Adeno-Associated Virus Toolkit to Target Diverse Brain Cells.

Recombinant adeno-associated viruses (AAVs) are commonly used gene delivery vehicles for neuroscience research. They have two engineerable features: the capsid (outer protein shell) and cargo (encapsulated genome). These features can be modified to enhance cell type or tissue tropism and control transgene expression, respectively. Several engineered AAV capsids with unique tropisms have been identified, including variants with enhanced central nervous system transduction, cell type specificity, and retrograde transport in neurons. Pairing these AAVs with modern gene regulatory elements and state-of-the-art reporter, sensor, and effector cargo enables highly specific transgene expression for anatomical and functional analyses of brain cells and circuits. Here, we discuss recent advances that provide a comprehensive (capsid and cargo) AAV toolkit for genetic access to molecularly defined brain cell types.

The menin inhibitor revumenib in KMT2A-rearranged or NPM1-mutant leukaemia.

Targeting critical epigenetic regulators reverses aberrant transcription in cancer, thereby restoring normal tissue function1-3. The interaction of menin with lysine methyltransferase 2A (KMT2A), an epigenetic regulator, is a dependence in acute leukaemia caused by either rearrangement of KMT2A or mutation of the nucleophosmin 1 gene (NPM1)4-6. KMT2A rearrangements occur in up to 10% of acute leukaemias and have an adverse prognosis, whereas NPM1 mutations occur in up to 30%, forming the most common genetic alteration in acute myeloid leukaemia7,8. Here, we describe the results of the first-in-human phase 1 clinical trial investigating revumenib (SNDX-5613), a potent and selective oral inhibitor of the menin-KMT2A interaction, in patients with relapsed or refractory acute leukaemia (ClinicalTrials.gov, NCT04065399). We show that therapy with revumenib was associated with a low frequency of grade 3 or higher treatment-related adverse events and a 30% rate of complete remission or complete remission with partial haematologic recovery (CR/CRh) in the efficacy analysis population. Asymptomatic prolongation of the QT interval on electrocardiography was identified as the only dose-limiting toxicity. Remissions occurred in leukaemias refractory to multiple previous lines of therapy. We demonstrate clearance of residual disease using sensitive clinical assays and identify hallmarks of differentiation into normal haematopoietic cells, including differentiation syndrome. These data establish menin inhibition as a therapeutic strategy for susceptible acute leukaemia subtypes.

MEN1 mutations mediate clinical resistance to menin inhibition.

Chromatin-binding proteins are critical regulators of cell state in haematopoiesis1,2. Acute leukaemias driven by rearrangement of the mixed lineage leukaemia 1 gene (KMT2Ar) or mutation of the nucleophosmin gene (NPM1) require the chromatin adapter protein menin, encoded by the MEN1 gene, to sustain aberrant leukaemogenic gene expression programs3-5. In a phase 1 first-in-human clinical trial, the menin inhibitor revumenib, which is designed to disrupt the menin-MLL1 interaction, induced clinical responses in patients with leukaemia with KMT2Ar or mutated NPM1 (ref. 6). Here we identified somatic mutations in MEN1 at the revumenib-menin interface in patients with acquired resistance to menin inhibition. Consistent with the genetic data in patients, inhibitor-menin interface mutations represent a conserved mechanism of therapeutic resistance in xenograft models and in an unbiased base-editor screen. These mutants attenuate drug-target binding by generating structural perturbations that impact small-molecule binding but not the interaction with the natural ligand MLL1, and prevent inhibitor-induced eviction of menin and MLL1 from chromatin. To our knowledge, this study is the first to demonstrate that a chromatin-targeting therapeutic drug exerts sufficient selection pressure in patients to drive the evolution of escape mutants that lead to sustained chromatin occupancy, suggesting a common mechanism of therapeutic resistance.

Social anxiety disorder-associated gut microbiota increases social fear.

Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance. However, the underlying biology of SAD is unclear and better treatments are needed. Recently, the gut microbiota has emerged as a key regulator of both brain and behaviour, especially those related to social function. Moreover, increasing data supports a role for immune function and oxytocin signalling in social responses. To investigate whether the gut microbiota plays a causal role in modulating behaviours relevant to SAD, we transplanted the microbiota from SAD patients, which was identified by 16S rRNA sequencing to be of a differential composition compared to healthy controls, to mice. Although the mice that received the SAD microbiota had normal behaviours across a battery of tests designed to assess depression and general anxiety-like behaviours, they had a specific heightened sensitivity to social fear, a model of SAD. This distinct heightened social fear response was coupled with changes in central and peripheral immune function and oxytocin expression in the bed nucleus of the stria terminalis. This work demonstrates an interkingdom basis for social fear responses and posits the microbiome as a potential therapeutic target for SAD.

