Impaired SHH responsiveness of induced pluripotent stem cell-derived floor plate cells carrying the LRRK2 I1371V mutation contributes to the ontogenic origin of lower dopaminergic-neuron yield.

Lower population of dopaminergic (DA)-neurons is known to increase susceptibility to PD, and our earlier study showed a lower yield of DA-neurons in LRRK2-I1371V mutation-carrying PD patient-iPSCs. While the role of SHH in DA-neurogenesis of Floor-Plate Cells (FPCs) is known, effect of LRRK2 mutations on SHH-responsiveness of FPCs impacting DA-neuronal yield has not been studied. We investigated SHH-responsiveness of FPCs derived from LRRK2-I1371V PD patient-derived iPSCs with regard to the expression of SHH receptors Patched1 (Ptch1) and Smoothened (Smo), in conjunction with nuclear Gli1 expression, intracellular Ca2+ rise, and cytosolic cAMP levels upon SHH induction. Additionally, we examined the mechanistic link with LRRK2-I1371V gain-of-function by assessing membrane-fluidity and Rab8A & Rab10 phosphorylation in SH-SY5Y cells and healthy control (HC)-FPCs overexpressing LRRK2-I1371V as well as FPCs. While total expression of Ptch1 and Smo was comparable, receptor expression on cell-surface was significantly lower in LRRK2-I1371V FPCs than in HC, with distinctly lower nuclear-expression of the downstream transcription factor Gli1. HC-FPCs transfected with LRRK2 I1371V exhibited a similarly reduced cell-surface expression of Ptch1 and Smo. Intracellular Ca2+ response was significantly lower with corresponding elevated cAMP levels in LRRK2-I1371V FPCs compared to HC upon SHH-stimulation. Both LRRK2-I1371V mutant FPCs and LRRK2-I1371V transfected SH-SY5Y and HC-FPCs further exhibited higher autophosphorylation of phospho LRRK2 (pLRRK2) serine1292 and serine935, as well as substrate phosphorylation of Rab8A & Rab10. Concurrent increase in membrane fluidity, accompanied by a decrease in membrane cholesterol, and lower expression of lipid raft marker Caveolin1 were also observed in them. These findings suggest that impaired SHH-responsiveness of LRRK2-I1371V PD FPCs indeed leads to lower yield of DA-neurons during ontogeny. Reduced cell-surface expression of SHH receptors is influenced by alteration in membrane fluidity owing to the increased substrate phosphorylation of Rab8A and reduced membrane protein trafficking due to pRab10, both results of the LRRK2-I1371V mutation.

Spectroscopic and imaging considerations of THz-TDS and ULF-Raman techniques towards practical security applications.

Nitrogen-containing high-energy organic compounds represent a class of materials with critical implications in various fields, including military, aerospace, and chemical industries. The precise characterization and analysis of these compounds are essential for both safety and performance considerations. Spectroscopic characterization in the far-infrared region has great potential for non-destructive investigation of high energetic and related compounds. This research article presents a comprehensive study of common organic energetic materials in the far-infrared region (5-200 cm-1), aiming to enhance security measures through the utilization of cutting-edge spectroscopic techniques. Broadband terahertz time-domain spectroscopy and ultra-low frequency Raman spectroscopy are employed as powerful tools to probe the vibrational and rotational modes of various explosive materials. One of the key objectives of this present work is unveiling the characteristic spectral features and optical parameters of five common nitrogen based high energy organic compounds towards rapid and accurate identification. Further, we have explored the potential of terahertz reflection imaging for non-contact through barrier sensing, a critical requirement in security applications. Based on the spectral features obtained from the spectroscopic studies and using advanced imaging algorithms we have been able to detect these compounds under various barriers including paper, cloth, backpack, etc. Subsequently, this study highlights the capabilities of the two techniques offering a pathway to enhance their utility over a wide range of practical security applications.

Multi-Functional Reconfigurable Intelligent Surfaces for Enhanced Sensing and Communication.

In this paper, we propose a reconfigurable intelligent surface (RIS) that can dynamically switch the transmission and reflection phase of incident electromagnetic waves in real time to realize the dual-beam or quad-beam and convert the polarization of the transmitted beam. Such surfaces can redirect a wireless signal at will to establish robust connectivity when the designated line-of-sight channel is disturbed, thereby enhancing the performance of wireless communication systems by creating an intelligent radio environment. When integrated with a sensing element, they are integral to performing joint detection and communication functions in future wireless sensor networks. In this work, we first analyze the scattering performance of a reconfigurable unit element and then design a RIS. The dynamic field scattering manipulation capability of the RIS is validated by full-wave electromagnetic simulations to realize six different functions. The scattering characteristics of the proposed unit element, which incorporates two p-i-n diodes have been substantiated through practical implementation. This involved the construction of a simple prototype and the subsequent examination of its scattering properties via the free-space measurement method. The obtained transmission and reflection coefficients from the measurements are in agreement with the anticipated outcomes from simulations.

