A snoRNA-tRNA modification network governs codon-biased cellular states.

The dynamic balance between tRNA supply and codon usage demand is a fundamental principle in the cellular translation economy. However, the regulation and functional consequences of this balance remain unclear. Here, we use PARIS2 interactome capture, structure modeling, conservation analysis, RNA-protein interaction analysis, and modification mapping to reveal the targets of hundreds of snoRNAs, many of which were previously considered orphans. We identify a snoRNA-tRNA interaction network that is required for global tRNA modifications, including 2'-O-methylation and others. Loss of Fibrillarin, the snoRNA-guided 2'-O-methyltransferase, induces global upregulation of tRNA fragments, a large group of regulatory RNAs. In particular, the snoRNAs D97/D133 guide the 2'-O-methylation of multiple tRNAs, especially for the amino acid methionine (Met), a protein-intrinsic antioxidant. Loss of D97/D133 snoRNAs in human HEK293 cells reduced target tRNA levels and induced codon adaptation of the transcriptome and translatome. Both single and double knockouts of D97 and D133 in HEK293 cells suppress Met-enriched proliferation-related gene expression programs, including, translation, splicing, and mitochondrial energy metabolism, and promote Met-depleted programs related to development, differentiation, and morphogenesis. In a mouse embryonic stem cell model of development, knockdown and knockout of D97/D133 promote differentiation to mesoderm and endoderm fates, such as cardiomyocytes, without compromising pluripotency, consistent with the enhanced development-related gene expression programs in human cells. This work solves a decades-old mystery about orphan snoRNAs and reveals a function of snoRNAs in controlling the codon-biased dichotomous cellular states of proliferation and development.

An Inflection Point in Cancer Protein Biomarkers: What was and What's Next.

Biomarkers remain the highest value proposition in cancer medicine today-especially protein biomarkers. Despite decades of evolving regulatory frameworks to facilitate the review of emerging technologies, biomarkers have been mostly about promise with very little to show for improvements in human health. Cancer is an emergent property of a complex system, and deconvoluting the integrative and dynamic nature of the overall system through biomarkers is a daunting proposition. The last 2 decades have seen an explosion of multiomics profiling and a range of advanced technologies for precision medicine, including the emergence of liquid biopsy, exciting advances in single-cell analysis, artificial intelligence (machine and deep learning) for data analysis, and many other advanced technologies that promise to transform biomarker discovery. Combining multiple omics modalities to acquire a more comprehensive landscape of the disease state, we are increasingly developing biomarkers to support therapy selection and patient monitoring. Furthering precision medicine, especially in oncology, necessitates moving away from the lens of reductionist thinking toward viewing and understanding that complex diseases are, in fact, complex adaptive systems. As such, we believe it is necessary to redefine biomarkers as representations of biological system states at different hierarchical levels of biological order. This definition could include traditional molecular, histologic, radiographic, or physiological characteristics, as well as emerging classes of digital markers and complex algorithms. To succeed in the future, we must move past purely observational individual studies and instead start building a mechanistic framework to enable integrative analysis of new studies within the context of prior studies. Identifying information in complex systems and applying theoretical constructs, such as information theory, to study cancer as a disease of dysregulated communication could prove to be "game changing" for the clinical outcome of cancer patients.

Neuroendoscopic access to the third ventricle in patients with narrow foramen of monro without stenosis/obstruction: role of foraminoplasty.