Mezigdomide is effective alone and in combination with menin inhibition in preclinical models of KMT2A-r and NPM1c AML.

ABSTRACT: Small molecules that target the menin-KMT2A protein-protein interaction (menin inhibitors) have recently entered clinical trials in lysine methyltransferase 2A (KMT2A or MLL1)-rearranged (KMT2A-r) and nucleophosmin-mutant (NPM1c) acute myeloid leukemia (AML) and are demonstrating encouraging results. However, rationally chosen combination therapy is needed to improve responses and prevent resistance. We have previously identified IKZF1/IKAROS as a target in KMT2A-r AML and shown in preclinical models that IKAROS protein degradation with lenalidomide or iberdomide has modest single-agent activity yet can synergize with menin inhibitors. Recently, the novel IKAROS degrader mezigdomide was developed with greatly enhanced IKAROS protein degradation. In this study, we show that mezigdomide has increased preclinical activity in vitro as a single-agent in KMT2A-r and NPM1c AML cell lines, including sensitivity in cell lines resistant to lenalidomide and iberdomide. Further, we demonstrate that mezigdomide has the greatest capacity to synergize with and induce apoptosis in combination with menin inhibitors, including in MEN1 mutant models. We show that the superior activity of mezigdomide compared with lenalidomide or iberdomide is due to its increased depth, rate, and duration of IKAROS protein degradation. Single-agent mezigdomide was efficacious in 5 patient-derived xenograft models of KMT2A-r and 1 NPM1c AML. The combination of mezigdomide with the menin inhibitor VTP-50469 increased survival and prevented and overcame MEN1 mutations that mediate resistance in patients receiving menin inhibitor monotherapy. These results support prioritization of mezigdomide for early phase clinical trials in KMT2A-r and NPM1c AML, either as a single agent or in combination with menin inhibitors.

NKG2A genetic deletion promotes human primary NK cell anti-tumor responses better than an anti-NKG2A monoclonal antibody.

Natural killer (NK) cells eliminate infected or cancer cells via their cytotoxic capacity. NKG2A is an inhibitory receptor on NK cells and cancer cells often overexpress its ligand HLA-E to evade NK cell surveillance. Given the successes of immune checkpoint blockade in cancer therapy, NKG2A is an interesting novel target. However, anti-NKG2A antibodies have shown limited clinical response. In the pursuit of enhancing NK cell-mediated anti-tumor responses, we devised a Cas9-based strategy to delete KLRC1, encoding NKG2A, in human primary NK cells. Our approach involved electroporation of KLRC1-targeting Cas9 ribonucleoprotein resulting in effective ablation of NKG2A expression. Compared with anti-NKG2A antibody blockade, NKG2AKO NK cells exhibited enhanced activation, reduced suppressive signaling, and elevated expression of key transcription factors. NKG2AKO NK cells overcame inhibition from HLA-E, significantly boosting NK cell activity against solid and hematologic cancer cells. We validated this efficacy across multiple cell lines, a xenograft mouse model, and primary human leukemic cells. Combining NKG2A knockout with antibody coating of tumor cells further enhanced cytotoxicity through ADCC. Thus, we provide a comprehensive comparison of inhibition of the NKG2A pathway using genetic ablation and antibodies and provide novel insight in the observed differences in molecular mechanisms, which can be translated to enhance adoptive NK cell immunotherapy.

Evidence Accumulation Rate Moderates the Relationship between Enriched Environment Exposure and Age-Related Response Speed Declines.