Botulinum Toxin A Use in the Gastrointestinal Tract: A Reappraisal After Three Decades.

The discovery of botulinum toxin A (BTX)'s therapeutic properties has led to studies evaluating its usefulness in multiple medical disorders. Its use in the gastrointestinal (GI) tract has been studied for 30 years. Multiple databases, including PubMed, AccessMedicine, ClinicalKey, Cochrane Library, Embase, and Medline, were used to review research from case series to randomized controlled trials on BTX use in the GI tract. This article reviews the current literature on the efficacy of BTX and the strength of recommendations for or against its use in various disorders, including cricopharyngeal dysphagia, achalasia, nonachalasia motility disorders, gastroparesis, obesity, sphincter of Oddi disorders, chronic anal fissure, chronic idiopathic anal pain, and anismus. The appeal of BTX comes from its simplicity of administration, good safety profile, and reliability in decreasing muscular tone. However, there are several drawbacks that limit its use, including the lack of long-term efficacy and/or limited data in many GI disorders.

Coherent terahertz laser feedback interferometry for hydration sensing in leaves.

The response of terahertz to the presence of water content makes it an ideal analytical tool for hydration monitoring in agricultural applications. This study reports on the feasibility of terahertz sensing for monitoring the hydration level of freshly harvested leaves of Celtis sinensis by employing a imaging platform based on quantum cascade lasers and laser feedback interferometry. The imaging platform produces wide angle high resolution terahertz amplitude and phase images of the leaves at high frame rates allowing monitoring of dynamic water transport and other changes across the whole leaf. The complementary information in the resulting images was fed to a machine learning model aiming to predict relative water content from a single frame. The model was used to predict the change in hydration level over time. Results of the study suggest that the technique could have substantial potential in agricultural applications.

Antibody Polymer Conjugates (APCs) for Active Targeted Therapeutic Delivery.

Antibody drug conjugates (ADCs) are poised to have an enormous impact on targeted nanomedicine, especially in many cancer pathologies. The reach of the current format of ADCs is limited by their low drug-to-antibody ratio (DAR) because of the associated physiochemical instabilities. Here, we design antibody polymer conjugates (APCs) as a modular strategy to utilize polymers to address ADC's shortcomings. We show here that conjugation of polymer-based therapeutic molecules to antibodies helps increase the DAR, owing to the hydrophilic comonomer in the polymer that helps in masking the increased hydrophobicity caused by high drug loading. We show that the platform exhibits cell targetability and selective cell killing in multiple cell lines expressing disease-relevant antigens, viz., HER2 and EGFR. The ability to use different functionalities in the drug as the handle for polymer attachment further demonstrates the platform nature of APCs. The findings here could serve as an alternative design strategy for the next generation of active targeted nanomedicine.

Facile synthesis and physicochemical characterization of κ-Carrageenan-silver-bentonite based nanocatalytic platform for efficient degradation of anionic azo dyes.

Water pollution due to textile industry effluents is a global concern that warrants versatile research solutions for degrading them, and for a sustainable environment. In the present work, by using the imperative role of nanotechnology, a facile one-pot synthesis has been devised to generate κ-carrageenan capped silver nanocatalyst (CSNC), and was immobilized on 2D bentonite (BT) sheets to generate nanocatalytic platform (BTCSNC) for the degradation of anionic azo dyes. The nanocomposite(s) were physicochemically characterized using UV-Vis, DLS, TEM, FESEM, PXRD, ATR-FTIR, TGA, BET and XPS etc., to obtain insights into the nanocomposite composition, structure, stability, morphology and mechanism of interaction. The obtained CNSC are monodispersed, spherical with a size of 4 ± 2 nm, and were stabilized by the functional groups (-OH, COO‾, and SO3‾) of κ-Crg. The broadening of peak corresponding to basal plane (001) of BT montmorillonite in PXRD spectra established its exfoliation upon addition of CSNC. XPS and ATR-FTIR data evidenced the absence of covalent interactions between CSNC and BT. The catalytic efficiency of CSNC and BTCSNC composites were compared for the degradation of methyl orange (MO) and congo red (CR). The reaction followed a pseudo first order kinetics, and immobilization of CSNC on BT resulted in a 3-4 fold enhancement in degradation rates. The rates achieved for the degradation kinetics are: MO degradation within 14 s (Ka 9.86 ± 2.00 min-1), and CR degradation within 120 s (Ka of 1.24 ± 0.13 min-1). Further, a degradation mechanism has been proposed by analyzing the products identified through LC-MS. The reusability studies of the BTCSNC evidenced the complete activity of the nanocatalytic platform for six cycles, and gravitational separation method for catalyst recycling. In a nutshell, the current study provided an environmentally friendly, sizable, and sustainable nano catalytic platform" for the remediation of industrial wastewater contaminated with hazardous azo dyes".

