IntroductionFebrile neutropenia is a commonly encountered medical emergency in patients undergoing cancer treatment and can delay and modify the course of treatment and even lead to dire outcomes, including death. The cause of fever in a post-chemotherapy-induced neutropenic patient can be confusing to treating physicians. A review of the literature demonstrated that blood culture results could determine the cause of febrile neutropenia in only approximately 10% to 25% of patients. The objective of our study was to measure the incidence of positive blood cultures, urine cultures, and other body fluid cultures resulting in chemotherapy-induced neutropenia and further classify fever episodes into three neutropenic fever syndromes, such as microbiologically documented, clinically suspected, or unknown causes of fever, respectively.MethodsWe conducted a prospective observational study on 399 chemotherapy-induced neutropenic fever episodes with the aim of classifying them into one of the three neutropenic syndromes. We tried to document the cause of the fever in these patients. We also noted the type of cancer treatment regimen they were on and correlated their clinical profile with their body fluid cultures, including blood cultures, urine cultures, and other body fluid cultures. We then categorized each fever episode into one of three neutropenic syndromes.ResultsEscherichia coli. Cumulatively, including blood, urine, and body fluid cultures, we were able to classify 39% (155 out of 399 cases) of febrile neutropenic episodes as microbiologically documented. The cause of fever was clinically suspected by means of careful history taking and an extensive physical examination in 31% (125 out of 399) without growth evidence in blood cultures, urine cultures, or any other body fluid culture. The cause of fever remained unknown in 119 cases (30%) of patients and was classified under the unknown cause of fever.We studied 399 febrile neutropenic episodes. We were able to microbiologically document the cause of fever in 39% of the cases, and we obtained growth in 51 out of 399 blood cultures (13%), which was comparable to the available literature, and urine culture showed growth in 62 out of 399 cultures (16%), while other body cultures such as pus culture, bile culture, and bronchioalveolar lavage cultures collectively showed growth in 42 out of 399 episodes (10%). The most common bacteria isolated in both blood and urine cultures were ConclusionsWe conclude by stating that the study of fever in a neutropenic patient should include a thorough history and clinical evaluation of blood, urine, and other body fluid cultures instead of solely relying on blood culture results. We recommend further classifying patients into one of the three neutropenic fever syndromes, such as those that are microbiologically documented, clinically suspected, or unknown. Our blood cultures were able to give us a 13% positivity rate, whereas microbiologically, we were able to isolate an organism likely causing fever in 39% of patients. The cause of fever was suspected clinically in 31% of patients, but we were unsuccessful in microbiologically documenting any culture growth in blood, urine, or any other body fluid culture. The cause of fever remained a mystery and unknown to us without any microbiological or clinical cues in 119 cases (30%) of febrile neutropenic episodes. Chemotherapy-induced neutropenia is characterized by a reduction in neutrophil counts, usually occurring within 7 to 12 days following cancer chemotherapy. Febrile neutropenia is a concerning complication of chemotherapy and a major cause of morbidity, with compromised efficacy resulting from delays and dose reductions in chemotherapy. The cause of fever in chemotherapy-induced neutropenic patients has always been a debated topic of discussion. Understanding, identifying, and proving the cause of fever has always been confusing for treating physicians. The presence of central lines and chemotherapy ports further complicates the approach. Some authors believe cancer patients receiving chemotherapy, which adversely affects cellular mitosis, myelopoiesis, and the developmental integrity of the gastrointestinal mucosa and other epidermal cell surfaces, are at risk for invasive infection due to colonizing or pathogenic bacteria and/or fungi that translocate across mucosal surfaces.The possibility of bloodstream infection is a major concern at the onset of fever since blood culture isolates account for only 10-25% of all febrile episodes in neutropenic patients [Researchers found that the occurrences of severe sepsis and septic shock in the setting of febrile neutropenia have been estimated to be, respectively, 20-30% and 5-10% .The following observations have been made about bacterial infections in neutropenic patients:Epidermidis is the most common gram-positive pathogen, accounting for approximately one-half of all infections due to gram-positive infections. It is much less virulent than other bacterial pathogens, is frequently a contaminant, and can misguide the treatment approach .Polymicrobial infections are rare, but their frequency appears to be rising.Evaluation of the date of insertion of catheters, tubes, and lines along with a general examination around the central line entry point for tenderness or signs of possible infection like pus pockets can help a clinician evaluate and approach an episode of fever in a neutropenic patient, especially in between chemotherapy cycles. It is also worthy of mention that fevers that occur when fluids are given through a particular line or cannula could possibly be due to infection of the venous access. A decrease in the intensity or frequency of fever spikes after stopping the use of a central line could be suggestive of a possible infection of the line. It is also useful to send cultures from the venous port and another site. A possible antibiotic lock could be attempted to clear up the infection from the line, but in advanced infections, we may need to remove the line in view of a possible clinical focus of infection.The Immunocompromised Host Society has classified initial neutropenic fever syndromes into the following three categories:1) Microbiologically documented infection: neutropenic fever with a clinical focus on infection and an associated pathogen on cultures.2) Clinically documented infection: neutropenic fever with a clinical focus , but without the isolation of an associated pathogen.3) Unexplained fever: neutropenic fever with neither a clinical focus on infection nor an identified pathogen.The classification and correlation of clinical presentations and microbiological manifestations help a clinician evaluate and approach an episode of fever in a neutropenic patient. We wanted to observe, classify, and compare the global literature on a series of 399 febrile neutropenic patients and classify the resultant trends into one of the three neutropenic syndromes.A prospective observational study was conducted over a period of 21 months, from September 2019 to June 2021. The study was conducted at Columbia Asia Referral Hospital Yeshwanthpur oncology clinic and involved 399 chemotherapy-induced neutropenic patients, including 219 hematological malignancies and 180 solid tumors. Febrile neutropenia was diagnosed in the occurrence of a single oral temperature of ≥38.3°C (101°F) or 38.0°C (100.4°F) for more than one hour along with an absolute neutrophil count (ANC) ≤500/µl or ≤1000/µl with a predicted rapid decline during the next 48 hours. The ANC was calculated by looking at the differential white cell count or by multiplying the total white cell count by * percentage of neutrophils in the differential count.All patients underwent a comprehensive clinical examination to assess indications of infection and potential source of infection. Additionally, blood, urine, and other body fluids were collected for aerobic and anaerobic cultures. Patients were given empirical antibiotic monotherapy within one hour of presentation with a broad-spectrum agent like cefepime, piperacillin-tazobactam, ceftazidime, or a carbapenem . The type of cancer treatment regimen and correlation of their clinical profile with their blood culture results, urine culture results, and other body fluid culture results were noted and then further classified into one of the three neutropenic fever syndromes as microbiologically documented, clinically suspected, or unknown causes of fever. The trial was conducted in accordance with the Declaration of Helsinki and all applicable national and local ethical requirements.Inclusion criteriaThe inclusion criteria include all patients attending