Older adults exposed to enriched environments (EEs) maintain relatively higher levels of cognitive function, even in the face of compromised markers of brain health. Response speed (RS) is often used as a simple proxy to measure the preservation of global cognitive function in older adults. However, it is unknown which specific selection, decision, and/or motor processes provide the most specific indices of neurocognitive health. Here, using a simple decision task with electroencephalography (EEG), we found that the efficiency with which an individual accumulates sensory evidence was a critical determinant of the extent to which RS was preserved in older adults (63% female, 37% male). Moreover, the mitigating influence of EE on age-related RS declines was most pronounced when evidence accumulation rates were shallowest. These results suggest that the phenomenon of cognitive reserve, whereby high EE individuals can better tolerate suboptimal brain health to facilitate the preservation of cognitive function, is not just applicable to neuroanatomical indicators of brain aging but can be observed in markers of neurophysiology. Our results suggest that EEG metrics of evidence accumulation may index neurocognitive vulnerability of the aging brain.Significance Statement Response speed in older adults is closely linked with trajectories of cognitive aging. Here, by recording brain activity while individuals perform a simple computer task, we identify a neural metric that is a critical determinant of response speed. Older adults exposed to greater cognitive and social stimulation throughout a lifetime could maintain faster responding, even when this neural metric was impaired. This work suggests EEG is a useful technique for interrogating how a lifetime of stimulation benefits brain health in aging.

HLA class I NK-epitopes and KIR diversities in patients with multiple myeloma.

Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of malignant plasma cells in the bone marrow. Myeloma cells are susceptible to killing by natural killer (NK) cells, but NK cells fail to control disease progression, suggesting immunosuppression. The activation threshold of NK-effector function is regulated by interaction between KIRs and self-HLA class I, during a process called "education" to ensure self-tolerance. NK cells can respond to diseased cells based on the absence of HLA class I expression ("Missing-self" hypothesis). The HLA and KIR repertoire is extremely diverse; thus, the present study aimed to characterize potential variances in genotypic composition of HLA Class I NK-epitopes and KIRs between MM patients and healthy controls. Genotypic expression of KIR and HLA (HLA-C group-C1/C2 and Bw4 motifs (including HLA-A*23, A*24, A*32) were analyzed in 172 MM patients and 195 healthy controls. Compared to healthy controls, we did not observe specific KIR genes or genotypes, or HLA NK-epitopes with higher prevalence among MM patients. The presence of all three HLA NK-epitopes (C1+C2+Bw4+) was not associated with MM occurrence. However, MM patients were more likely to be C1-/C2+/Bw4+ (p = 0.049, OR 1.996). In line with this, there was a trend of increased genetic co-occurrence of Bw4 and KIR3DL1 in MM patients (p = 0.05, OR 1.557). Furthermore, MM patients were more likely to genetically express both C2/KIR2DL1 and Bw4/KIR3DL1 (p = 0.019, OR 2.453). Our results reveal an HLA NK-epitope combination that is associated with the occurrence of MM. No specific KIR genotypes were associated with MM.

In Situ Single Particle Reconstruction Reveals 3D Evolution of PtNi Nanocatalysts During Heating.

Tailoring nanoparticles' composition and morphology is of particular interest for improving their performance for catalysis. A challenge of this approach is that the nanoparticles' optimized initial structure often changes during use. Visualizing the three dimensional (3D) structural transformation in situ is therefore critical, but often prohibitively difficult experimentally. Although electron tomography provides opportunities for 3D imaging, restrictions in the tilt range of in situ holders together with electron dose considerations limit the possibilities for in situ electron tomography studies. Here, an in situ 3D imaging methodology is presented using single particle reconstruction (SPR) that allows 3D reconstruction of nanoparticles with controlled electron dose and without tilting the microscope stage. This in situ SPR methodology is employed to investigate the restructuring and elemental redistribution within a population of PtNi nanoparticles at elevated temperatures. The atomic structure of PtNi is further examined and a heat-induced transition is found from a disordered to an ordered phase. Changes in structure and elemental distribution are linked to a loss of catalytic activity in the oxygen reduction reaction. The in situ SPR methodology employed here can be extended to a wide range of in situ studies employing not only heating, but gaseous, aqueous, or electrochemical environments to reveal in-operando nanoparticle evolution in 3D.

Secondary structure prediction of long noncoding RNA: review and experimental comparison of existing approaches.