OBJECT: One of the critical steps for the success of intraventricular neuroendoscopic procedures is the entry into the third ventricle and passage of the endoscopy system through the foramen of Monro (FM). A diameter larger than that of the instrument used is considered a prerequisite for safely performing the technique, as damage to this structure can lead to alterations in the fornix and vascular structures. When the foramen diameter is narrow and there is no obstruction/stenosis, the role of foraminoplasty in reducing the risk of complications has not been adequately assessed in the literature. METHODS: A review of endoscopic procedures conducted at our center since 2018 was undertaken. Cases in which preoperative imaging indicated a FM diameter < 6 mm and foraminoplasty technique was applied were examined to determine the technical and functional success of the procedure. The technical success was determined by completing the neuroendoscopic procedure with the absence of macroscopic lesions in the various structures comprising the foramen and without complications in the follow-up imaging tests. Functional success was defined as the absence of cognitive/memory alterations during the 3-month postoperative follow-up. Additionally, a review of the various forms of foraminoplasty described in the literature is conducted. RESULTS: In our cohort, six patients were identified with a preoperative FM diameter < 6 mm without obstruction or stenosis. Foraminoplasty was planned for these cases to facilitate various intraventricular neuroendoscopic procedures. In all instances, the technique was successfully performed without causing macroscopic damage to the structures comprising the foramen. Follow-up visits included various cognitive tests to assess potential sequelae related to microscopic damage to the fornix. None of the patients exhibited anomalies. CONCLUSION: Foraminoplasty in patients with a narrow FM without signs of stenosis/obstruction is a useful technique to reduce the risk of complications during the passage of the endoscopy system through this structure, enabling the safe performance of neuroendoscopic procedures.

Chronic Exposure to Palmitic Acid Down-Regulates AKT in Beta-Cells through Activation of mTOR.

High circulating lipids occurring in obese individuals and insulin-resistant patients are considered a contributing factor to type 2 diabetes. Exposure to high lipid concentration is proposed to both protect and damage beta-cells under different circumstances. Here, by feeding mice a high-fat diet (HFD) for 2 weeks to up to 14 months, the study showed that HFD initially causes the beta-cells to expand in population, whereas long-term exposure to HFD is associated with failure of beta-cells and the inability of animals to respond to glucose challenge. To prevent the failure of beta-cells and the development of type 2 diabetes, the molecular mechanisms that underlie this biphasic response of beta-cells to lipid exposure were explored. Using palmitic acid (PA) in cultured beta-cells and islets, the study demonstrated that chronic exposure to lipids leads to reduced viability and inhibition of cell cycle progression concurrent with down-regulation of a pro-growth/survival kinase AKT, independent of glucose. This AKT down-regulation by PA is correlated with the induction of mTOR/S6K activity. Inhibiting mTOR activity with rapamycin induced Raptor and restored AKT activity, allowing beta-cells to gain proliferation capacity that was lost after HFD exposure. In summary, a novel mechanism in which lipid exposure may cause the dipole effects on beta-cell growth was elucidated, where mTOR acts as a lipid sensor. These mechanisms can be novel targets for future therapeutic developments.

ETV as treatment for obstructive hydrocephalus in an aneurysmal malformation of the vein of Galen in infants: case report and review of literature.

INTRODUCTION: A vein of Galen aneurysmal malformation (VGAM) is a high-flow arteriovenous malformation that typically presents in early childhood. Complications associated with this condition include heart failure and hydrodynamic disorders resulting from high blood flow. Hydrocephalus is one of the hydrodynamic disorders. It can present in a chronic form due to a defect in the absorption of cerebrospinal fluid (CSF) resulting from venous hypertension or in an acute/subacute form due to obstruction of normal circulation routes caused by the mass effect of the VGAM. Currently, endovascular closure of the lesion is considered the treatment of choice. However, in acute/subacute presentations of obstructive hydrocephalus, progression may occur despite endovascular treatment, necessitating a cerebrospinal fluid diversion procedure. Prior to the advent of endoscopic treatment, ventricular shunts were utilized, but outcomes were poor due to the pathological hydrodynamic parameters associated with the malformation. The role of endoscopic third ventriculostomy as a treatment option in these situations remains unclear, and there is limited literature available. Therefore, we present the case of a patient with a vein of Galen aneurysmal malformation and obstructive hydrocephalus, which was treated via ETV. Furthermore, a literature review was conducted. CASE DESCRIPTION: We present a 5-month-old infant who was diagnosed at birth with VGAM. At 2 months of age, a partial closure of the malformation was performed via endovascular. Subsequently, the patient presented at the emergency department with symptoms of irritability, lethargy, vomiting, feeding refusal, and "setting sun" sign of several days' duration due to obstructive hydrocephalus. The patient was successfully treated via ETV. Following this, a new arteriography was performed and revealed occlusion of the VGAM. The child clinically improved and currently exhibits mild psychomotor impairment after 1-year follow-up. CONCLUSION: In the literature, there are a limited number of reports on the treatment of obstructive hydrocephalus associated with VGAM via ETV. These reports have demonstrated good outcomes with minimal surgical complications. Our patient also exhibited good results. As such, ETV is a viable and safe option for the treatment of obstructive hydrocephalus associated with VGAM in pediatric patients. However, more research is needed to establish the effectiveness of ETV in comparison to other treatment options and to understand the long-term outcomes.

