Strategic development of aceclofenac loaded organosomes for topical application: An explorative ex-vivo and in-vivo investigation for arthritis.

Present study intends to develop aceclofenac-encapsulated organosomes (OS), which consist of phospholipids coupled with a combination of organic solvents, for the management of arthritis. The formulation was characterized and tested for efficacy using formalin-induced hyperalgesia, air pouch, and CFA-induced arthritic rat models. OS system exhibited spherical dimension, nanometric size with low PDI (278.3 ± 12.21 nm; 0.145), zeta potential (-24.56 ± 7.53 mV), drug entrapment (85.62 ± 7.2 %) and vesicles count (4.2x104 mm3). The gelled OS formulation demonstrated increased drug permeability and accumulation rate (51.77 ± 7.1 % and 396.19 ± 59.21 µg/cm2) compared to the MKT product (102.93 ± 13.78 µg/cm2 and 16.14 ± 4.3 %). Dermatokinetic assessments exhibited significantly higher drug levels in dermal layers compared to MKT product (p < 0.001), and CLSM studies further supported the OS system's deeper penetration. The results of arthritic index significantly better (9 times) in the OS-treated group than the MKT product. OS system treatment significantly reduced biochemicals and cytokines levels, such as CRP, ESR, TLC, lymphocytes, TNF-α, IL-6, and IL-1ß to levels of the control group (p < 0.001). Pseudoplastic behaviour of the developed product was indicated by the rheological results, and it also demonstrated biocompatibility through skin compliance studies. Based on the current findings, it appears that OS may be a better choice for managing arthritis and related inflammations.

Complete genome assembly of Candida auris representative strains of three geographical clades.

The complete genome assembly of Candida auris strains B11103, B11221, and B11244 is reported in this manuscript. These strains represent the three geographical clades, namely, South Asian (Clade I), South African (Clade III), and South American (Clade IV).

Tofacitinib in dermatology: a potential opportunity for topical applicability through novel drug-delivery systems.

Tofacitinib is a first-generation JAK inhibitor approved by the US FDA for treating rheumatoid arthritis. It exhibits a broad-spectrum inhibitory effect with abilities to block JAK-STAT signalling. The primary objective of this review is to obtain knowledge about cutting-edge methods for effectively treating a variety of skin problems by including tofacitinib into formulations that are based on nanocarriers. The review also highlights clinical trials and offers an update on published clinical patents. Nanocarriers provide superior performance compared to conventional treatments in terms of efficacy, stability, drug bioavailability, target selectivity and sustained drug release. Current review has the potential to make significant contributions to the ongoing discussion involving dermatological treatments and the prospective impact of nanotechnology on transforming healthcare within this field.

QbD-driven development of phospholipid-embedded lipidic nanocarriers of raloxifene: extensive in vitro and in vivo evaluation studies.

Raloxifene (RLX) is popularly indicated in treatment of osteoporosis and prevention of breast cancer. Owing to its poor aqueous solubility, high pre-systemic metabolism, intestinal glucuronidation, and P-glycoprotein (P-gp) efflux, however, it demonstrates low (< 2%) and inconsistent oral bioavailability. The current work, Quality by Design (QbD)-driven development of phospholipid-embedded nanostructured lipidic carriers (NLCs) of RLX, accordingly, was undertaken to potentiate its lymphatic uptake, augment oral bioavailability, and possibly reduce drug dosage. Factor screening and failure mode effect analysis (FMEA) studies were performed to delineate high-risk factors using solid lipid (glyceryl monostearate), liquid lipid (vitamin E), and surfactant (Tween 80). Response surface optimization studies were performed employing the Box-Behnken design. Mathematical and graphical methods were adopted to embark upon the selection of optimized NLCs with various critical quality attributes (CQAs) of mean particle size as 186 nm, zeta potential of - 23.6 mV, entrapment efficiency of 80.09%, and cumulative drug release at 12 h of 83.87%. The DSC and FTIR studies, conducted on optimized NLCs, indicated successful entrapment of drug into the lipid matrix. In vitro drug release studies demonstrated Fickian diffusion mechanism. In vivo pharmacokinetic studies in rats construed significant improvement in AUC0-72 h (4.48-folds) and in Cmax (5.11-folds), unequivocally indicating markedly superior (p < 0.001) oral bioavailability of RLX-NLCs vis-à-vis marketed tablet formulation. Subsequently, level "A" in vitro/in vivo correlation (IVIVC) was also successfully attempted between the percentages of in vitro drug dissolved and of in vivo drug absorbed at the matching time points. In vitro cytotoxicity and cellular uptake studies also corroborated higher efficacy and successful localization of coumarin-6-loaded NLCs into MG-63 cells through microfluidic channels.

