Generation of resonance-dependent oscillation by mGluR-I activation switches single spiking to bursting in mesencephalic trigeminal sensory neurons.

The primary sensory neurons supplying muscle spindles of jaw-closing muscles are unique in that they have their somata in the mesencephalic trigeminal nucleus (MTN) in the brainstem, thereby receiving various synaptic inputs. MTN neurons display bursting upon activation of glutamatergic synaptic inputs while they faithfully relay respective impulses arising from peripheral sensory organs. The persistent sodium current (IN aP ) is reported to be responsible for both the generation of bursts and the relay of impulses. We addressed how IN aP is controlled either to trigger bursts or to relay respective impulses as single spikes in MTN neurons. Protein kinase C (PKC) activation enhanced IN aP only at low voltages. Spike generation was facilitated by PKC activation at membrane potentials more depolarized than the resting potential. By injection of a ramp current pulse, a burst of spikes was triggered from a depolarized membrane potential whereas its instantaneous spike frequency remained almost constant despite the ramp increases in the current intensity beyond the threshold. A puff application of glutamate preceding the ramp pulse lowered the threshold for evoking bursts by ramp pulses while chelerythrine abolished such effects of glutamate. Dihydroxyphenylglycine, an agonist of mGluR1/5, also caused similar effects, and increased both the frequency and impedance of membrane resonance. Immunohistochemistry revealed that glutamatergic synapses are made onto the stem axons, and that mGluR1/5 and Nav1.6 are co-localized in the stem axon. Taken together, glutamatergic synaptic inputs onto the stem axon may be able to switch the relaying to the bursting mode.

Hydrogel Crosslinked with Nanoparticles for Prevention of Surgical Hemorrhage and Recurrence of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is acknowledged as an immunosuppressive neoplasm, whereby the inactive microenvironment facilitates immune tolerance and evasion of HCC. Post-surgical resected liver cancer exhibits a proclivity for relapse, rendering prevention of recurrence challenging as it may transpire at any point subsequent to surgery. Among the various anti-recurrence interventions, the primary clinical approach involving the administration of regimens atezolizumab and bevacizumab (A+T) is deemed the most efficacious in reversing the tumor microenvironment, albeit still lacking in complete satisfaction. Therefore, the objective is to utilize a recently developed block copolymer as a protective carrier for two specific monoclonal antibody drugs. Subsequently, a modified hemostatic hydrogel will be synthesized for application during hepatic surgery. The immunotherapy impact of this approach is significantly prolonged and intensified due to the combined hemostasis properties and controlled release of the constituents within the synthesized nanocomposite hydrogel. Furthermore, these nanocomposite hydrogels exhibit remarkable efficacy in preventing postoperative wound bleeding and substantially enhancing the safety of liver cancer resection. This research on the anti-recurrence hydrogel system presents a novel therapeutic approach for addressing local recurrence of liver cancer, potentially offering a substantial contribution to the field of surgical treatment for liver cancer in the future.

Long-term outcomes following hepatectomy in patients with lean non-alcoholic fatty liver disease-associated hepatocellular carcinoma versus overweight and obese counterparts: A multicenter analysis.

BACKGROUND & AIMS: With the rising prevalence of non-alcoholic fatty liver disease (NAFLD) as a significant etiology for hepatocellular carcinoma (HCC), lean NAFLD-HCC has emerged as a specific distinct subtype. This study sought to investigate long-term outcomes following curative-intent hepatectomy for early-stage NAFLD-HCC among lean patients compared with overweight and obese individuals. METHODS: A multicenter retrospective analysis was used to assess early-stage NAFLD-HCC patients undergoing curative-intent hepatectomy between 2009 and 2022. Patients were stratified by preoperative body mass index (BMI) into the lean (<23.0 kg/m2), overweight (23.0-27.4 kg/m2) and obese (≥27.5 kg/m2) groups. Study endpoints were overall survival (OS) and recurrence-free survival (RFS), which were compared among groups. RESULTS: Among 309 patients with NAFLD-HCC, 66 (21.3 %), 176 (57.0 %), and 67 (21.7 %) were lean, overweight, and obese, respectively. The three groups were similar relative to most liver, tumor, and surgery-related variables. Compared with overweight patients (71.3 % and 55.6 %), the lean individuals had a worse 5-year OS and RFS (55.4 % and 35.1 %, P = 0.017 and 0.002, respectively), which were comparable to obese patients (48.5 % and 38.2 %, P = 0.939 and 0.442, respectively). After adjustment for confounding factors, multivariable Cox-regression analysis identified that lean bodyweight was independently associated with decreased OS (hazard ratio: 1.69; 95 % confidence interval: 1.06-2.71; P = 0.029) and RFS (hazard ratio: 1.72; 95 % confidence interval: 1.17-2.52; P = 0.006) following curative-intent hepatectomy for early-stage NAFLD-HCC. CONCLUSIONS: Compared with overweight patients, individuals with lean NAFLD-HCC had inferior long-term oncological survival after hepatectomy for early-stage NAFLD-HCC. These data highlight the need for examination of the distinct carcinogenic pathways of lean NAFLD-HCC and its potential consequences in HCC recurrence.