Neuronavigated endoscopic aqueductoplasty with panventricular stent plus septostomy for isolated fourth ventricle in complex hydrocephalus and syringomyelia associated with myelomeningocele: how I do it.

BACKGROUND: Isolated fourth ventricle (IFV) is a challenging entity to manage. In recent years, endoscopic treatment for aqueductoplasty has been on the rise. However, in patients with complex hydrocephalus and distorted ventricular system, its implementation can be complex. METHODS: We present a 3-year-old patient with myelomeningocele and postnatal hydrocephalus treated by ventriculoperitoneal shunt. In follow-up, a progressive IFV and isolated lateral ventricle with symptoms of the posterior fossa developed. An endoscopic aqueductoplasty (EA) with panventricular stent plus septostomy guided with neuronavigation was decided due to the complexity of the ventricular system. CONCLUSION: In IFV associated with complex hydrocephalus with distortion of the ventricular system, navigation can be of great help for planning and as a guide for performing EA.

Inhibition of Estrogen-Related Receptor α Blocks Liver Steatosis and Steatohepatitis and Attenuates Triglyceride Biosynthesis.

The estrogen-related receptor (ERR) family of orphan nuclear receptors are transcriptional activators for genes involved in mitochondrial bioenergetics and metabolism. The goal of this study was to explore the role of ERRα in lipid metabolism and the potential effect of inhibiting ERRα on the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In the current study, three experimental mouse models: high-fat diet, high-carbohydrate diet, and a genetic model of hepatic insulin resistance where the liver hyperinsulinemia signal is mimicked via hepatic deletion of Pten (phosphatase and tensin homolog deleted on chromosome 10), the negative regulator of the insulin/phosphatidylinositol 3-kinase signaling pathway, were used. A recently developed small-molecule inhibitor for ERRα was used to demonstrate that inhibiting ERRα blocked NAFLD development induced by either high-carbohydrate diet or high-fat diet feeding. ERRα inhibition also diminished lipid accumulation and attenuated NASH development in the Pten null mice. Glycerolipid synthesis was discovered as an additional mechanism for ERRα-regulated NAFLD/NASH development and glycerophosphate acyltransferase 4 was identified as a novel transcriptional target of ERRα. In summary, these results establish ERRα as a major transcriptional regulator of lipid biosynthesis in addition to its characterized primary function as a regulator for mitochondrial function. This study recognizes ERRα as a potential target for NAFLD/NASH treatment and elucidates novel signaling pathways regulated by ERRα.

Hydra-Elastin-like Polypeptides Increase Rapamycin Potency When Targeting Cell Surface GRP78.

Rapalogues are powerful therapeutic modalities for breast cancer; however, they suffer from low solubility and dose-limiting side effects. To overcome these challenges, we developed a long-circulating multiheaded drug carrier called 5FA, which contains rapamycin-binding domains linked with elastin-like polypeptides (ELPs). To target these "Hydra-ELPs" toward breast cancer, we here linked 5FA with four distinct peptides which are reported to engage the cell surface form of the 78 kDa glucose-regulated protein (csGRP78). To determine if these peptides affected the carrier solubility, this library was characterized by light scattering and mass spectrometry. To guide in vitro selection of the most potent functional carrier for rapamycin, its uptake and inhibition of mTORC1 were monitored in a ductal breast cancer model (BT474). Using flow cytometry to track cellular association, it was found that only the targeted carriers enhanced cellular uptake and were susceptible to proteolysis by SubA, which specifically targets csGRP78. The functional inhibition of mTOR was monitored by Western blot for pS6K, whereby the best carrier L-5FA reduced mTOR activity by 3-fold compared to 5FA or free rapamycin. L-5FA was further visualized using super-resolution confocal laser scanning microscopy, which revealed that targeting increased exposure to the carrier by ∼8-fold. This study demonstrates how peptide ligands for GRP78, such as the L peptide (RLLDTNRPLLPY), may be incorporated into protein-based drug carriers to enhance targeting.

