Parvalbumin-positive neurons are the largest class of GABAergic, inhibitory neurons in the central nervous system. In the cortex, these fast-spiking cells provide feedforward and feedback synaptic inhibition onto a diverse set of cell types, including pyramidal cells, other inhibitory interneurons, and themselves. Cortical inhibitory networks broadly, and cortical parvalbumin-expressing interneurons (cPVins) specifically, are crucial for regulating sensory plasticity during both development and adulthood. Here we review the functional properties of cPVins that enable plasticity in the cortex of adult mammals and the influence of cPVins on sensory activity at four spatiotemporal scales. First, cPVins regulate developmental critical periods and adult plasticity through molecular and structural interactions with the extracellular matrix. Second, they activate in precise sequence following feedforward excitation to enforce strict temporal limits in response to the presentation of sensory stimuli. Third, they implement gain control to normalize sensory inputs and compress the dynamic range of output. Fourth, they synchronize broad network activity patterns in response to behavioral events and state changes. Much of the evidence for the contribution of cPVins to plasticity comes from classic models that rely on sensory deprivation methods to probe experience-dependent changes in the brain. We support investigating naturally occurring, adaptive cortical plasticity to study cPVin circuits in an ethologically relevant framework, and discuss recent insights from our work on maternal experience-induced auditory cortical plasticity. The cerebral cortex has a remarkable capacity to remodel its synaptic structures and refine its neuronal activity in response to changing conditions throughout life. Such cortical plasticity interacts with a wide range of fundamental biological processes including aging , stress The neocortex is built around a “canonical circuit,” a set of vertically connected circuit motifs composed of diverse excitatory and inhibitory cell types that establish common hierarchical neuronal computations . This arIn the last two decades, the contributions of specific inhibitory interneuron subtypes to sensory learning, memory, and plasticity have been studied in the visual, auditory, somatosensory, and olfactory cortices. Here we review some of that literature, focusing on cortical parvalbumin-expressing interneurons (cPVins), which are the most abundant inhibitory cell type in the brain. We discuss how the physiological and molecular features of cPVins equip sensory networks for plasticity. We argue that cPVins across sensory cortices share core intrinsic features and mechanisms that enable periods of experiential learning. We further propose that approaches exploiting ethologically relevant behaviors are important for understanding how cPVin directed plasticity is engaged naturally in the adult brain. While there are many varieties and mechanisms of “plasticity,” our use of the term here denotes adjustments to intrinsic and extrinsic connectivity in sensory cortices that optimize representation of stimuli. We particularly focus on the mechanisms that open and close episodes of heightened sensitivity of cortex to stimuli in response to developmental programs or novel sensory experience.Many of the fundamental features of cortical plasticity were first identified by studies examining the visual cortex during developmental critical periods e.g., . Much ofThe onset and offset of developmental critical periods are defined by changes in cortical GABAergic transmission , 2010. PGAD mutants rescues the capacity for plasticity in response to visual deprivation  is a complex structure composed of elastin, fibronectin, integrin, glycoprotein, and polysaccharide macromolecules that surrounds cells, and which accounts for 10–20% of the brain’s volume . The ECMExtracellular matrix components are not uniformly distributed across brain regions or cell types . For exaPerineuronal nets envelop cPVins and their synapses as developmental windows of plasticity close . This deExpression of the parvalbumin (PV) protein itself also fluctuates according to cPVin activity . DownregWell-developed PNNs appear to be a necessary component for termination of developmental critical periods. Manipulations that disrupt critical period closure  delay disinhibition and slow the formation of PNNs . MoreoveConversely, plasticity can be reinstated by pharmacological dissolution of PNNs in the adult cortex, which allows for enhanced synaptic plasticity and physical restructuring of mature PV+ synapses . For exaPerineuronal net-fluctuations as a marker of plasticity can also be observed outside of the context of monocular deprivation. For example, reintroduction of light in dark-exposed animals triggers V1 plasticity through the endogenous degradation of the ECM by MMP-9, and resulting disinhibition of fast-spiking interneurons . In the cPVins represent an estimated 5–20% of cells in the brain, and up 40–50% of the inhibitory population, based on developmental progenitor and tracing studies . Despitein vivo or in response to somatic current injection  or depression (LTD). These mechanisms rely on coincidence detection of pre- and post- synaptic neuronal spiking. Spike timing-dependent plasticity (STDP), which modifies synapses based on the precise relative timing of individual pre- and post- synaptic spikes , has beeAnother important cPVin feature is their broad tuning relative to neighboring pyramidal cells , and othMany studies have examined the specific operations that cPVins perform on sensory responses through optogenetic activation and/or inactivation of the population. Collectively, these studies have uncovered a panoply of conflicting transformations of sensory representations by cPVins. These include non-selective divisive gain control , receptiBroad inhibition of cortical output by cPVins derives from their ability to integrate excitatory activity across a wide area via their extensive dendritic fields . This alAt the broadest spatiotemporal scale, cPVin networks have a capacity to coordinate cortical output of large areas. On a population level, the rhythmic firing of cPVins establishes gamma oscillations, a high frequency, (30–80 Hz) periodic signal that results from synchrony of local field potentials and synaptic activity . GeneticGamma oscillations critically depend on NMDA receptor expression by cPVins . In contThe functional roles of gamma oscillations are less well understood. Oscillations reflect cPVin task-dependent activity and recruitment of greater numbers of cPVins during sensory learning . ChangesFurther, the presence of gamma oscillations also correlates with the familiarity of sensory stimuli, which suggests they facilitate memory traces in sensory cortices , 2020. IFinally, gamma power in sensory cortices correlates with behavioral states, such as attention , locomotIn mice, plasticity in the auditory cortex (ACtx) is triggered by maternal experience with pups. A broad base of evidence supports the conclusion that auditory plasticity in adult females helps to sharpen and amplify responses to behaviorally salient distress vocalizations from the pups. Here we review these data, highlighting work by our lab identifying cPVin-specific physiological mechanisms underlying “maternal,” experience-dependent auditory plasticity. These mechanisms share features of classical models of experience-dependent cortical plasticity, including those observed in developmental critical periods. Importantly, however, this plasticity is activated not by an exogenous experimental manipulation, but simply by social experience.Primiparous mice learn to recognize and respond to pup ultrasonic vocalizations (USVs), which signal distress when pups are isolated and become hypothermic. This learning is manifested behaviorally in the retrieval of pups back to the nest by the dams . HoweverMecp2 mutant mouse models. While wild-type (WT) maternal surrogates readily learn to perform pup retrieval, adult female mice that are missing one copy of the X chromosome -linked Mecp2 gene (HETMecp2) fail to perform this task (HETMecp2 subjects and wild type littermates (WTMecp2)  . Howevercontrols . In the HETMecp2 subjects (HETMecp2 subjects to respond behaviorally to USV cues. We further linked cPVins to maternal learning by showing that deletion of Mecp2 in cPVins was sufficient to disrupt early retrieval (Further, we predicted that dissolution of PNNs might reinstate ACtx plasticity, as has been found in other sensory cortices. Indeed, PNN dissolution in the ACtx just prior to birth of the pups ameliorated overexpression of PNNs and facilitated retrieval performance in subjects . Again tetrieval .WTMecp2 subjects, responses of cPVins to USVs were weaker after experience with pups (WTMecp2. This is complemented by increased pyramidal neuron responses to USVs.We next examined the effects of pup exposure on stimulus-driven activity in the ACtx of awake mice. Consistent with a central role of cPVin inhibitory drive in the pup-induced ACtx plasticity, we found that, in ith pups . The dimith pups . That isHetMecp2. More specifically, cPVin activity in response to USVs remained high despite experience with pups. These firing patterns matched the observed elevation in PV protein expression in HetMecp2, but not WTMecp2 subjects. That is, given the activity-dependent expression of PV, the continued high stimulus-evoked firing rates of cPVins in HetMecp2 links the cPVin-specific molecular expression to a functional lack of plasticity.In contrast, these physiological changes were not observed in the ACtx of This pattern of results is also consistent with our understanding of sensory cortical plasticity in other systems, which is often initiated by disinhibition. In sum, inhibitory ACtx plasticity maximizes neural “contrast” and appears to align temporal dynamics of cortical response to USVs, enabling pup retrieval . These fAs others have suggested, studying sensory processing in natural and/or socially salient contexts may be particularly effective at triggering rapid or robust plasticity . Our worHere we briefly summarize the shared features of plasticity during visual, developmental critical periods and during adult, auditory learning in natural contexts. First, both are marked by dynamic downregulation of cortical inhibition that results from decreased stimulus-evoked firing by cPVins, and leads to a concomitant increase in excitability of principal cortical neurons. This likely reflects changes to relative synaptic strengths from cPVins that lower the LTP threshold of pyramidal cells . Second,Here we have focused on the known contributions of functional and structural cPVin plasticity for supporting sensory learning. However, the current understanding is far from complete. There are many areas of on-going investigation which promise to enhance this understanding including: contributions of cPVin to encoding natural or other complex stimuli , real-tiWe have also emphasized, by highlighting our own work, the need for further dissection of cell type specific plasticity in naturally occurring, socially salient contexts. Technical advancements, such as the development of less invasive approaches, are particularly important for implementing such investigations. For example, extracranial delivery of optogenetic  and ultrAdvancing our understanding of cPVin plasticity has implications beyond scientific inquiry. Aberrant cPVin circuitry has been implicated in a diverse set of neurocognitive conditions . TherefoBoth authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.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.