A Novel Robust Method Mimicking Human Substratum To Dissect the Heterogeneity of Candida auris Biofilm Formation.

Candida auris is a pathogen of urgent threat level as marked by the CDC. The formation of biofilms is an essential property of this fungus to establish infection and escape drug treatment. However, our understanding of pathogenesis through biofilm is hampered by heterogeneity in C. auris biofilms observed in different studies. It is imperative to replicate in vivo conditions for studying C. auris biofilm formation in vitro. Different methods are standardized, but the surface used to form biofilms lacks consistency as well as the architecture of a typical biofilm. Here, we report an in vitro technique to grow C. auris biofilms on gelatin-coated coverslips. Interestingly, C. auris cells grown on gelatin-coated coverslips either on modified synthetic sweat media or RPMI 1640 resulted in similar multilayer biofilm formation with extracellular polymeric substances (EPS). This method is also consistent with the biofilm formation of other Candida species, such as Candida glabrata and Candida albicans. Biofilms of C. glabrata developed through this method show pseudohyphae and EPS. This method can be used to understand the molecular basis of biofilm formation, associated pathogenesis, and drug tolerance. The technique is cost-effective and would thus serve in rightful screening and repurposing drug libraries for designing new therapeutics against the less-studied high-alarm pathogen C. auris. IMPORTANCE Heterogeneity is seen when multidrug-resistant C. auris biofilm is cultured using different reported methods. Biofilm formed on the gelatin surface mimics the condition of a host environment that has multilayers and EPS. This method has feasibility for drug screening and analyzing biofilms through three-dimensional (3D) reconstruction. This in vitro biofilm formation technique is also exploited to study the formation of biofilm of other Candida species. The biofilms of C. glabrata and C. albicans can also be correctly mimicked using gelatin in the biofilm-forming environment. Thus, the novel in vitro method for biofilm formation reported here can be widely used to understand the mechanism of biofilm formation, related virulence properties, and drug tolerance of C. auris and other Candida species. This simple and low-cost technique is highly suitable for screening novel inhibitors and repurposed libraries and to design new therapeutics against Candida species.

Candida auris biofilm: a review on model to mechanism conservation.

INTRODUCTION: Candida auris is included in the fungal infection category 'critical' by WHO because of associated high drug tolerance and spread at an alarming rate which if remains untouched may result in serious outbreaks. Since its discovery in 2009, several assiduous efforts by mycologists across the world have deciphered its biology including growth physiology, drug tolerance, biofilm formation, etc. The differential response of various strains from different clades poses a hurdle in drawing a final conclusion. AREAS COVERED: This review provides brief insights into the understanding of C. auris biofilm. It includes information on various models developed to understand the biofilms and conservation of different signaling pathways. Significant development has been made in the recent past with the generation of relevant in vivo and ex vivo models. The role of signaling pathways in the development of biofilm is largely unknown. EXPERT OPINION: The selection of an appropriate model system is a must for the accuracy and reproducibility of results. The conservation of major signaling pathways in C. auris with respect to C. albicans and S. cerevisiae highlights that initial inputs acquired from orthologs will be valuable in getting insights into the mechanism of biofilm formation and associated pathogenesis.

Rapamycin and Torin2 inhibit Candida auris TOR: Insights through growth profiling, docking, and MD simulations.