Rotation flap closure of a giant dorsolumbar myelomeningocele: technical note.

PURPOSE: Myelomeningocele (MMC) is the most prevalent form of spina bifida aperta. Here we present the surgical repair technique of a dorsolumbar myelomeningocele with a large associated soft tissue defect. METHODS: Data concerning the anamnesis and complementary studies were obtained from the clinical history. Surgical images were obtained in the operation room during surgery. RESULT: We describe the case of a newborn with a dorsal myelomeningocele with a placode in the central area and a large associated skin defect of 12 x× 12 cm. Urgent intervention was carried out on the day of birth with placode reconstruction. Dorsal and gluteus maximus muscle rotation and skin rotation flap were performed in order to achieve complete closure of the myocutaneous defect. The patient presented a good recovery with no new neurological deficit. CONCLUSION: Myelomeningocele may be associated with large myocutaneous defects that can be difficult to correct by primary closure. In these cases, rotation flaps may be necessary to achieve complete closure.

Neuroendoscopic training in neurosurgery: a simple and feasible model for neurosurgical education.

BACKGROUND: The development of high levels of technical competence and excellent decision-making skills are key goals of all neurosurgical residency training programs. This acquisition of technical skills is becoming increasingly difficult due to many factors including less exposure to operative cases, demand for more time and cost-effective practices, and resident work hour restrictions. We describe a step-by-step method for how to build a low-cost and feasible model that allows residents to improve their neuroendoscopic skills. METHODS: The bell pepper-based model was developed as an endoscopic training model. Using continuous irrigation, several hands-on procedures were proposed under direct endoscopic visualization. Endoscope setup, endoscopic third ventriculostomy, septostomy, and tumor biopsy procedures were simulated and video recorded for further edition and analysis. RESULTS: The model can be setup in less than 15 min with minimal cost and infrastructure requirements. A single model allows simulation of all the exercises described above. The model allows exposure to the camera skills, instrument handling, and hand-eye coordination inherent to most neuroendoscopic procedures. CONCLUSION: Minimal infrastructure requirements, simplicity, and easily setup models provide a proper environment for regular training. The bell pepper-based model is inexpensive, widely available, and a feasible model for routine training. Neurosurgery residents may benefit from the use of this model to accelerate their learning curve and familiarize themselves with the neuroendoscopic core principles in a risk-free environment without time or resource constraints.

Microsurgical training: vascular control and intraoperative vessel rupture in the human placenta infusion model.

BACKGROUND: Microsurgery is a challenging discipline. Regular lab training under the operating microscope has been the environment where most surgeons have mastered the skills and techniques inherent to most microneurosurgical procedures. However, some critical scenarios remain difficult to master or simulate. We describe a step-by-step method for how to build a low-cost, feasible, and widely available model that allows residents to familiarize themselves with demanding critical situations such as intraoperative rupture of major vessels. METHODS: After delivery, nine fresh human placentas were transferred to the lab. The umbilical vein was cannulated for normal saline infusion. Several hands-on procedures were performed under direct microscope vision. Operating microscope setup, allantoic membrane splitting, vascular dissection and vessel injury, and repair exercises were simulated and video recorded. Indocyanine green was administered to simulate intraoperative angiography. RESULTS: The model can be setup in less than 15 min, with minimal cost and infrastructure requirements. All the exercises described above can be conducted with a single placenta. Umbilical vein cannulation adds realism and allows quantification of the volume of saline required to complete the exercise. The final check with indocyanine green simulates intraoperative angiography and allows the assessment of distal vessel patency. CONCLUSIONS: Minimal infrastructure requirements, simplicity, and easy setup models provide a suitable environment for regular training. The human placenta is inexpensive and widely available, making it a feasible model for residents training. Neurosurgery residents may benefit from this model to familiarize with microsurgery and critical scenarios in a risk-free environment without time or resource constraints.

Transcortical transcatheter ultrasound-assisted technique for deep-seated brain tumors. Technical note.

