Therapeutic efficacy of intracerebral hematopoietic stem cell gene therapy in an Alzheimer's disease mouse model.

The conditions supporting the generation of microglia-like cells in the central nervous system (CNS) after transplantation of hematopoietic stem/progenitor cells (HSPC) have been studied to advance the treatment of neurodegenerative disorders. Here, we explored the transplantation efficacy of different cell subsets and delivery routes with the goal of favoring the establishment of a stable and exclusive engraftment of HSPCs and their progeny in the CNS of female mice. In this setting, we show that the CNS environment drives the expansion, distribution and myeloid differentiation of the locally transplanted cells towards a microglia-like phenotype.

Design and synthesis of a shikimoyl-functionalized cationic di-block copolypeptide for cancer cell specific gene transfection.

Targeted and efficient gene delivery systems hold tremendous potential for the improvement of cancer therapy by enabling appropriate modification of biological processes. Herein, we report the design and synthesis of a novel cationic di-block copolypeptide, incorporating homoarginine (HAG) and shikimoyl (LSA) functionalities (HDA-b-PHAGm-b-PLSAn), tailored for enhanced gene transfection specifically in cancer cells. The di-block copolypeptide was synthesized sequential -carboxyanhydride (NCA) ring-opening polymerization (ROP) techniques and its physicochemical properties were characterized, including molecular weight, dispersity, secondary conformation, size, morphology, and surface charge.

An empowered, clinically viable hematopoietic stem cell gene therapy for the treatment of multisystemic mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (MPS II), or Hunter syndrome, is a rare X-linked recessive lysosomal storage disorder due to a mutation in the lysosomal enzyme iduronate-2-sulfatase (IDS) gene. IDS deficiency leads to a progressive, multisystem accumulation of glycosaminoglycans (GAGs) and results in central nervous system (CNS) manifestations in the severe form. We developed up to clinical readiness a new hematopoietic stem cell (HSC) gene therapy approach for MPS II that benefits from a novel highly effective transduction protocol.

Hagfish genome elucidates vertebrate whole-genome duplication events and their evolutionary consequences.

Polyploidy or whole-genome duplication (WGD) is a major event that drastically reshapes genome architecture and is often assumed to be causally associated with organismal innovations and radiations. The 2R hypothesis suggests that two WGD events (1R and 2R) occurred during early vertebrate evolution. However, the timing of the 2R event relative to the divergence of gnathostomes (jawed vertebrates) and cyclostomes (jawless hagfishes and lampreys) is unresolved and whether these WGD events underlie vertebrate phenotypic diversification remains elusive.

Evolution of two distinct variable lymphocyte receptors in lampreys: VLRD and VLRE.

Jawless vertebrates possess an alternative adaptive immune system in which antigens are recognized by variable lymphocyte receptors (VLRs) generated by combinatorial assembly of leucine-rich repeat (LRR) cassettes. Three types of receptors, VLRA, VLRB, and VLRC, have been previously identified. VLRA- and VLRC-expressing cells are T cell-like, whereas VLRB-expressing cells are B cell-like.

Inhibitory and excitatory synaptic neuroadaptations in the diazepam tolerant brain.

Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation.

An Engineered Adeno-Associated Virus Capsid Mediates Efficient Transduction of Pericytes and Smooth Muscle Cells of the Brain Vasculature.

Neurodegeneration and cerebrovascular disease share an underlying microvascular dysfunction that may be remedied by selective transgene delivery. To date, limited options exist in which cellular components of the brain vasculature can be effectively targeted by viral vector therapeutics. In this study, we characterize the first engineered adeno-associated virus (AAV) capsid mediating high transduction of cerebral vascular pericytes and smooth muscle cells (SMCs).

An innovative hematopoietic stem cell gene therapy approach benefits CLN1 disease in the mouse model.

Hematopoietic stem and progenitor cells (HSPCs) can establish a long-lasting microglia-like progeny in the central nervous system of properly myeloablated hosts. We exploited this approach to treat the severe CLN1 neurodegenerative disorder, which is the most aggressive form of neuronal ceroid lipofuscinoses due to palmitoyl-protein thioesterase-1 (PPT1) deficiency. We here provide the first evidence that (i) transplantation of wild-type HSPCs exerts partial but long-lasting mitigation of CLN1 symptoms; (ii) transplantation of HSPCs over-expressing hPPT1 by lentiviral gene transfer enhances the therapeutic benefit of HSPCs transplant, with first demonstration of such a dose-effect benefit for a purely neurodegenerative condition like CLN1 disease; (iii) transplantation of hPPT1 over-expressing HSPCs by a novel intracerebroventricular (ICV) approach is sufficient to transiently ameliorate CLN1-symptoms in the absence of hematopoietic tissue engraftment of the transduced cells; and (iv) combinatorial transplantation of transduced HSPCs intravenously and ICV results in a robust therapeutic benefit, particularly on symptomatic animals.

Boron-Thioketonates: A New Class of S,O-Chelated Boranes as Acceptors in Optoelectronic Devices.

Development of new n-type semiconductors with tunable band gap and dielectric constant has significant implication in dissociating bound charge carrier relevant for demonstrating high performance optoelectronic devices. Boron-β-thioketonates (MTDKB), analogues to boron-β-diketonates containing a sulfur atom in the framework of β-diketones were synthesized. Bulk transport measurement exhibited an outstanding bulk electron mobility of ≈0.

Genomic characterization of genes associated with anti-folate drug resistance and treatment outcomes in eastern India: A molecular surveillance study from 2008 to 2017.