Water scarcity is one of the greatest concerns for agronomy worldwide. In recent years, many water resources have been depleted due to multiple factors, especially mismanagement. Water resource shortages lead to cropland expansion, which likely influences climate change and affects global agriculture, especially horticultural crops. Fruit yield is the final aim in commercial orchards; however, drought can slow tree growth and/or decrease fruit yield and quality. It is therefore necessary to find approaches to solve this problem. The main objective of this review is to discuss the most recent horticultural, biochemical, and molecular strategies adopted to improve the response of temperate fruit crops to water stress. We also address the viability of cultivating fruit trees in dry areas and provide precise protection methods for planting fruit trees in arid lands. We review the main factors involved in planting fruit trees in dry areas, including plant material selection, regulated deficit irrigation (DI) strategies, rainwater harvesting (RWH), and anti-water stress materials. We also provide a detailed analysis of the molecular strategies developed to combat drought, such as Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) through gene overexpression or gene silencing. Finally, we look at the molecular mechanisms associated with the contribution of the microbiome to improving plant responses to drought. Global warming, a decrease in precipitation, and population growth (the United Nations predicts that by 2050 the population could exceed 10 billion)—resulting in a 60% increase in the demand for food—are set to pose increasingly serious challenges to world food production, and especially temperate fruit production, in the coming years. Drought is one of the most destructive abiotic stresses for crop productivity, affecting more than a third of the world’s population. The water crisis afflicts human societies, affecting the economy and both human and animal health. In recent decades, the expansion of drylands has become a tremendous issue for many countries .Due to the fact that the average temperature is increasing worldwide, it is predicted that changes in precipitation patterns will occur in the following century, intensifying drought in many regions. This climate change affects water availability in orchards .The Food and Agriculture Organization (FAO) estimates that drought resulted in a direct loss of nearly USD 30 billion for agriculture in developing countries from 2005 to 2015. Drought stress, as the major abiotic stress in many regions, limits the fruitfulness of horticultural crops and agricultural development in arid and semi-arid regions . The ultThere is great potential for developing the horticultural sector in arid lands worldwide . ImproveAs global human population growth has increased, cropland expansion has risen as well; this expansion imposes intense pressure on water resources . In ordeThe main objective of this review Is to integrate and discuss the most recent horticultural strategies adopted to improve the response of temperate fruit crops to water stress, addressing the viability of cultivating fruit trees in dry areas, and to provide precise protection methods for planting fruit trees in these areas. Emphasis will be placed on the analysis of the physiological, biochemical, and molecular aspects associated with drought tolerance. These new approaches  are of pIn establishing new orchards, the cultivation needs for the specific fruit tree must be considered. The tree should be compatible with the soil, water, and weather conditions ,20.Selecting drought-tolerant species is a promising solution in arid and semi-arid regions . These kPrunus besseyi Χ P. cerasifera), and ‘Rootpac R’ (P. cerasifera Χ P. dulcis) grafted with ‘Catherina’ peach increased the level of proline (in roots and leaves), sorbitol (in leaves), and raffinose (in roots) under water-deficit conditions [To increase water-use efficiency (WUE), Jiménez et al.  indicatenditions . Interspnditions . In anotnditions , peach gnditions .Pyrus syriaca), the only wild species in Lebanon and Turkey, is drought tolerant and has higher grafting compatibility with Pyrus communis than quince (Cydonia oblonga) rootstocks [Using wild varieties as rootstocks is also recommended for pome fruit trees . As a caotstocks .Pomologists have proved that the canopy architecture can play a key role in the adaptation of trees to abiotic conditions . When itThe adverse impacts of water deficit on fruit yield can be alleviated by changing the canopy architecture and removing the outer 30% of all major branches via pruning; severe summer pruning (SSP) is especially effective ,30. WhenAnother technique for ameliorating the damaging effect of drought stress is removing flowers or young fruits, known as thinning . Fruit tRecent studies have focused on investigating the interaction between different materials and methods in plants in order to introduce more efficient and practical strategies to withstand DI . Chen etNet shading is another horticultural technique that can help decrease the water demand in fruit trees . By instThe use of mulches is another practical method for decreasing the evaporation of water from soil surfaces in order to alleviate soil desiccation in arid areas . Crop re2 concentration [Some mulches—such as straw mulching—are thought to be relatively more environmentally friendly than others, such as the widespread use of plastic film . Mulch entration .Pyrus ussuriensis seedlings showed significantly delayed soil moisture loss and effectively changed the chlorophyll fluorescence parameters, increasing the photochemical efficiency of the photosystem II [Biochar is a mainly steady resistant organic carbon compound obtained by heating biomass at temperatures typically between 300 and 1000 °C in an oxygen-limited environment . Biocharystem II .Deficit Irrigation (DI) is a water-saving irrigation strategy used to manage limited water resources for fruit trees in dryland areas . ImproveSustained deficit irrigation (SDI) originated in the 1970s with a strategy called deficit high-frequency irrigation (DHFI), which was very similar to SDI . It was Regulated deficit irrigation (RDI) is a strategy in which irrigation is fully applied during critical periods for fruit trees—the drought-sensitive phenological stages—and limited during the non-critical periods—the drought-tolerant phenological stages . This woThe partial root-zone drying technique (PRD) involves irrigating only one part of the root zone, leaving the other side dry, and rewetting by shifting irrigation to the dry side through alternate furrow irrigation . PRD canDifferent techniques are used to harvest and save rainwater to protect the soil . Such teOn the other hand, Zai pits are made by burying planting holes and filling them with organic matters during the dry season, to enhance soil moisture retention and available nutrients ,74. The Negarims are tiny, diamond-shaped basins that are enclosed by embankments . These bA half-moon is a semi-circular, mechanical structure that gathers and retains running water and improves soil permeability . It thusFinally, other materials used for generating water-retaining soil include grass strips, stone lines, trash lines, contour stone bunds, and Cocoons. Contour stone bunds are low lines of stones measuring 25 cm high and 35 cm wide on average . These sAzotobacter, Serratia, Bacillus, Pseudomonas, and Ochrobactrum are microbial genera that are known as growth promoters under water stress [It has been reported that stress-adapted microorganisms from either the rhizosphere, internal tissues, or aerial parts of plants help plants cope with drought and promote growth through various mechanisms. These mechanisms include the accumulation of osmolytes, also lowering the level of ethylene inhibition by the enzyme aminocyclopropane-1-carboxylate deaminase (ACC) and providing unavailable nutrients for plants. r stress .Serratia