Impact of intensity-modulated proton therapy in reducing radiation-induced lymphopenia in glioma patients.

Background: Current standard management in adult grades 2-4 gliomas includes maximal safe resection followed by adjuvant radiotherapy (RT) and chemotherapy. Radiation-induced lymphopenia (RIL) has been shown to possibly affect treatment outcomes adversely. Proton beam therapy (PBT) may reduce the volume of the normal brain receiving moderate radiation doses, and consequently RIL. Our aim was to evaluate the incidence and severity of RIL during proton beam therapy (PBT). Methods: We identified patients with grades 2-4 glioma treated with PBT at our center between January 2019 and December 2021. We evaluated the incidence and severity of RIL from weekly complete blood count (CBC) data collected during PBT and compared it to the patients who were treated with photon-based RT (XRT) at our center during the same time. Results: The incidence of any degree of lymphopenia (48% in PBT, vs. 81.2% in XRT, P value = .001) and severe lymphopenia (8% in PBT, vs. 24.6% in XRT, P value = .093) were both significantly lesser in patients who received PBT. Severe RIL in patients receiving PBT was seen in only CNS WHO Gr-4 tumors. Mean whole brain V20GyE and V25GyE inversely correlated to nadir ALC and were both significantly lower with PBT. Patients with lymphopenia during PBT showed a trend toward poorer progression-free survival (P = .053) compared to those with maintained lymphocyte counts. Conclusions: Proton therapy seems to have a superior sparing of normal brain to moderate dose radiation than photon-based RT and reduces the incidence of lymphopenia. Glioma patients with lymphopenia possibly have worse outcomes than the ones with maintained lymphocyte counts.

Improved efficiency using sequential automated immunoassays for syphilis screening in blood donors.

Using sequential immunoassays for the screening of blood donors is well described for viral serology testing but not for the screening of syphilis. In this study, we report the evaluation results and 2-year sequential testing data using two highly sensitive automated serology assays, the Alinity s Syphilis chemiluminescent immunoassay for screening, with all repeatedly reactive samples then tested on the Elecsys Syphilis electrochemiluminescence immunoassay. We screened 1,767,782 blood donor samples between 7 July 2021 and 6 July 2023 and found the Alinity false-positive rate to be low at 0.08% (1,456/1,767,782). The common false-positive rate between the two assays was also low (3.83%, 58/1,514). Concordantly reactive samples were further tested using a Treponema pallidum particle agglutination test, a rapid plasma reagin test, and a fluorescent treponemal antibody absorption test. There were 262/1,376 concordantly reactive Alinity and Elecsys blood donor samples with reactivity on one or more of the confirmatory tests. A total of 26/1,376 donors had a current syphilis infection, 152/1,376 reported a past history of syphilis and had been treated, and 84/1,376 did not report a past history of syphilis. We suggest that future studies could explore the use of sequential immunoassays to aid in the serodiagnosis for syphilis. IMPORTANCE: The serodiagnosis for syphilis usually follows two methodologies-a "traditional" algorithm using a non-treponemal test followed by confirmation using a treponemal test, or a "reverse" algorithm using a treponemal test followed by a non-treponemal test. There are limited reports in the literature of using a modified reverse algorithm (treponemal test followed by a second treponemal test), and to the best of knowledge, there are currently no published articles using two highly sensitive automated immunoassays to aid the serodiagnosis of syphilis. In addition, the Treponema pallidum particle agglutination (TPPA) assay is commonly used as a confirmatory test for the diagnosis of syphilis. With the withdrawal of the TPPA assay from Australia and presumably from the global market also, alternative testing algorithms are now required. This study provides proof of concept for using sequential immunoassays in the diagnosis of syphilis.

Functional-Molecular Mechanisms of Sympathetic-Parasympathetic Dysfunction in PVC-Induced Cardiomyopathy Revealed by Dual Stressor PVC-Exercise Challenge.