The fungus Candida auris is a pathogen of utmost concern due to its rapid emergence across the globe, acquired antifungal drug tolerance, thermotolerance, and ability to survive in hospital settings and preserved foods. Recent incidences of comorbidity of corona patients with its infection in hospital settings highlighted the importance of understanding the pathobiology and drug tolerance of this fungus on priority. The Target of rapamycin (TOR) is a central regulator of growth across eukaryotes with an illustrated role in fungal pathology. The role of the TOR signalling pathway in the growth of C. auris is yet to be described. In-silico, analysis revealed the presence of highly conserved Tor kinase, components of TORC, and key downstream components in C. auris. Rapamycin and Torin2, the specific inhibitors of Tor reduce the growth of C. auris. An inhibition of Tor leads to cell cycle arrest at the G1 phase with a defect in cytokinesis. Interestingly, with an insignificant difference in growth at 30 and 37 °C, a sharp decline in growth is seen with Torin2 at 37 °C. The heterogeneous response emphasizes the importance of physiology-based differential cellular response at different temperatures. In addition, the inhibition of Tor suppresses the biofilm formation. In silico studies through docking and simulations showed rapamycin and torin2 as specific inhibitors of C. auris Tor kinase (CauTor kinase) and hence can be exploited for a thorough understanding of the TOR signalling pathway in pathobiology and drug tolerance of C. auris. HIGHLIGHTSConservation of TOR signalling pathway in Candida aurisRapamycin and torin2 are specific inhibitors of Cau TorUnderstanding of the role of TOR signalling pathway through the use of inhibitors rapamycin and torin2.Heterogenous response of C. auris to torin2 at different physiological conditions.Communicated by Ramaswamy H. Sarma.

Foam-Based Drug Delivery: A Newer Approach for Pharmaceutical Dosage Form.

Foam is a dispersal of gas in solid foam or liquid foam. Solid foams are generally formed through quick curing of liquid foams. Because of their positive characteristics, simplicity of application, and improved patient acceptability/compliance, foams are an appealing and promising delivery strategy for medical, cosmetic, and pharmaceutical, applications. Recent breakthroughs in topical foams for cosmetic and dermal applications are described here, as well as categorization based on foam formulation and recent assessment techniques of critical physical properties of the topical foam. Despite the expanding amount of knowledge on topical foams for cutaneous applications, the majority of research has focused on the stability and structure of foam in contact with solid nonporous surfaces. It is still difficult to figure out how such foams destabilize when they come into touch with porous surfaces like skin or skin-like membranes. The foam-covered wide surface area and easily applied to the affected area. This type of delivery system also eliminates the chance of secondary infection that is associated with ointment and creams, which need to be applied to the affected area with help of fingers or an applicator.

Cyclodextrin Derivative Enhances the Ophthalmic Delivery of Poorly Soluble Azithromycin.

Azithromycin (AZM), a macrolide antibiotic used for the treatment of chlamydial conjunctivitis, is less effective for the treatment of this disease due to its poor bioavailability (38%). Various alternatives have been developed for improving the physicochemical properties (i.e., solubility) of the AZM without much success. To overcome the problems associated with AZM, an inclusion complex employing a modified cyclodextrin, i.e., sulfobutylether-ß-cyclodextrin (SBE-ß-CD), was prepared and characterized by phase solubility studies and PXRD techniques. The results portrayed the formation of an inclusion complex of AZM with SBE-ß-CD in 1:2 molar stoichiometric ratios. This inclusion complex was later incorporated into a polymer matrix to prepare an in situ gel. Various combinations of Carbopol 934P and hydroxypropyl methylcellulose (HPMC K4M) polymers were used and evaluated by rheological and in vitro drug release studies. The optimized formulation (F4) containing Carbopol 934P (0.2% w/v) and HPMC K4M (0.2% w/v) was evaluated for clarity, pH, gelling capacity, drug content, rheological properties, in vitro drug release pattern, ocular irritation test, and antimicrobial efficacy. Finally, owing to the improved antimicrobial efficacy and increased residence time, the AZM:SBE-ß-CD in situ gel was found to be a promising formulation for the efficient treatment of bacterial ocular disease.