plymuthica and Pseudomonas lini rhizobacteria have been found to increase drought tolerance in jujube seedlings [Plant growth-promoting rhizobacteria (PGPR) are found around the plant root system and interact with plants, increasing their growth and thereby helping them maintain a promising water status in drought conditions . Plant reedlings .Arbuscular mycorrhizal fungi (AMF) establish symbiotic associations with the roots of approximately 80% land plant species. Such symbiotic associations help the host plants absorb soil water and nutrients in exchange for 20% of the host plant’s photosynthetic carbohydrates . StudiesPlant resilience in response to environmental pressures may be increased by the exogenous application of favorable molecules . DiffereAscorbic acid, for instance, is a well-known antioxidant used to regulate photosynthesis in plants ,97. The Triazoles are chemical compounds belonging to the group of ergosterol biosynthesis inhibitors . These cChitosan, a marine cationic polysaccharide, has special bioactive attributes that make it an efficient scavenger of reactive oxygen species (ROS) . The usePutrescine, spermidine, and spermine  are the most abundant polyamines (PAs)—organic polycations—and are involved in several growth processes in plants . PolyamiThe DL-β-aminobutyric acid (BABA) compound has also been shown to protect plants against environmental stresses . GrapeviGlycine betaine (GB) is an osmoprotectant organic solute whose foliar application (50 mM) has a positive effect on papaya drought reaction, leading to a decrease in water stress . GB can The plant hormone ABA (abscisic acid) is linked to the plant response to water stress ,116. WheKaolin is a kind of clay found in nature and is non-toxic when sprayed on plants, providing a thin coating that protects the plants against abiotic and biotic stress . The covSilicon is reported to enhance drought resistance in plants by retaining photosynthetic activity, plant water balance, and vascular structure under high transpiration . The useBrassinosteroid (BR) phytohormones can also provide tolerance to abiotic and biotic stresses . SprayinAntitranspirant compounds enhance drought resistance by reducing water transpiration in plants . AccordiMelatonin is an indole-based structure found in various organisms . The appThe application of superabsorbent polymers or hydrogels (synthetic polyacrylamide) can enhance the water holding capacity and decrease water deficiency by permeation . A mediuEthylene buildup increases the permeation of cell membranes under drought stress, and, in turn, the production of ethylene is prevented by aminovinylglycine (AVG) . In lineSalicylic acid, a plant growth regulator, has been shown to regulate different metabolic and physiological activities in plants against environmental stresses, and it can be used in combination with AVG ,144. ThePhosphatidylcholine is a type of lipid found in the cell membrane of many eukaryotes . The useNitric oxide (NO) is an unstable free radical with many biological functions in plants . It can Plant biostimulants consist of various organic and inorganic substances or microorganisms that can enhance fruit quality, nutrient uptake, and resistance to abiotic or biotic stresses . The useAscophyllum nodosum, used at 5 and 10 mL·L−1 as either a soil drench or foliar spray, had a significant effect on plant-water relations and may be an effective means for improving water stress resistance in citrus trees [Seaweed and seaweed extracts have long been applied as fertilizers . Seaweedus trees .Amino acids are obtained by protein hydrolysis and have an important role in tree growth and conservation against abiotic stresses . They ar2, thus improving photosynthesis, nutrition status, and apple yield and quality [Saccharomyces cerevisiae 10 g) improved the length and diameter of the roots in olive trees [Yeast extract contains many growth substances—such as vitamins B1, pyridoxine, riboflavin, cytokinins, proteins, and carbohydrates ,157 and  quality . Foliar ve trees .Garlic possesses sulfur compounds such as trisulfide, aliin, ajoene, allylpropl, allicin, sallylcysteine, and diallyl. In addition to these compounds, garlic possesses different types of amino acids, arginine and glycosides and enzymes such as peroxidases and alliinase . Garlic Fulvic acid is a type of organic acid that plays an important role in increasing plant growth and plant drought resistance . In grap3 plays a vital role in mitigating environmental stress [Finally, Gibberellins (GAs) are hormones involved in plant growth that regulate different processes of metabolism and gene expression . GA3 plal stress . Droughtl stress . Combinel stress .The ability of a population to adapt to stressful conditions such as drought and disease depends on the presence of individuals with the gene alleles required to adapt to these conditions .Pathogenesis Related 1 (NPR1) in drought resistance [Plant breeders are now progressively focusing on the latest genome-editing instruments to improve significant agricultural attributes . The emesistance . On the sistance .Dehydratation-Responsive Element Binding Factors (DREBs) control the expression of some target genes induced by cold and drought stress [MsDREB6.2 overexpression leads to a decrease in stomatal density and apertures and an increase in the hydraulic conductivity of roots, which boosts the drought resistance of overexpressing plants [Gene expression changes are usually the first response to stress situations in plants . Among tt stress . MsDREB6g plants . In thesg plants . It is ig plants .MYB1 and MYB2 transcription factors, which are involved in the dehydration response through the ABA signaling pathway [Papaya, basic helix loop-helix (bHLH) TF genes and members of the WD40 protein family have been found to regulate abiotic stress responses, which can provide knowledge for understanding responses under cold, salinity, and water stress [CpHSF, CpMYB, CpNAC, CpNFY-A, CpERF, and CpWRKY [WRKY TFs in the pear genome and showed that drought tolerance was improved by PbWRKY manipulation. WRKY TFs may also therefore play an important role in regulating the water stress response. In addition, WUSCHEL-related homeobox (WOX) transcription factors are important in plant development processes and evolutionary novelties. Recently, Lv et al. [MdWOX13–1 increased the callus weight and enhanced ROS scavenging against drought stress in different Rosacea species including prune (Prunus domestica), apple , pear (Pirus communis), almond (Prunus dulics), peach (Prunus persica), mei (Prunus mume), and cherry (Prunus avium).Transcription factors (TFs) are the key regulators of gene transcription. Transcription factors also act as proteins that can bind to DNA sequences and regulate transcription . In wild pathway . In mangr stress . Eukaryor stress . Researcd CpWRKY . Huang ed CpWRKY  classifiv et al.  showed tRNA interference (RNAi) is a rapid method to induce gene silencing in a variety of organisms . In peacIn a context of global climate change, drought conditions are one of the main limiting parameters for plant yield and growth in agriculture around the world and thus impact global food security. To deal with the global drought conditions, different agricultural management strategies have been studied, including mulching, rainwater harvesting, net shading, the use of tolerant rootstocks and early-maturing cultivars, fruit thinning, pruning and regulated DI strategies, as well as the exogenous application of anti-water stress substances such as ascorbic acid, ABA, melatonin, and proline. Such procedures and strategies can maintain orchard growth and productivity, but new technologies can also enhance plant tolerance to abiotic stress. The CRISPR/Cas9 gene editing system, as well as overexpressing drought-responsive genes, contributes to the promise of fruit tree cultivation in arid regions with high yields and quality, increasing the supply of food for humans around the world.