BACKGROUND: The significance of autonomic dysfunction in premature ventricular contraction-induced cardiomyopathy (PVC-CM) remain unknown. OBJECTIVE: Utilizing a novel "dual stressor" provocative challenge combining exercise with premature ventricular contraction (PVCs), the authors characterized the functional and molecular mechanisms of cardiac autonomic (cardiac autonomic nervous system) remodeling in a PVC-CM animal model. METHODS: In 15 canines (8 experimental, 7 sham), we implanted pacemakers and neurotelemetry devices and subjected animals to 12 weeks of bigeminal PVCs to induce PVC-CM. Sympathetic nerve activity (SNA), vagal nerve activity (VNA), and heart rate were continuously recorded before, during, and after treadmill exercise challenge with and without PVCs, at baseline and after development of PVC-CM. Western blot and enzyme-linked immunosorbent assay were used to evaluate molecular markers of neural remodeling. RESULTS: Exercise triggered an increase in both SNA and VNA followed by late VNA withdrawal. With PVCs, the degree of exercise-induced SNA augmentation was magnified, whereas late VNA withdrawal became blunted. After PVC-CM development, SNA was increased at rest but failed to adequately augment during exercise, especially with PVCs, coupled with impaired VNA and heart rate recovery after exercise. In the remodeled cardiac autonomic nervous system, there was widespread sympathetic hyperinnervation and elevated transcardiac norepinephrine levels but unchanged parasympathetic innervation, indicating sympathetic overload. However, cardiac nerve growth factor was paradoxically downregulated, suggesting an antineurotrophic counteradaptive response to PVC-triggered sympathetic overload. CONCLUSIONS: Sympathetic overload, sympathetic dysfunction, and parasympathetic dysfunction in PVC-CM are unmasked by combined exercise and PVC challenge. Reduced cardiac neurotrophic factor might underlie the mechanisms of this dysfunction. Neuromodulation therapies to restore autonomic function could constitute a novel therapeutic approach for PVC-CM.

Shape-tunable two-dimensional assemblies from chromophore-conjugated crystallizable poly(L-lactides) with chain-length-dependent photophysical properties.

This work reports temperature-dependent shape-changeable two-dimensional (2D) nanostructures by crystallization-driven self-assembly (CDSA) from a chromophore-conjugated poly(L-lactide) (PLLA) homopolymer (PTZ-P1) that contained a polar dye, phenothiazine (PTZ), at the chain-end of the crystallizable PLLA. The CDSA of PTZ-P1 in a polar solvent, isopropanol (iPrOH), by an uncontrolled heating-cooling process, majorly generates lozenge-shaped 2D platelets via chain-folding-mediated crystallization of the PLLA core, leading to the display of the phenothiazines on the 2D surface that confers colloidal stability and orange-emitting luminescent properties to the crystal lamellae. Isothermal crystallization at 60 °C causes a morphological change in PTZ-P1 platelets from lozenge to truncated-lozenge to perfect hexagon under different annealing times, while no shape change was noticed in the structurally similar PTZ-P2 polymer with a longer PLLA chain under similar conditions. This study unveils the complex link between the 2D platelet morphologies and degree of polymerization (DP) of PLLA and the corona-forming dye character. Further, the co-assembly potential of PTZ-P1 with hydrophobic pyrene-terminated PLLAs of varying chain lengths (PY-P1, PY-P2, and PY-P3) was examined, as these two dyes could form a Förster Resonance Energy Transfer (FRET) pair on the 2D surface. The impact of the length of the crystallizable PLLA on the photophysical properties of the surface-occupied chromophores revealed crucial insights into interchromophoric interactions on the platelet surface. A reduction in the propensity for π-stacking with increasing chain-folding in longer PLLAs is manifested in the chain-length-dependent FRET efficiencies and excimer emission lifetimes within the resultant monolayered 2D assemblies. The unconventional "butterfly-shaped" molecular architecture of the tested phenothiazine, combined with its varied functional features and polar character, adds a distinctive dimension to the underdeveloped field of CDSA of chromophore-conjugated poly(L-lactides), opening future avenues for the development of advanced nanostructured biodegradable 2D materials with programmable morphology and optical functions.

Cholesterol modulates the structural dynamics of the paddle motif loop of KvAP voltage sensor.

