Distributable, metabolic PET reporting of tuberculosis.

Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [18F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose - 2-[18F]fluoro-2-deoxytrehalose ([18F]FDT) - is a mechanism-based reporter of Mycobacteria-selective enzyme activity in vivo. Use of [18F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-mediated processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [18F]FDT from the most globally-abundant organic 18F-containing molecule, [18F]FDG. The full, pre-clinical validation of both production method and [18F]FDT now creates a new, bacterium-selective candidate for clinical evaluation. We anticipate that this distributable technology to generate clinical-grade [18F]FDT directly from the widely-available clinical reagent [18F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.

Kuragel: A biomimetic hydrogel scaffold designed to promote corneal regeneration.

Cornea-related injuries are the most common cause of blindness worldwide. Transplantation remains the primary approach for addressing corneal blindness, though the demand for donor corneas outmatches the supply by millions. Tissue adhesives employed to seal corneal wounds have shown inefficient healing and incomplete vision restoration. We have developed a biodegradable hydrogel - Kuragel, with the ability to promote corneal regeneration. Functionalized gelatin and hyaluronic acid form photo-crosslinkable hydrogel with transparency and compressive modulus similar to healthy human cornea. Kuragel composition was tuned to achieve sufficient adhesive strength for sutureless integration to host tissue, with minimal swelling post-administration. Studies in the New Zealand rabbit mechanical injury model affecting corneal epithelium and stroma demonstrate that Kuragel efficiently promotes re-epithelialization within 1 month of administration, while stroma and sub-basal nerve plexus regenerate within 3 months. We propose Kuragel as a regenerative treatment for patients suffering from corneal defects including thinning, by restoration of transparency and thickness.

Spinning with exosomes: electrospun nanofibers for efficient targeting of stem cell-derived exosomes in tissue regeneration.

Electrospinning technique converts polymeric solutions into nanoscale fibers using an electric field and can be used for various biomedical and clinical applications. Extracellular vesicles (EVs) are cell-derived small lipid vesicles enriched with biological cargo (proteins and nucleic acids) potential therapeutic applications. In this review, we discuss extending the scope of electrospinning by incorporating stem cell-derived EVs, particularly exosomes, into nanofibers for their effective delivery to target tissues. The parameters used during the electrospinning of biopolymers limit the stability and functional properties of cellular products. However, with careful consideration of process requirements, these can significantly improve stability, leading to longevity, effectiveness, and sustained and localized release. Electrospun nanofibers are known to encapsulate or surface-adsorb biological payloads such as therapeutic EVs, proteins, enzymes, and nucleic acids. Small EVs, specifically exosomes, have recently attracted the attention of researchers working on regeneration and tissue engineering because of their broad distribution and enormous potential as therapeutic agents. This review focuses on current developments in nanofibers for delivering therapeutic cargo molecules, with a special emphasis on exosomes. It also suggests prospective approaches that can be adapted to safely combine these two nanoscale systems and exponentially enhance their benefits in tissue engineering, medical device coating, and drug delivery applications.

The Minimum Protein Staple? - Towards 'bio'-Baldwin's rules via inter-phosphosite linking in the MEK1 activation loop.

In small molecule organic chemistry, the heuristic insight into ring-forming processes that was enabled by Baldwin's rules some 50 years ago proved a step-change in the role of mechanistically guided synthesis. It created a lens upon and marker of fundamental stereoelectronic and conformation-guided chemical processes. However, despite the widespread role of stereoelectronics and conformational control in Biology, no equivalent coherent exploitation of trapped, ring-forming processes yet exists in biomolecules. In the development of a minimal ring-closing process in intact proteins that might prove suitable in a coherent rule-set, we have tested endo-trig ring-closing conjugate thioether lanthionine (Lan) -CH2-S-CH2- formation as a limiting cyclization. Spontaneous Lan formation in proteins is rare if not non-existent and when found in natural product cyclic peptides it requires the mediation of corresponding biosynthetic enzymes as well as productive reactive conformations to guide it. Here, we show that within a conformationally flexible and functionally important protein loop - the MAPK kinase phosphorylation-targeted activation loop - Lan ring-closing is possible. Ring-closing proves to be critically dependent on the location of a trig electrophilic site in just one of two regioisomeric potential precursors to allow phosphosite-to-phosphosite 'stapling'. This first example of spontaneous protein thioether ring-closing/'stapling' and its accessibility from just one precursor (despite the potential for both to form an identical 'staple') now reveals the potential for Lan formation not only as an accessible form of minimal stapling in proteins but also as an exquisitely sensitive probe of associated protein geometries. We suggest that the use of this (as well as the development of other such, intramolecular protein traps that are dependent on inherent protein-controlled reactivity rather than forced crosslinking) may allow the broader trapping and mapping of relevant, even minor, protein states. In this way, protein ring formation may enable a form of extended 'bio-Baldwin's rules' that help to delineate relevant protein conformational space.