MOTIVATION: In contrast to messenger RNAs, the function of the wide range of existing long noncoding RNAs (lncRNAs) largely depends on their structure, which determines interactions with partner molecules. Thus, the determination or prediction of the secondary structure of lncRNAs is critical to uncover their function. Classical approaches for predicting RNA secondary structure have been based on dynamic programming and thermodynamic calculations. In the last 4 years, a growing number of machine learning (ML)-based models, including deep learning (DL), have achieved breakthrough performance in structure prediction of biomolecules such as proteins and have outperformed classical methods in short transcripts folding. Nevertheless, the accurate prediction for lncRNA still remains far from being effectively solved. Notably, the myriad of new proposals has not been systematically and experimentally evaluated. RESULTS: In this work, we compare the performance of the classical methods as well as the most recently proposed approaches for secondary structure prediction of RNA sequences using a unified and consistent experimental setup. We use the publicly available structural profiles for 3023 yeast RNA sequences, and a novel benchmark of well-characterized lncRNA structures from different species. Moreover, we propose a novel metric to assess the predictive performance of methods, exclusively based on the chemical probing data commonly used for profiling RNA structures, avoiding any potential bias incorporated by computational predictions when using dot-bracket references. Our results provide a comprehensive comparative assessment of existing methodologies, and a novel and public benchmark resource to aid in the development and comparison of future approaches. AVAILABILITY: Full source code and benchmark datasets are available at: https://github.com/sinc-lab/lncRNA-folding. CONTACT: lbugnon@sinc.unl.edu.ar.

The menin-MLL1 interaction is a molecular dependency in NUP98-rearranged AML.

Translocations involving the NUP98 gene produce NUP98-fusion proteins and are associated with a poor prognosis in acute myeloid leukemia (AML). MLL1 is a molecular dependency in NUP98-fusion leukemia, and therefore we investigated the efficacy of therapeutic blockade of the menin-MLL1 interaction in NUP98-fusion leukemia models. Using mouse leukemia cell lines driven by NUP98-HOXA9 and NUP98-JARID1A fusion oncoproteins, we demonstrate that NUP98-fusion-driven leukemia is sensitive to the menin-MLL1 inhibitor VTP50469, with an IC50 similar to what we have previously reported for MLL-rearranged and NPM1c leukemia cells. Menin-MLL1 inhibition upregulates markers of differentiation such as CD11b and downregulates expression of proleukemogenic transcription factors such as Meis1 in NUP98-fusion-transformed leukemia cells. We demonstrate that MLL1 and the NUP98 fusion protein itself are evicted from chromatin at a critical set of genes that are essential for the maintenance of the malignant phenotype. In addition to these in vitro studies, we established patient-derived xenograft (PDX) models of NUP98-fusion-driven AML to test the in vivo efficacy of menin-MLL1 inhibition. Treatment with VTP50469 significantly prolongs survival of mice engrafted with NUP98-NSD1 and NUP98-JARID1A leukemias. Gene expression analysis revealed that menin-MLL1 inhibition simultaneously suppresses a proleukemogenic gene expression program, including downregulation of the HOXa cluster, and upregulates tissue-specific markers of differentiation. These preclinical results suggest that menin-MLL1 inhibition may represent a rational, targeted therapy for patients with NUP98-rearranged leukemias.

Indirect 1H-[13C] MRS of the human brain at 7 T using a 13C-birdcage coil and eight transmit-receive 1H-dipole antennas with a 32-channel 1H-receive array.

The neuronal tricarboxylic acid and glutamate/glutamine (Glu/Gln) cycles play important roles in brain function. These processes can be measured in vivo using dynamic 1H-[13C] MRS during administration of 13C-labeled glucose. Proton-observed carbon-edited (POCE) MRS enhances the signal-to-noise ratio (SNR) compared with direct 13C-MRS. Ultra-high field further boosts the SNR and increases spectral dispersion; however, even at 7 T, Glu and Gln 1H-resonances may overlap. Further gain can be obtained with selective POCE (selPOCE). Our aim was to create a setup for indirect dynamic 1H-[13C] MRS in the human brain at 7 T. A home-built non-shielded transmit-receive 13C-birdcage head coil with eight transmit-receive 1H-dipole antennas was used together with a 32-channel 1H-receive array. Electromagnetic simulations were carried out to ensure that acquisitions remained within local and global head SAR limits. POCE-MRS was performed using slice-selective excitation with semi-localization by adiabatic selective refocusing (sLASER) and stimulated echo acquisition mode (STEAM) localization, and selPOCE-MRS using STEAM. Sequences were tested in a phantom containing non-enriched Glu and Gln, and in three healthy volunteers during uniformly labeled 13C-glucose infusions. In one subject the voxel position was alternated between bi-frontal and bi-occipital placement within one session. [4-13C]Glu-H4 and [4-13C]Gln-H4 signals could be separately detected using both STEAM-POCE and STEAM-selPOCE in the phantom. In vivo, [4,5-13C]Glx could be detected using both sLASER-POCE and STEAM-POCE, with similar sensitivities, but [4,5-13C]Glu and [4,5-13C]Gln signals could not be completely resolved. STEAM-POCE was alternately performed bi-frontal and bi-occipital within a single session without repositioning of the subject, yielding similar results. With STEAM-selPOCE, [4,5-13C]Glu and [4,5-13C]Gln could be clearly separated. We have shown that with our setup indirect dynamic 1H-[13C] MRS at 7 T is feasible in different locations in the brain within one session, and by using STEAM-selPOCE it is possible to separate Glu from Gln in vivo while obtaining high quality spectra.