KvAP is a prokaryotic Kv channel, which has been widely used as a model system to understand voltage- and lipid-dependent gating mechanisms. In phospholipid membranes, the KvAP-VSD adopts the activated/'Up' conformation, whereas the presence of non-phospholipids in membranes favours the structural transition to resting/'Down' state. The S3b-S4 paddle motif loop of KvAP-VSD is functionally important as this participates in protein-protein interactions and is the target for animal toxins. In this study, we have monitored the modulatory role of cholesterol - the physiologically-relevant non-phospholipid - on the organization and dynamics of the S3b-S4 loop of the isolated KvAP-VSD in membranes by site-directed fluorescence approaches using the environmental sensitivity of 7-nitrobenz-2-oxa-1,3-diazol-4-yl-ethylenediamine (NBD) fluorescence. Our results show that cholesterol alters the dynamic nature (rotational and hydration dynamics) of S3b-S4 loop in a segmental fashion, i.e., the residues 110 to 114 and 115 to 117 behave differently in the presence of cholesterol, which is accompanied by considerable change in conformational heterogeneity. Further, quantitative depth measurements using the parallax quenching method reveal that the sensor loop is located at the shallow interfacial region of cholesterol-containing membranes, suggesting that the sensor loop organization is not directly correlated with S4 helix movement. Our results clearly show that cholesterol-induced changes in bilayer properties may not be the predominant factor for the sensor loop's altered structural dynamics, but can be attributed to the conformational change of the KvAP-VSD in cholesterol-containing membranes. Overall, these results are relevant for gating mechanisms, particularly the lipid-dependent gating, of Kv channels in membranes.

Encouraging Experience with Image-Guided Pencil Beam Scanning Proton Therapy in Craniopharyngioma-First Case Series From India.

OBJECTIVE: We report our early clinical experience with image-guided, pencil beam scanning proton beam therapy (PBS-PBT) for residual and recurrent craniopharyngioma. METHODS: Between September 2019 and January 2023, 19 consecutive patients with residual or recurrent craniopharyngioma, suitable for radiotherapy and treated with image-guided PBS-PBT were analyzed. We documented detailed dosimetric data, acute toxicities, early outcomes, and imaging response on follow-up magnetic resonance imaging scans. RESULTS: A total of 19 patients (11 males and 8 females) with residual or recurrent craniopharyngioma were treated during the study period. The median age of the cohort was 14 years (range, 3-33 years). The histology of most lesions was the adamantinomatous subtype (95%). The most common clinical presentation (before PBT) and most common endocrine deficit was visual disturbance (79%) and hypocortisolism (74%), respectively. Of the 19 patients, 13 had recurrent craniopharyngioma, and 5 had undergone radiotherapy previously. Five patients (26%) had undergone surgery ≥3 times before proton therapy. The median dose delivered was 54 GyE. The most common acute toxicity was grade 1 alopecia (63%). No patient experienced grade ≥3 acute toxicity. With a median follow-up of 18 months (range, 3-40 months), 12 patients showed shrinkage of the residual tumor and/or cyst, and 4 showed a dramatic cyst reduction at 3-9 months of follow-up. Two patients experienced a reduction in both solid and cystic components, with the remaining experiencing a reduction in the cystic component only. The remaining 8 patients had stable disease on magnetic resonance imaging, with 100% disease control and overall survival. Visual function remained stable after treatment. CONCLUSIONS: Our preliminary experience with modern PBS-PBT and image guidance for craniopharyngioma is encouraging. Proton therapy in our cohort was well tolerated, resulting in limited toxicity and promising early outcomes.

Seed-Induced Living Two-Dimensional (2D) Supramolecular Polymerization in Water: Implications on Protein Adsorption and Enzyme Inhibition.

In biological systems, programmable supramolecular frameworks characterized by coordinated directional non-covalent interactions are widespread. However, only a small number of reports involve pure water-based dynamic supramolecular assembly of artificial π-amphiphiles, primarily due to the formidable challenge of counteracting the strong hydrophobic dominance of the π-surface in water, leading to undesired kinetic traps. This study reveals the pathway complexity in hydrogen-bonding-mediated supramolecular polymerization of an amide-functionalized naphthalene monoimide (NMI) building block with a hydrophilic oligo-oxyethylene (OE) wedge. O-NMI-2 initially produced entropically driven, collapsed spherical particles in water (Agg-1); however, over a span of 72 h, these metastable Agg-1 gradually transformed into two-dimensional (2D) nanosheets (Agg-2), favoured by both entropy and enthalpy contributions. The intricate self-assembly pathways in O-NMI-2 enable us to explore seed-induced living supramolecular polymerization (LSP) in water for controlled synthesis of monolayered 2D assemblies. Furthermore, we demonstrated the nonspecific surface adsorption of a model enzyme, serine protease α-Chymotrypsin (α-ChT), and consequently the enzyme activity, which could be regulated by controlling the morphological transformation of O-NMI-2 from Agg-1 to Agg-2. We delve into the thermodynamic aspects of such shape-dependent protein-surface interactions and unravel the impact of seed-induced LSP on temporally controlling the catalytic activity of α-ChT.