Case report: a rare case of gastroduodenal intussusception caused by GIST in an elderly patient and literature review.

Gastroduodenal intussusception is a rare phenomenon in adults and is caused by gastrointestinal stromal tumors (GIST) in the majority of the documented cases. It commonly presents with abdominal pain, vomiting and melena. GIST is the most common gastrointestinal mesenchymal tumor in gastric and non-gastric locations. It is characterized classically by KIT or PGDFRA expression, and immunohistochemical analysis is the mainstay of diagnosis. Surgical resection provides definitive treatment in 70% of the cases. Here, we present a rare case of gastroduodenal intussusception caused by GIST in an elderly patient.

Comparison of Physical and System Factors Impacting Hydration Sensing in Leaves Using Terahertz Time-Domain and Quantum Cascade Laser Feedback Interferometry Imaging.

To reduce the water footprint in agriculture, the recent push toward precision irrigation management has initiated a sharp rise in photonics-based hydration sensing in plants in a non-contact, non-invasive manner. Here, this aspect of sensing was employed in the terahertz (THz) range for mapping liquid water in the plucked leaves of Bambusa vulgaris and Celtis sinensis. Two complementary techniques, broadband THz time-domain spectroscopic imaging and THz quantum cascade laser-based imaging, were utilized. The resulting hydration maps capture the spatial variations within the leaves as well as the hydration dynamics in various time scales. Although both techniques employed raster scanning to acquire the THz image, the results provide very distinct and different information. Terahertz time-domain spectroscopy provides rich spectral and phase information detailing the dehydration effects on the leaf structure, while THz quantum cascade laser-based laser feedback interferometry gives insight into the fast dynamic variation in dehydration patterns.

Targeted Drug Delivery Using a Plug-to-Direct Antibody-Nanogel Conjugate.

Targeted drug delivery using antibody-drug conjugates has attracted great attention due to its enhanced therapeutic efficacy compared to traditional chemotherapy. However, the development has been limited due to a low drug-to-antibody ratio and laborious linker-payload optimization. Herein, we present a simple and efficient strategy to combine the favorable features of polymeric nanocarriers with antibodies to generate an antibody-nanogel conjugate (ANC) platform for targeted delivery of cytotoxic agents. Our nanogels stably encapsulate several chemotherapeutic agents with a wide range of mechanisms of action and solubility. We showcase the targetability of ANCs and their selective killing of cancer cells over-expressing disease-relevant antigens such as human epidermal growth factor receptor 2, epidermal growth factor receptor, and tumor-specific mucin 1, which cover a broad range of breast cancer cell types while maintaining low to no toxicity to non-targeted cells. Overall, our system represents a versatile approach that could impact next-generation nanomedicine in antibody-targeted therapeutics.

Accurate optimization technique for phase-gradient metasurfaces used in compact near-field meta-steering systems.

Near-Field Meta-Steering (NFMS) is a constantly evolving and progressively emerging novel antenna beam-steering technology that involves an elegant assembly of a base antenna and a pair of Phase-Gradient Metasurfaces (PGMs) placed in the near-field region of the antenna aperture. The upper PGM in an NFMS system receives an oblique incidence from the lower PGM at all times, a fact that is ignored in the traditional design process of upper metasurfaces. This work proposes an accurate optimization method for metasurfaces in NFMS systems to reduce signal leakage by suppressing the grating lobes and side lobes that are innate artifacts of beam-steering. We detail the design and optimization approach for both upper and lower metasurface. Compared to the conventionally optimized compact 2D steering system, the proposed system exhibits higher directivity and lower side-lobe and grating lobe levels within the entire scanning range. The broadside directivity is 1.4 dB higher, and the side-lobe level is 4 dB lower in comparison. The beam-steering patterns for the proposed 2D compact design are experimentally validated, and the measured and predicted results are in excellent concurrence. The versatile compatibility of truncated PGMs with a low gain antenna makes it a compelling technology for wireless backhaul mesh networks and future antenna hardware.

Utility of Perioperative Measurement of Cell-Free DNA and Circulating Tumor DNA in Informing the Prognosis of GI Cancers: A Systematic Review.