Columbia Asia Referral Hospital Yeshwanthpur oncology clinic with febrile neutropenia.Exclusion criteriaThe exclusion criteria include all non-oncology febrile neutropenia and febrile neutropenic patients with COVID-positive status.Classification of febrile neutropenia episodes into neutropenic syndromesA total of 399 cases of febrile neutropenia were subclassified into neutropenic syndromes. Microbiologically documented cases are those neutropenic fevers in which a bacterium has been successfully cultured and demonstrated. Clinically suspected cases are those in which we found clinical signs of infection but were unable to culture any organism. Unknown cases are those in which the patients were febrile without any clear-cut clinical reasoning or microbiological proof. The results of our study are shown below in tabular format in Table Blood culturesA total of 399 blood cultures from neutropenic patients who were febrile were collected. The number of positive blood cultures was 51 (13%) with a positivity rate as shown in graphical format in Figure Blood culture organism trendsE. coli was the most commonly cultured organism, with 19 cases. In context with the demonstrated literature, the next most cultured group was the coagulase-negative staphylococcus group, with seven cases. Staphylococcus epidermidis was the next to follow with five cases. The trends in blood culture organisms are shown in graphical format in Figure Bacteremia was identified in 51 cases out of 399 patients' blood cultures, with a blood culture-only positivity rate of 13%. Urine culturesA total of 399 febrile neutropenic episodes were studied. We obtained positive urine cultures in 62 cases, with a 16% positivity rate. We obtained a negativity rate of 84% in urine cultures as well, as shown in graphical format in Figure Urine culture organism trendsE. coli was the most commonly cultured organism, with 24 cases. The next most cultured group was the Klebsiella group, with 12 cases. Enterococcus was next to follow with 11 cases. The trends in urine culture organisms are shown in graphical format in Figure Bacteremia was identified in 62 cases out of 399 patients' urine cultures, with a urine culture-only positivity rate of 16%. Patients usually follow up in the outpatient clinic a few days after chemotherapy administration. Clinical signs and symptoms that could predict the development of severe neutropenic complications are listed below:a) Septic appearanceb) Severe mucositisc) Intravascular catheter in-situ and suspected site of infectiond) possibility of lower respiratory tract infection in chronic obstructive pulmonary diseasee) Uncontrolled or progressive cancerBacteremia was identified and confirmed by blood cultures as a source of infection in 51 (13%) patients, which approximately correlated to the available literature.We were able to microbiologically document the source of fever in an additional 26% of patients by collectively looking at all body fluid cultures. The International Immunocompromised Host Society neutropenic syndrome classification is listed in Table Our blood culture positivity rate of 13% was comparable to the study done by Babu et al. at Kidwai Hospital, in which 15% of cases isolated and cultured an identifiable organism .A review of the literature shows surprisingly low levels of positive blood cultures in febrile neutropenic patients. The possible causes for the same could be listed below:1) Missing the organism2) Systemic inflammatory response syndrome v/s sepsis 3) ViralTreatment of febrile neutropeniaEach cancer center should have an updated standard regimen of choice, which contributes to the utility of this study. The following points are to be considered when dealing with febrile neutropenic patients:In culture-positive patients, we change the antibiotic to the most susceptible option based on the culture plate resistance pattern, as we are dealing with a bacterial pathogen.Broad-spectrum antibiotics should be given as early as possible, with recommendations to give antibiotics in the first 60 minutes and at full doses, adjusted for renal and/or hepatic function . It is cStaphylococcus aureus, community-acquired pneumonia, or severe mucositis is suspected. Vancomycin is also chosen as the first regimen for hemodynamic instability [Vancomycin is chosen after clinical evaluation if a skin-based infection like methicillin-resistant tability . Linezoltability .In culture-negative sepsis, we recommend the concept of de-escalation of antibiotics in clinically stable patients .We follow the following stages of antibiotic administration in febrile patients admitted to the hospital:Stage 1: Early administration of broad-spectrum antibiotics to get blanket coverage (before blood culture results have arrived)Stage 2: Focused, targeted therapy based on the culture sensitivity profile Stage 3: Procalcitonin can be used as an adjunct to deescalate antibiotics, and literature has demonstrated that tracking procalcitonin improves mortality Stage 4:ProphylaxisGenerally, prophylactic antibiotics are recommended only for patients expected to have fewer than 100 neutrophils/μL for more than seven days . With inThe Current National Comprehensive Cancer Network guidelines recommend consideration of bacterial prophylaxis with fluoroquinolone in intermediate- and high-risk patients . The InfAntifungal therapyAspergillus galactomannan antigen and the beta-D-glucan assay, should also be considered in high-risk patients. If the fever is persistent, recommendations direct us toward antifungal medications like voriconazole, echinocandins, or amphotericin-B [Consider antifungal prophylaxis with fluconazole-like medicine for either an obvious fungal infection determined by imaging or a clinically unexplained persistent or recurrent fever if it lasts for more than four to seven days. Checking for fungal markers in the serum, such as the ericin-B .Colony stimulating factorsAlthough most neutropenic patients are treated with colony-stimulating factors, the recommendations do not recommend the use of colony-stimulating factors like C-GSF. For catheter removal, the central venous catheter should also be removed in patients with complicated infections .Anaerobes in febrile neutropeniaAnaerobic bacteria are abundant in the alimentary tract, but they are rare pathogens isolated from patients with neutropenic fever. This could be because blood cultures require separate aerobic and anaerobic tubes. Anaerobes could be the cause of necrotizing mucositis, periodontal cellulitis, mucositis, neutropenic enterocolitis, and intraabdominal and pelvic infections, but they have not been cultured frequently.Treatment failureNo fever defervescence within 30 days of the start of treatment or persistence, progression, or recurrence of signs and symptoms of infection despite initial broad-spectrum therapy were considered treatment failures.We do not have the exact documented rate of treatment failures and deaths, but a general observation we made in keeping with the available literature was that poor baseline status of the patients led to more severe infections where patients were escalated to the intensive care unit, where they were lost to follow-up .The treatment failure rate is higher in documented infections than in unknown febrile episodes . TreatmeEscherichia coli.Our study included 399 febrile neutropenic episodes. We obtained growth in 51 out of 399 blood cultures (13%), and urine cultures showed growth in 62 out of 399 cultures (16%), whereas other body cultures like pus culture, bile culture, and bronchoalveolar lavage cultures collectively showed growth in 42 out of 399 episodes (10%). In all, we were able to microbiologically document the cause of fever in 155 out of 399 cases (39%), and the cause of fever was clinically suspected in 125 cases (31%). The cause of fever was unknown in 119 (30%) of the patients. About 219 episodes of febrile neutropenia were seen in hematological malignancies, whereas 180 episodes belong to advanced solid tumors. The most common bacteria isolated in both blood and urine cultures were We conclude by recommending a thorough clinical examination and review of other bodily fluid cultures in febrile neutropenic patients, as we found a positivity of 13% in blood cultures alone but a positivity of 39% in microbiologically documented infections (including urine and other body fluid cultures). We recommend the classification of neutropenic patients into neutropenic syndromes, such as those that are microbiologically documented, clinically suspected, or of unknown cause. The process of classification helped us approach and manage neutropenic patients better.