A comparative dose-escalation analysis for reirradiated cancer patients with and without appropriate dose mapping.

This study aims to compare dose escalation between two groups of reirradiated cancer patients, one with the previous contour and radiotherapy plan available on the treatment planning system and the other without. First group is identified as DICOM-group, while the other one is called non-DICOM group. The current study included 89 patients, 57 in the DICOM, and 32 in the non-DICOM group, who received reirradiation for recurrent or second primary tumours between 2019 and 2021. For the DICOM group, doses to 0.2cc volume for spine, brainstem, and optic apparatus from first radiation were converted into structures and transferred to reirradiation CT using deformable registration. First, one radiotherapy plan was created using the doctor prescribed dose (baseline prescription RxD_B); further an escalated dose (RxD_E) plan, taking into account all the dose volume parameters from previous radiation, was created only for DICOM group. In non-DICOM group patients were planned only for RxD_B. The maximum accepted dose escalation was 21 Gy. Radiotherapy prescription dose during earlier (first) treatment in DICOM and non-DICOM groups were 61 ± 5.6 Gy and 30-66 Gy, respectively. DICOM and non-DICOM groups had nearly identical baseline doses: 52.5 ± 10.7 Gy and 50.6 ± 6.9 Gy (difference 1.9 ± 12.7 Gy). Dose escalation was possible for 51 out of 57 patients in the DICOM-group. Average escalated dose in DICOM-group was 59.2 ± 6.2 Gy, with an incremental dose of 6.7 ± 12.4 Gy from the baseline prescription. No dose escalation was opted for in the non-DICOM group due to the unavailability of dose volume information from previous radiation. Reirradiation for head and neck cases allowed for a moderate to high dose escalation, facilitated by the presence of pertinent DICOM information from the initial radiotherapy.

Integrated Analysis of lncRNA-miRNA-mRNA Regulatory Network in Rapamycin-Induced Cardioprotection against Ischemia/Reperfusion Injury in Diabetic Rabbits.

The inhibition of mammalian target of rapamycin (mTOR) with rapamycin (RAPA) provides protection against myocardial ischemia/reperfusion (I/R) injury in diabetes. Since interactions between transcripts, including long non-coding RNA (lncRNA), microRNA(miRNA) and mRNA, regulate the pathophysiology of disease, we performed unbiased miRarray profiling in the heart of diabetic rabbits following I/R injury with/without RAPA treatment to identify differentially expressed (DE) miRNAs and their predicted targets of lncRNAs/mRNAs. Results showed that among the total of 806 unique miRNAs targets, 194 miRNAs were DE after I/R in diabetic rabbits. Specifically, eight miRNAs, including miR-199a-5p, miR-154-5p, miR-543-3p, miR-379-3p, miR-379-5p, miR-299-5p, miR-140-3p, and miR-497-5p, were upregulated and 10 miRNAs, including miR-1-3p, miR-1b, miR-29b-3p, miR-29c-3p, miR-30e-3p, miR-133c, miR-196c-3p, miR-322-5p, miR-499-5p, and miR-672-5p, were significantly downregulated after I/R injury. Interestingly, RAPA treatment significantly reversed these changes in miRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated the participation of miRNAs in the regulation of several signaling pathways related to I/R injury, including MAPK signaling and apoptosis. Furthermore, in diabetic hearts, the expression of lncRNAs, HOTAIR, and GAS5 were induced after I/R injury, but RAPA suppressed these lncRNAs. In contrast, MALAT1 was significantly reduced following I/R injury, with the increased expression of miR-199a-5p and suppression of its target, the anti-apoptotic protein Bcl-2. RAPA recovered MALAT1 expression with its sponging effect on miR-199-5p and restoration of Bcl-2 expression. The identification of novel targets from the transcriptome analysis in RAPA-treated diabetic hearts could potentially lead to the development of new therapeutic strategies for diabetic patients with myocardial infarction.

Successful Implementation of Image-Guided Pencil-Beam Scanning Proton Therapy in Medulloblastomas.