Translation of novel therapies for brain cancer into clinical practice is of the utmost importance as primary brain tumors are responsible for more than 200,000 deaths worldwide each year. While many research efforts have been aimed at improving survival rates over the years, prognosis for patients with glioblastoma and other primary brain tumors remains poor. Safely delivering chemotherapeutic drugs and other anti-cancer compounds across the blood–brain barrier and directly to tumor cells is perhaps the greatest challenge in treating brain cancer. Polymeric nanoparticles (NPs) are powerful, highly tunable carrier systems that may be able to overcome those obstacles. Several studies have shown appropriately-constructed polymeric NPs cross the blood–brain barrier, increase drug bioavailability, reduce systemic toxicity, and selectively target central nervous system cancer cells. While no studies relating to their use in treating brain cancer are in clinical trials, there is mounting preclinical evidence that polymeric NPs could be beneficial for brain tumor therapy. This review includes a variety of polymeric NPs and how their associated composition, surface modifications, and method of delivery impact their capacity to improve brain tumor therapy. Malignant tumors of the central nervous system (CNS), the vast majority of which originate in the brain , are theNumerous approaches aimed at overcoming these limitations have been developed over the years, with variable success . Some ofIn recent years, polymeric NPs developed for CNS tumor treatment have been modified with various moieties capable of interacting with the BBB and tumor cells. Appropriate subtypes can be selected by assessing the polymer pharmacokinetics, modifiability, and payload delivery best suited for any given study. Additionally, polymers can be engineered to form other nanomaterials that may be useful for therapeutic development. For example, a recent review detailed the ability to produce optical nanofibers from polymers that can aid in phototherapy, drug delivery, sensing, and more . Others ® wafer, is a biodegradable carmustine-loaded polyanhydride-based implant that was first approved by the US Federal Drug Administration (FDA) in 1996 for patients with recurrent GBM as an adjunct to surgery [Polyanhydride is formed by carboxylic acid polymerization with anhydride linkages  and is a surgery . In 2003 surgery .® wafers were the first FDA-approved method of delivering local, sustained-release chemotherapy to brain tumors [® wafers have become part of the gold standard for treatment of GBM and have significantly improved median patient survival times [® wafers reported a median overall survival of 18.0 months, with 39.8% and 31.5% of patients surviving two and three years, respectively [Gliadeln tumors . In combal times . A 2022 ectively . Buildin® wafer, polyanhydride NPs have been investigated as a potential platform for novel brain cancer therapeutics. Polyanhydride NPs are highly tunable and their degradation profile can be modified from days to months, depending on their copolymer composition [® wafers suggest polyanhydrides could be an effective platform for nanomedicine.With the success of the Gliadelposition . Like otposition . Polyanhposition . Howeverposition . Additioposition . Neverthposition . While fPoly (lactic-co-glycolic acid) (PLGA) is an FDA and European Medicine Agency (EMA)-approved biodegradable anionic polymer that is widely used to encapsulate chemotherapy drugs, anti-inflammatory drugs, antibiotics, and proteins for the treatment of a variety of conditions ,22. In aPLGA NPs are degraded into lactate and glycolate, compounds that can be further metabolized through the Krebs cycle . The ovePoly (β-amino ester) (PBAE) is an easily synthesized, biodegradable, and biocompatible cationic polymer commonly used to construct NPs that can deliver polynucleotides and other acid-labile compounds . PBAE NPChitosan is a biodegradable polymer created by deacetylation of the widely abundant, naturally occurring polymer chitin . Given iChitosan can also be used as a polymer coating and in hybrid NP carriers. In vitro and in vivo studies have demonstrated the potential for these NP drug delivery systems for GBM. Shevtsov et al. reported that hybrid chitosan-dextran superparamagnetic NPs demonstrated enhanced internalization in U87 and C6 glioma cells compared to those coated with dextran alone, and further demonstrated accumulation of these particles in orthotopic C6 gliomas in rats . SuccessPoly(amidoamine) (PAMAM) dendrimers are flexible, non-toxic, and biocompatible branched NPs that were first synthesized in 1985 . The strThe cationic nature of PAMAMs, coupled with their large hydrophilic surface area, has made them of particular interest in drug delivery . Sarin ePoly(caprolactone) (PCL) is a biodegradable and non-toxic polymer characterized as a semi-crystalline aliphatic polyester that is obtained from a monomer ε-caprolactone ring opening . PCL is PCL is a highly stable polymer, due in part to its strong hydrophobicity and crystallinity , that rePoly (PACA) NPs are typically made from alkyl cyanoacrylate monomers and their mixtures through a one-step mini-emulsion process that results in varying levels of PACA particle degradability . ParticlPolyethylene glycol (PEG) is a hydrophilic polymer that can be covalently attached to NPs and other therapeutics to increase their systemic circulation time . PEG is 7K(R2)2, a pH responsive peptide, to the surface of PLGA-based, PEGylated NPs in order to enhance targeting of malignant glioma cells in vivo [7K(R2)2, remained unexposed under physiological conditions due to hydrophobic interactions between PLGA and the H7 residues, the acidic tumor environment protonated the imidazole ring of H7, thus making the H7K(R2)2 more hydrophilic and selectively exposing the cell-penetrating ligand to glioma cells [The extracellular pH in solid tumors is more acidic compared to normal tissue . Normal  in vivo . While Hma cells . Similarma cells ,78. Addima cells . LaboratWhile NPs are 10–1000 nm in diameter by definition, the optimal NP size for clinical brain tumor therapy remains unclear for a variety of reasons. Size plays a key role in NP stability, ability to pass through the BBB/BBTB and spread throughout the brain parenchyma, and likelihood of being endocytosed for cell-mediated delivery ,71. SystNP size also impacts their ability to spread throughout the brain parenchyma, thus affecting therapeutic delivery to tumor regions after crossing the BBB . SimilarPolymeric NPs can be engineered in a variety of shapes, though spherical particles are the most studied form. Shape has been shown to influence NP pharmacokinetics, cellular uptake, and BBB penetration ,87. SpheDelivering NPs to the brain for tumor therapy remains a significant challenge due to the BBB. In order to cross the BBB, NPs can be engineered to take advantage of transport processes such as adsorptive-mediated transcytosis (AMT), receptor-mediated transcytosis (RMT), and cell-based delivery (described in the Mechanisms of Delivery section below) . AMT invSome receptors, like TfR, are also overexpressed on GBM cells and may be suitable targets for enhancing delivery of NPs through both the BBB and ultimately to brain tumor tissue . TfR is Various groups have investigated targeting the insulin receptor, which is expressed on BBB endothelial cells, as well . A studyConjugating ligands capable of binding LDLR to NPs is another potential strategy for enhancing brain delivery  as this Melanotransferrin, or melanoma tumor antigen p97, binds to LDL receptor related protein 1 (LRP1) and is a type of iron-binding transferrin protein . Karkan CD98 is a transmembrane, glycoprotein heterodimer composed of CD98 heavy chain (CD98hc) and various CD98 light chains  and is eVascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and promotes angiogenesis. It is expressed by various cell types, including endothelial cells and several types of tumor cells . While VBevacizumab is a monoclonal antibody against VEGF that has been approved by the FDA for GBM patients whose condition did not improve following treatment with TMZ, a staple chemotherapy drug for treating GBM . BevacizEpidermal growth factor receptor (EGFR) is one of four types of receptor tyrosine kinases within the ErbB protein family and is overexpressed in many cancers, including in 40–50% of patients with GBM ,121. SevNPs conjugated to EGFR-targeting antibodies or loaded with EGFR inhibitors have been increasingly studied in recent years  with theFocused ultrasound (FUS), is a promising technique that uses a minimally invasive approach to treat a variety of diseases, including those related to the brain . FUS hasThe BBB, which is primarily formed by capillary endothelial cells, astrocyte end-feet, and pericytes, serves as a biological barrier that only allows channel-mediated and small molecules to pass through, under normal conditions. While the BBB primarily functions to protect the brain, it also restricts the types of drugs that can reach the brain. In combination with the use of microbubbles, which are similar to red blood cells in size at ~10 μm in diameter , FUS impSeveral studies in recent years have investigated the use of FUS for polymeric NP delivery across the BBB. Yang et al. recently reported successful delivery of lipid-polymer hybrid NPs loaded with clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) plasmids targeting a temozolomide drug-resistance gene to glioblastoma cells in vivo . They suThrough the combined use of FUS to generate oscillation openings and microbubbles—most commonly Optison, Definity, and Sonovue—to transport drugs, medications are more likely to reach their target sites in the brain and have increased efficacy . DespiteConvection-enhanced delivery (CED) was developed at the National Institutes of Health in the early 1990s as a way to bypass the BBB for localized drug delivery . CED invOne example illustrating the potential of CED in brain tumor nanomedicine investigated the delivery of PBAE NPs complexed with DNA plasmids coding for the luciferase protein (for fluorescent tracking) and p53 tumor suppressor protein to the brain parenchyma in tumor-bearing rats . MastoraThe nose-to-brain technique offers a minimally invasive and relatively convenient option for NP delivery . Drugs dStudies have shown modified NPs are capable of protecting their contents from enzymatic degradation and clearance via nasal cilia . While mHydrogels are three-dimensional, hydrophilic gel polymer networks that provide the benefits of minimal toxicity, localized and stimuli-responsive drug delivery, and passively controlled drug release . These sThe combined use of NPs and hydrogels has emerged as a potentially powerful tool for improving brain tumor therapy through safe and localized delivery of hydrophobic drugs. Using this combination strategy, drugs can be injected intratumorally or implanted following surgical resection . Still, NPs can be internalized by monocytes, neutrophils, and stem cells for delivery to brain tumor tissue. The utilization of immune cells such as monocytes and neutrophils as vectors for NP delivery is especially appealing as these cells readily cross the BBB to sites of injury, inflammation, and tumor growth . This ceThe potential for cell-based delivery of NPs in brain tumor therapy has been increasingly studied in recent years. In 2020, Ibarra et al. reported the efficient delivery of monocytes loaded with conjugated polymer NPs to GBM spheroids and an orthotopic mouse model . In anotMesenchymal stem cells (MSCs) have also been increasingly studied as potential vectors for glioma treatment, as they are hypoimmunogenic and known to migrate toward tumor cells . In a prThe increasing number of encouraging findings from preclinical studies suggests polymeric NPs may ultimately serve as one of the next great innovations in clinical CNS cancer therapy. Nevertheless, questions regarding their ideal size, surface characteristics, loaded contents, and mechanism of delivery remain, which continues to limit their translation to clinical practice. NP-based systems continue to encounter roadblocks such as low delivery to brain tissue due to mononuclear phagocyte-mediated clearance, despite the widespread adoption of modifications like PEGylation to reduce this barrier . FindingThe most effective NP formulations for treating CNS malignancies may include hybrid systems, such as those combining gold NPs coated with PEG for improved magnetic resonance imaging of brain tumor periphery . SimilarIntravenous injection is the least invasive method for NP-based therapies and minimizes risk of complications such as infection and compromised BBB integrity. However, concerns of limited delivery across the BBB and BBTB, as well as systemic toxicity, remain. Much of the recent CNS-targeted NP literature investigates alternative delivery mechanisms like nose-to-brain, FUS, CED, hydrogels or nanogels, and cell-based delivery to overcome these challenges. Of course, these approaches must continue to be studied to ensure their safe use and effectiveness in clinical practice. Nevertheless, these delivery techniques are proving to be a powerful tool for nanotherapeutics. Bringing an effective polymeric NP-based therapy to CNS malignancies will require carefully constructed polymers loaded with biotherapeutics that can selectively target tumor cells while minimizing toxicity to healthy brain tissue and other organs.While numerous studies utilizing polymer-based NPs for brain tumor therapy have reported promising findings, few approaches have made it to clinical trial, and none have proven to be effective replacements or additions to the current therapeutic regimens. Pitfalls, including low therapeutic delivery and inconsistent study results, must be overcome if polymeric NP-based therapeutics are to be leveraged in the treatment of brain cancer. While PLGA is the most widely-used polymeric platform in studies of nanocarrier application to the treatment of neurological disease, there is no consensus on the most effective polymer for use in brain cancer treatment, as their variable composition influences the specific targeting ligands, contents, mechanisms of delivery, tumor characteristics, and other factors selected for each study. Furthermore, the ideal NP size and shape is dependent on those same factors and similar studies have reported variable findings in BBB and tumor localization. The differences in physiology and permeability in various in vivo and in vitro models compared to humans has been documented and likely also contributes to the challenges in standardization of effective polymeric NP characteristics. While further investigation is warranted, polymeric NPs remain a promising therapeutic method. Ongoing clinical trials and future studies will hopefully shed more light on the optimal polymeric NP composition for managing brain cancer.


Antidepressants are the most prescribed medications in the United States, and the most frequently prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs) followed by serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), serotonin antagonist and reuptake inhibitors (SARIs), and norepinephrine-dopamine reuptake inhibitors (NDRI). On the other hand, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are the most prescribed lipid-lowering medications, and because the majority of patients with cardiovascular disease (CVD) have depressive symptoms, it is essential to understand the possible drug-drug interactions these two classes of medications can have, their potential synergistic mechanisms, and possible risks. In our research, we tried to understand the facts and uncover any missing links regarding the potential risks and benefits of statins and antidepressant co-prescription in the current clinical scenario. We reviewed all the relevant information from inception up to October 2022 regarding the antidepressant and statin polypharmacy. The databases we used were PubMed and PubMed Central, and the 11 keywords were "statins," "SSRI," "SNRI," "selective serotonin reuptake inhibitors," "serotonin-norepinephrine reuptake inhibitors," "antidepressants," "HMG-CoA reductase inhibitors," "tricyclic antidepressants," "monoamine oxidase inhibitors," "serotonin antagonist and reuptake inhibitors," and "norepinephrine-dopamine reuptake inhibitors." We carefully screened each of the relevant articles, including animal and human studies. In our study, we concluded that co-prescription of statins and SSRIs/SNRIs was generally safe and should be encouraged due to the potential synergistic nature of their effects in patients with CVD and major depression, and caution is advised with all other classes of antidepressants. We would like to encourage the undertaking of large-scale observational studies and proactive postmarketing surveillance to improve our knowledge regarding this topic considering the immense clinical importance it holds by directly and indirectly affecting half the population worldwide. Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors and the most commonly used lipid-lowering drug around the world . We knowAt any one point in time, it may be estimated that more than 10% of the population of the United States may be concurrently taking an antidepressant and statin. While most of the patients are prescribed SSRI/SNRI for depressive symptoms, patients who are on statins may be concurrently taking tricyclic antidepressants (TCAs) and/or other classes of antidepressants for various other indications such as pain syndromes. Therefore, it is essential to gain a better understanding of the potential drug-drug interactions with statin and antidepressant co-prescription.Our research focuses on the potential synergistic mechanisms between statins and antidepressants such as SSRIs and SNRIs, potential drug-drug interactions, and adverse effects. The relevant data for our review was gathered from the PubMed and PubMed Central databases. We utilized 11 keywords, which are "statins," "SNRI," "SSRI," "HMG-CoA reductase inhibitors," "selective serotonin reuptake inhibitors," "serotonin-norepinephrine reuptake inhibitors," "antidepressants," "tricyclic antidepressants," "monoamine oxidase inhibitors," "serotonin antagonist and reuptake inhibitors," and "norepinephrine-dopamine reuptake inhibitors," and the search was performed using Medical Subject Headings (MeSH) strategy. We have carefully screened and included all the relevant articles we could find since inception till October 10, 2022. All data is sourced from PubMed and PubMed Central.A brief note on the association between cardiovascular disease and major depressionOver the next few decades, heart disease will continue to be the single