Cerebral ischemia–reperfusion injury (CIRI) is a series of cascade reactions that occur after blood flow recanalization in the ischemic zone in patients with cerebral infarction, causing an imbalance in intracellular homeostasis through multiple pathologies such as increased oxygen free radicals, inflammatory response, calcium overload, and impaired energy metabolism, leading to mitochondrial dysfunction and ultimately apoptosis. Rescue of reversibly damaged neurons in the ischemic hemispheric zone is the key to saving brain infarction and reducing neurological deficits. Complex and active neurological functions are highly dependent on an adequate energy supply from mitochondria. Mitochondrial biogenesis (MB), a process that generates new functional mitochondria and restores normal mitochondrial function by replacing damaged mitochondria, is a major mechanism for maintaining intra-mitochondrial homeostasis and is involved in mitochondrial quality control to ameliorate mitochondrial dysfunction and thus protects against CIRI. The main regulator of MB is peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which improves mitochondrial function to protect against CIRI by activating its downstream nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) to promote mitochondrial genome replication and transcription. This paper provides a theoretical reference for the treatment of neurological impairment caused by CIRI by discussing the mechanisms of mitochondrial biogenesis during cerebral ischemia–reperfusion injury. Cerebral ischemia is a major health problem worldwide, with a high morbidity rate and a very high rate of disability and mortality . An ischMitochondrial homeostasis is composed of mitochondrial fusion and fission, degradation of dysfunctional mitochondria through mitochondrial autophagy or the ubiquitin-proteasome system, and generation of new mitochondria from the existing mitochondrial pool through mitochondrial biogenesis (MB) . MitochoCerebral ischemia–reperfusion injury is a complex process, and after ischemia and hypoxia, blood flow recanalization in brain tissue triggers a series of pathological responses including increased oxygen free radicals, inflammatory response, calcium overload, impaired energy metabolism, and apoptosis, among other processes . MitochoOxidative stress is one of the main mechanisms of CIRI. Under normal conditions, moderate amounts of reactive oxygen species (ROS) play an important role in several physiological processes and they can be eliminated by endogenous antioxidant systems . In patiInflammatory cells are rapidly activated after CIRI, and glial cells are considered to be one of the key factors triggering the inflammatory response. Inflammatory effector cells infiltrate and then release large amounts of inflammatory mediators to cause local brain tissue edema eventually leading to tissue injury . After t2+ in a complex increasing the release of vasoconstrictor factors, causing vasospastic constriction affecting blood flow and aggravating the ischemic–hypoxic injury after CIRI. Calcium overload also increases the synthesis of free fatty acids by activating phospholipases A and C, which disrupts the neuronal skeleton and leads to cellular edema  synthesis of the inner mitochondrial membrane (IMM) and outer mitochondrial membrane (OMM) (2) synthesis of mitochondrial-encoded proteins (3) synthesis and import of nuclear-encoded mitochondrial proteins; and (4) replication of mtDNA . Mitochoynthesis . mtDNA iynthesis .PGC-1α expression also mediates mitochondrial uncoupling through the induction of proteins such as uncoupling protein-2 (UCP2), an internal mitochondrial membrane protein that dissipates mitochondrial membrane potential to uncouple electron transport from ATP synthesis, thereby reducing ROS production . UCP2 haIn summary, NRF1, UCP2, and PON2 play key roles in PGC-1α-induced mitochondrial biosynthesis, and they improve oxidative stress, reduce apoptosis, and protect normal mitochondrial function by reducing ROS release, updating our current knowledge and understanding of the mechanisms of mitochondrial biosynthesis in PGC-1α-induced cerebral ischemic diseases, so mitochondrial biosynthesis may become a potential new target for CIRI therapy.Ischemia–reperfusion (IR) can trigger apoptotic pathways by increasing the production of reactive oxygen species, disrupting calcium homeostasis and inducing an inflammatory response, and mitochondria are affected by post-IR cascade events resulting in dysfunction; mitochondrial dysfunction in turn exacerbates neuronal damage after IR, as neurons rely heavily on mitochondrial ATP production to support their high energy requirements . ExperimGiven that mitochondria act as energy centers and are important for cellular homeostasis, exploring the role of mitochondrial biogenesis as an endogenous protective response to ischemic injury may help us develop a strategy to enhance this beneficial effect and counteract the deleterious effects associated with ischemia. In previous studies, it was found that the PGC-1α signaling pathway is activated under transient global ischemia, which may trigger UCP2 and SOD2 expression and promote mitochondrial biogenesis in the CA1 region of the hippocampus, consistent with the role of mitochondrial biogenesis as a potential endogenous protective mechanism . TherefoThe ROS detoxification system and mitochondrial biogenesis may play an important role as endogenous protective mechanisms in cerebral ischemia. It has been demonstrated that increased mitochondrial biosynthesis can exert neuroprotective effects and reduce ischemic brain injury by increasing the number of mitochondria . PreviouNeurons have high energy requirements and therefore mitochondrial homeostasis is critical for maintaining the normal neuronal function, and exploring the role of mitochondrial biosynthesis in response to ischemic injury may help to develop strategies to enhance this beneficial effect and ameliorate the pathological consequences associated with ischemia. Several studies have shown that ischemia disrupts mitochondrial structure and function, with significantly reduced mitochondrial respiratory function, increased levels of oxidative stress, and changes in mitochondrial permeability induced by calcium ion overload in Middle cerebral artery occlusion model (MACO) rats, ultimately leading to neuronal apoptosis in ischemic brain tissue . PreviouTherefore, from the perspective of promoting PGC-1α-mediated mitochondrial biosynthesis and attenuating oxidative stress to protect mitochondrial function, it may be a promising therapeutic direction for neuroprotective treatment strategies against ischemic brain injury.The ischemic–hypoxic state after cerebral ischemia leads to an imbalance in mitochondrial functional homeostasis. The massive generation of reactive oxygen species after reperfusion activates the expression of pro-oxidant enzymes, decreases the antioxidant capacity of neurons, and impairs mitochondrial function eventually leading to cell death. The massive inward flow of calcium ions in mitochondria and oxidative stress can lead to the opening of MPTP through lipid peroxidation and damage to the mitochondrial respiratory chain, resulting in a decrease in mitochondrial membrane potential and the release of substances such as pro-apoptotic proteins, which then activate apoptotic pathways and eventually lead to neuronal death . The orgActivation of the PGC-1α pathway and subsequent MB plays a protective role in CIRI, as PGC-1α reduces the release of ROS by increasing the expression of its downstream targets, such as UCP2 and SOD2, thereby improving neuronal damage and reducing apoptosis. It can also enhance the antioxidant and anti-inflammatory ability of neurons. Therefore, enhancing PGC-1α-mediated MB may be a new way to promote neurological recovery after cerebral infarction. Improving mitochondrial biosynthesis, promoting the replacement of damaged mitochondria in the cerebral ischemic zone, inhibiting oxidative stress and thus accelerating neurological recovery may be a new strategy for the treatment of CIRI and provide new ideas for the clinical treatment of IR.YY: conceptualization and writing—original draft preparation. YY, YT, HJ, LYC, and XMZ: writing—review and editing. JS, RP and YY: edited the final version of the manuscript, and JS and YY: participated in the drawing of the figures. All authors have read and agreed to the published version of the manuscript.This research was funded by the National Natural Science Foundation of China, grant number No. 81704188 and the Natural Science Research Program of the Hubei Provincial Education Department, grant number No. D20202006.