Medulloblastoma is the most common malignant brain tumour in children, while much rarer in adults. Although the prognosis and outcomes have greatly improved in the era of modern multidisciplinary management, long-term treatment-induced toxicities are common. Craniospinal irradiation followed by a boost to the primary and metastatic tumour sites forms the backbone of treatment. Proton therapy has been endorsed over conventional photon-based radiotherapy due to its superior dosimetric advantages and subsequently lower incidence and severity of toxicities. We report here our experience from South-East Asia's first proton therapy centre of treating 40 patients with medulloblastoma (38 children and adolescents, 2 adults) who received image-guided, intensity-modulated proton therapy with pencil-beam scanning between 2019 and 2023, with a focus on dosimetry, acute toxicities, and early survival outcomes. All patients could complete the planned course of proton therapy, with mostly mild acute toxicities that were manageable on an outpatient basis. Haematological toxicity was not dose-limiting and did not prolong the overall treatment time. Preliminary data on early outcomes including overall survival and disease-free survival are encouraging, although a longer follow-up and data on long-term toxicities are needed.

mTORC1 and SGLT2 Inhibitors-A Therapeutic Perspective for Diabetic Cardiomyopathy.

Diabetic cardiomyopathy is a critical diabetes-mediated co-morbidity characterized by cardiac dysfunction and heart failure, without predisposing hypertensive or atherosclerotic conditions. Metabolic insulin resistance, promoting hyperglycemia and hyperlipidemia, is the primary cause of diabetes-related disorders, but ambiguous tissue-specific insulin sensitivity has shed light on the importance of identifying a unified target paradigm for both the glycemic and non-glycemic context of type 2 diabetes (T2D). Several studies have indicated hyperactivation of the mammalian target of rapamycin (mTOR), specifically complex 1 (mTORC1), as a critical mediator of T2D pathophysiology by promoting insulin resistance, hyperlipidemia, inflammation, vasoconstriction, and stress. Moreover, mTORC1 inhibitors like rapamycin and their analogs have shown significant benefits in diabetes and related cardiac dysfunction. Recently, FDA-approved anti-hyperglycemic sodium-glucose co-transporter 2 inhibitors (SGLT2is) have gained therapeutic popularity for T2D and diabetic cardiomyopathy, even acknowledging the absence of SGLT2 channels in the heart. Recent studies have proposed SGLT2-independent drug mechanisms to ascertain their cardioprotective benefits by regulating sodium homeostasis and mimicking energy deprivation. In this review, we systematically discuss the role of mTORC1 as a unified, eminent target to treat T2D-mediated cardiac dysfunction and scrutinize whether SGLT2is can target mTORC1 signaling to benefit patients with diabetic cardiomyopathy. Further studies are warranted to establish the underlying cardioprotective mechanisms of SGLT2is under diabetic conditions, with selective inhibition of cardiac mTORC1 but the concomitant activation of mTORC2 (mTOR complex 2) signaling.

Cascade Energy Transfer and White-Light Emission in Chirality-Controlled Crystallization-Driven Two-Dimensional Co-assemblies from Donor and Acceptor Dye-Conjugated Polylactides.

Achieving predictable and programmable two-dimensional (2D) structures with specific functions from exclusively organic soft materials remains a scientific challenge. This article unravels stereocomplex crystallization-driven self-assembly as a facile method for producing thermally robust discrete 2D-platelets of diamond shape from biodegradable semicrystalline polylactide (PLA) scaffolds. The method involves co-assembling two PLA stereoisomers, namely, PY-PDLA and NMI-PLLA, which form stereocomplex (SC)-crystals in isopropanol. By conjugating a well-known Förster resonance energy transfer (FRET) donor and acceptor dye, namely, pyrene (PY) and naphthalene monoimide (NMI), respectively, to the chain termini of these two interacting stereoisomers, a thermally robust FRET process can be stimulated from the 2D array of the co-assembled dyes on the thermally resilient SC-PLA crystal surfaces. Uniquely, by decorating the surface of the SC-PLA crystals with an externally immobilized guest dye, Rhodamine-B, similar diamond-shaped structures could be produced that exhibit pure white-light emission through a surface-induced two-step cascade energy transfer process. The FRET response in these systems displays remarkable dependence on the intrinsic crystalline packing, which could be modulated by the chirality of the co-assembling PLA chains. This is supported by comparing the properties of similar 2D platelets generated from two homochiral PLLAs (PY-PLLA and NMI-PLLA) labeled with the same FRET pair.