Patients' evaluation of aftercare following hospitalization for COVID-19: satisfaction and unmet needs.

BACKGROUND: Patient experiences with COVID-19 aftercare remain largely unknown. We evaluated COVID-19 aftercare from a patient perspective one year after hospitalization, assessing satisfaction and its associated factors, and unmet needs. METHODS: The Satisfaction with COVID-19 Aftercare Questionnaire (SCAQ) was developed as part of a multicenter prospective cohort study and administered one year after hospital discharge. The SCAQ assesses (1) patient satisfaction, comprising information provision, rehabilitation, follow-up by hospitals and general practitioners (GPs), the most important aftercare topics, and overall satisfaction, and (2) unmet needs. RESULTS: 487/561 (87%) COVID-19 patients completed the SCAQ, all had been discharged from the hospital between March 2020 and May 2021. Among responders, the median age of patients was 60 (IQR 54-67) years, 338 (69%) were male, and the median length of stay in the hospital was 13 (6-27) days. Patients were least satisfied with information on who could be contacted with questions when health problems arise (59% satisfied or very satisfied). Many patients (75%) received rehabilitation, most frequently community-based (70%). Across the different community-based therapies, ≥ 60% of patients were satisfied with shared-decision making and ≥ 70% with the received therapy; a majority (≥ 79%) indicated a preference for receiving the same therapy again if needed. Regarding follow-up by hospitals, 86% of patients received this follow-up, most frequently visiting a pulmonologist (96%), being generally satisfied with the received aftercare. Aftercare from GPs was received by 39% of patients, with 88% being satisfied with the GP's availability and 79% with referral to appropriate aftercare providers. Patients (> 50%) considered information-related items most important in aftercare. Overall, patients rated their satisfaction with aftercare 8/10 (7-9) points. Those who received medical rehabilitation (versus no rehabilitation, adjusted beta 0.61 [95%CI 0.11 to 1.11], p = 0.02) or aftercare by a hospital medical specialist (1.1 [0.46 to 1.64], p < 0.001) or GP (0.39 [0.053 to 0.72], p = 0.023) reported significantly higher satisfaction than those without such aftercare. Unmet needs were reported by 35% of patients, with lack of information (20%) and lack of additional aftercare and/or involvement of their GP (19%) being the most frequently reported. CONCLUSION: Despite the forced quick development of COVID-19 aftercare, patients were generally satisfied. Follow-up by healthcare professionals and information provision is important to meet patients' aftercare needs.

Social fear extinction susceptibility is associated with Microbiota-Gut-Brain axis alterations.

Social anxiety disorder is a common psychiatric condition that severely affects quality of life of individuals and is a significant societal burden. Although many risk factors for social anxiety exist, it is currently unknown how social fear sensitivity manifests biologically. Furthermore, since some individuals are resilient and others are susceptible to social fear, it is important to interrogate the mechanisms underpinning individual response to social fear situations. The microbiota-gut-brain axis has been associated with social behaviour, has recently been linked with social anxiety disorder, and may serve as a therapeutic target for modulation. Here, we assess the potential of this axis to be linked with social fear extinction processes in a murine model of social anxiety disorder. To this end, we correlated differential social fear responses with microbiota composition, central gene expression, and immune responses. Our data provide evidence that microbiota variability is strongly correlated with alterations in social fear behaviour. Moreover, we identified altered gene candidates by amygdalar transcriptomics that are linked with social fear sensitivity. These include genes associated with social behaviour (Armcx1, Fam69b, Kcnj9, Maoa, Serinc5, Slc6a17, Spata2, and Syngr1), inflammation and immunity (Cars, Ckmt1, Klf5, Maoa, Map3k12, Pex5, Serinc5, Sidt1, Spata2), and microbe-host interaction (Klf5, Map3k12, Serinc5, Sidt1). Together, these data provide further evidence for a role of the microbiota-gut-brain axis in social fear responses.