Antibody-imprinted membrane adsorber via two-step surface grafting.

In this work, a recently established, novel two-step imprinting strategy combining surface imprinting and scaffold imprinting was applied successfully to prepare a molecularly imprinted polymer (MIP) adsorber for immunoglobulin G (IgG). Track-etched polyethylene terephthalate (PET) membranes with previously introduced aliphatic C-Br groups as initiator on the pore surface were used to prepare first a functional polymer scaffold, grafted poly(methacrylic acid), via surface-initiated atom transfer radical polymerization (SI-ATRP). After template protein (IgG) binding to the scaffold, UV-initiated cross-linking copolymerization of acrylamide and methylenebisacrylamide (MBAA) as second step lead to a grafted MIP hydrogel layer. The influences of the three independent parameters, scaffold chain length by SI-ATRP time, degree of cross-linking of the MIP layer by MBAA content, and grafted MIP layer thickness by UV irradiation time, were studied to optimize protein binding capacity and selectivity. The results were also compared to previously obtained data for lysozyme imprinting using the same method, and significant effects of protein size on imprinting efficiency could be identified. The best IgG MIP membrane adsorber was then used to separate IgG from mixtures with human serum albumin (HSA), demonstrating IgG binding capacities and eluted IgG purities, which were almost independent of the excess of HSA. The results of this study are a significant extension of the scope of molecular imprinting toward large target bionanoparticles. The transfer of the approach from the model PET to other base membranes with higher specific surface area is straightforward, and the resulting affinity materials would, in principle, be suited for "capturing" of an antibody from a complex mixture.

ASAP Score versus GALAD Score for detection of hepatitis C-related hepatocellular carcinoma: A multicenter case-control analysis.

Background: The GALAD and ASAP scores are two well-recognized algorithms to estimate the risk of hepatocellular carcinoma (HCC) based on gender, age, alpha-fetoprotein (AFP), protein induced by vitamin K absence or Antagonist-II (PIVKA-II) and AFP-L3 (included in the GALAD score but not in the ASAP score). The current study sought to compare the diagnostic performance of each score to detect HCC among patients infected with hepatitis C virus (HCV). Methods: A multicenter case-control study was undertaken in which blood samples were collected from HCVinfected patients with and without HCC. Using the area under the receiver operating characteristic curve (AUROC), ASAP and GALAD scores were compared relative to diagnostic performance to detect any stage HCV-HCC and early-stage HCV-HCC. Results: The analytic cohort included 168 HCV-HCC patients and a control group of 193 HCV-infected patients. The ASAP score had a higher AUROC to detect any stage HCV-HCC versus the GALAD score, both in the overall group (0.917 vs. 0.894, P=0.057) and in the cirrhosis subgroup (0.909 vs. 0.889, P=0.132). Similar results were noted relative to the detection of early-stage HCV-HCC, whether defined by BCLC staging (stage 0-A: 0.898 vs. 0.860, P=0.026) or 8th TNM staging (stage I: 0.899 vs. 0.870, P=0.070). In subgroup analysis to detect AFP-negative HCV-HCC, the ASAP score also demonstrated a higher AUROC than the GALAD score to detect any stage HCV-HCC in the AFP-negative subgroup (0.815 vs. 0.764, P=0.063). Conclusions: The ASAP score had better diagnostic performance for early detection of HCV-HCC compared with the GALAD score. The ASAP score may be preferrable to the GALAD score for HCC screening and surveillance among HCV-infected patients.