Safety Analysis of Extended Platelet Shelf-Life with Large-Volume Delayed Sampling on BACT/ALERT® VIRTUO® in Australia.

Transfusion-transmitted bacterial infection (TTBI) is the leading cause of transfusion-transmitted infections. Platelet components are more likely to be associated with bacterial contamination due to their storage requirements. Australian Red Cross Lifeblood introduced the bacterial contamination screening (BCS) of all platelet components in 2008. The process was recently updated with the use of BACT/ALERT® VIRTUO®, a large-volume delayed sampling (LVDS) protocol and extending platelet shelf-life to seven days. This article describes the results from the routine BCS of platelet components in Australia. Use of VIRTUO has resulted in lower false-positive rates, reducing wastage and improving platelet inventory. Our findings show that the combination of LVDS and VIRTUO improves the safety of platelet transfusions through earlier time to detection, especially for pathogenic bacterial species. Pathogenic bacteria grew within 24 h of incubation with a clear delineation between pathogenic and non-pathogenic species. The data show this protocol is very safe, with no TTBI cases during this time. There were no TTBI reports in recipients of platelet components that subsequently had a positive culture with Cutibacterium species, probably due to the low pathogenic potential of these organisms and slow replication in aerobic platelet bags. We conclude there is no advantage in incubating culture bottles beyond five days.

Dopaminergic error signals retune to social feedback during courtship.

Hunger, thirst, loneliness and ambition determine the reward value of food, water, social interaction and performance outcome1. Dopamine neurons respond to rewards meeting these diverse needs2-8, but it remains unclear how behaviour and dopamine signals change as priorities change with new opportunities in the environment. One possibility is that dopamine signals for distinct drives are routed to distinct dopamine pathways9,10. Another possibility is that dopamine signals in a given pathway are dynamically tuned to rewards set by the current priority. Here we used electrophysiology and fibre photometry to test how dopamine signals associated with quenching thirst, singing a good song and courting a mate change as male zebra finches (Taeniopygia guttata) were provided with opportunities to retrieve water, evaluate song performance or court a female. When alone, water reward signals were observed in two mesostriatal pathways but singing-related performance error signals were routed to Area X, a striatal nucleus specialized for singing. When courting a female, water seeking was reduced and dopamine responses to both water and song performance outcomes diminished. Instead, dopamine signals in Area X were driven by female calls timed with the courtship song. Thus the dopamine system handled coexisting drives by routing vocal performance and social feedback signals to a striatal area for communication and by flexibly re-tuning to rewards set by the prioritized drive.

mTOR Signaling: New Insights into Cancer, Cardiovascular Diseases, Diabetes and Aging.

The mechanistic/mammalian target of rapamycin (mTOR), a member of the phosphoinositide 3-kinase (PI3K) related kinase family, integrates intracellular and environmental cues that coordinate a diverse set of cellular/tissue functions, such as cell growth, proliferation, metabolism, autophagy, apoptosis, longevity, protein/lipid/nucleotide synthesis, and tissue regeneration and repair [...].

Partial agonism in heteromeric GLUK2/GLUK5 kainate receptor.

Kainate receptors are a subtype of ionotropic glutamate receptors that form transmembrane channels upon binding glutamate. Here, we have investigated the mechanism of partial agonism in heteromeric GluK2/K5 receptors, where the GluK2 and GluK5 subunits have distinct agonist binding profiles. Using single-molecule Förster resonance energy transfer, we found that at the bi-lobed agonist-binding domain, the partial agonist AMPA-bound receptor occupied intermediate cleft closure conformational states at the GluK2 cleft, compared to the more open cleft conformations in apo form and more closed cleft conformations in the full agonist glutamate-bound form. In contrast, there is no significant difference in cleft closure states at the GluK5 agonist-binding domain between the partial agonist AMPA- and full agonist glutamate-bound states. Additionally, unlike the glutamate-bound state, the dimer interface at the agonist-binding domain is not decoupled in the AMPA-bound state. Our findings suggest that partial agonism observed with AMPA binding is mediated primarily due to differences in the GluK2 subunit, highlighting the distinct contributions of the subunits towards activation.

Single-Dose Treatment with Rapamycin Preserves Post-Ischemic Cardiac Function through Attenuation of Fibrosis and Inflammation in Diabetic Rabbit.

