexes in cancer research stems from their high cytotoxicity to human cancer cells, their stability, as well as their ease of functionalization. However, the development of these new molecules as anticancer agents still faces multiple challenges, in particular solubility in aqueous media. Here, we synthesized platinum-NHC bioconjugates that combine water-solubility and cytotoxicity by using polyethyleneimine as polymer carrier. We showed that the activity of these conjugates is modulated by the size of the polymer and the overall density of metal ions onto polymer chains. They displayed an effective activity after only 45 minutes of exposure in vitro correlated with a quick uptake by the cells as shown by the use of various fluorescent-tagged derivatives.

Acute myeloid leukaemia (AML) is characterized by the accumulation of undifferentiated blast cells in the bone marrow and blood. In most AMLs, relapse frequently occurs due to resistance to chemotherapy. Compelling research results indicate that drug resistance in cancer cells is highly dependent on the intracellular levels of reactive oxygen species (ROS). Modulating ROS levels is therefore a valuable strategy to overcome the chemotherapy resistance of leukemic cells. In this study, we evaluated the efficiency of diphenyleneiodonium (DPI), a well-known inhibitor of ROS production, in targeting AML cells. Results showed that although inhibiting cytoplasmic ROS production, DPI triggered an increase in the mitochondrial ROS levels caused by the disruption of the mitochondrial respiratory chain. We also demonstrated that DPI blocks the mitochondrial oxidative respiration (OxPhos) in a dose-dependent manner and that AML cells with high OxPhos status were highly sensitive to treatment with DPI, which synergizes with the chemotherapeutic agent cytarabine (Ara-C). Thus, our results suggest that targeting mitochondrial function by DPI might be exploited to target AML cells with high OxPhos status.

This study used established biomarkers of death due to ischemic stroke (IS) and performed network, enrichment, and annotation analysis. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-β1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell surface interactions, and the proteoglycan-integrin-extra cellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: a) that NFKB1, RELA and SP1 were the major regulating actors of the PPI network; and b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, VEGFA, proteoglycan-integrin-ECM complex, NFKB/RELA and SP1.

Hyperkalemia burden in non-dialysis CKD under nephrology care is undefined. We prospectively followed 2443 patients with two visits (referral and control with 12-month interval) in 46 nephrology clinics. Patients were stratified in four categories of hyperkalemia (sK≥5.0 mEq/L) by sK at visit 1 and 2: Absent (no-no), Resolving (yes-no), New Onset (no-yes), Persistent (yes-yes). We assessed competing risks of ESKD and death after visit 2. Age was 65±15 y, eGFR 35±17 mL/min/1.73 m2, proteinuria 0.40 (0.14-1.21) g/24h. In the two visits sK was 4.8±0.6 and levels ≥6 mEq/L were observed in  4%. Hyperkalemia was absent in 46%, resolving 17%, new onset 15% and persistent 22%. Renin-angiotensin-system inhibitors (RASI) were prescribed in 79% patients. During 3.6-year follow-up, 567 patients reached ESKD and 349 died. Multivariable competing risk analysis [sub-hazard ratio-sHR, 95%Confidence Interval-CI] evidenced that new onset [sHR 1.34, 95%CI 1.05-1.72] and persistent [sHR 1.27, 95%CI 1.02-1.58] hyperkalemia predicted higher ESKD risk versus absent, independently from main determinants of outcome including eGFR change. Conversely, no effect on mortality was observed. Results were confirmed by testing sK as continuous variable. Therefore, in CKD under nephrology care, mild-to-moderate hyperkalemia status is common (37%) and predicts per se higher ESKD risk but not mortality.

Our previous study has found the anti-tumor activity of oleandrin in osteosarcoma cells in vitro, but the signal transduction process of cell apoptosis induced by oleandrin is uncertain, which is explored in this study. Fluorescence staining and flow cytometry (FCM) was performed to detect the cell apoptosis, intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP). Caspase-3 activity was detected using a commercial kit. The protein expression of cytoplasmic cytochrome c, mitochondrial cytochrome c, bcl-2, bax, caspase-9, Fas, FasL, caspase-8 and caspase-3 was detected using western blot. A pan-caspase inhibitor, z-VAD-fmk, was applied to block the apoptotic pathway and the apoptosis status were re-tested. We found that oleandrin significantly induced the increased apoptosis of U2OS cells. Meanwhile, the intracellular ROS was elevated, but the MMP decreased. The cytochrome c in mitochondria was notably decreased but increased in cytoplasm. The caspase-3 activity was also enhanced with the increase of drug concentration and treatment time. Oleandrin also down-regulated the level of bcl-2, but remarkably up-regulated the expression of bax, cleaved caspase-9, Fas, FasL, cleaved caspase-8 and cleaved caspase-3. Furthermore, the pre-treatment with z-VAD-fmk almost completely reverted the oleandrin-induced apoptosis. The results suggested that oleandrin induces the apoptosis of osteosarcoma cells via mitochondrial- and death receptor-dependent pathways.