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Post-traumatic vertebral necrosis and pseudarthrosis represents one of the most concerning and unpredictable challenges in spinal traumatology. The evolution of this disease at the thoracolumbar transition usually courses with progressive bone resorption and necrosis, leading to vertebral collapse, retropulsion of the posterior wall and neurological injury. As such, the therapeutic goal is the interruption of this cascade, seeking to stabilize the vertebral body and avoid the negative consequences of its collapse.We present a clinical case of a pseudarthrosis of T12 vertebral body with severe posterior wall collapse, treated with removal of intravertebral pseudarthrosis focus by transpedicular access, T12 armed kyphoplasty with VBS® stents filled with cancellous bone autograft, laminectomy and stabilization with T10-T11-L1-L2 pedicle screws. We present clinical and imaging detailed results at 2-year follow-up and discuss our option for this biological minimally invasive treatment for vertebral pseudarthrosis that mimics the general principles of atrophic pseudarthrosis therapeutic and allows to perform an internal replacement of the necrotic vertebral body, avoiding the aggression of a total corpectomy.This clinical case demonstrates a successful outcome of the surgical treatment of pseudarthrosis of vertebral body  in which expandable intravertebral stents allow to perform an internal replacement of the necrotic vertebral body by creating intrasomatic cavities and filling them with bone graft, obtaining a totally bony vertebra with a metallic endoskeleton, which is biomechanically and physiologically more similar to the original one. This biological internal replacement of the necrotic vertebral body technique can be a safe and effective alternative over cementoplasty procedures or total vertebral body corpectomy and replacement for vertebral pseudarthrosis and may have several advantages over them, however long-term prospective studies are needed in order to prove the effectiveness and advantages of this surgical option in this rare and difficult pathological entity. Avascular necrosis of the vertebral body diagnosis in post-traumatic context has been increasing, probably due to population aging, being more commonly found in the thoracolumbar transition and in elderlies with osteoporosis –7. It isVisual Analog Pain Scale—VAS) and had progressively worsened over 2 weeks, leading to the patient being currently unable to sit or walk (Oswestry score (ODI) was 96% (We present a 71-year-old male patient, previously autonomous in daily living activities, with a history of type II diabetes mellitus, arterial hypertension and dyslipidemia, who came to our center emergency department bedridden with complaints of thoracolumbar axial pain. This pain was severe (grade 7/10 on  or walk . The pat was 96% . The pat was 96%  Rad-APf.ad inicium T12 armed kyphoplasty in order to guarantee the anterior column support, stabilize it and thus precisely prevent vertebral collapse due to non-union. The repeated excessive loads on the mobile thoracolumbar transition, in view of the weakened fractured T12 vertebral body with marked destruction of the anterior column, led to insufficient stability to provide bone healing, which led to progressive bone reabsorption and necrosis, with consequent loss of its structural integrity and support function, following vertebral flattening and collapse with retropulsion of the posterior wall and neurological risk (In the present clinical case, the marked destruction of the intrasomatic trabeculae in the initial fracture associated with its location in the thoracolumbar transition, a region of important mobility, would, in our opinion, be a criterion for performing an cal risk –11. Durical risk , 27, 28.Based on the scarce scientific literature available, the authors propose post-traumatic vertebral necrosis evolution stages  built onIn mobile vertebrae (pseudarthrosis, that is, with intravertebral clefts—Authors usually choose VBS® stent implants in vertebrae with mobile deformity , an implIn this way, we consider this surgical technique a useful minimally invasive biological option that preserves the vertebral body in vertebral pseudarthrosis, avoiding corpectomy, which is thus only reserved for situations of non-union with immobile vertebra plana characteristics , that isIn view of this suggested post-traumatic vertebral necrosis evolution stages, it is easily understood that we should early intervene in situations of post-traumatic vertebral necrosis, ideally in vertebrae non-plana stages (stages 1i and 1 m—In conclusion, this clinical case demonstrates that the treatment of pseudarthrosis of vertebral body, even in vertebra plana stage, can be carried out as an internal replacement of the necrotic vertebral body performed by posterior transpedicular access in which expandable intravertebral stents allow to create intrasomatic cavities, which are filled with bone graft, obtaining a totally bony vertebra with a metallic endoskeleton. This biological internal replacement of the necrotic vertebral body technique can be a safe and effective alternative over cementoplasty procedures or total vertebral body corpectomy and replacement for vertebral pseudarthrosis and may have several advantages over them, like allowing by a less invasive posterior technique to obtain a totally bony vertebra biomechanically and physiologically more similar to the original one and avoiding the risks of bone cement leakage. Our clinical case shows quite satisfactory clinical and radiographic results regarding this technique in a vertebra plana pseudarthrosis; however, long-term prospective studies are needed in order to prove the effectiveness and advantages of this surgical option in a rare and difficult pathological entity.


Eukaryotic genomes are spatially organized inside the cell nucleus, forming a threedimensional (3D) architecture that allows for spatial separation of nuclear processes and for controlled expression of genes required for cell identity specification and tissue homeostasis. Hence, it is of no surprise that mis-regulation of genome architecture through rearrangements of the linear genome sequence or epigenetic perturbations are often linked to aberrant gene expression programs in tumor cells. Increasing research efforts have shed light into the causes and consequences of alterations of 3D genome organization. In this review, we summarize the current knowledge on how 3D genome architecture is dysregulated in cancer, with a focus on enhancer highjacking events and their contribution to tumorigenesis. Studying the functional effects of genome architecture perturbations on gene expression in cancer offers a unique opportunity for a deeper understanding of tumor biology and sets the basis for the discovery of novel therapeutic targets. More than 40 years after their discovery, enhancers are considered to play a central role in the spatio-temporal control of gene transcription, underlying human development and homeostasis . Enhanceails see ]. For excificity . More reem cells  and dros embryos , respectA variety of genetic and epigenetic mechanisms can disrupt 3D genome architecture and, in turn, cause aberrant gene expression in cancer cells, as summarized in genes - a marker used for prostate cancer malignancy stratification -     reinforcing or activating its transcription. Alternatively, SVs can trigger a fusion between contiguous TADs, leading to the emergence of long-range contacts between a promoter of a tumor-driving gene from one TAD, and an enhancer from the second TAD that normally serves other gene(s)  . Enhance gene(s)   and shoopFinder , which incogenes . Future The three-dimentional architecture of the genome is vital for gene expression regulation and its disruption by genetic or epigenetic alterations is