Long-term physical inactivity induces significant changes in biochemical pathways related to metabolism of proteins and glycerophospholipids in mice.

Physical inactivity affects multiple organ systems, including the musculoskeletal system, which upsets the delicate balance of several secretory factors leading to metabolic derailment. This reduces contractile recruitment of the skeletal muscle with dampening of its oxidative capacity resulting in impaired intramuscular lipid metabolism and substrate utilization. We hypothesized that this altered phenotype would also have an indispensable effect on circulatory cytokines and the level of metabolic intermediates. In this study, comparison between sedentary (SED) and exercised (EXER) animal models showed that organismal metabolic parameters (body mass, oxygen utilization and glucose tolerance) are altered based on physical activity. Our data suggest that cytokines linked to glycemic excursions (insulin, c-peptide, glucagon) and their passive regulators (leptin, BDNF, active ghrelin, and GIP) exhibit changes in the SED group. Furthermore, some of the proinflammatory cytokines and myokines were upregulated in SED. Interestingly, serum metabolite analysis showed that the levels of glucogenic amino acids (alanine, glycine, tryptophan, proline and valine), nitrogenous amino acids (ornithine, asparagine, and glutamine) and myogenic metabolites (taurine, creatine) were altered due to the level of physical activity. A pyrimidine nucleoside (uridine), lipid metabolite (glycerol) and ketone bodies (acetoacetate and acetate) were found to be altered in SED. A Spearman rank correlation study between SED and CTRL showed that cytokines build a deformed network with metabolites in SED, indicating significant modifications in amino acids, phosphatidylinositol phosphate and glycerophospholipid metabolic pathways. Overall, long-term physical inactivity reorganizes the profile of proinflammatory cytokines, glucose sensing hormones, and protein and glycerophospholipid metabolism, which might be the initial factors of metabolic diseases due to SED.

Clinical metabolomics by NMR revealed serum metabolic signatures for differentiating sarcoidosis from tuberculosis.

BACKGROUND: Pulmonary sarcoidosis (SAR) and tuberculosis (TB) are two granulomatous lung-diseases and often pose a diagnostic challenge to a treating physicians. OBJECTIVE: The present study aims to explore the diagnostic potential of NMR based serum metabolomics approach to differentiate SAR from TB. MATERIALS AND METHOD: The blood samples were obtained from three study groups: SAR (N = 35), TB (N = 28) and healthy normal subjects (NC, N = 56) and their serum metabolic profiles were measured using 1D 1H CPMG (Carr-Purcell-Meiboom-Gill) NMR spectra recorded at 800 MHz NMR spectrometer. The quantitative metabolic profiles were compared employing a combination of univariate and multivariate statistical analysis methods and evaluated for their diagnostic potential using receiver operating characteristic (ROC) curve analysis. RESULTS: Compared to SAR, the sera of TB patients were characterized by (a) elevated levels of lactate, acetate, 3-hydroxybutyrate (3HB), glutamate and succinate (b) decreased levels of glucose, citrate, pyruvate, glutamine, and several lipid and membrane metabolites (such as very-low/low density lipoproteins (VLDL/LDL), polyunsaturated fatty acids, etc.). CONCLUSION: The metabolic disturbances not only found to be well in concordance with various previous reports, these further demonstrated very high sensitivity and specificity to distinguish SAR from TB patients suggesting serum metabolomics analysis can serve as surrogate method in the diagnosis and clinical management of SAR.

Salbutamol ameliorates skeletal muscle wasting and inflammatory markers in streptozotocin (STZ)-induced diabetic rats.