biggest cause of death on the planet and the majority of patients with heart disease are known to have comorbid depression, while it is also well-established that major depression/major depressive disorder (MD/MDD) alone is an immense factor leading to long-term disability worldwide -6. The rFurthermore, it is important to remember that metabolic syndrome (MetS) affects almost 25% of the population worldwide, and 60%-65% of the patients with mental health disorders die from causes linked to CVD, which are frequently comorbid with MetS .Patients with comorbid CVD with psychological disorders have a three times lower rate of medication compliance in comparison to patients with healthy social support systems. They also have a higher risk of new-onset diabetes, malnutrition, tobacco abuse, morbid obesity, alcohol use disorder, sleep abnormalities, substance abuse, higher incidence of hospitalizations, and increased risk of all-cause mortality ,9,11,12.On a national level, we can see that in the United States, almost nine million people are currently affected by heart failure (HF) with a 50% risk of mortality over the next five to six years, and more than four and half million of them have comorbid depression ,11. The Looking at the economic point of view, in the United States, more than $1 trillion has been spent over the last two decades on the medical costs related to CHF alone, with a further 30%-40% greater expenditure for patients with associated mental health disorders ,12. It iStatins, SSRIs, and SNRIs: properties and mechanismsWe shall first discuss the basics of statin pharmacotherapy followed by SSRI and SNRI pharmacotherapy.Statins are HMG-CoA reductase inhibitors and the most commonly prescribed medications in patients with CVD due to their effectiveness in lowering blood lipid levels . StatinsStatins in widely known the be safe in combination with SSRIs and have no or minimal drug-drug interactions . It is aThe effects of SSRIs inhibition on platelet activity, stabilization of the vascular endothelium, and reduction in the levels of circulating inflammatory markers directly counteract effects such as higher platelet activation observed in major depression ,18. SSRISNRIs have dual serotonergic and noradrenergic activity . SNRIs aWe should recall that the level of pro-inflammatory cytokines is predictive for the development of major depression in patients post-ACS and statins have significant attenuating effects on the inflammatory cytokines decreasing the risk of incidence for major depression . StatinsClinical trials based on patients with moderate-to-severe depression while being treated with citalopram or fluoxetine with adjuvant statin therapy showed that atorvastatin, lovastatin, and simvastatin showed improvement in depressive symptoms . At a onThe overall risk of depression was decreased by 80% in patients post-MI with statin therapy . The preBesides statins, various drugs such as aspirin, metformin, angiotensin-converting enzyme inhibitors, and angiotensin II receptor inhibitors have also exhibited antidepressant effects , whereasTCAs and statinsTCAs were available on the market since the late 1950s for the treatment of MDD . TCAs stTCAs act through five different neurotransmitter pathways. The primary mechanism for their antidepressant actions is by blocking the reuptake of serotonin and norepinephrine. Similar to SSRIs and SNRIs, they act as competitive antagonists on the postsynaptic alpha cholinergic receptors, muscarinic receptors, and histaminergic receptors .The TCAs that are approved for the treatment of MDD include amitriptyline, nortriptyline, protriptyline, amoxapine, doxepin, desipramine, imipramine, and trimipramine . TCAs arTCAs can cause significant adverse effects of their anticholinergic properties . TCAs anThe majority of antidepressant drugs are eliminated via kidneys after metabolism in the liver; hence, liver disease may lead to dangerous levels of antidepressants building up in the body . Due to The most important side effects of statins are an asymptomatic increase in liver transaminases and myopathy . ElevatiTCAs are notoriously known for their cardiovascular adverse effects, importantly arrhythmias, due to QTc prolongation, ventricular fibrillation, and sudden cardiac death (SCD) . A perioAcute hepatitis is rare but can be induced by various TCAS, but cross-hepatotoxicity is not commonly seen between agents . TCAs arSerotonin antagonists and reuptake inhibitors and statinsThe serotonin antagonist and reuptake inhibitors (SARIs) approved for clinical use are etoperidone, lorpiprazole, mepiprazole, nefazodone, trazodone, vilazodone, vortioxetine, niaprazine, and medifoxamine . NefazodThere is limited availability of information regarding the interactions between SARIs and statins, even though the general mechanisms of action are nonoverlapping as in the case of most of the SARIs and statins. Further research should be conducted to gauge the risks and benefits as the prevalence of co-prescription of these two classes of medication is increasing significantly day by day.Norepinephrine-dopamine reuptake inhibitors and statinsBupropion is the only norepinephrine-dopamine reuptake inhibitor (NDRI) currently used in the treatment of depression, and it is a moderate inhibitor of CYP2D6 and must also be used with caution with statins .Considering drugs related to P-glycoprotein (gp) transporter interactions could potentially occur with statin substrates of P-gp with antidepressants substrates or inhibitors of the transporter, resulting in an increase in drug concentrations, which needs to be studied in depth in the future .Monoamine oxidase inhibitors and statinsMonoamine oxidase inhibitors (MAOIs), including nonselective MAOIs such as phenelzine, isocarboxazid, and tranylcypromine; selective type B MAO inhibitors such as selegiline; and reversible type A MAO inhibitors such as moclobemide are not prescribed as often as the other antidepressants due to apprehension regarding side effects and MAOI diet .The common side effects include orthostatic hypotension, nausea, dizziness, drowsiness, and insomnia . Other sEven in light of the lower frequency of their prescriptions, MAOIs are still utilized in the treatment of patients with atypical or treatment-resistant depression .Therefore, we must be cautious of the potential risk of adverse effects due to co-prescription, especially musculoskeletal and hepatotoxic adverse effects.Possible risks and benefits of concomitant treatment with statins and antidepressantsWe know that one-third of the patients with CAD are prescribed either SSRIs or SNRIs as antidepressant medications . The resThe occurrence of drug-drug interactions between statins and antidepressants is rare, as statins are highly selective inhibitors of HMG-CoA reductase and have no significant effects on other enzymes or direct effects on serotonin and noradrenaline receptors .But it is clinically known that the antidepressant effects of statins are indirectly linked to serotonergic system modulation, which is why they act synergistically with SSRIs and SNRIs . It is pSSRIs are known to substantially improve the patient's mood post-MI and also have a relatively benign cardiac side effect profile without any significant adverse effects on heart rate (HR), blood pressure (BP), or left ventricular ejection fraction (LVEF) . The mosNumerous studies based on various antidepressants such as mirtazapine, reboxetine, citalopram, escitalopram, venlafaxine, nefazodone, paroxetine, fluoxetine, and fluvoxamine focused on the drug-drug interaction and plasma level of statins based on the effects on cytochrome system, corroborating the general safety profile of statins as add-on therapy to antidepressants . ElderlySome incidents of rhabdomyolysis with pravastatin treatment in patients with MDD have been rarely reported . Co-presOur research shows that statins and antidepressants such as SSRIs and SNRIs are generally safe in combination and can be quite useful for patients with comorbid conditions such as CVD, MDD, and MetS due to the various synergistic mechanisms of action. Lower rates of depression and higher remission rates are seen in clinical practice when patients with depressive symptoms post-cardiac events are on statins and antidepressants compared to patients prescribed monotherapy of either class of medications. Out of all the SSRIs, sertraline seems to be the safest drug of choice due to its minimal effect on cardiovascular conduction and safety profile in overdose. In general, there are very few drug-drug interactions between the two classes of medications, and regular monitoring for side effects or adverse drug reactions in patients with co-prescription of statins and antidepressants such as SSRIs and SNRIs is not necessary except in potential high-risk individuals at the discretion of the physician. TCAs, MAOIs, SARIs, and drugs such as Bupropion are also generally safe when taken along with statins even though there are rare incidences of musculoskeletal and hepatic adverse effects. In general, statins seem to be quite safe and effective when co-prescribed with all the major classes of antidepressants. We encourage further studies such as large-scale observational studies and proactive postmarketing surveillance regarding this topic as it is of immense clinical importance by directly or indirectly affecting the lives of half of the population worldwide.