emerging as an important contributor to the pathogenesis of cancer. Several mechanisms by which the 3D genome gets perturbed in cancer have been described, including mutations in proteins shaping genome architecture or in their binding motifs, rewiring of A/B compartments and TADs and enhancer hijacking. However, several major questions in this arena remain unanswered: are genomic rearrangements and consequent 3D genome architecture perturbation the only cause for enhancers hijacking? Can enhancer hijacking be caused by non-genetic mechanisms such as reactivation of transposable elements within specific genomic regions? Can specific nucleotide sequence features  affect enhancer hijacking? Are there any shared enhancers hijacking events among different tumor types? And, most importantly, can we target dysfunctional enhancers or aberrant TADs/loops for therapeutic purposes?in silico tools in clinical trials, will be useful to assess the diagnostic and predictive value of SVs and associated 3D genome changes. Ultimately, developing cost-effective and scalable approaches for screening the effect of drugs or genetic perturbations on 3D genome architecture will be needed to develop the first generation of 3D genome targeted therapies.Answering these questions will require charting the 3D genome directly in patient-derived tumor samples and, integrating 3D genome measurements to WGS data and new


Control of gene expression, including transcription, is central in dictating the outcome of viral infection. One of the profound alterations induced by viruses is modification to the integrity and function of eukaryotic RNA polymerase II (Pol II). Here, we discuss how infection perturbs the Pol II complex by altering subunit phosphorylation and turnover, as well as how cellular genotoxic stress (e.g. DNA damage) elicits similar outcomes. By highlighting emerging parallels and differences in Pol II control during viral infection and abiotic stress, we hope to bolster identification of pathways that target Pol II and regulate the transcriptome. The battle between a virus and its infected cell is one that centers on the control of gene expression. On the cellular side, these are the responses that drive antiviral signaling, while the ability of a virus to block those signals and simultaneously redirect gene expression machinery toward viral genes can define whether an infection will amplify or be restricted. Viruses thus frequently manipulate transcriptional regulators such as activators and repressors, as well as chromatin structure . HoweverPol II is a 12-subunit complex that is responsible for mRNA transcription in eukaryotic cells. Its activity relies on accessory proteins such as general transcription factors (GTFs), TATA-associated factors, and the mediator complex; the ensemble of this machinery is collectively referred to as the Pol II holoenzyme  –6. ViralDespite the prevalence of stress-linked Pol II abundance changes, much remains to be discovered about the mechanistic basis of these phenotypes, particularly in the case of infection. However, emerging evidence suggests that there is at least some conservation in the pathways that control Pol II during viral and nonviral stress, which we explore herein to create a framework to guide future studies on how stress modulates the cellular transcriptional landscape.I), composed mainly of serine 5-phosphorylated (Ser5-P), a modification that is usually associated with transcription initiation and splicing [I and hypophosphorylated Pol II are present in viral replication compartments following recruitment by the IE protein ICP27, while Ser2-P Pol II is specifically excluded or degraded [Regulation of the Pol II holoenzyme occurs through post-translational modifications that influence the stages of transcription . Rpb1 . For RNA viruses that encode their own RNA-dependent RNA polymerase (RdRp), targeting Pol II enables selective dampening of host gene expression because viral genes are transcribed by the RdRp. Old World alphaviruses, including Sindbis, Chikungunya, and Semliki Forest virus, potentiate a rapid disappearance of vertebrate Rpb1 that involves proteasomal degradation. This is linked to viral nonstructural protein 2 (nsP2), as viruses unable to cleave and release nsP2 do not elicit Rpb1 degradation, and nsP2 expressed from a noncytopathic replication vector is sufficient to reduce Rpb1 levels . Bunyavinduction ,22••, annduction ,24, whilnduction .Some DNA viruses achieve similar outcomes, despite many of these viruses relying on host Pol II for viral transcription. This paradox is presumably resolved by recruitment of the remaining Pol II to viral lytic replication compartments by the open, comparatively nucleosome-depleted chromatin environment of the viral genome ,27. As mRemoval of Pol II occurs with many stressors, often resulting in proteasomal degradation of Rpb1 . Here, wThe best-defined mechanism of Pol II subunit turnover occurs in the context of the DNA damage response (DDR) in uninfected cells . More unbiased screening approaches to determine the contributions of different E3s or ubiquitylation residues are needed to reveal links to DDR pathways as well as identify alternate or new pathways. If these mechanisms were inhibited in the presence of virus, this could also permit assessment of the functional implications of Pol II destruction for both virus and host. Furthermore, given that proteasome inhibition yields incomplete rescue of Pol II abundance during viral infection, regulation of Pol II abundance likely relies on the convergence of multiple processes.Rpb1 turnover during UV DNA damage does not result in co-depletion of other complex subunits in yeast, suggesting that individual subunits may be independently rather than interdependently regulated ,33. ThatOther possible mechanisms are that MHV68 targets multiple subunits independently for protein turnover, or that select protein subunit(s) are targeted directly while others deplete due to a failure to replenish the protein pool upon degradation of their mRNA. In this regard, widespread mRNA degradation is a well-established feature of lytic gammaherpesvirus infection and Pol II subunit levels are not reduced upon infection with an MHV68 mutant that is deficient for mRNA decay ,45,46. VMHV68-induced mRNA decay also prompts the redistribution of RNA binding proteins to the nucleus, which is both necessary and sufficient to induce host transcriptional repression . While tThe Pol II holoenzyme is critical for maintaining and regulating the cellular transcriptome. The consequences of shifting Pol II activity and abundance are particularly important for stress responses; thus, understanding how this occurs in the context of viral infection is crucial for predicting host–virus interactions. Data suggest that some protein-level Pol II adjustments occur via conserved pathways during infection and genotoxic conditions, but there are major gaps in our knowledge of how these are activated, as well as the functional consequences.While many viral Pol II depletion strategies seem to be at least partially dependent on proteasomal degradation, in general, the E3-mediated pathways leading to this outcome have not been identified. Regulation of Pol II abundance likely results from the combined effects of converging pathways — individually testing the few E3s implicated in other stress responses probably cannot provide a complete picture. Moreover, not all Pol II turnover occurs via the proteasome. UV radiation is reported to induce a less prominent, caspase-mediated cleavage event near the Rpb1 CTD , and anoScreening approaches are needed to flesh out the pathways involved in infection-induced changes to Pol II. Identification of these pathway components could additionally provide more targeted tools beyond inhibitors of the ubiquitin–proteasome system or transcription (which are often toxic and have pleotropic effects) to interrogate the impact of Pol II depletion or modification on the viral lifecycle. In this way, we could identify new players similarly involved in Pol II regulation during abiotic stress. While much remains to be discovered about the dynamics of Pol II regulation, viral research has and will continue to provide critical insight into this fundamental cellular process.