Diabetes accelerates muscle atrophy, leading to the deterioration of skeletal muscles. This study aimed to assess the potential of the ß2-adrenoceptor agonist, salbutamol (SLB), to alleviate muscle atrophy in streptozotocin (STZ)-induced diabetic rats. Male Sprague Dawley rats were randomized into four groups (n=6): control, SLB, STZ (55 mg/kg, single i.p.), and STZ + SLB (6 mg/kg, orally for 4 weeks). After the final SLB dose, animals underwent tests to evaluate muscle strength and coordination, including forelimb grip strength, wire-hanging, actophotometer, rotarod, and footprint assessments. Rats were then sacrificed, and serum and gastrocnemius (GN) muscles were collected for further analysis. Serum evaluations included proinflammatory markers (tumor necrosis factor α, interleukin-1ß, interleukin-6), muscle markers (creatine kinase, myostatin), testosterone, and lipidemic markers. Muscle oxidative stress (malonaldehyde, protein carbonyl), antioxidants (glutathione, catalase, superoxide dismutase), and histology were also performed. Additionally, 1H nuclear magnetic resonance serum profiling was conducted. SLB notably enhanced muscle grip strength, coordination, and antioxidant levels, while reduced proinflammatory markers and oxidative stress in STZ-induced diabetic rats. Reduced serum muscle biomarkers, increased testosterone, restored lipidemic levels, and improved muscle cellular architecture indicated SLB's positive effect on muscle condition in diabetic rats. Metabolomics profiling revealed that the STZ group significantly increased the phenylalanine-to-tyrosine ratio (PTR), lactate-to-pyruvate ratio (LPR), acetate, succinate, isobutyrate, and histidine. SLB administration restored these perturbed serum metabolites in the STZ-induced diabetic group. In conclusion, salbutamol significantly protected against skeletal muscle wasting in STZ-induced diabetic rats.

Implications of In Vitro Multi-Serine Phosphorylation of Alpha-Synuclein in Aggregation and Cytotoxicity.

Post-translational modifications guide the functional diversity and identity of proteins. Phosphorylation is one such post-translational modification that has been reported in pathological proteins related to various neurodegenerative disorders such as α-synuclein (α-syn) phosphorylation in Parkinson's disease and other synucleinopathies. In α-syn, the phosphorylation has mostly been observed at S129; however, the occurrence of other serine modifications at S9, S42, and S87 is partially explored. In pathogenic conditions, where α-syn is phosphorylated by complex kinase pathways, multi-site modifications may happen and alter the mechanism of α-syn aggregation. Here, using Polo-like kinase 2 and G-protein coupled receptor kinase 4, the in vitro phosphorylation of α-syn was performed, which revealed multi-serine phosphorylation. Mass spectrometry with customized proteolytic digestion showed prominent phosphorylation at S129 and modifications at S87 and S42 with PLK2 and S87 with GRK4. The phosphorylation at the identified serine residues was further validated with NMR and western blotting. Multi-serine phosphorylation aggravates the aggregation potential of monomeric α-syn, seeding capacity, and cytotoxicity in the SH-SY5Y cell line. This study proposes evidence for in vitro multi-site phosphorylation and its significance in α-syn aggregation, toxicity, and related pathogenesis.

A natural small molecule-mediated inhibition of alpha-synuclein aggregation leads to neuroprotection in Caenorhabditis elegans.

Small molecules are being explored intensively for their applications as therapeutic molecules in the management of metabolic and neurological disorders. The natural small molecules can inhibit protein aggregation and underlying cellular pathogenesis of neurodegenerative diseases involving multi-factorial mechanisms of action. Certain natural small molecular inhibitors of pathogenic protein aggregation are highly efficient and have shown promising therapeutic potential. In the present study, Shikonin (SHK), a natural plant-based naphthoquinone has been investigated for its aggregation inhibition activity against α-synuclein (α-syn) and the neuroprotective potential in Caenorhabditis elegans (C. elegans). SHK significantly inhibited aggregation of α-syn at sub-stochiometric concentrations, delayed the linear lag phase and growth kinetics of seeded and unseeded α-syn aggregation. The binding of SHK to the C-terminus of α-syn maintained α-helical and disordered secondary structures with reduced beta-sheet content and complexity of aggregates. Further, in C. elegans transgenic PD models, SHK significantly reduced α-syn aggregation, improved locomotor activity and prevented dopaminergic (DA) neuronal degeneration, indicating the neuroprotective role of SHK. The present study highlights the potential of natural small molecules in the prevention of protein aggregation that may further be explored for their therapeutic efficacy in the management of protein aggregation and neurodegenerative diseases.

Microrobots for Biomedicine: Unsolved Challenges and Opportunities for Translation.