In this study, a case of acute cattle death was investigated. The pathogen was identified, and its molecular characteristics and vector were analysed. This study provides a reference for the prevention and control of babesiosis and the healthy breeding of cattle. In this study, unengorged and engorged Rhipicephalus microplus ticks were collected from the Chongqing area. The unengorged ticks were cultured on cattle under laboratory conditions, and the engorged ticks were cultured to lay eggs. In the process, the cattle suddenly died at 12 days from the bite of an unengorged R. microplus tick. In addition, the larvae hatched from R. microplus eggs, which were cultured on the other cattle, and the experimental cattle died in approximately 14 days. Blood was collected from a second dying and stored at 4 ℃ for one week. Two millilitres of anticoagulated blood was injected subcutaneously into the third cow without piriformis infection. On the fourth day, the body temperature rose to 41 ℃ with slight lymphadenopathy. On the fifth day, the cow suddenly fell and died approximately 4 hours later. DNA was extracted from the blood of all dead cattle and amplified by PCR with piriformis universal primers. The results showed that the cattle were infected with Babesia bovis. The phylogenetic tree based on 18S rRNA showed that the Chongqing strain of B. bovis, which caused the death of cattle, was closely related to the Yunnan strain in China and had the same taxonomic status as the Spanish strain. This case report will draw people's attention to B. bovis once again, and positive control measures should be taken to reduce the losses of farmers to achieve the goal of healthy breeding.

Background: The aim of this study was to investigate the persistence of SARS-CoV-2 in post-mortem swabs of subjects who died from SARS-CoV-2 infection. Methods: The presence of the virus was evaluated post-mortem from airways of 27 SARS-CoV-2 positive patients at three different time points (T1 2 hours; T2 12 hours – T3 24 hours) by real-time PCR. Detection of antibodies to SARS-CoV-2 was performed by Maglumi 2019-nCoV IgM/IgG chemiluminescence assay. Results: SARS-CoV-2 viral RNA was still detectable in 70,3% of cases within 2 hours after death and in 66,6% of cases up to 24 hours after death. Our data showed an increase of the viral load in 78,6% of positive individuals 24 hours post-mortem (T3) in comparison to that evaluated 2 hours after death (T1). Noteworthy, we detected a positive T3 post-mortem swab (24 hours after death) from 4 subjects who were negative at T1 (2 hours after death). Conclusion: The results of our study may have an important value in the management of deceased subjects not only with a suspected or confirmed diagnosis of SARS-CoV-2, but also for unspecified causes and in the absence of clinical documentation or medical assistance.

Nowadays, healthcare-associated infections (HAIs) represent a major global public health problem and the burden of these infections is high. In order to reduce the incidence of HAIs and to prevent the spread antibi-otics resistant organisms is mandatory to develop surveillance systems. We undertook a retrospective case-control study of all patients presenting HAIs admitted in Intensive Care Unit (ICU) in order to assess risk factors associated with death among patients with HAIs. Patients admitted to Intensive Care Unit who died were more likely to present an infection with a multidrug resistant bacteria, an infection with Acineto-bacter baumannii, and to suffer from acute myocardial infarction. Among the patients enrolled in the study, a higher probability of death was also observed in association with certain gram-negative pathogens: Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa. The longer the patient remains admitted in ICU, the higher the risk of getting an infection that can often become fatal. Acquiring a noso-comial infection also increases the length of hospitalization which will lead to increased financial damage.

Hepatitis C virus (HCV) core protein is a multifunctional protein that is involved in proliferation, inflammation and apoptosis mechanism of hepatocytes. HCV core protein genetic variability has been implicated in various outcomes of HCV pathology and treatment. In the present study, we aimed to analyze the role of HCV core protein in tumor necrosis factor α (TNFα)-induced death under the viewpoint of HCV genetic variability. Immortalized hepatocytes (IHH), and not the Huh7.5 hepatoma cell line, stably expressing HCV subtype 4a and HCV subtype 4f core proteins showed that only HCV 4a core protein could increase sensitivity to TNFα-induced death. Development of two transgenic mice expressing the two different core proteins under the liver-specific promoter of transthyretin (TTR) allowed for the in vivo assessment of the role of core in TNFα-induced death. Using the TNFα-dependent model of lipopolysaccharide/D-galactosamine (LPS/Dgal) we were able to recapitulate the in vitro results in IHH cells in vivo. Transgenic mice expressing HCV 4a core protein were more susceptible to the LPS/Dgal model while mice expressing HCV 4f core protein had the same susceptibility as their littermate controls. Transcriptome analysis in liver biopsies from these transgenic mice gave insights into HCV core molecular pathogenesis, while linking HCV core protein genetic variability to differential pathology in vivo.