Hierarchical self-assembling and helical structure in focal conic domains in meniscus of ferroelectric liquid crystal.

We investigate experimentally the formation of focal conic domains of the ferroelectric phase of a liquid crystal, chiral smectic C (SmC^{*}), in the meniscus geometry. The meniscus geometry is formed in the gap between two glass plates which are placed on a common substrate. This gap is called here a physical cavity. Focal conic domains (FCDs) in the physical cavity with dimensions of micrometer scale are investigated under an optical polarizing microscope which enables us to extract the information on the helical structure formation in the constraint and gradient topological meniscus interface. The helical pitch in the FCD is observed to be shorter than in planar confined geometry. A crucial phenomenon of unwrapping and wrapping of helical structure from one FCD to another is also observed. In-plane application of an electric field on a FCD revealed the asymmetric helical unwinding process whereas an increase in temperature has shown symmetrical unwinding. The helical structure based observation is significant for understanding the ferroelectric phase in focal conic domains and their application in microlenses and optical components.

Post-transcriptional and translational control of the morphology and virulence in human fungal pathogens.

Host-pathogen interactions at the molecular level are the key to fungal pathogenesis. Fungal pathogens utilize several mechanisms such as adhesion, invasion, phenotype switching and metabolic adaptations, to survive in the host environment and respond. Post-transcriptional and translational regulations have emerged as key regulatory mechanisms ensuring the virulence and survival of fungal pathogens. Through these regulations, fungal pathogens effectively alter their protein pool, respond to various stress, and undergo morphogenesis, leading to efficient and comprehensive changes in fungal physiology. The regulation of virulence through post-transcriptional and translational regulatory mechanisms is mediated through mRNA elements (cis factors) or effector molecules (trans factors). The untranslated regions upstream and downstream of the mRNA, as well as various RNA-binding proteins involved in translation initiation or circularization of the mRNA, play pivotal roles in the regulation of morphology and virulence by influencing protein synthesis, protein isoforms, and mRNA stability. Therefore, post-transcriptional and translational mechanisms regulating the morphology, virulence and drug-resistance processes in fungal pathogens can be the target for new therapeutics. With improved "omics" technologies, these regulatory mechanisms are increasingly coming to the forefront of basic biology and drug discovery. This review aims to discuss various modes of post-transcriptional and translation regulations, and how these mechanisms exert influence in the virulence and morphogenesis of fungal pathogens.

eIF2α interactions with mRNA control accurate start codon selection by the translation preinitiation complex.

In translation initiation, AUG recognition triggers rearrangement of the 48S preinitiation complex (PIC) from an open conformation to a closed state with more tightly-bound Met-tRNAi. Cryo-EM structures have revealed interactions unique to the closed complex between arginines R55/R57 of eIF2α with mRNA, including the -3 nucleotide of the 'Kozak' context. We found that R55/R57 substitutions reduced recognition of a UUG start codon at HIS4 in Sui- cells (Ssu- phenotype); and in vitro, R55G-R57E accelerated dissociation of the eIF2·GTP·Met-tRNAi ternary complex (TC) from reconstituted PICs with a UUG start codon, indicating destabilization of the closed complex. R55/R57 substitutions also decreased usage of poor-context AUGs in SUI1 and GCN4 mRNAs in vivo. In contrast, eIF2α-R53 interacts with the rRNA backbone only in the open complex, and the R53E substitution enhanced initiation at a UUG codon (Sui- phenotype) and poor-context AUGs, while reducing the rate of TC loading (Gcd- phenotype) in vivo. Consistently, R53E slowed TC binding to the PIC while decreasing TC dissociation at UUG codons in vitro, indicating destabilization of the open complex. Thus, distinct interactions of eIF2α with rRNA or mRNA stabilize first the open, and then closed, conformation of the PIC to influence the accuracy of initiation in vivo.