Microrobots are being explored for biomedical applications, such as drug delivery, biological cargo transport, and minimally invasive surgery. However, current efforts largely focus on proof-of-concept studies with nontranslatable materials through a "design-and-apply" approach, limiting the potential for clinical adaptation. While these proof-of-concept studies have been key to advancing microrobot technologies, we believe that the distinguishing capabilities of microrobots will be most readily brought to patient bedsides through a "design-by-problem" approach, which involves focusing on unsolved problems to inform the design of microrobots with practical capabilities. As outlined below, we propose that the clinical translation of microrobots will be accelerated by a judicious choice of target applications, improved delivery considerations, and the rational selection of translation-ready biomaterials, ultimately reducing patient burden and enhancing the efficacy of therapeutic drugs for difficult-to-treat diseases.

Distributable, Metabolic PET Reporting of Tuberculosis.

Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [18F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose - 2-[18F]fluoro-2-deoxytrehalose ([18F]FDT) - can act as a mechanism-based enzyme reporter in vivo. Use of [18F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-specific processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [18F]FDT from the most globally-abundant organic 18F-containing molecule, [18F]FDG. The full, pre-clinical validation of both production method and [18F]FDT now creates a new, bacterium-specific, clinical diagnostic candidate. We anticipate that this distributable technology to generate clinical-grade [18F]FDT directly from the widely-available clinical reagent [18F]FDG, without need for either bespoke radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer.

Copper transporter protein (MctB) as a therapeutic target to elicit antimycobacterial activity against tuberculosis.

Tuberculosis (TB) is a prehistoric infection and major etiologic agent of TB, Mycobacterium tuberculosis, which is considered to have advanced from an early progenitor species found in Eastern Africa. By the 1800s, there were approximately 800 to 1000 fatality case reports per 100,000 people in Europe and North America. This research suggests an In-silico study to identify potential inhibitory compounds for the target Mycobacterial copper transport protein (Mctb). ADME-based virtual screening, molecular docking, and molecular dynamics simulations were conducted to find promising compounds to modulate the function of the target protein. Four chemical compounds, namely Anti-MCT1, Anti-MCT2, Anti-MCT3 and Anti-MCT4 out of 1500 small molecules from the Diverse-lib of MTiOpenScreen were observed to completely satisfy Lipinski rule of five and Veber's rule. Further, significantly steady interactions with the MctB target protein were observed. Docking experiments have presented 9 compounds with less than -9.0 kcal/mol free binding energies and further MD simulation eventually gave 4 compounds having potential interactions and affinity with target protein and favorable binding energy ranging from -9.2 to -9.3 kcal/mol. We may propose these compounds as an effective candidate to reduce the growth of M. tuberculosis and may also assist present a novel therapeutic approach for Tuberculosis. In vivo and In vitro validation would be needed to proceed further in this direction.Communicated by Ramaswamy H. Sarma.

Atenolol Ameliorates Skeletal Muscle Atrophy and Oxidative Stress Induced by Cast Immobilization in Rats.

(1) Background: Skeletal muscle atrophy is a common and debilitating condition associated with disease, bed rest, and inactivity. We aimed to investigate the effect of atenolol (ATN) on cast immobilization (IM)-induced skeletal muscle loss. (2) Methods: Eighteen male albino Wistar rats were divided into three groups: a control group, an IM group (14 days), and an IM+ATN group (10 mg/kg, orally for 14 days). After the last dose of atenolol, forced swimming test, rotarod test, and footprint analysis were performed, and skeletal muscle loss was determined. Animals were then sacrificed. Serum and gastrocnemius (GN) muscles were then collected, serum creatinine, GN muscle antioxidant, and oxidative stress levels were determined, and histopathology and 1H NMR profiling of serum metabolites were performed. (3) Results: Atenolol significantly prevented immobilization-induced changes in creatinine, antioxidant, and oxidative stress levels. Furthermore, GN muscle histology results showed that atenolol significantly increased cross-sectional muscle area and Feret's diameter. Metabolomics profiling showed that glutamine-to-glucose ratio and pyruvate, succinate, valine, citrate, leucine, isoleucine, phenylalanine, acetone, serine, and 3-hydroxybutyrate levels were significantly higher, that alanine and proline levels were significantly lower in the IM group than in the control group, and that atenolol administration suppressed these metabolite changes. (4) Conclusions: Atenolol reduced immobilization-induced skeletal muscle wasting and might protect against the deleterious effects of prolonged bed rest.