We previously found a novel a new sirtuin (SIRT) inhibitor MHY2256 that exerts anticancer activity through p53 acetylation in MCF-7 human breast cancer cells. Here, we investigated the anticancer activity of MHY2256 against hormone-related cancer, which is an endometrial cancer with poor prognosis. We found that MHY2256 markedly reduced cellular proliferation at low concentrations against Ishikawa endometrial cancer cells. The IC50 values of MHY2256 were much lower than that of salermide. Furthermore, MHY2256 significantly reduced the protein expression and activities of SIRT1, 2, and 3 with similar effects as salermide, a well-known SIRT inhibitor. Particularly, MHY2256 markedly inhibited tumor growth in a tumor xenograft mouse model of Ishikawa cancer cells. During the experimental period, there was no significant change in the body weight of mice treated with MHY2256. Detailed analysis of the sensitization mechanisms of Ishikawa cells revealed that late apoptosis was largely increased by MHY2256. Additionally, MHY2256 increased G1 arrest and reduced cell cyclic-related proteins, suggesting that apoptosis by MHY2256 was achieved by cellular arrest. Particularly, p21 was greatly increased by MHY225656, suggesting that cell cycle arrest by p21 is a major factor in MHY2256 sensitization in Ishikawa cells. We also detected a significant increase in acetylated p53, a target protein of SIRT1, in Ishikawa cells after MHY2256 treatment. In a mouse xenograft model, MHY2256 significantly reduced tumor growth and weight without apparent side effects. These results suggest that MHY2256 exerts its anticancer activity through p53 acetylation in endometrial cancer and can be used for targeting hormone-related cancers.

Various studies indicate that vaccination, especially with pneumococcal vaccines, protects against symptomatic cases of SARS-CoV-2 infection and death. This paper explores the possibility that pneumococcal vaccines in particular, but perhaps other vaccines as well, contain antigens that might be cross-reactive with SARS-CoV-2 antigens. Comparison of the glycosylation structures of SARS-CoV-2 with the polysaccharide structures of pneumococcal vaccines yielded no obvious similarities. However, while pneumococcal vaccines are primarily composed of capsular polysaccharides, some are conjugated to CRM197, a modified diphtheria toxin, and all contain about three percent protein contaminants, including the pneumococcal surface proteins PsaA, PspA and probably PspC. All of these proteins have very high degrees of similarity, using very stringent criteria, with several SARS-CoV-2 proteins including the spike protein, membrane protein and replicase 1a. CRM197 is also present in Hib and meningitis vaccines. Equivalent similarities were found at lower rates, or were completely absent, among the proteins in diphtheria, tetanus, pertussis, measles, mumps, rubella, and poliovirus vaccines. Notably, PspA and PspC are highly antigenic and new pneumococcal vaccines based on them are currently in human clinical trials so that their effectiveness against SARS-CoV-2 disease is easily testable.

Cryptococcosis is a leading cause of death among people with HIV in sub-Saharan Africa. Limited diagnostic and therapeutic options significantly impair treatment options in Africa. We investigated the burden of cryptococcosis and related mortality among people with HIV and suspected sepsis in Ethiopia. We conducted a prospective cohort at 1) Adama Hospital Medical College and 2) Asella Referral and Teaching Hospital from September 2019 to November 2020. We enrolled adult HIV-infected patients presenting with suspected sepsis and assessed 28-day survival. We performed blood cultures and cryptococcal antigen (CrAg) testing. In total, 82 participants were enrolled with a median age of 35 years and 61% being female. Overall, 11(13%) had positive CrAg tests, of which 5 had Cryptococcus detected in blood cultures. Despite high-dose fluconazole (1200mg/d) monotherapy in patients with positive CrAg tests, the 28-day mortality was 64%(7/11), being significantly higher than in CrAg-negative patients (9%(6/71); p&lt;0.001). Cryptococcosis is the leading cause of mortality among HIV-infected sepsis patients. CrAg screening in HIV-infected patients attending emergency department can minimize the cryptococcosis missing case irrespective of CD4 count and viral load. These findings warrant the need of a bundle approach for diagnosis of HIV-infected persons presenting with sepsis in low- and middle-income countries.

Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein – MLKL – shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that inhibit necroptosis by targeting the kinase activity of RIPK1, one of the main upstream conduits to MLKL activation, have shown promise in several murine models of non-infectious disease and in phase II human clinical trials. This has triggered multi-billion-dollar investments into the emerging class of necroptosis blocking drugs, and the potential utility of targeting the terminal effector is being closely scrutinised. Here we review murine models of disease, both genetic deletion and mutation, that investigate the role of MLKL. We summarize a series of examples from several broad disease categories including ischemia reperfusion injury, sterile inflammation, pathogen infection and haematological stress. Elucidating MLKL’s contribution to mouse models of disease is an important first step to identify human indications that stand to benefit most from MLKL-targeted drug therapies.

Exactly one year ago, between February and March 2020, the SARS-CoV2 infection went from an epidemic confined to China to a worldwide pandemic that was particularly lethal in Italy. This study examined media accounts during that period by analysing the representation of death-related constructs in Corriere della Sera, the most widely read newspaper in Italy. A textual and thematic analysis of articles published between period A (epidemic: 23 January–22 February 2020) and period B (pandemic: 23 February–31 March 2020) was conducted using Nvivo-11. A total of 141 articles comprising 48,524 words was collected. The most utilized words and meanings linked to SARS-CoV2 were computed. In the rank distribution, ‘China’ and ’virus’ were the terms most frequently used in both periods. The terms ‘death’ and ‘dead’ were completely absent in period A and appeared in the 535th position in period B. The term ‘dead’ was used primarily to indicate the number of deceased. From a Terror Management Theory perspective, it is possible that the minimal reference to death-related issues was a reflection of death denial and a manifestation of efforts to deny death to manage terror. These findings highlight the ambiguities and ambivalence surrounding any issue pertaining to death; on one side, undue alarmism may provoke exaggerated reactions, such as moral panic, while on the other denial-based messages that minimize references to mortality may reduce safe behaviour during a pandemic.

In the ongoing Covid-19 pandemic, in the global data on the case fatality ratio and other indices reflecting death rate, there is a consistent downward trend from mid-April to mid-August. The downward trend can be an illusion caused by biases and limitations of data or it could faithfully reflect a declining death rate. A variety of explanations for this trend are possible, but a systematic analysis of the testable predictions of the alternative hypotheses has not yet been attempted. We state six testable alternative hypotheses, analyse their testable predictions using public domain data and evaluate their relative contributions to the downward trend. We show that a decline in the death rate is real; changing age structure of the infected population and evolution of the virus towards reduced virulence are the most supported hypotheses and together contribute to major part of the trend. The testable predictions from other explanations including altered testing efficiency, time lag, improved treatment protocols and herd immunity are not consistently supported, or do not appear to make a major contribution to this trend although they may influence some other patterns of the epidemic.

Geranylgeranyl acetone (GGA) protects against various types of cell damages by upregulating heat shock proteins. We investigated whether GGA protect neuronal cells from cell death induced by oxidative stress. Glutamate exposure was lethal to HT-22 cells which comprise a neuronal line derived from mouse hippocampus. This configuration is often used as a model for hippocampus neurodegeneration in vitro. In the present study, GGA protected HT-22 cells from glutamate-induced oxidative stress. GGA pretreatment did not induce Hsps. Moreover, reactive oxygen species increased to the same extent in both GGA-pretreated and untreated cells exposed to glutamate. In contrast, glutamate exposure and GGA pretreatment increased mitochondrial membrane potential. However, increases in intracellular Ca2+ concentration were inhibited by GGA pretreatment. In addition, the increase of phosphorylated ERKs by the glutamate exposure was inhibited by GGA pretreatment. These findings suggest that GGA protects HT-22 cells from glutamate-provoked cell death without Hsp induction and that the mitochondrial calcium buffering capacity plays an important role in this protective effect.

Pyruvate kinase M2 (PKM2) is essential for aerobic glycolysis and is highly expressed in various cancer tissues. Although high PKM2 expression is observed in prostate cancer tissues, its functional role in cancer metabolism is unclear. Here, we investigated the role of PKM2 in regulating autophagy and its associated pathways in prostate cancer cells. PKM2 expression was silenced using various PKM2 small interfering RNAs (siRNAs) and then we measured PKM2-related cellular pathways associated with autophagy. PKM2 siRNA-transfected prostate cancer cells showed significantly reduced viability. Acridine orange staining and immunoblotting analysis showed that PKM2 downregulation markedly increased autophagic cell death. Results of western blotting analysis showed that PKM2 knockdown affected protein kinase B/mechanistic target of rapamycin 1 pathway, which consequently downregulated the expression of glycolytic enzymes lactate dehydrogenase A and glucose transporter 1. To the best of our knowledge, this is the first study to show that PKM2 inhibition alters cancer cell metabolism and induces autophagy. Thus, the present study provides a strategy for the development of PKM2-targeted novel anticancer drugs for the treatment of prostate cancer.