Feed your microbes to deal with stress: a psychobiotic diet impacts microbial stability and perceived stress in a healthy adult population.

The impact of diet on the microbiota composition and the role of diet in supporting optimal mental health have received much attention in the last decade. However, whether whole dietary approaches can exert psychobiotic effects is largely understudied. Thus, we investigated the influence of a psychobiotic diet (high in prebiotic and fermented foods) on the microbial profile and function as well as on mental health outcomes in a healthy human population. Forty-five adults were randomized into either a psychobiotic (n = 24) or control (n = 21) diet for 4 weeks. Fecal microbiota composition and function was characterized using shotgun sequencing. Stress, overall health and diet were assessed using validated questionnaires. Metabolic profiling of plasma, urine and fecal samples was performed. Intervention with a psychobiotic diet resulted in reductions of perceived stress (32% in diet vs. 17% in control group), but not between groups. Similarly, biological marker of stress were not affected. Additionally, higher adherence to the diet resulted in stronger decreases in perceived stress. While the dietary intervention elicited only subtle changes in microbial composition and function, significant changes in the level of 40 specific fecal lipids and urinary tryptophan metabolites were observed. Lastly, microbial volatility was linked to greater changes in perceived stress scores in those on the psychobiotic diet. These results highlight that dietary approaches can be used to reduce perceived stress in a human cohort. Using microbiota-targeted diets to positively modulate gut-brain communication holds possibilities for the reduction of stress and stress-associated disorders, but additional research is warranted to investigate underlying mechanisms, including the role of the microbiota.

Behavioral Interventions on Surgeons' Preoperative Decision-Making: A Scoping Review and Critical Analysis.

INTRODUCTION: Consensus is lacking regarding the optimal strategy to influence surgeons' behaviors to reduce low-value surgical care. Comprehensively describing the existing body of literature that seeks to intervene on surgeons' preoperative decision-making may aid in structuring future behavior change strategies. METHODS: We performed a scoping review using four databases (Medical Literature Analysis and Retrieval System Online, Embase, Web of Science, and Cumulated Index to Nursing and Allied Health Literature) for articles that tested the effect of behavioral-based interventions on any aspect of surgeons' decision-making in the preoperative setting. Abstracted data were characterized by summative descriptions and analyzed using the Tailored Implementation for Chronic Disease framework, mapping aspects of deimplementation strategies in the studies onto the determinant(s) that they altered. Data abstraction and mapping tools were piloted and iteratively revised before two researchers independently assessing studies and categorizing determinants, and then meeting to discuss their decisions. RESULTS: There were 1460 articles identified from the initial search, with 17 full text articles ultimately included in the scoping review. Eight studies relied on a multidisciplinary preoperative conference to accomplish their aims, while five were multifaceted in their approach to deimplementation, and four studies used only a clinical decision support tool to accomplish their aims. Mapping determinants addressed in these studies onto the Tailored Implementation for Chronic Disease framework demonstrated that most strategies attempted to close knowledge gaps, leverage communication between providers, and broadcast institutional prioritization of change. CONCLUSIONS: There is a small but growing field of implementation and deimplementation strategies in preoperative surgical decision-making, and different approaches may be equally effective in varied clinical contexts. Deliberate measurement and comparison of outcomes, as well as selection of control groups, are areas for improvement in future work.

Haze factor of silver nanowires in variable refractive index environment: experimental and simulation approaches.

While silver nanowires (Ag NWs) have been demonstrated as a highly efficient transparent conducting material, they suffer from strong light scattering, which is quantified by a large haze factor (HF) in the optical spectrum. Here we investigate the influence of the dielectric environment on the light scattering of Ag NWs by comparing experimental measurements and simulations. In air, two peaks on the HF spectra are observed experimentally at the wavelength ofλI= 350 nm andλII= 380 nm and are attributed by simulations to the influence of the Ag NWs pentagonal shape on the localized surface plasmon resonance. The relative intensity between the two peaks is found to be dependent on whether the Ag NWs are in contact with the glass substrate or not. The HF behaviour in the near IR region seems to be dominated by Rayleigh scattering following simulations results. Dielectric environments of Ag NWs with various refractive indexes were obtained experimentally by the conformal deposition of different metal oxide coatings using atomic layer deposition, including Al-doped zinc oxide, Al2O3and SiO2coatings. The HF is found to be correlated with the refractive index environment in terms of HF peaks position, intensity and broadening. This trend of HF peaks is supported by a theoretical model to understand the optical mechanism behind this phenomenon.