Comparison and evaluation of single-use LMA supreme versus the reusable proseal LMA in paralyzed patients undergoing surgery with controlled ventilation.

BACKGROUND AND AIMS: The objective of this prospective randomized blinded study was to assess the safety and efficacy of the laryngeal mask airway (LMA) Supreme as compared with the LMA Proseal. MATERIAL AND METHODS: A total of 60 patients were randomised into two groups to either receive a Proseal LMA (PLMA) or Supreme LMA (SLMA) for airway management. The primary outcome was to measure oropharyngeal leak pressure (OLP) in both groups. The secondary outcomes were the measurement of insertion time, insertion success rate, fibreoptic grading, intracuff pressure, ease of ventilation, and airway pressure on standard ventilatory settings and postoperative complications. RESULTS: Intracuff pressure increase after 60 minutes of induction was significantly higher in the PLMA group (PLMA 97.43 ± 11.03 cm of H2O and SLMA 75.17 ± 8.95 cm of H2O). OLP was recorded after device insertion, after 30 min and after 60 min in each group and was found to be 28.71 ± 2.97, 30.93 ± 2.87, and 31.93 ± 2.72 cm of H2O in PLMA and 24.84 ± 2.08, 26.73 ± 2.26, and 27.95 ± 2.55 cm of H2O in SLMA group, respectively. The mean OLP with the SLMA was significantly (p=<.001) lower than PLMA. All the other parameters were comparable in both groups. CONCLUSION: PLMA is better than SLMA as airway device to ventilate at higher airway pressure in paralyzed adult patients. On the basis of our study, we recommend Proseal over Supreme LMA.

Comparative study of fiber-optic guided tracheal intubation through intubating laryngeal mask airway LMA Fastrach™ and i-gel in adult paralyzed patients.

BACKGROUND: The i-gel is a novel and innovative supraglottic airway management device used both as an airway rescue device and as a conduit for fiberoptic intubation. In this prospective randomized study, we compared fiberoptic-guided tracheal intubation through the i-gel and LMA Fastrach™ in adult paralyzed patients. MATERIALS AND METHODS: After ethical committee approval and written informed consent, 60 patients of either sex were randomly allocated to either group of supraglottic airway device (SGAD). After successful insertion of the SGAD, the fiberoptic bronchoscope (FOB)-guided tracheal intubation was done through the respective SGAD. The primary objectives were the ease and time taken for fiberoptic-guided intubation in either group. Secondary variables included time taken for successful placement of SGAD, ease of insertion of SGAD, airway seal pressure, ease and time of removal of SGAD, variation in hemodynamic parameters, and complications if any. RESULTS: Time taken for tracheal intubation in LMA Fastrach™ group was 69.53 ± 5.09 s and for the i-gel group it was 72.33 ± 6.73 s. It was seen that it was easy to insert the endotracheal tube (ETT) in 93.3% patients in the LMA Fastrach™ group and 96.7% patients in the i-gel group. Airway seal pressure was higher for the LMA Fastrach™ group. Both the SGADs were comparable in the number of attempts of insertion, ease of insertion, and insertion time. In addition, the hemodynamic variables noted did not show any increase after insertion of SGAD. There was no difficulty encountered in removal of either SGAD. CONCLUSION: I-gel may be a reliable and cost-effective alternative to LMA Fastrach™ for fibreoptic-guided tracheal intubation.

A network of eIF2ß interactions with eIF1 and Met-tRNAi promotes accurate start codon selection by the translation preinitiation complex.