More and more strains of cyanobacteria are identified that show great promise as cell platforms for the generation of bioproducts. However, strain development is still required to optimize their biosynthesis and increase titers for industrial applications. This review describes the most well-known, newest and most promising strains available to the community and gives an overview of current cyanobacterial biotechnology and the latest innovative strategies used for engineering cyanobacteria. We summarize advanced synthetic biology tools for modulating gene expression and their use in metabolic pathway engineering to increase the production of value-added compounds, such as terpenoids, fatty acids and sugars, to provide a go-to source for scientists starting research in cyanobacterial metabolic engineering.Cyanobacteria are photosynthetic microorganisms capable of using solar energy to convert CO Re. ReArthrfections  67]. Fu. FuArthrminophen  68]. Th. ThArthrFremyella diplosiphon is a freshwater cyanobacterium isolated from a Connecticut lake in 1952, which possesses one of the largest genomes amongst bacteria  and most abundant photosynthetic organism in the ocean . . cpcG2 n Pcpc560 . T7 RNA  Pcpc560 , Syn7942 Pcpc560  and Syn2 Pcpc560  for stroE. coli under anaerobic conditions . A. A230]. −1 of culture  from mouse, jojoba and Arabidopsis, leading to a low initial product titer of around 10 µg L−1 [Liu et al. engineered Syn6803 to produce and secrete fatty acids to circumvent the biomass separation and extracting steps needed in other cases, producing a majority of 43% of C16:0 and a secretion yield of 197 mg L culture  , C18:3, production in Syn7942 via the introduction of two desaturases, deletion of bacteria , which e profile . Thus, tvipp1. The latter manipulation increases the formation of thylakoid membrane to which the desaturase reactions are localized [More recently, a higher amount of polyunsaturated fatty acids (PUFA) was produced in two engineered cyanobacteria strains: Lep0902, known to naturally produce a high amount of FA and Syn7002. Both strains produced ALA, but also stearidonic acid (SDA), C18:4 and eicosatetraenoic acid, C20:4, up to 40% of total FAs . To achiocalized .Despite these advancements, maximal titers of various fatty acids are typically 10–50 times lower than those obtained with heterotrophs , a limitCyanobacteria naturally keep a high carbohydrate content as part of their osmotic regulatory system and accumulate them under stress conditions. Engineering high carbohydrate-producing strains has, therefore, the potential for enhancement via metabolic engineering. The primary use for high carbohydrate-producing cyanobacteria strains is as feedstock for growing industrially relevant microorganisms .cscB and knocked out invertase and an ADP-glucose pyro-phosphorylase [−1 h−1. The same phenotype was created in the UTEX 2973 strain  and a maltooligosyl trehalose trehalo-hydrolase (MTH). They also expressed the insect trehalose transporter 1 TRET1 to secrete the sugar and engineered the glycogen metabolism to reach a titer of 5.7 g L−1  [−1 of secreted EPS  as ingredients for the cosmetics and food industry as adjuvants and texture modifiers. With that aim in mind, Arias and Uggetti fully characterized a polysaccharide produced by healing) ,241 and eted EPS .Although not inherently highly valuable, cyanobacterial carbohydrate production has clear potential for various industrial applications, both for biofuel production and as a cosmetic ingredient and pharmaceutical additive production.Unicellular, photosynthetic organisms are in the spotlight of microbial terpenoid production because these organisms possess traits that might benefit terpenoid production. Cyanobacteria synthesize terpenoids via the MEP pathway, of which a complete set of homologous genes has been identified. The flux through the terpenoid synthesis pathways is assumed to be higher, as in heterotrophs, because of the demand for chlorophyll and carotenoids to sustain photosynthesis and combat oxidative stress. Microalgae deliver the reducing equivalents strongly demanded by terpenoid production via photosynthesis while having a simpler cellular architecture and being more straightforwardly genetically manipulated than higher plants . Despite−1 of isoprene within three weeks in Syn7942 through upregulation of the native methylerythritol 4-phosphate (MEP) pathway . However, single overexpression of ispG did not result in higher isoprene production. Likely, the HMBPP synthase activity is not the primary limiting step of the Synechococcus MEP pathway and this strategy only becomes effective when other flux-constraining enzyme activities are upregulated [Following these results, Englund et al.  observedegulated . Productegulated ,253,261.cpcB. In the engineered strain, the abundance of the synthase was significantly increased and, in combination with the expression of a heterologous isopentenyl isomerase, resulted in a 62-fold improvement of the isoprene titer [Chaves and Melis addressed low productivity by fusing the isoprene synthase characterized by low catalytic efficiency to the β-subunit of the highly expressed photosynthesis pigment phycocyanin encoded by ne titer . The grone titer .Besides the canonical MEP Pathway, cyanobacteria are assumed to operate a shunt that channels intermediates of the pentose phosphate pathway into the lower MEP pathway under phototrophic conditions . This hyrpi and rpe, which pushed the limonene titers to more than 6 mg L−1 when combined with the simultaneous upregulation of geranyl pyrophosphate synthase (GPPS) activity. It remains to be elucidated if this increase is caused by a higher flux through the proposed PPP-MEP shunt (This shunt might fuel the MEP pathway with intermediates from the pentose phosphate pathway (PPP), thereby bypassing the rate-limiting Dxs step and may have contributed to the increased limonene synthesis observed in Lin et al. . The autEP shunt .E. coli, the recombinant expression of a mevalonate pathway likewise resulted in increased terpenoid production [As described above for oduction .Bacterial nano-compartments (BNC) are intracellular structures composed of a selective proteinaceous scaffold that enclose a segment of a metabolic pathway . SimilarExploring and gaining knowledge about cyanobacterial nano-compartments and their roles, is an interesting avenue for enhancing stress resistance and engineering novel metabolic pathways in nano-compartments.2 to obtain the highest possible activity of the RuBisCO enzyme, which is essential for carbon fixation [One of the most commonly studied cyanobacterial nano-compartments are carboxysomes. Caroboxysomes were discovered in cyanobacteria in 1956 by Drew and Niklowitz; these protein compartments concentrate the COfixation . Plant sfixation . Deliverfixation ,267.E. coli using 19 genes split onto two synthetic plasmids [Stable integration of carboxysomes genes in the chloroplast is notoriously quite challenging . Fang etplasmids . Carboxyplasmids .Besides carboxysomes, other nano-compartments exist in prokaryotic organisms, such as encapsulins . Many diS. cerevisiae.The direct use of cyanobacteria as feedstock involves mixing the cells with other microorganisms, allowing them to either feed on the biomass and/or ferment the carbohydrates. Another strategy is integrating both cultures into a synthetic ecosystem to achieve production of the final compound of interest. Ideally the organisms of such a consortium would interact with and be mutually dependent on each other. Such a symbiotic culture could, for instance, be realized using cyanobacteria as the photosynthetic producer of carbon food sources used by an established industrial biotechnology workhorse such as Bacillus, E. coli and Saccharomyces strains. The stability of each consortium over extended periods was assessed, as well as their response to various stresses and, finally, their ability to produce alpha-amylase and PHB. Challenges encountered were that heterotrophs needed a higher amount of sucrose than what was produced by the cyanobacteria to sustain growth after 24 h and the fact that a high optical density (OD) of cyanobacteria led to inhibition of the heterotrophs independently from the level of sucrose [Recent work has explored the use of cyanobacteria in fully characterized synthetic consortia of microorganisms symbiotically interacting to produce various compounds of interest, including the biopolymer polyhydroxy-butyrate (PHB) alpha-amylase  and has  sucrose . Potenti sucrose , which ccscB, of E. coli) and the carotenogenic yeast Rhodotorula glutinis was able to achieve a higher rate of linoleic acid and palmitoleic acids compared to the yeast alone. Similarly, a positive impact of the heterotroph on the cyanobacteria growth was noticed [In another consortium involving a sucrose-producing cyanobacterium and three yeast strains, a similar issue of growth inhibition due to the presence of reactive oxygen species (ROS) was observed and alleviated by using a catalase enzyme . The co- noticed .Other systems have been studied involving a semi-controlled ecosystem growing cyanobacteria on wastewater, leading to high production of the biopolymer poly-hydroxy-alkanoate (PHA), a natural product made by some cyanobacteria when under stress, reviewed by Arias and Uggetti .Although this consortium approach appears as a seducing alternative offering a sustainable and integrated system, harnessing various microorganisms’ strengths and combining them needs careful optimization. Optimizing such complex systems will probably require advanced metabolic engineering to design perfect partnerships. The potential for a photoproduction system involving cyanobacteria associated with one or multiple heterotroph microorganisms is vast and ecosystem engineering could allow tuning and controlling metabolite production at another level. Nevertheless, studies exploring the potential of these ecosystem approaches highlighted that, rather than focusing purely on metabolic engineering, product yield can also significantly be optimized by intentionally applying stress or other external factors; sometimes aiming for slowing growth purposefully or tuning down the expression to balance metabolic activities can lead to the best production.This review covered the current state of cyanobacterial biotechnology, including cyanobacteria with industrially relevant traits, the synthetic biology tools available to control gene expression and a description of several metabolic engineering approaches applied for photosynthetic bioproduction.E. coli, to improve understanding of cyanobacterial metabolism and physiology and to develop advanced photobioreactors, these capabilities will enable the full potential of cyanobacteria and sustainable and photosynthetic bioproduction to be realized.We anticipate that more synthetic biology tools for the efficient development of cyanobacterial cell factories will be rapidly developed. Combined with large-scale efforts to generate genetic libraries (overexpression and deletion mutants), such as those available for