Robust activation of mTOR (mammalian target of rapamycin) signaling in diabetes exacerbates myocardial injury following lethal ischemia due to accelerated cardiomyocyte death with cardiac remodeling and inflammatory responses. We examined the effect of rapamycin (RAPA, mTOR inhibitor) on cardiac remodeling and inflammation following myocardial ischemia/reperfusion (I/R) injury in diabetic rabbits. Diabetic rabbits (DM) were subjected to 45 min of ischemia and 10 days of reperfusion by inflating/deflating a previously implanted hydraulic balloon occluder. RAPA (0.25 mg/kg, i.v.) or DMSO (vehicle) was infused 5 min before the onset of reperfusion. Post-I/R left ventricular (LV) function was assessed by echocardiography and fibrosis was evaluated by picrosirius red staining. Treatment with RAPA preserved LV ejection fraction and reduced fibrosis. Immunoblot and real-time PCR revealed that RAPA treatment inhibited several fibrosis markers (TGF-ß, Galectin-3, MYH, p-SMAD). Furthermore, immunofluorescence staining revealed the attenuation of post-I/R NLRP3-inflammasome formation with RAPA treatment as shown by reduced aggregation of apoptosis speck-like protein with a caspase recruitment domain and active-form of caspase-1 in cardiomyocytes. In conclusion, our study suggests that acute reperfusion therapy with RAPA may be a viable strategy to preserve cardiac function with the alleviation of adverse post-infarct myocardial remodeling and inflammation in diabetic patients.

Plasmonic nanoparticle-based surface-enhanced Raman spectroscopy-guided photothermal therapy: emerging cancer theranostics.

Optical imaging modalities have emerged as a keystone in oncological research, capable of providing molecular and cellular information on cancer with the advantage of being minimally invasive toward healthy tissues. Photothermal therapy (PTT) has shown great potential, with the exceptional advantages of high specificity and noninvasiveness. Combining surface-enhanced Raman spectroscopy (SERS)-based optical imaging with PTT has shown tremendous potential in cancer theranostics (therapeutics + diagnosis). This comprehensive review article provides up-to-date information by exploring recent works focused mainly on the development of plasmonic nanoparticles for medical applications using SERS-guided PTT, including the fundamental principles behind SERS and the plasmon heating effect for PTT.

A first glance into mixed phosphine-stibine moieties as protecting ligands for gold clusters.

Atomically precise gold clusters have attracted considerable research interest as their tunable structure-property relationships have resulted in widespread applications, from sensing and biomedicine to energetic materials and catalysis. In this article, the synthesis and optical properties of a novel [Au6(SbP3)2][PF6]2 cluster are reported. Despite the lack of spherical symmetry in the core, the cluster shows exceptional thermal and chemical stability. Detailed structural attributes and optical properties are evaluated experimentally and theoretically. This, to the best of our knowledge, is the first report of a gold cluster protected via synergistic multidentate coordination of stibine (Sb) and phosphine moieties (P). To further show that the latter moieties give a set of unique properties that differs from monodentate phosphine-protected [Au6(PPh3)6]2+, geometric structure, electronic structure, and optical properties are analyzed theoretically. In addition, this report also demonstrates the critical role of overall-ligand architecture in stabilizing mixed ligand-protected gold clusters.

Optimization of lignin extraction from bamboo by ultrasound-assisted organosolv pretreatment.

For a sustainable biorefinery, reduction in the recalcitrance of lignocellulosic biomass is very crucial for the efficient utilization of each fraction. The present work investigated an integrated pretreatment method to recover high-quality lignin along with the cellulose-rich pulp. An optimization study employing response surface methodology investigated the synergistic effects of ultrasound and organosolv pretreatment from Bambusa tulda (bamboo). The optimal condition (180 °C, 55 min, and 30 min sonication) resulted in 65.81 ± 2.40% of lignin yield with 95.37 ± 1.17% purity. A reduction in 7.85% yield and 1.54% purity of lignin with organosolv pretreatment highlighted the efficacy of sonication in lignin extraction. Ultrasound resulted in homolytic cleavage of the lignin-carbohydrate bond that enhanced delignification and increase the cellulose crystallinity. NMR, FTIR, GPC, and TGA of lignin suggested the superiority of sonication in maintaining lignin quality. A significant amount of ß-O-4 linkages in extracted lignin is favorable for its subsequent valorization.