PURPOSE: Current surveillance imaging and tumor markers lack sensitivity for the early detection of recurrence in GI cancers. This study critically evaluates the current literature on the role of sequential measurement of circulating tumor DNA (ctDNA) before and after curative resection in informing recurrence. METHODS: A systematic search using a predefined, registered protocol was conducted for studies published between January 2010 and May 2020. Included studies described patients with GI cancers treated with curative-intent surgical resection and measurement of ctDNA both before and after surgery. Patients were divided into three groups on the basis of the presence or absence of ctDNA at these time points. The primary outcome was recurrence-free survival (RFS). RESULTS: The search yielded 3,873 articles; five met the inclusion criteria and collectively evaluated 57 patients. Pooled median RFS was 62 months (interquartile range 19 to not reached). Although median RFS was not reached in group 1 (- to -) or group 2 (+ to -), median RFS in group 3 (+ to +) was 15 months (interquartile range 9.6-60.4 months). Cox hazard ratio was 4.46 (95% CI, 1.17 to 16.99; P = .028) between group 1 and group 2, and 10.47 (95% CI, 2.91 to 37.74; P < .001) between group 2 and group 3. CONCLUSION: Detectable ctDNA, either preoperatively or postoperatively, and its persistence after curative surgery are associated with a greater risk of recurrence and decreased RFS in GI cancers. Thus, perioperative measurement of ctDNA may be a useful postoperative risk stratification tool and guide additional therapies.

Dual spectroscopic detection of THz energy modes of critical chemical compounds.

Precise identification and sensing of organic and inorganic molecular systems are key factors in several applications in present industrial and scientific domains. While high energy modes, due to electronic interactions, are mostly impervious to the initial thermodynamic or chemical conditions, the low energy modes are sensitive to such alterations which makes them suitable for quality control purpose with sensitive spectral identification methods. Here we report for the first time, several low frequency peaks of specific nitrogen-based compounds and their derivatives, using the dual spectroscopic approach of Terahertz Time-Domain Spectroscopy (THz-TDS) and THz Raman Spectroscopy (THz-RS). Two different isomeric molecular systems have also been investigated to assess both the selectivity and specificity of low energy modes in their identification and spectral correlation in terms of molecular interactions. This information of low frequency modes can be utilized readily by pharmaceutical and agri-food industries, chemical engineering and crystal growth communities in identification, detection, quality control and industrial waste management.

Evaluation of Cellular Targeting by Fab' vs Full-Length Antibodies in Antibody-Nanoparticle Conjugates (ANCs) Using CD4 T-cells.

Targeted delivery of chemotherapeutic drugs can improve their therapeutic efficiency by localizing their toxic effects at the diseased site. This is often achieved either by direct conjugation of drugs to antibodies targeting overexpressed receptors on cancer cells (antibody-drug conjugates/ADCs) or by conjugating antibodies to nanoparticles bearing drugs (antibody-nanoparticle conjugates/ANCs). Here, we report a platform for utilizing hinge cysteines on antigen-binding fragment (Fab') of an anti-CD4 antibody for site-specific conjugation to nanoparticles giving rise to anti-CD4 Fab'-nanoparticle conjugates (Fab'-NCs). We demonstrate a convenient route for obtaining functional anti-CD4 Fab' from full-length antibody and examine the targeted delivery efficiencies of anti-CD4 Fab'-NCs vs ANCs for selective delivery to CD4high mT-ALL cells. Our results indicate that higher avidity of full-length anti-CD4 antibody, i.e., protein alone translated to higher binding ability to CD4high mT-ALL cells in comparison with anti-CD4 Fab' alone. However, the targeted delivery efficiency of anti-CD4 Fab'-NCs was comparable to ANCs indicating that the avidity of Fab' is restored in a nanoparticle-conjugate format. Fab'-NCs are equally capable of achieving targeted drug delivery to CD4high T-cells as ANCs and are a versatile alternative to ANCs by offering site-selective modification strategy while retaining their advantages.

A cross-sectional study to develop an early risk prediction tool for gestational diabetes mellitus for antenatal women diagnosed with this condition based on their characteristics and past obstetric history.