Genomic and EST microsatellites for Rhododendron aureum (Ericaceae) and cross-amplification in other congeneric species.

PREMISE OF THE STUDY: Our objective of this study was to develop genomic and expressed sequence tag (EST)-derived microsatellites for the endangered species Rhododendron aureum and access their transferability in R. dauricum and R. brachycarpum. • METHODS AND RESULTS: Twelve genomic microsatellites were isolated in R. aureum using the Fast Isolation by AFLP of Sequences Containing repeats (FIASCO) protocol and seven EST-derived microsatellites were characterized by screening the Rhododendron dbEST database of GenBank. The number of alleles per locus ranged from one to eight. The observed and expected heterozygosity varied from 0.00 to 1.00 and from 0.00 to 0.73, respectively. • CONCLUSIONS: A total of 19 microsatellite loci were developed for R. aureum. Sixteen and 10 of these loci were successfully amplified in R. brachycarpum and R. dauricum, respectively. These microsatellite markers will have potential applications in genetic diversity and conservation genetics studies.

Population genetic structures of two ecologically distinct species Betula platyphylla and B. ermanii inferred based on nuclear and chloroplast DNA markers.

Climatic oscillations during the last glacial maximum (LGM) significantly affected the distribution patterns and genetic structure of extant plants. Northeast China (NEC) is a major biodiversity center in East Asia, and the influence of historical climate change on NEC populations is critical for understanding species responses to future climate change. However, only a few phylogeographic studies of cool temperate deciduous tree species have been conducted in the area, and results are inconsistent for species with different niches or distribution areas. We employed multiple chloroplast and nuclear markers to investigate the genetic structure of two ecologically contrasting species, Betula platyphylla and B. ermanii, in NEC. Rare haplotypes were identified in the chloroplast genome of these species, and both exhibited high levels of nucleotide diversity based on a fragment of the nuclear gene G3PDH and microsatellites. Moreover, significant phylogeographic structure was detected for B. platyphylla, suggesting that these populations had recolonized from independent glacial refuges, whereas no genetic structure was found for B. ermanii. OPEN RESEARCH BADGES: The nSSR datasets used in the current study and the table of pairwise FST (below diagonal) and its standardized F'ST (above diagonal) among 25 populations based on seven SSRs are available from the Dryad (DOI: https://doi.org/10.5061/dryad.230d176). Sequences generated from this study were deposited in GenBank under Accession nos. KY199568-KY200162 and MK819541-MK819970.

Protein-selective adsorbers by molecular imprinting via a novel two-step surface grafting method.

Molecularly imprinted polymers (MIP) offer in principle a robust, cost-efficient alternative to antibodies, but it is still a challenge to develop such materials for protein recognition. Here, we report the molecular imprinting of a functional polymeric hydrogel layer with lysozyme as the template in a two-step grafting procedure by a novel initiation approach on track-etched polyethylene terephthalate membrane surface. This is based on surface functionalization with aliphatic C-Br groups which can be used as an initiator for surface-initiated atom transfer radical polymerization (SI-ATRP) and photo-initiated copolymerization. At first, the scaffold poly(methacrylic acid) (PMAA) was obtained through SI-ATRP of poly(tert-butyl methacrylate) and subsequent hydrolysis. Thereafter, it was assembled with the template to form a stable PMAA/lysozyme complex. In the second step, a polyacrylamide (PAAm) hydrogel was synthesized via UV-initiated surface grafting/crosslinking copolymerization around the scaffold/protein complex. Finally, the template was eluted to yield the grafted hydrogel layer with binding sites having complementary size, shape and appropriate arrangement of the functional groups to rebind lysozyme. The selectivity of lysozyme recognition, relative to cytochrome C with a similar size and isoelectric point, was increased by optimization of the scaffold chain length, UV grafting/crosslinking time and the chemical crosslinking degree of the PAAm-based hydrogel. The feasibility for the development of protein MIP in a straightforward way by independent optimization of crucial parameters - structures of scaffold with functional groups and of the crosslinked hydrogel matrix - have been demonstrated.