Since early 2020, while the worldwide focus was on the COVID-19 pandemic, highly pathogenic avian influenza (HPAI) A(H5) viruses of clade 2.3.4.4b caused the worst ever observed epidemics in birds during the 2020/21, 2021/22 and ongoing 2022/23 epidemic years in Europe. They caused 14,325 reported outbreaks with devastating consequences for farmed poultry, resulting in the culling of roughly 96 million farmed birds in Europe. Some remarkable changes of epidemiology have been observed over the last years in relation to circulating HPAI viruses of the H5 subtype.Highly pathogenic avian influenza epidemics in Europe used to be a seasonal phenomenon associated with migratory waterfowl returning to the overwintering sites in Europe in autumn, causing spill-over to farmed birds and outbreaks in poultry in the autumn/winter with some limited circulation in the spring. In 2021, for the first time, a few HPAI virus findings in wild birds continued over the summer in some breeding areas in northern Europe [In addition to the change in seasonality there was notable large global expansion and in 2020, A(H5) HPAI viruses of clade 2.3.4.4b spread west to east along migratory bird routes and were detected in south-east Asia [The rapid spread of AH5N1) viruses to many previously unaffected areas globally and their successful persistence during the summer months was likely facilitated by the ongoing evolution and reassortment with local low pathogenic avian (LPAI) viruses, leading to their adaptation to newly or previously very rarely affected wild bird species such as barnacle geese or sea birds. This impactfully introduced HPAI viruses into local wild bird populations representing a threat for endangered bird species. Massive die-off events were observed in colony-breeding seabirds in Europe . In SoutN1 viruseSeveral transmission events to various free-living and captive mammalian species have been reported from many countries globally . TransmiReports of infected dead or sick wild birds and terrestrial wild mammals (foxes) in urban or peri-urban areas have contributed to an increased environmental viral contamination and increased the risk of spill-over events to pet animals. Mammals infected with HPAI A(H5N1) virus clade 2.3.4.4b have been found ill or dead with severe neurological and, to a lower extend, with respiratory signs. High viral load was detected in the brain tissue of many of those infected mammals in line with the neurological clinical signs.A few A(H5N1) virus clade 2.3.4.4b detections in humans without or with very mild symptoms such as fatigue, have been reported from the United Kingdom , Spain  and the Similar to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) situation, the widespread circulation of HPAI viruses has been driving the high speed diversification for HPAI viruses with the emergence of different genotypes and reassortment events with local LPAI viruses independently in different geographical regions after introduction.Although currently circulating avian influenza viruses retain a preference for avian-type receptors, different mutations associated with transmission to and pathogenicity in mammals have been observed. These mutations were detected sporadically in infected wild and domestic birds and more often emerged upon transmission events to mammals .Highly pathogenic avian influenza viruses have become persistent in many regions globally, including Europe, and represent a constant threat for wild birds and mammals, the farming sector as well as public health. Ongoing evolutionary processes with ongoing virus circulation, diversification, and transmission to mammals, will continue and might increase mammalian-adaptive mutations associated with enhanced risk of transmission to and between mammals, including humans, which needs to be monitored across the kingdom of animals also in the light of the risk of a new pandemic.So far only dead or sick wild animals have been tested for A(H5) viruses; information about asymptomatic infections in wild mammals, however, is lacking due to the absence of systematic monitoring. Studies in different wild and domesticated animal species, particularly in terrestrial and marine mammals, need to be conducted, including serological and molecular investigations, to identify the magnitude of the spread.Further studies are needed to link clinical signs in infected animals with different organ affection over time, and to investigate the potential routes of infection in animals but also humans, duration of viral shedding in different animal species and optimal testing scheme for monitoring purposes to better assess the risk for human infection and propose prevention and mitigation measures.Introduction of avian influenza viruses into mammalian populations is of concern because of the potential increased risk of reassortment between different influenza viruses, adaptation to and spread between mammals.The risk for human health is currently limited to the animal-human interface when people are in contact with infected animals  or contaminated environment. Introduction of the virus into urban areas with exposure of pets to infected birds increases this risk to humans and pet holders in affected areas should prevent contact between pets and sick or dead wild birds or mammals. Also, awareness of veterinarians is important to test pets  for avian influenza and identify infected animals as early as possible.Despite the massive occurrence of wild bird mortality, poultry outbreaks and spill-over to wild carnivore species including environmental contamination and human exposure during these events, only sporadic human infections have been reported globally. In the latest instances, severe disease was observed following exposure to infected poultry in backyard settings, as well as to a contaminated environment or infected animals -17. MildCirculating A(H5N1) viruses have been assessed in the World Health Organization vaccine composition meeting to be antigenically similar to the recently developed A(H5) candidate vaccine viruses for pandemic preparedness considered for use in humans . Some muTo tackle the threat of avian influenza, a One Health approach is needed through rapid sharing of information about outbreaks, provision of sequence data and reference viruses, and close collaboration between the different sectors locally and globally. Communication campaigns may help to increase awareness in the population and recognise avian influenza viruses as a threat to animal and human health, in order to reduce the risk of contact with potentially infected animals.With the ongoing global presence of A(H5) HPAI viruses, further sporadic spill-over events to humans cannot be excluded. It is crucial to identify such events as early as possible to timely initiate appropriate measures across all sectors.


In the mammalian brain information processing and storage rely on the complex coding and decoding events performed by neuronal networks. These actions are based on the computational ability of neurons and their functional engagement in neuronal assemblies where precise timing of action potential firing is crucial. Neuronal circuits manage a myriad of spatially and temporally overlapping inputs to compute specific outputs that are proposed to underly memory traces formation, sensory perception, and cognitive behaviors. Spike-timing-dependent plasticity (STDP) and electrical brain rhythms are suggested to underlie such functions while the physiological evidence of assembly structures and mechanisms driving both processes continues to be scarce. Here, we review foundational and current evidence on timing precision and cooperative neuronal electrical activity driving STDP and brain rhythms, their interactions, and the emerging role of glial cells in such processes. We also provide an overview of their cognitive correlates and discuss current limitations and controversies, future perspectives on experimental approaches, and their application in humans. How do brain circuits manage a plethora of highly diverse inputs to generate precise outputs without functional failure? Neurons—widely regarded as the main functional units of the brain—perform crucial computational tasks by non-linear integration of synaptic inputs and subsequent generation of electrical action potentials (spikes). This computation is governed by multiple factors, including neuronal passive membrane properties, geometry, and active currents , 2. HoweA plausible explanation for the brain’s operational capacity emerges from the formation and dissolution of neuronal ensembles supported by timely coincident and mainly cooperative activity across activity-synchronized brain circuits , 4. Acti+ current decreases spike time precision in response to single EPSPs [Therefore, it is assumed that in the mammalian neocortex, information processing relies on the timing precision of neuronal activity within neuronal circuits and oscillators, –17 althole EPSPs . On the le EPSPs . Moreovele EPSPs , 23–25. le EPSPs .Irrespective of the complex mechanisms underlying timing precision, it is known that coincident firing (in a window ranging from 10 ms to ~100 ms) leads to long-lasting changes in synaptic efficacy: namely spike timing-dependent plasticity (STDP) , 27. STDTimely cooperation, correlated activity, and consequent synchronization of the electrical activity of neurons that are organized in networks also give rise to the emergence of what is known as brain rhythms or neuronal network oscillations. In generalized models, brain rhythms are supported by rhythmic interplay of pyramidal cells connected with inhibitory interneurons within discrete circuits. Inhibitory interneurons play key roles in the rhythm’s generation and maintenance, mainly by efficiently controlling and strengthening the timing of pyramidal cells outputs , 39–42. In local brain circuits, diverse neuronal subtypes are embedded in an organized puzzle of other cellular players