Pongo abelii, P. pygmaeus) to tease apart variation on the individual level from population-level and species-level differences. Our results showed that mothers not only differed in the composition of their infant-directed gestural repertoires, but also in communicative tactics, such as gestural redoings (i.e. persistence) and responsiveness to infants' requests. These differences remained after controlling for essential moderators, including species, setting, parity and infant age. Importantly, mothers differed in how they adjusted their behaviour across social contexts, making a strong case for investigating within-individual variation. Our findings highlight that partitioning behavioural variation into its within-individual, between-individual and environmental sources allows us to estimate the extent of plastic responses to the immediate environment in great ape communication.Between-individual variation in behavioural expression, such as social responsiveness, has been shown to have important eco-evolutionary consequences. However, most comparative research on non-human primate communication has focused on species- or population-level variation, while among- and within-individual variation has been largely ignored or considered as noise. Here, we apply a behavioural reaction norm framework to repeated observations of mother–offspring interactions in wild and zoo-housed orang-utans ( PrimateIndividual variation in the way primate mothers respond to their infants has been noted since the earliest detailed records of maternal behaviour –6. Even and individual variation in the degree of behavioural plasticity towards changing environmental conditions )In the light of what we already know about primate mother–offspring relationships, orang-utan mothers will likely adjust their communication according to infant age, their previous mothering experience and the specific behavioural context ,16,33–35sensu Hobaiter & Byrne )Since great apes’ communication is strongly tailored to the recipient, behavioural differences between individual infants will of course also contribute to the variation observed within orang-utan mothers . In othMacaca arctoides) showed that individual differences in maternal responsiveness to infant calls were related to variation in the tendency for infants to leave the mother [Another caveat of this study is that it did not include vocalizations, due to several methodological constraints, discussed in , hamperie mother . Moreovee mother . In any Pan paniscus) and chimpanzees (Pan troglodytes). While both species scored similarly on protectiveness, differences were found for distance and refusal behaviours. The authors argued that these interspecies differences in maternal styles mirror species-specific infant development, infant vulnerability to aggression and female sociality. However, this study did not investigate these behavioural correlations on the individual level . Studying whether communicative behaviours are structured into behavioural syndromes will be a fruitful avenue for further research, since it would allow getting better insight into the existence of maternal communication styles in great apes. Such evidence would matter for at least two important reasons. First, comparing correlated suites of communicative behaviours among individuals of different species living in the same setting (i.e. captivity) would be highly insightful for revealing the variation of reversible behavioural plasticity across species. Second, if communicative patterns are organized in behavioural syndromes, they are restricted in their potential to evolve independently [There are two central concepts in behavioural ecology research on individual differences that have not been analysed in the current study, mainly due to our relatively small sample size: predictability  and behendently , which aIn sum, with this study, we make a case for not only considering between-individual, but also within-individual variation in communicative behaviour. On the one hand, we demonstrated that there is significant between-individual variation in addition to the expected effects of orang-utan species, research setting and other external variables. On the other hand, orang-utan mothers demonstrated reversible plasticity  by differing in how they shift their behaviour across social contexts. Thus far, studies on primate communication analyse behaviour mainly on the population level, but communicative patterns detected in a population or social community may be driven by just a few specific individuals. Therefore, only by partitioning behavioural variation into its within- and between-individual as well as environmental components can we assess the role of plastic responses to the immediate environment in great ape communication and understand whether such behavioural flexibility has potential to evolve.


Thus, undertaking the needed research efforts to evaluate the effectiveness of promising REPAIR-themed candidates has the potential to enable near-term solutions for optimizing musculoskeletal injuries recovery, thereby addressing a top priority within the United States. Armed Forces. Herein, the REPAIR paradigm is presented, including example targets of opportunity as well as practical considerations for potential technical solutions for the translation of existing therapeutics into clinical practice for musculoskeletal injuries.Musculoskeletal injuries (MSKIs) are a great hindrance to the readiness of the United States Armed Forces through lost duty time and reduced operational capabilities. While most musculoskeletal injuries result in return-to-duty/activity with no  limitations, the healing process is often long. Long healing times coupled with the high frequency of musculoskeletal injuries make them a primary cause of lost/limited duty days. Thus, there exists an urgent, clinically unmet need for interventions to expedite tissue healing kinetics following musculoskeletal injuries to lessen their impact on military readiness and society as a whole. There exist several treatments with regulatory approval for other indications that have pro-regenerative/healing properties, but few have an approved indication for treating musculoskeletal injuries. With the immediate need for treatment options for musculoskeletal injuries, we propose a paradigm of Repurposing Existing Products to Accelerate Injury Recovery (REPAIR). Developing treatments  Combat- and non-combat related musculoskeletal injuries (MSKIs) are major causes of lost duty days within the United States Armed Forces. The amount of MSKI-related medically-restricted duty time is a significant impediment to the medical readiness of the United States Armed Forces. While combat-related MSKIs are often more severe, non-combat-related musculoskeletal injuries are more common and account for the majority of the lost duty time . MSKIs aOwing to the body’s endogenous capacity to repair some damaged tissues, the majority of MSKIs result in eventual return-to-duty/activity with no long-term limitations. This is especially true for those on the minor end of the severity spectrum. As such, traditional non-surgical treatment approaches for MSKIs focus on pain management, immobilization, managing inflammation, and physical rehabilitation . Even wide novo. However, given the current existence of a broad portfolio of interventions already under regulatory approval for other indications, there potentially exists an opportunity to leverage or repurpose existing clinically available agents for the accelerated healing of MSKIs to enable near-term, clinically meaningful improvements in the current standard of care, subsequent MSKI outcomes, and readiness of the United States Armed Forces. Notably, historic efforts which utilize a repurposed intervention are up to 10 times less expensive to bring to market and do so in about half the amount of time, compared to novel interventions  ventions . Thus, RIn the United States Armed Forces, the most common acute MSKIs are sprains/strains (48.5%), contusion/superficial injuries (13.9%), and fractures (10.5%) . Acute MOveruse MSKIs are four times more common than acute MSKIs in Service members and most commonly include stress fractures, tendinitis, bursitis, and fasciitis . These iAcute and overuse MSKIs present unique challenges that likely require different treatment modalities . A succeTo this end, performing research using the REPAIR paradigm has the potential to identify therapeutics that target endogenous musculoskeletal recovery mechanisms. By developing these candidates for specific MSKI indications, they can aid in the faster healing of injured tissue and a more timely return of function to pre-injury levels. Doing so would culminate in earlier return-to-duty/activity and mitigate re-injury risks, further reducing long term loss of duty.The following sections provide high-level overviews of some physiologic targets of opportunity for potential REPAIR candidates which may warrant consideration for further research investigations. Information is summarized in The reconstitution of damaged tissue to restore tissue mechanics, end organ function , and limb utility is the crux of MSKI recovery. Substantial anabolic activity is required to synthesize and arrange the biomolecules needed for this rebuilding effort. Thus, the targeted, well-controlled and timed boosting of anabolic pathways may be an opportunity to accelerate tissue repair and shorten MSKI recovery time . AdditioBlood flow is essential to provide oxygen, nutrients, and cells to tissue while also removing wastes. This is especially important for tissue repair, due to the high amount of cellular activity that occurs during this process. Injuries often hyper-neovascularizatize  within the affected tissue during the repair process, which then returns to pre-injury levels over the course of tissue remodeling . Rapid vde novo bone formation in both pre-clinical and clinical applications (Bone morphogenic proteins (BMPs) are a family of potent osteogenic activators that have been shown to facilitate ications . While Bications . Small mications , lovastaications , and simications . InvestmThere exist other therapeutic candidates with different mechanisms that may prove beneficial for treating MSKIs. For example a receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitor, Denosumab, can act as a potent osteoclastogenesis inhibitor and may increase bone formation following an MSKI . The emeWhile the sections above -term implications. MSKIs can increase the risk for a subsequent MSKI by seven times . A speci,. There is an unmet need for therapies that accelerate MSKI recovery time and mitigate MSKI recurrence risks. There are existing therapies for other indications that, pending beneficial efficacy data from needed research investigations, may fill this need. Notably, if/when forthcoming research data support its use, rather than the monumental investment of resources  needed to develop and evaluate an intervention de novo, the REPAIR paradigm described herein has the benefit of leveraging prior investments, often from the federal sector , such that research and design of potential MSKI specific indications would occur in a more cost and time effective manner. Thus, utilizing the REPAIR paradigm to leverage existing technologies for the development of treatments for common MSKIs could make more significant near-term progress at decreasing the present MSKI burden and increasing overall military readiness.MSKIs result in a significant burden on the United States Armed Forces in terms of both costs and lost duty time, and thus are a major impediment to readiness ,. There