Myotube growth is associated with cancer-like metabolic reprogramming and is limited by phosphoglycerate dehydrogenase.

The Warburg effect links growth and glycolysis in cancer. A key purpose of the Warburg effect is to generate glycolytic intermediates for anabolic reactions, such as nucleotides → RNA/DNA and amino acids → protein synthesis. The aim of this study was to investigate whether a similar 'glycolysis-for-anabolism' metabolic reprogramming also occurs in hypertrophying skeletal muscle. To interrogate this, we first induced C2C12 myotube hypertrophy with IGF-1. We then added 14C glucose to the differentiation medium and measured radioactivity in isolated protein and RNA to establish whether 14C had entered anabolism. We found that especially protein became radioactive, suggesting a glucose → glycolytic intermediates → non-essential amino acid(s) → protein series of reactions, the rate of which was increased by IGF-1. Next, to investigate the importance of glycolytic flux and non-essential amino acid synthesis for myotube hypertrophy, we exposed C2C12 and primary mouse myotubes to the glycolysis inhibitor 2-Deoxy-d-glucose (2DG). We found that inhibiting glycolysis lowered C2C12 and primary myotube size. Similarly, siRNA silencing of PHGDH, the key enzyme of the serine biosynthesis pathway, decreased C2C12 and primary myotube size; whereas retroviral PHGDH overexpression increased C2C12 myotube size. Together these results suggest that glycolysis is important for hypertrophying myotubes, which reprogram their metabolism to facilitate anabolism, similar to cancer cells.

Quality of in-hospital care in traumatic spinal column and cord injuries (TSC/SCI) in I.R Iran.

PURPOSE: This study aimed to implement the Quality of Care (QoC) Assessment Tool from the National Spinal Cord/Column Injury Registry of Iran (NSCIR-IR) to map the current state of in-hospital QoC of individuals with Traumatic Spinal Column and Cord Injuries (TSCCI). METHODS: The QoC Assessment Tool, developed from a scoping review of the literature, was implemented in NSCIR-IR. We collected the required data from two primary sources. Questions regarding health system structures and care processes were completed by the registrar nurse reviewing the hospital records. Questions regarding patient outcomes were gathered through patient interviews. RESULTS: We registered 2812 patients with TSCCI over six years from eight referral hospitals in NSCIR-IR. The median length of stay in the general hospital and intensive care unit was four and five days, respectively. During hospitalization 4.2% of patients developed pressure ulcers, 83.5% of patients reported satisfactory pain control and none had symptomatic urinary tract infections. 100%, 80%, and 90% of SCI registration centers had 24/7 access to CT scans, MRI scans, and operating rooms, respectively. Only 18.8% of patients who needed surgery underwent a surgical operation in the first 24 h after admission. In-hospital mortality rate for patients with SCI was 19.3%. CONCLUSION: Our study showed that the current in-hospital care of our patients with TSCCI is acceptable in terms of pain control, structure and length of stay and poor regarding in-hospital mortality rate and timeliness. We must continue to work on lowering rates of pressure sores, as well as delays in decompression surgery and fatalities.

The 'a, b, c's of pretangle tau and their relation to aging and the risk of Alzheimer's Disease.

Braak has described the beginnings of Alzheimer's Disease as occurring in the locus coeruleus. Here we review these pretangle stages and relate their expression to recently described normal features of tau biology. We suggest pretangle tau depends on characteristics of locus coeruleus operation that promote tau condensates. We examine the timeline of pretangle and tangle appearance in locus coeruleus. We find catastrophic loss of locus coeruleus neurons is a late event. The strong relationship between locus coeruleus neuron number and human cognition underscores the utility of a focus on locus coeruleus. Promoting locus coeruleus health will benefit normal aging as well as aid in the prevention of dementia. Two animal models offering experimental approaches to understanding the functional change initiated by pretangles in locus coeruleus neurons are discussed.