such as microglia and astrocytes, which not only modulate but could actively control the concert of information processing. In this regard, astrocytes have been revealed as master regulators of synaptic activity, with diverse functions impacting the computational capacity of synapses and neuronal ensembles –59. ThisA bi-directional interplay also exists between STDP and neuronal network rhythms where the strength and features of the rhythms are also affected by the occurrence of plastic changes of the synapses involved in the neuronal ensemble . In addiSTDP is a ubiquitous learning rule that has been found experimentally in all species in which it has been studied—from insects to humans . Several2+ signals, and the level of adenosine-mediated inhibition due to astrocytic release of adenosine/ATP in these synapses [Since the emergence of the tripartite synapse concept, mounting evidence has revealed that pre-NMDARs could ally with astrocytes to control information flow in a circuit-specific way, particularly for STDP , framingsynapses , 91, 92.2+ signals combined with the release of gliotransmitters and actions on neuronal slowly desensitizing and high-affinity receptors. In turn, astrocytes also possess slowly desensitizing and high-affinity receptors for neurotransmitters, which determines the selectivity and the sensitivity of their activation and thus their role on the regulation of synaptic transmission and plasticity. Particularly, the kinetics of astrocyte Ca2+ signals (and the subsequent gliotransmitter release) encodes neuronal activity and supports the astrocytic ability to integrate information from different levels of neuronal activity [2+ elevations in response to low synaptic activity modulates synaptic transmission just in the synapse involved, [2+ elevations in response to strong synaptic activity diffuse to nearby processes affecting neighboring synapses [2+ elevations at multiple processes in response to coincident activity from multiple synapses drive to an integrated Ca2+ elevation, resulting in the control of the synaptic transmission within the whole area occupied by this astrocyte). This decoding and integrating ability provide finely tuned and easily adjustable feedback or feedforward responses that regulate neuronal communication in different time and spatial domains -dependent manner at synapses between excitatory neurons in somatosensory cortical layer 4 and layer 2/3 (L4-L2/3 synapses) [Our hypothesis also finds support in three previous unifying hypotheses  . Interesynapses) . This haynapses) , 76.2+ oscillations and Ca2+-mediated signaling in astrocytes [GABAergic activation of astrocytes also triggers cytosolic Catrocytes , 103, whtrocytes , 105. Notrocytes , 104. Sutrocytes , leadingIt is of particular relevance to note that STDP shows specific developmental profiles in different brain regions , 71, 76 1R), respectively [2ARs prevents this by counteracting the shift of microglia toward a pro-inflammatory phenotype [Likewise, during postnatal development, microglia play a pivotal role in synapse pruning, aided by fractalkine (CX3CL1) and its receptor. The expression of CX3CL1 increases in the Central Nervous System during embryonic and postnatal maturation, promoting microglial recruitment to neuronal circuits that undergo rewiring during periods of activity-dependent remodeling . In turnectively . Additiohenotype .Finally, diverse studies indicate that astrocytes possess mechanisms that allow them to integrate and store synaptic information . TherefoBrain rhythms emerge from the entrainment of circuits established by direct synaptic contact between neurons and indirect feedforward and feedback connections giving rise to rhythmic electrical fluctuations that can be measured extracellularly , 111–113A possible controversy may arise assuming that the neuronal firing rate instead of the firing synchronization and phase-lock solely underlie the strength and features of brain rhythms. Such current controversy could lie in the experimental configurations, neuronal class recorded, models of study, and/or analytical approaches. For instance, the assumptions needed to analyze spike-LFP phase coupling, the common pitfalls that could bias the analysis , and possible ways to avoid these pitfalls based on in vivo studies and computational models have been pointed out . In turnRegarding how action potential synchronization in the major neuronal classes contributes to the emergence of brain rhythms, two major models have been proposed. These models focus on explaining the generation and maintenance of the brain rhythm in the gamma frequency band . Gamma oscillations have emerged as crucial for cognitive processes in the brain and the two mechanistic models attempting to explain their generation are (1) synchronization of the interneuronal networks by mutual GABAergic and gap junction connectivity (the ING model of network entrainment)  and (2) In particular, parvalbumin-positive fast-spiking interneurons (PV-FSN) play a pivotal role in the synchronization of PCs during the emergence of the intrinsic hippocampal theta rhythm , 131. ThIn general, brain rhythms at different frequencies can occur separately, but they can also co-exist (nest in each other) and interact. This phenomenon is termed cross-frequency coupling. The most common interactions that have been studied is the coupling between certain features  of theta and gamma rhythms –149. ThiB receptors in astrocytes diminishes the power of sensory-evoked theta and low gamma rhythms and impairs theta-gamma phase-amplitude coupling [+). This points to the possible direct involvement of these cells in the regulation of ion flow across cortical layers, thus participating in the entrainment [Brain oscillations have classically been considered as purely dependent on the physical and functional contacts between the neurons involved in the ensemble. Non-neuronal contributions have been largely overlooked until recently, but they are starting to be the subject of comprehensive reviews . Glial ccoupling . Furthercoupling . In turncoupling , 156. Onrainment . On the rainment , 159.2+ levels by several stimuli provokes repetitive NMDAR-mediated responses mainly in CA1 pyramidal neurons. A noticeable feature of this response is that it arises with a high degree of synchrony in multiple neurons through the activation of extrasynaptic NMDARs [A second hypothesis for the role of microglia in the induction of network rhythms claims a secondary effect instead of a direct involvement in the entrainment . Consequc NMDARs . An addic NMDARs . This hi2+ imaging of astrocytes combined with STDP protocols).Does a group of neurons that are firing locked to a specific rhythm-entrained ensemble undergo STDP within the group or with neurons from other rhythm-entrained ensembles at the same time? Do these neurons disengage from the “primary” ensemble to achieve spike timing precision related to STDP, or do neurons undergoing STDP “interrupt” the coincident firing for STDP and start to uniquely fire in a rhythm’s phase-locked manner? These questions represent a technical and intellectual challenge, particularly because of difficulties in determining the ensembles sizes due to their ability to dynamically engage and disengage . HoweverOn the other hand, in the hippocampal area CA1, it was found that the timing of tempero-ammonic input relative to theta phase controls the sign of plasticity . Dependistratum radiatum, the intrinsic oscillatory dynamics of neurons has been found to be plastic owing to the plasticity of voltage-gated ion channel and spatial heterogeneity of pyramidal CA1 neurons. In this region, theta-burst pairing of orthodromic and antidromic stimulations induce t-LTP, and this plasticity is associated with spatially widespread plasticity in resonance and excitability [+ channels that are proposed as “good” readers and transmitters of the levels of input synchrony to the postsynaptic cell [As mentioned, PV-FSN offer a suitable target to modify the progression of instability in neuronal ensembles that might impact cognition. This has been observed in promising studies in an Alzheimer’s disease mouse model using optogenetic stimulation of PV-FSN at central gamma frequencies . In additability . Recentltability . Interestic cell . These fAs in many circuits of the brain, strong theta and gamma oscillations coexist in the perforant pathway (PP). In this remarkable input from the entorhinal cortex to the hippocampus, the distal apical dendrites of the basket cell interneurons (BC) preferentially transmit the lower frequencies to the soma , thus coTogether, these findings reveal that there is a finely tuned bi-directional interplay between STDP and neuronal network rhythms that also includes glial contribution. However, rules governing the occurrence of spike coincidence for STDP relative to ongoing brain rhythms and inputs external to the involved synapse are yet to be unveiled. Based on these findings of brain rhythms and STDP interactions, it is tempting to propose that STDP occurring at key synapses of a neuronal ensemble will strengthen or weaken  the neuronal contribution and their engagement  to the rhythm generated within the network. This could impact the computational ability of the involved neuronal network, probably serving homeostatic mechanisms with cognitive consequences , as has Translation of the knowledge on STDP and brain rhythms accumulated experimentally in humans is a considerable challenge. Experimental STDP finds support in mathematical modeling and vice-versa, while the physiological evidence of assembly structures driving STDP and rhythms emergence has only arisen recently , 172. A Brain oscillations have been largely documented in humans aided by the use of EEG recordings , 179–182However, the basal state of the region of interest, the spontaneous occurring rhythms, and their nesting should be further considered in future studies. Whether the induction of de novo formation of neuronal ensembles affects the ongoing rhythms and STDP, its interaction and firing homeostasis demand profound studies of the underlying mechanisms.Progress has been made towards understanding of how the brain processes information, stores it, and generates reliable and efficien outputs in the form of memories, learning, and other cognitive behaviors. Timing precision is important for brain information processing and such precision is subjected to diverse features and properties at neuronal and circuits levels . As such