Computational Intelligence in Cancer Diagnostics: A Contemporary Review of Smart Phone Apps, Current Problems, and Future Research Potentials.

Cancer is a dangerous and sometimes life-threatening disease that can have several negative consequences for the body, is a leading cause of mortality, and is becoming increasingly difficult to detect. Each form of cancer has its own set of traits, symptoms, and therapies, and early identification and management are important for a positive prognosis. Doctors utilize a variety of approaches to detect cancer, depending on the kind and location of the tumor. Imaging tests such as X-rays, Computed Tomography scans, Magnetic Resonance Imaging scans, and Positron Emission Tomography (PET) scans, which may provide precise pictures of the body's interior structures to spot any abnormalities, are some of the tools that doctors use to diagnose cancer. This article evaluates computational-intelligence approaches and provides a means to impact future work by focusing on the relevance of machine learning and deep learning models such as K Nearest Neighbour (KNN), Support Vector Machine (SVM), Naïve Bayes, Decision Tree, Deep Neural Network, Deep Boltzmann machine, and so on. It evaluates information from 114 studies using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). This article explores the advantages and disadvantages of each model and provides an outline of how they are used in cancer diagnosis. In conclusion, artificial intelligence shows significant potential to enhance cancer imaging and diagnosis, despite the fact that there are a number of clinical issues that need to be addressed.

Bubble-Based Microrobots with Rapid Circular Motions for Epithelial Pinning and Drug Delivery.

Remotely powered microrobots are proposed as next-generation vehicles for drug delivery. However, most microrobots swim with linear trajectories and lack the capacity to robustly adhere to soft tissues. This limits their ability to navigate complex biological environments and sustainably release drugs at target sites. In this work, bubble-based microrobots with complex geometries are shown to efficiently swim with non-linear trajectories in a mouse bladder, robustly pin to the epithelium, and slowly release therapeutic drugs. The asymmetric fins on the exterior bodies of the microrobots induce a rapid rotational component to their swimming motions of up to ≈150 body lengths per second. Due to their fast speeds and sharp fins, the microrobots can mechanically pin themselves to the bladder epithelium and endure shear stresses commensurate with urination. Dexamethasone, a small molecule drug used for inflammatory diseases, is encapsulated within the polymeric bodies of the microrobots. The sustained release of the drug is shown to temper inflammation in a manner that surpasses the performance of free drug controls. This system provides a potential strategy to use microrobots to efficiently navigate large volumes, pin at soft tissue boundaries, and release drugs over several days for a range of diseases.

Assessment of anti-arthritic activity of lipid matrix encased berberine in rheumatic animal model.

The purpose of this study was to evaluate the drug delivery and therapeutic potential of berberine (Br) loaded nanoformulation in rheumatoid arthritis (RA)-induced animal model. The Br-loaded NLCs (nanostructured lipid carriers) were prepared employing melt-emulsification process, and optimised through Box-Behnken design. The prepared NLCs were assessed for in-vitro and in-vivo evaluations. The optimised NLCs exhibited a mean diameter of 180.2 ± 0.31 nm with 88.32 ± 2.43% entrapment efficiency. An enhanced anti-arthritic activity with reduced arthritic scores to 0.66 ± 0.51, reduction in ankle diameter to 5.80 ± 0.27 mm, decline in paw withdrawal timing, and improvements in walking behaviour were observed in the Br-NLCs treated group. The radiographic images revealed a reduction in bone and cartilage deformation. The Br-NLCs showed promising results in the management of RA disease, can be developed as an efficient delivery system at commercial levels, and may be explored for clinical application after suitable experiments in the future.

An unusual association of type II Mayer-Rokitansky-Kuster-Hauser syndrome, turner mosaic syndrome and tubo-ovarian inguinal hernia- case report and review of literature.

BACKGROUND: Herniation of ovaries and Mullerian structures into inguinal canal is usually reported in infants and is rare among adults. We are presenting a rare case of Mullerian agenesis and Turner mosaic syndrome with tubo-ovarian inguinal hernia. CASE PRESENTATION: A 17-year-old girl presented with complaints of primary amenorrhea, phenotypical features of Turner syndrome with left inguinal hernia and severe hypertension. Baseline hormonal analysis was normal. Karyotype revealed Turner mosaic with 46XX (85%); 45XO (15%). MRI showed Mullerian agenesis with normally located right ovary in pelvis and left ovary prolapsed through deep inguinal ring into the canal of Nuck. Anti-hypertensives were started and patient optimized for surgery. Laparoscopic hernia repair and repositioning of left ovary into the pelvis was done. Patient had uneventful post-operative course and was discharged in stable condition on anti-hypertensive medication. Future reproductive issues and need of passive vaginal dilatation or vaginoplasty before marriage were explained to the patient and family. CONCLUSION: This is the first ever reported case with unusual association of atypical MRKH, Turner mosaic syndrome and tubo-ovarian hernia into the inguinal canal. The case emphasizes the need and importance of complete work up of these atypical cases as patients may have more than one cause of primary amenorrhea and complete evaluation is must before any medical or surgical intervention.