Introduction: After being used vigorously for the previous two decades to treat P. falciparum, chloroquine and sulfadoxine-pyrimethamine were replaced in 2009 with an artemisinin-based combination therapy (artesunate-sulfadoxine-pyrimethamine) in an effort to combat multidrug-resistant parasites.

Methods: We set out to assess the genetic variants of sulfadoxine-pyrimethamine resistance and the effectiveness of its treatment in eastern India prior to, during, and 6 to 8 years following the introduction of the new pharmacological regime.

Technological avenues and market mechanisms to accelerate methane and nitrous oxide emissions reductions.

Strategies targeting methane (CH) and nitrous oxide (NO) emissions are critical to meeting global climate targets. Existing literature estimates the emissions of these gases from specific sectors, but this knowledge must be synthesized to prioritize and incentivize CH and NO mitigation. Accordingly, we review emissions sources and mitigation strategies in all key sectors (fuel extraction and combustion, landfilling, agriculture, wastewater treatment, and chemical industry) and the role of carbon markets in reducing emissions.

Plastics to fuel or plastics: Life cycle assessment-based evaluation of different options for pyrolysis at end-of-life.

Pyrolysis is a leading technology to convert non-recyclable plastic waste to fuels or chemicals. As interest in the circular economy grows, the latter option has seemingly become more attractive. Once waste plastic is pyrolyzed to, for example, naphtha, however, additional steps are required to produce a polymer product.

Treatment of long bone infection by a biodegradable bone cement releasing antibiotics in human.

Repair of methicillin-resistant Staphylococcal (MRSA) chronic osteomyelitis and resulting bone defect is one of the major challenges in orthopaedics. Previous study has shown the effectiveness of antibiotic loaded biodegradable composite bone cement with in vitro tests and in the treatment of experimental osteomyelitis. The cement is composed of poly(lactide-co-glycolide) encapsulated antibiotic-biphasic calcium phosphate granule complex and additive antibiotic powder in gypsum binder.

Lysosome-Targeting Strategy Using Polypeptides and Chimeric Molecules.

Lysosomes are membranous compartments containing hydrolytic enzymes, where cellular degradation of proteins and enzymes among others occurs in a controlled manner. Lysosomal dysfunction results in various pathological situations, such as several lysosomal storage disorders, neurodegeneration, infectious diseases, cancers, and aging. In this review, we have discussed different strategies for synthesizing peptides/chimeric molecules, their lysosome-targeting ability, and their ability to treat several lysosomal associated diseases, including lysosomal storage diseases and cancers.

Evolution of variable lymphocyte receptor B antibody loci in jawless vertebrates.

Three types of variable lymphocyte receptor (VLR) genes, , , and encode antigen recognition receptors in the extant jawless vertebrates, lampreys and hagfish. The somatically diversified repertoires of these VLRs are generated by serial stepwise copying of leucine-rich repeat (LRR) sequences into an incomplete germline gene. Lymphocytes that express VLRA or VLRC are T cell-like, while VLRB-expressing cells are B cell-like.

Artemisinin combination therapy fails even in the absence of Plasmodium falciparum kelch13 gene polymorphism in Central India.

Artemisinin is the frontline fast-acting anti-malarial against P. falciparum. Emergence and spread of resistant parasite in eastern-India poses a threat to national malaria control programs.

Political institutions and policy responses during a crisis.

How do countries with differing political institutions respond to national crises? We examine policy responses to the coronavirus pandemic in a sample of 125 countries, using high frequency data on two measures: (i) containment policies, i.e., closure of public spaces and restrictions on movement of people, and (ii) health policies, i.

Preservation of Aloe vera and soybean flour fortified Granny Smith apple through optimised quartz-halogen radiated vacuum drying: kinetics and quality evaluation.

Background: Granny Smith (GS) apple has low protein content and poor antimicrobial properties; hence it has been blended with Aloe vera (AV; high ascorbic acid, antimicrobial and antioxidant properties) and soybean flour (SF; rich in phenols, flavonoids, ascorbic acid, total antioxidant and protein) in different proportions to obtain fortified GS, i.e. GSAVSF.

All India difficult airway association (AIDAA) consensus guidelines for airway management in the operating room during the COVID-19 pandemic.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) which causes coronavirus disease (COVID-19) is a highly contagious virus. The closed environment of the operation room (OR) with aerosol generating airway management procedures increases the risk of transmission of infection among the anaesthesiologists and other OR personnel. Wearing complete, fluid impermeable personal protective equipment (PPE) for airway related procedures is recommended.

Ancient -like Genes Herald B Cell Regulation in Lampreys.

The TNF superfamily ligands BAFF and APRIL interact with three receptors, BAFFR, BCMA, and TACI, to play discrete and crucial roles in regulating B cell selection and homeostasis in mammals. The interactions between these ligands and receptors are both specific and redundant: BAFFR binds BAFF, whereas BCMA and TACI bind to either BAFF or APRIL. In a previous phylogenetic inquiry, we identified and characterized a -like gene in lampreys, which, with hagfish, are the only extant jawless vertebrates, both of which have B-like and T-like lymphocytes.

Diazepam Accelerates GABAR Synaptic Exchange and Alters Intracellular Trafficking.

Despite 50+ years of clinical use as anxiolytics, anti-convulsants, and sedative/hypnotic agents, the mechanisms underlying benzodiazepine (BZD) tolerance are poorly understood. BZDs potentiate the actions of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, through positive allosteric modulation of γ2 subunit containing GABA type A receptors (GABARs). Here we define key molecular events impacting γ2 GABAR and the inhibitory synapse gephyrin scaffold following initial sustained BZD exposure and .