Poultry are one of the most valuable resources for human society. They are also recognized as a powerful experimental animal for basic research on embryogenesis. Demands for the supply of low-allergen eggs and bioreactors have increased with the development of programmable genome editing technology. The CRISPR/Cas9 system has recently been used to produce transgenic animals and various animals in the agricultural industry and has also been successfully adopted for the modification of chicken and quail genomes. In this review, we describe the successful establishment of genome-edited lines combined with germline chimera production systems mediated by primordial germ cells and by viral infection in poultry. The avian intracytoplasmic sperm injection (ICSI) system that we previously established and recent advances in ICSI for genome editing are also summarized. Gallus domesticus), turkey , and Japanese quail (Coturnix japonica), are commercially important species because they serve as major food sources worldwide. The poultry industry is indispensable for supporting sustainable development worldwide and is expected to significantly contribute to the United Nations’ Sustainable Development Goals. Studies on the embryos of these birds have contributed to a more detailed understanding of organogenesis i) immediately after sperm-egg binding or fusion [2+]i plays a pivotal role in the progression of cell cycle events in animal eggs that are arrested in a species-specific phase of meiosis (metaphase of the second meiotic division in most vertebrate eggs) [2+]i associated with egg activation varies widely among species, and we previously revealed a unique pattern of changes in [Ca2+]i in quail eggs after a microinjection of sperm extracts (SE) i required for the initiation of egg activation [2+ signals in quail eggs [PLCZ1, CS, and ACO2 mRNAs underwent normal blastoderm development by 24 h, and hatchlings were obtained from the treated eggs [In mammalian and newt eggs, phospholipase Czeta1 (ase (CS) ,105, restivation ,103,106.ail eggs ,103, witted eggs . The sucThe microinjection technique of foreign DNA into one-cell stage avian eggs was established in the 1980s–1990s, with injected DNA being effectively expressed in the developing embryos. However, DNA expression was gradually lost during embryo development due to the low integration efficiency of the injected DNA into the host chromosome, in contrast to mammals ,109,110.CCND1) locus-targeted quail mutant was obtained (CCND1 mutant blastoderm showed developmental arrest at the predicted stage [CCND1 locus in all blastoderms, suggesting that the CRISPR/Cas9 system mediated by ICSI has the potential to produce genome-edited birds in one generation. Genome-edited efficiency was compared between the px330 plasmid and synthesized CRISPR/hCas9 RNAs, and the mutagenesis in the plasmid injection was lower than that of RNAs due to the delayed onset of the Cas9 mRNA transcription or subsequent translation (We previously attempted to microinject an RNA mixture of hCas9 mRNA and sgRNA synthesized in vitro into a one-cell stage quail egg 2 h after ICSI, and a cyclin D1 (obtained A. As exped stage . Notablynslation B. In addSince the conventional PGC gene targeting strategy is time consuming, involving the cultivation of PGCs, the selection of genome-edited PGCs, and the production of germline chimera and progeny, the current approach to one-cell stage eggs significantly shortens the period needed for the production of mutants in birds. Therefore, we conclude that the current ICSI-mediated genome editing technology is a straightforward and fast approach to generate targeted gene knockout poultry. However, this technique requires considerable technical skill and labor in addition to several instruments used in micromanipulation and microinjection, such as the micromanipulator and microinjection systems. Since the hatching rate is still low, further studies are also warranted.Genome editing technology has rapidly advanced in recent years, providing an adaptable tool for the effective manipulation of the genomes of various animals. Although genome editing in avian species has historically been challenging, the emergence of the CRISPR/Cas system has accelerated avian research. Poultry contributes eggs and meat as a major source of protein. They also provide numerous opportunities to produce allergen-reduced eggs and many drugs that are related to human health and diseases in egg whites as a bioreactor for potential pharmaceutical and industrial applications via the CRISPR/Cas9 system. PGC-mediated mutagenesis is currently only available for chickens but is driving the development of alternative technologies, such as adenoviral infection and ICSI in quails. Therefore, avian CRISPR/Cas9 techniques are still in their infancy but are swiftly evolving. In mammalian studies, the nanoparticle-mediated targeting delivery of the CRISPR/Cas9 system to the intended cells or organs has begun to be intensively pursued by many researchers ,34,112,


Maternal stress experienced during pregnancy has potential lasting consequences on child development. One mechanism that can explain certain links between the activity of the maternal stress axis during pregnancy and the developmental trajectory of children is the maternal hypothalamic pituitary-adrenal (HPA) axis. Nevertheless, further exploration is needed as there are methodological limits in the existing literature, such as the lack of longitudinal data.To fill this gap, this DEVSTRESS research project was created with the aim of increasing our understanding of the mechanisms linking prenatal maternal stress to child development using longitudinal data from the EDEN cohort study.In this sample, various bio-psycho-social data were collected: (1) maternal stress was measured during pregnancy via questionnaires assessing childhood adversity, major life events, work-related stress, anxiety, and depressive symptoms; (2) children’s emotional and behavioural problems were reported at 3, 5, 8 and 11 years, and cognitive development was assessed by psychologists at 5 years of age; (3) maternal and child hair samples provided data on the level of cortisol in the hair, which were used as a biological marker of stress and were collected at birth for both mother and child, as well as 1, 3, and 5 years after birth from children.Various statistical analyses have been conducted using this data to explore the longitudinal links between self-reported maternal prenatal stress and child outcomes.This research project will be concluded in 2023, thus findings from the overall DEVSTRESS project and practical recommendations will be provided.None Declared


I am writing to provide a comment on the recent article  publisheFirst, according to the current international guidelines , 100% in2) fails to capture the intricate dynamics of oxygenation in critically ill patients, and this limitation is particularly significant in the context of cardiac arrest patients, who often exhibit dynamic and rapidly changing physiological states. One recent study [2 data of 2,028 patients with brain injury. Based on the dynamic value of PaO2 within 72 h, they identified three PaO2 trajectories: Traj-1 (mild hyperoxia), Traj-2 (transient severe hyperoxia), and Traj-3 (persistent severe hyperoxia). The multivariable model revealed that the risk of death was higher only in patients with Traj-3 (persistent severe hyperoxia), but was similar for patients with Traj-1 (mild hyperoxia) and Traj-2 (transient severe hyperoxia). Although the study cohorts are different, the study also suggests that transient hyperoxia may have different effects on outcomes than sustained hyperoxia. This finding underscores the dynamic nature of oxygen status and the inherent variability in its trajectories, which may significantly influence patient outcomes. Moreover, these variations in PaO2 trajectories emphasize the need for a comprehensive approach to oxygen management that extends beyond a singular focus on static PaO2 values.Secondly, understanding the complexities of oxygen status assessment is pivotal in guiding clinical decision-making and ensuring optimal patient care. In clinical practice, oxygen partial pressure can be easily affected by parameters in mechanical ventilation , such asnt study  analyzedThird, the complex interplay between oxygen delivery, consumption, and utilization in these patients necessitates a comprehensive approach to oxygenation assessment. Factors such as tissue perfusion, oxygen extraction, and the potential for oxygen toxicity should be carefully considered to obtain a more nuanced understanding of the true oxygen status and its impact on patient outcomes. For instance, continuous monitoring of tissue oxygenation, as proposed by Rose et al.  and AlleIn light of these considerations, I encourage further research that incorporates a multidimensional assessment of oxygen status, including markers of tissue perfusion and oxygen utilization, to elucidate the complex relationship between hyperoxemia and prognosis in cardiac arrest patients. A comprehensive understanding of these dynamics is crucial for the development of evidence-based guidelines that can effectively guide clinical practice and improve patient outcomes. Finally, this study contributed significantly to oxygen management in patients after cardiac arrest, and this work is very much appreciated!