Background: In India, the prevalence of gestational diabetes mellitus (GDM) is estimated to be 10%-14.3%, which is higher than in Western countries. Out of 10 pregnancies, one is associated with diabetes, and 90% of them are GDM. GDM influences not only maternal complications but also neonatal complications. Moreover, women with GDM and their children are at increased risk of developing type-2 diabetes later. Method and Material: A cross-sectional study was conducted on 220 patients to develop an early risk prediction tool for GDM for antenatal women diagnosed with this condition based on their characteristics and past obstetric history. Results: The mean age (in years) of patients in the study was 27.69 ± 5.07. One hundred and twenty-six patients (57.27%) had a family history of DM in their first relatives. Eighty-three (58.86%) patients had a history of complications in a previous pregnancy. Conclusion: The early risk predictor tool with age, prepregnancy, body mass index (BMI), family history of DM, gravidity, past history of menstrual cycle, and complications in a previous pregnancy was easy to operate, and all predictors were easily obtained in the first trimester in primary healthcare centers.

Peptide bond planarity constrains hydrogen bond geometry and influences secondary structure conformations.

An extensive database study of hydrogen bonds in different protein environments showed systematic variations in donor-acceptor-acceptor antecedent angle (H) and donor-acceptor distance. Protein environments were characterized by depth (distance of amino acids from bulk solvent), secondary structure, and whether the donor/acceptor belongs to the main chain (MC) or side chain (SC) of amino acids. The MC-MC hydrogen bonds (whether in secondary structures or not) have H angles tightly restricted to a value of around 155°, which was distinctly different from other H angles. Quantum chemical calculations attribute this characteristic MC-MC H angle to the nature of the electron density distribution around the planar peptide bond. Additional classical simulations suggest a causal link between MC-MC H angle and the conformation of secondary structures in proteins. We also showed that donor-acceptor distances are environment dependent, which has implications on protein stability. Our results redefine hydrogen bond geometries in proteins and suggest useful refinements to existing molecular mechanics force fields.

A Rare Case of Peripheral Ossifying Fibroma in an Infant.

Peripheral ossifying fibroma (POF) associated with natal/neonatal teeth is extremely rare. In general, POF occurs as a soft-tissue gingival nodule occurring in young adults. We report an unusual and a rare case in a 5-month-old male child who had two, localized, soft-tissue growth over the mandibular anterior alveolar ridge. History revealed the presence of natal teeth in the same mandibular anterior region, which exfoliated at the age of 2 months. Intraoral periapical radiograph showed soft tissue density with evidence of calcifications that also corroborated with the histopathological finding of masses of mineralized areas. Excision of the lesions followed by histopathological examination proved the final diagnosis of POF. Inspite of being a benign reactive lesion, a high recurrence rate has been reported. Such lesions require long-term follow-up subsequent to excision with histopathological examination due to a high recurrence rate.

Protein-Antibody Conjugates (PACs): A Plug-and-Play Strategy for Covalent Conjugation and Targeted Intracellular Delivery of Pristine Proteins.

We report here on protein-antibody conjugates (PACs) that are used for antibody-directed delivery of protein therapeutics to specific cells. PACs have the potential to judiciously combine the merits of two prolific therapeutic approaches-biologics and antibody-drug conjugates. We utilize spherical polymer brushes to construct PACs using the combination of two simple and efficient functionally orthogonal click chemistries. In addition to the synthesis and characterization of these nanoparticles, we demonstrate that PACs are indeed capable of specifically targeting cells based on the presence of target antigen on the cell surface to deliver proteins. The potentially broad adaptability of PACs opens up new opportunities for targeted biologics in therapeutics and sensing.

Dissecting the anti-biofilm potency of kappa-carrageenan capped silver nanoparticles against Candida species.

Global antimicrobial crisis and advent of drug resistant fungal strains has substantially distressed disease management for clinicians. Biodegradable silver nanoparticles (AgNps) emerge as an excellent alternative remedial option. In the current study, the anti-biofilm activity of microwave irradiated kappa-carrageenan (CRG) capped AgNps against Candida albicans, and Candida glabrata was investigated in terms of their effect on reactive oxygen species (ROS) generation, cellular morphology, biochemical composition, and the activity of enzymes of extracellular matrix. Minimum inhibitory concentration and fungicidal concentration value of CRG-AgNps against both Candida spp. ranged between 400 and 500 µg/mL. The 80% of Candida biofilm was inhibited and eradicated by CRG-AgNps at a concentration of ~300 µg/mL. Microscopic studies indicate that CRG-AgNps caused morphological damage through membrane disruption and pore formation. Further, CRG-AgNps generated ROS in a concentration-dependent manner and modulated the composition of Candida biofilm ECM by increasing the carbohydrate and eDNA content. CRG-AgNps also significantly inactivated the hydrolytic enzymes, thus hindering the biofilm forming ability. In conclusion, all these results suggest that the CRG-AgNps are potential antifungal agents against Candida biofilms, and they inhibit/eradicate the fungal biofilms through multiple signalling mechanisms.