In translation initiation, a 43S preinitiation complex (PIC) containing eIF1 and a ternary complex (TC) of GTP-bound eIF2 and Met-RNAi scans the mRNA for the start codon. AUG recognition triggers eIF1 release and rearrangement from an open PIC conformation to a closed state with more tightly-bound Met-tRNAi (PIN state). Cryo-EM models reveal eIF2ß contacts with eIF1 and Met-tRNAi exclusive to the open complex that should destabilize the closed state. eIF2ß or eIF1 substitutions disrupting these contacts increase initiation at UUG codons, and compound substitutions also derepress translation of GCN4, indicating slower TC recruitment. The latter substitutions slow TC loading while stabilizing TC binding at UUG codons in reconstituted PICs, indicating a destabilized open complex and shift to the closed/PIN state. An eIF1 substitution that should strengthen the eIF2ß:eIF1 interface has the opposite genetic and biochemical phenotypes. eIF2ß is also predicted to restrict Met-tRNAi movement into the closed/PIN state, and substitutions that should diminish this clash increase UUG initiation in vivo and stabilize Met-tRNAi binding at UUG codons in vitro with little effect on TC loading. Thus, eIF2ß anchors eIF1 and TC to the open complex, enhancing PIC assembly and scanning, while impeding rearrangement to the closed conformation at non-AUG codons.

Two dimensional allotropes of arsenene with a wide range of high and anisotropic carrier mobility.

Considering the rapid development of experimental techniques for fabricating 2D materials in recent years, various monolayers are expected to be experimentally realized in the near future. Motivated by the recent research activities focused on the honeycomb arsenene monolayers, the stability and carrier mobility of non-honeycomb and porous allotropic arsenene are determined using first principles calculations. In addition to five honeycomb structures of arsenene, a total of eight other structures are considered in this study. An extensive analysis comprising energetics, phonon spectra and mechanical properties confirms that these structures are energetically and dynamically stable. All these structures are semiconductors with a broad range of band gaps varying from ∼1 eV to ∼2.5 eV. Significantly, these monolayer allotropes possess anisotropic carrier mobilities as high as several hundred cm2 V-1 s-1 which is comparable with well-known 2D materials such as black phosphorene and monolayer MoS2. Combining such broad band gaps and superior carrier mobilities, these monolayer allotropes can be promising candidates for the superior performance of the next generation nanoscale devices. We further explore these monolayer allotropes for photocatalytic water splitting and find that arsenene monolayers have potential for usage in visible light driven photocatalytic water splitting.

eIF1 Loop 2 interactions with Met-tRNAi control the accuracy of start codon selection by the scanning preinitiation complex.

The eukaryotic 43S preinitiation complex (PIC), bearing initiator methionyl transfer RNA (Met-tRNAi) in a ternary complex (TC) with eukaryotic initiation factor 2 (eIF2)-GTP, scans the mRNA leader for an AUG codon in favorable context. AUG recognition evokes rearrangement from an open PIC conformation with TC in a "POUT" state to a closed conformation with TC more tightly bound in a "PIN" state. eIF1 binds to the 40S subunit and exerts a dual role of enhancing TC binding to the open PIC conformation while antagonizing the PIN state, necessitating eIF1 dissociation for start codon selection. Structures of reconstituted PICs reveal juxtaposition of eIF1 Loop 2 with the Met-tRNAi D loop in the PIN state and predict a distortion of Loop 2 from its conformation in the open complex to avoid a clash with Met-tRNAi We show that Ala substitutions in Loop 2 increase initiation at both near-cognate UUG codons and AUG codons in poor context. Consistently, the D71A-M74A double substitution stabilizes TC binding to 48S PICs reconstituted with mRNA harboring a UUG start codon, without affecting eIF1 affinity for 40S subunits. Relatively stronger effects were conferred by arginine substitutions; and no Loop 2 substitutions perturbed the rate of TC loading on scanning 40S subunits in vivo. Thus, Loop 2-D loop interactions specifically impede Met-tRNAi accommodation in the PIN state without influencing the POUT mode of TC binding; and Arg substitutions convert the Loop 2-tRNAi clash to an electrostatic attraction that stabilizes PIN and enhances selection of poor start codons in vivo.

Tunnelling characteristics of Stone-Wales defects in monolayers of Sn and group-V elements.