PURPOSE: Surgery of deep-seated brain tumors can be challenging. Several methods have been described to facilitate transcortical approaches, including ultrasound-assisted resection. Ultrasound-guided placement of a standard ventricular catheter is a widely reported technique and has been used to approach these lesions via the transcortical route. We describe how we usually perform this useful technique to assist and enhance the transcortical resection of some deep-seated brain tumors. METHODS: Standard electromagnetic frameless navigation (S8 Neuronavigation System, Medtronic, Minneapolis, USA) was employed to focus the craniotomy and to plan the trajectory of the ventricular catheter. After dural opening, an ultrasound device (Arietta 850, Hitachi-Aloka Medical, Tokyo, Japan) was used for intraoperative ultrasound (IOUS) assessment. A ventricular catheter was placed from the cortex to the lateral wall of the tumor under direct real-time IOUS visualization to guide the further transcortical dissection. RESULTS: Transcortical transcatheter ultrasound-assisted technique involved minimal time and infrastructure requirements. There were no major technical difficulties during its use, providing confidence and improving subcortical white matter dissection by guiding the route to the tumor. CONCLUSIONS: Recent improvement of IOUS image-quality devices offers several attractive options for real-time navigation. The combination of conventional neuronavigation systems with real-time IOUS assessment during the intradural step provides a higher degree of control by improving the execution of the surgery. We hope this description may be a useful tool for some selected cases and contribute to the further enhancement and improvement of this widely used technique.

Microneurosurgical training in the anatomical specimen: A structured plan for endoscopic and microsurgical skull base training during the residency.

BACKGROUND AND OBJECTIVE: The development of a high level of competence and technical proficiency is one of the main objectives of any neurosurgical training program. Due to many factors, this progressive skill development can be complex during the residency. Despite its high cost and infrastructure requirements, there is renewed interest regarding the role of anatomy labs. The study and dissection of the human cadaver has been the environment where many surgeons have developed the necessary skills for microneurosurgery. We propose a structured endoscopic and microsurgical training dissection program to enable residents to maximize the benefits of their training in the lab. MATERIAL AND METHODS: During the months of September, October and November 2021, a stay was done at the Microneurosurgery and Skull Base Laboratory of the Miguel Hernández University of Alicante. A total of 2 specimens were used. The first specimen underwent a first endoscopic endonasal dissection phase. After completing the endonasal part, a set of incisions were made to perform the transcranial part. In the second specimen, the transcranial part was performed first, leaving the endonasal endoscopic work for the last phase. RESULTS: The results of the dissection program are presented. During the endonasal endoscopic phase, the transsphenoidal approach to the sella was simulated while focusing on the extended approaches in the sagittal plane. During the transcranial phase, right and left anterolateral approaches, a left anterior transcallosal interhemispheric approach, a left transcondylar posterolateral approach and a combined right lateral approach were performed. CONCLUSIONS: The structured dissection of the specimen allowed both endonasal endoscopic and transcranial microsurgical training in the same specimen. This design facilitated the realization of the core skull base approaches in the same specimen. According to our initial experience, we believe that developing common dissection programs is a powerful tool to maximize the results of our residents' laboratory training.

Dorsum Sellae as Key Landmark in ETV With Disminished Prepontine Cistern: Technical Note and Case Series.

BACKGROUND AND OBJECTIVES: One of the key aspects in the surgical technique of endoscopic third ventriculostomy (ETV) is the perforation of the floor of the third ventricle because of the high risk of injuring vital structures located in that region. According to the standard technique, this perforation should be performed in the midline halfway between mammillary bodies and the infundibular recess to avoid damage to the structures. This can be performed without excessive complications when the diameter of the prepontine cistern is wide. However, in situations where the diameter is reduced (defined in the literature as having a prepontine interval [PPI] ≤1 mm), the probability of complications increases exponentially.In this article, we propose using dorsum sellae as a key point to safely perform ETV in patients with a decreased PPI, guiding the trajectory and its marking using neuronavigation. METHODS: A review was conducted on the latest 100 ETV procedures performed by our team in the past 5 years. The measurement of the PPI was conducted using archived preoperative MRI imaging studies, specifically between the dorsum sellae and the basilar artery. In cases where the PPI was ≤1 mm and, therefore, the use of the dorsum sellae was applied as a reference point, the technical results and procedural functions were documented. RESULTS: In the cohort, 7 patients with a PPI ≤1 mm were identified. In all 7 cases, fenestration of the tuber cinereum was successfully performed without causing vascular damage or associated complications. ETV was successful in 6 patients, with only one experiencing ETV failure necessitating the placement of a ventriculoperitoneal shunt. CONCLUSION: The utilization of the dorsum sellae as a reference point to perform ETV in reduced PPI constitutes a safe alternative to the classical technique.