Breast cancer treatment mostly revolved around radiation therapy and surgical interventions, these treatments doesn’t provide satisfactory relief to the patients and carry unmanageable side-effects. Nanomaterials show promising results in treating cancer cells and have many advantages such as high biocompatibility, bioavailability and effective therapeutic capabilities. Interestingly, fluorescent magnetic nanoparticles have been used in many biological and diagnostic applications, but there is no report of use of fluorescent magnetic submicronic polymer nanoparticles (FMSP-nanoparticles) in the treatment of human breast cancer cells. In the present study, we have tested the effect FMSP-nanoparticles on human breast cancer cells (MCF-7). We have tested different concentrations (1.25µg/1mL, 12.5µg/mL and 50µg/1mL) of FMSP-nanoparticles in MCF-7 cells and evaluated the nanoparticles response morphometrically. Our results revealed that FMSP-nanoparticles produced a concentration dependent effect on the cancer cells, dose of 1.25µg/mL produced no significant effect on the cancer cell morphology and cell death, whereas dosages of 12.5µg/mL and 50µg/mL respectively showed significant nuclear augmentation, disintegration, chromatic condensation followed by dose dependent cell death. Our results demonstrate FMSP-nanoparticles have ability to induce cell death in MCF-7 cells and may be considered as a potential anti-cancer agent for breast cancer treatments.

We reviewed the association between seasonal influenza vaccination and the risk of SARS-CoV-2 infection or complicated illness or poor outcome (e.g. severe disease, need for hospitalization or ventilatory support, or death) among COVID-19 patients. None of the studies that were reviewed (n=12) found a significant increase in the risk of infection or in the illness severity or lethality, while some reported significantly inverse associations. Our findings support measures aimed at raising influenza vaccination coverage in the coming months.

Vibrio parahaemolyticus is an important human pathogen that is currently the leading cause of shellfish-borne gastroenteritis in the world. Particularly, the pandemic strain has the capacity to induce cytotoxicity and enterotoxicity through its Type 3 Secretion System (T3SS2) that leads to massive cell death. However, the specific mechanism by which T3SS2 induces cell death remain unclear and the contribution in mitochondrial stress is not fully understood. In this work, we evaluated the contribution of T3SS2 of V. parahaemolyticus to generate mitochondrial stress and cell death during infection in human intestinal HT-29 cells. To evaluate this, infection assays were carried out to evaluate mitochondrial transition pore opening, mitochondrial fragmentation, ATP quantification, and cell viability during infection. Our results showed that the Δvscn1 (T3SS2+) mutant strain contributes to generating the sustained opening of the mitochondrial transition pore. Furthermore, it generates perturbations in the ATP production in infected cells, leading to a significant decrease in cell viability and loss of membrane integrity. Our results suggest that T3SS2 from V. parahaemolyticus plays a role in generating mitochondrial stress and cell death in human intestinal HT-29 cells. It is important to highlight that this study represents the first report indicating the involvement of T3SS2 from V. parahaemolyticus in generating mitochondrial stress, its impact on the mitochondrial pore, and its effect on ATP production in human cells.

Colon cancer is a common malignancy of digestive tract and has high incidence and mortality worldwide. As a normal flora in the human gastrointestinal tract, lactic acid bacteria have been proved to have health benefits, such as immune-regulation, anti-infection, and anti-tumor. In the present study, the inhibitory effects of 19 heat-inactivated plant-derived lactic acid bacteria on human colon cancer cell HCT116 were investigated. The results showed that heat-inactivated plant-derived lactic acid bacteria strain 729 had the strongest inhibitory effect on HCT116 cells among all tested bacteria. Treatment with heat-inactivated bacteria strain 729 could inhibit the proliferation of HCT-116 cells in dose-dependent manner, with 54.52% inhibition at a final concentration of 1×10⁸ CFU/mL. Moreover, the heat-inactivated bacteria strain 729 could block the cell cycle, induce apoptosis, and promote cellular ferroptosis by downregulating the expression of GPX4 and xCT at protein level. According to the 16S rDNA sequencing, the plant-derived lactic acid bacteria strain 729 was Lactobacillus plantarum. Collectively, the results indicates that lactic acid bacteria strain 729 may be developed as special ingredients targeting colon cancer, but further in vivo studies are required.