Topological defects in ultrathin layers are often formed during synthesis and processing, thereby strongly influencing the electronic properties of layered systems. For the monolayers of Sn and group-V elements, we report the results based on density functional theory determining the role of Stone-Wales (SW) defects in modifying their electronic properties. The calculated results find the electronic properties of the Sn monolayer to be strongly dependent on the concentration of SW defects, e.g. defective stanene has nearly zero band gap (≈0.03 eV) for the defect concentration of 2.2 × 1013 cm-2 which opens up to 0.2 eV for the defect concentration of 3.7 × 1013 cm-2. In contrast, SW defects appear to induce conduction states in the semiconducting monolayers of group-V elements. These conduction states act as channels for electron tunnelling, and the calculated tunnelling characteristics show the highest differential conductance for the negative bias with the asymmetric current-voltage characteristics. On the other hand, the highest differential conductance was found for the positive bias in stanene. Simulated STM topographical images of stanene and group-V monolayers show distinctly different features in terms of their cross-sectional views and distance-height profiles. These distinctive features can serve as fingerprints to identify the topological defects in experiments for the monolayers of group-IV and group-V elements.

Rps3/uS3 promotes mRNA binding at the 40S ribosome entry channel and stabilizes preinitiation complexes at start codons.

The eukaryotic 43S preinitiation complex (PIC) bearing Met-tRNAiMet in a ternary complex (TC) with eukaryotic initiation factor (eIF)2-GTP scans the mRNA leader for an AUG codon in favorable "Kozak" context. AUG recognition provokes rearrangement from an open PIC conformation with TC bound in a state not fully engaged with the P site ("POUT") to a closed, arrested conformation with TC tightly bound in the "PIN" state. Yeast ribosomal protein Rps3/uS3 resides in the mRNA entry channel of the 40S subunit and contacts mRNA via conserved residues whose functional importance was unknown. We show that substitutions of these residues reduce bulk translation initiation and diminish initiation at near-cognate UUG start codons in yeast mutants in which UUG selection is abnormally high. Two such substitutions-R116D and R117D-also increase discrimination against an AUG codon in suboptimal Kozak context. Consistently, the Arg116 and Arg117 substitutions destabilize TC binding to 48S PICs reconstituted in vitro with mRNA harboring a UUG start codon, indicating destabilization of the closed PIN state with a UUG-anticodon mismatch. Using model mRNAs lacking contacts with either the mRNA entry or exit channels of the 40S subunit, we demonstrate that Arg116/Arg117 are crucial for stabilizing PIC-mRNA contacts at the entry channel, augmenting the function of eIF3 at both entry and exit channels. The corresponding residues in bacterial uS3 promote the helicase activity of the elongating ribosome, suggesting that uS3 contacts with mRNA enhance multiple phases of translation across different domains of life.

Skull Base Surgery with Minimal Resources.

BACKGROUND: Skull base surgery needs advanced equipment and is performed at few public sector hospitals in India. For financial and infrastructure reasons, the facilities available are insufficient for the large number of poor patients who need this surgery. METHODS: Neurologically deteriorating poor patients who failed to receive skull base surgery at overloaded public sector hospitals underwent surgery with basic neurosurgical instruments, using the available resources and indigenously designed instruments adhering to the basic principles of skull base surgery. Various lesions operated on in the study were analyzed based on their location and surgical approach. RESULTS: Ninety-one skull base surgeries in 84 patients were performed during 2013-2015. There were 46 males and 38 females, with an average age of 35 years. Surgical treatment included surgery of the craniovertebral junction (n = 43) and lesions of the anterior skull base (n = 7), middle skull base (n = 10), and posterior skull base (n = 31). Lesions were operated on through anterior (n = 10), lateral (n = 14), and posterior and posterolateral (n = 67) skull base approaches. CONCLUSIONS: The facilities available in low-income countries such as India are insufficient to take care of poor patients who need skull base surgery. Indigenous innovations, use of the available resources, and interdisciplinary coordination help overcome the challenges of resource scarcity to a reasonable extent in many ill-equipped public sector hospitals for the safe and efficient management of many patients who need skull base surgery.