Dynamic Workflow Proposal for Continuous Frameless Electromagnetic Neuronavigation in Rigid Neuroendoscopy.

BACKGROUND: Ventriculoscopic neuronavigation has been described in several articles. However, there are different ventriculoscopes and navigation systems. Due to these different combinations, it is difficult to find detailed neuronavigation protocols. We describe, step-by-step, a simple method to navigate both the trajectory until reaching the ventricular system, as well as the intraventricular work. METHODS: We use a rigid ventriculoscope (LOTTA, KarlStorz) with an electromagnetic stylet (S8-StealthSystem, Medtronic). The protocol is based on a modified or 3-dimensionally printed trocar for navigating the extraventricular step and on a modified pediatric nasogastric tube for the intraventricular navigation. RESULTS: This protocol can be set up in less than 10 minutes. The extraventricular part is navigated by introducing the electromagnetic stylet inside the modified or 3-dimensionally printed trocar. Intraventricular navigation is done by combining a modified pediatric nasogastric tube with the electromagnetic stylet inside the endoscope's working channel. The most critical point is to obtain a blunt-bloodless ventriculostomy while achieving perfect alignment of all targeted structures via pure straight trajectories. CONCLUSIONS: This protocol is easy-to-set-up, avoids head rigid-fixation and bulky optical-based attachments to the ventriculoscope, and allows continuous navigation of both parts of the surgery. Since we have implemented this protocol, we have noticed a significant enhancement in both simple and complex ventriculoscopic procedures because the surgery is dramatically simplified.

Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development.

Liver cancer is a malignancy developed from underlying liver disease that encompasses liver injury and metabolic disorders. The progression from these underlying liver disease to cancer is accompanied by chronic inflammatory conditions in which liver macrophages play important roles in orchestrating the inflammatory response. During this process, bioactive lipids produced by hepatocytes and macrophages mediate the inflammatory responses by acting as pro-inflammatory factors, as well as, playing roles in the resolution of inflammation conditions. Here, we review the literature discussing the roles of bioactive lipids in acute and chronic hepatic inflammation and progression to cancer.

Intraoperative ultrasound-assisted surgery in orbital apex tumours: technical note.

BACKGROUND: Since the introduction of ultrasonography (US) in the operating theatre in the early 1970s, intraoperative ultrasound (IOUS) has become a very useful tool for real-time neurosurgical procedures. The main limitation of US is its innately reduced capacity to penetrate the intact skull. This is the reason why most IOUS-assisted procedures are usually performed via transfontanellar or after a craniotomy or laminotomy is done. OBJECTIVE: We present a 54-year-old woman with a right optic nerve sheath meningioma, who was operated on by a right cranio-orbital approach and IOUS-assisted tumour removal. METHODS: Data concerning the anamnesis and complementary studies were obtained from the clinical history. Surgical images were obtained in the operating room during surgery. Images obtained by US were compared with the preoperative and postoperative imaging scans. IOUS imaging was also compared with the intraoperative findings. RESULTS: The correlation between US and both preoperative and postoperative studies was very high. During surgery, both transpalpebral and transperiorbital IOUS facilitated the resection with no specific technical difficulties or significant time consumption. CONCLUSION: Recent improvements in the image quality of IOUS devices offer several attractive options for real-time neuronavigation. We describe our initial experience with the IOUS-assisted technique for orbital apex tumours. In our patient transpalpebral and transperiorbital IOUS provided an excellent source of control over location and over the extent of tumour resection. We hope that this description of how we usually perform this procedure may be useful for some selected cases and contribute to the further enhancement and improvement of the technique.

Hepatic macrophage mediated immune response in liver steatosis driven carcinogenesis.