Two-dimensional diffusiophoretic colloidal banding: optimizing the spatial and temporal design of solute sinks and sources.

Diffusiophoresis refers to the phenomenon where colloidal particles move in response to solute concentration gradients. Existing studies on diffusiophoresis, both experimental and theoretical, primarily focus on the movement of colloidal particles in response to one-dimensional solute gradients. In this work, we numerically investigate the impact of two-dimensional solute gradients on the distribution of colloidal particles, i.e., colloidal banding, induced via diffusiophoresis. The solute gradients are generated by spatially arranged sources and sinks that emit/absorb a time-dependent solute molar rate. First we study a dipole system, i.e., one source and one sink, and discover that interdipole diffusion and molar rate decay timescales dictate colloidal banding. At timescales shorter than the interdipole diffusion timescale, we observe a rapid enhancement in particle enrichment around the source due to repulsion from the sink. However, at timescales longer than the interdipole diffusion timescale, the source and sink screen each other, leading to a slower enhancement. If the solute molar rate decays at the timescale of interdipole diffusion, an optimal separation distance is obtained such that particle enrichment is maximized. We find that the partition coefficient of solute at the interface between the source and bulk strongly impacts the optimal separation distance. Surprisingly, the diffusivity ratio of solute in the source and bulk has a much weaker impact on the optimal dipole separation distance. We also examine an octupole configuration, i.e., four sinks and four sources, arranged in a circle, and demonstrate that the geometric arrangement that maximizes enrichment depends on the radius of the circle. If the radius of the circle is small, it is preferred to have sources and sinks arranged in an alternating fashion. However, if the radius of the circle is large, a consecutive arrangement of sources and sinks is optimal. Our numerical framework introduces a novel method for spatially and temporally designing the banded structure of colloidal particles in two dimensions using diffusiophoresis and opens up new avenues in a field that has primarily focused on one-dimensional solute gradients.

Association of altered metabolic profiles and long non-coding RNAs expression with disease severity in breast cancer patients: analysis by 1H NMR spectroscopy and RT-q-PCR.

INTRODUCTION: Globally, one of the major causes of cancer related deaths in women is breast cancer. Although metabolic pattern is altered in cancer patients, robust metabolic biomarkers with a potential to improve the screening and disease monitoring are lacking. A complete metabolome profiling of breast cancer patients may lead to the identification of diagnostic/prognostic markers and potential targets. OBJECTIVES: The aim of this study was to analyze the metabolic profile in the serum from 43 breast cancer patients and 13 healthy individuals. MATERIALS & METHODS: We used 1H NMR spectroscopy for the identification and quantification of metabolites. q-RT-PCR was used to examine the relative expression of lncRNAs. RESULTS: Metabolites such as amino acids, lipids, membrane metabolites, lipoproteins, and energy metabolites were observed in the serum from both patients and healthy individuals. Using unsupervised PCA, supervised PLS-DA, supervised OPLS-DA, and random forest classification, we observed that more than 25 metabolites were altered in the breast cancer patients. Metabolites with AUC value > 0.9 were selected for further analysis that revealed significant elevation of lactate, LPR and glycerol, while the level of glucose, succinate, and isobutyrate was reduced in breast cancer patients in comparison to healthy control. The level of these metabolites (except LPR) was altered in advanced-stage breast cancer patients in comparison to early-stage breast cancer patients. The altered metabolites were also associated with over 25 signaling pathways related to metabolism. Further, lncRNAs such as H19, MEG3 and GAS5 were dysregulated in the breast tumor tissue in comparison to normal adjacent tissue. CONCLUSION: The study provides insights into metabolic alteration in breast cancer patients. It also provides an avenue to examine the association of lncRNAs with metabolic patterns in patients.

GPC3-Unc5 receptor complex structure and role in cell migration.

Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.