Obesity confers an independent risk for carcinogenesis. Classically viewed as a genetic disease, owing to the discovery of tumor suppressors and oncogenes, genetic events alone are not sufficient to explain the progression and development of cancers. Tumor development is often associated with metabolic and immunological changes. In particular, obesity is found to significantly increase the mortality rate of liver cancer. As its role is not defined, a fundamental question is whether and how metabolic changes drive the development of cancer. In this review, we will dissect the current literature demonstrating that liver lipid dysfunction is a critical component driving the progression of cancer. We will discuss the involvement of inflammation in lipid dysfunction driven liver cancer development with a focus on the involvement of liver macrophages. We will first discuss the association of steatosis with liver cancer. This will be followed with a literature summary demonstrating the importance of inflammation and particularly macrophages in the progression of liver steatosis and highlighting the evidence that macrophages and macrophage produced inflammatory mediators are critical for liver cancer development. We will then discuss the specific inflammatory mediators and their roles in steatosis driven liver cancer development. Finally, we will summarize the molecular pattern (PAMP and DAMP) as well as lipid particle signals that are involved in the activation, infiltration and reprogramming of liver macrophages. We will also discuss some of the therapies that may interfere with lipid metabolism and also affect liver cancer development.

De novo determination of mosquitocidal Cry11Aa and Cry11Ba structures from naturally-occurring nanocrystals.

Cry11Aa and Cry11Ba are the two most potent toxins produced by mosquitocidal Bacillus thuringiensis subsp. israelensis and jegathesan, respectively. The toxins naturally crystallize within the host; however, the crystals are too small for structure determination at synchrotron sources. Therefore, we applied serial femtosecond crystallography at X-ray free electron lasers to in vivo-grown nanocrystals of these toxins. The structure of Cry11Aa was determined de novo using the single-wavelength anomalous dispersion method, which in turn enabled the determination of the Cry11Ba structure by molecular replacement. The two structures reveal a new pattern for in vivo crystallization of Cry toxins, whereby each of their three domains packs with a symmetrically identical domain, and a cleavable crystal packing motif is located within the protoxin rather than at the termini. The diversity of in vivo crystallization patterns suggests explanations for their varied levels of toxicity and rational approaches to improve these toxins for mosquito control.

Patients awaiting surgery for neurosurgical diseases during the first wave of the COVID-19 pandemic in Spain: a multicentre cohort study.

OBJECTIVES: The large number of infected patients requiring mechanical ventilation has led to the postponement of scheduled neurosurgical procedures during the first wave of the COVID-19 pandemic. The aims of this study were to investigate the factors that influence the decision to postpone scheduled neurosurgical procedures and to evaluate the effect of the restriction in scheduled surgery adopted to deal with the first outbreak of the COVID-19 pandemic in Spain on the outcome of patients awaiting surgery. DESIGN: This was an observational retrospective study. SETTINGS: A tertiary-level multicentre study of neurosurgery activity between 1 March and 30 June 2020. PARTICIPANTS: A total of 680 patients awaiting any scheduled neurosurgical procedure were enrolled. 470 patients (69.1%) were awaiting surgery because of spine degenerative disease, 86 patients (12.6%) due to functional disorders, 58 patients (8.5%) due to brain or spine tumours, 25 patients (3.7%) due to cerebrospinal fluid (CSF) disorders and 17 patients (2.5%) due to cerebrovascular disease. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was mortality due to any reason and any deterioration of the specific neurosurgical condition. Second, we analysed the rate of confirmed SARS-CoV-2 infection. RESULTS: More than one-quarter of patients experienced clinical or radiological deterioration. The rate of worsening was higher among patients with functional (39.5%) or CSF disorders (40%). Two patients died (0.4%) during the waiting period, both because of a concurrent disease. We performed a multivariate logistic regression analysis to determine independent covariates associated with maintaining the surgical indication. We found that community SARS-CoV-2 incidence (OR=1.011, p<0.001), degenerative spine (OR=0.296, p=0.027) and expedited indications (OR=6.095, p<0.001) were independent factors for being operated on during the pandemic. CONCLUSIONS: Patients awaiting neurosurgery experienced significant collateral damage even when they were considered for scheduled procedures.