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Se presenta un análisis de las recomendaciones que dan los códigos que se utilizan en Costa Rica en relación con el cálculo de longitudes de empalmes y de anclajes del refuerzo del concreto. Se realiza una comparación de las recomendaciones de los códigos y se realiza un análisis sobre la importancia de los factores que determinan las longitudes citadas. Se plantean los problemas de cumplir la totalidad de las recomendaciones, y las contradicciones que se pueden generar al aplicarlas directamente.

Body representations (BR) for action are critical to perform accurate movements. Yet, behavioral measures suggest that BR are distorted even in healthy people. However, the upper limb has mostly been used as a probe so far, making difficult to decide whether BR are truly distorted or whether this depends on the effector used as a readout. Here, we aimed to assess in healthy humans the accuracy of the eye and hand effectors in localizing somatosensory targets, to determine whether they may probe BR similarly. Twenty-six participants completed two localization tasks in which they had to localize an unseen target (proprioceptive or tactile) with either their eyes or hand. Linear mixed model revealed in both tasks a larger horizontal (but not vertical) localization error for the ocular than for the manual localization performance. However, despite better hand mean accuracy, manual and ocular localization performance positively correlated to each other in both tasks. Moreover, target position also affected localization performance for both eye and hand responses: accuracy was higher for the more flexed position of the elbow in the proprioceptive task and for the thumb than for the index finger in the tactile task, thus confirming previous results of better performance for the thumb. These findings indicate that the hand seems to beat the eyes along the horizontal axis when localizing somatosensory targets, but the localization patterns revealed by the two effectors seemed to be related and characterized by the same target effect, opening the way to assess BR with the eyes when upper limb motor control is disturbed., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cadmium, a heavy metal, disrupts cellular homeostasis and is highly toxic, with no effective treatments currently available against its toxicity. According to studies, phytochemicals provide a promising strategy for mitigating cadmium toxicity. Naringenin (NG), a potent antioxidant found primarily in citrus fruits, showed protective properties against cadmium toxicity in rats. Nonetheless, the precise mechanism of cadmium cytotoxicity in fibroblasts remains unknown. This study evaluated NG against cadmium (CdCl 2 ) toxicity utilizing network pharmacology and in silico molecular docking, and was further validated experimentally in rat fibroblast F111 cells. Using network pharmacology, 25 possible targets, including the top 10 targets of NG against cadmium, were identified. Molecular docking of interleukin 6 (IL6), the top potential target with NG, showed robust binding with an inhibition constant (Ki) of 58.76 μM, supporting its potential therapeutic potential. Pathway enrichment analysis suggested that "response to reactive oxygen species" and "negative regulation of small molecules metabolic process" were the topmost pathways targeted by NG against cadmium. In vitro analysis showed that NG (10 μM) attenuated CdCl 2 -induced oxidative stress by reducing altered intracellular ROS, mitochondrial mass, and membrane potential. Also, NG reversed CdCl 2 -mediated nuclear damage, G2/M phase arrest, and apoptosis. GC/MS-based metabolomics of F111 cells revealed CdCl 2 reduced cholesterol levels, which led to alterations in primary bile acid, steroid and steroid hormone biosynthesis pathways, whereas, NG restored these alterations. In summary, combined in silico and in vitro analysis suggested that NG protected cells from CdCl 2 toxicity by mitigating oxidative stress and metabolic pathway alterations, providing a comprehensive understanding of its protective mechanisms against cadmium-induced toxicity., (© 2024 Wiley Periodicals LLC.)

Purpose: SHR-A1811 is an antibody-drug conjugate composed of an anti-human epidermal growth factor receptor 2 (HER2) antibody trastuzumab, a cleavable linker, and a topoisomerase I inhibitor payload. We assessed the safety, tolerability, antitumor activity, and pharmacokinetics of SHR-A1811 in heavily pretreated HER2-expressing or mutated advanced solid tumors., Methods: This global, multi-center, first-in-human, phase I trial was conducted at 33 centers. Patients who had HER2-expressing or mutated unresectable, advanced, or metastatic solid tumors and were refractory or intolerant to standard therapies were enrolled. SHR-A1811 was administered intravenously at doses ranging from 1.0 to 8.0 mg/kg once every 3 weeks. The primary end points were dose-limiting toxicity, safety, and the recommended phase II dose., Results: From September 7, 2020, to February 27, 2023, 307 patients who had undergone a median of three (IQR, 2-5) previous treatment regimens in the metastatic setting received SHR-A1811 treatment. As of data cutoff (February 28, 2023), one patient from the 6.4 mg/kg group experienced dose-limiting toxicities (pancytopenia and colitis). The most common grade 3 or higher adverse events (AEs) included decreased neutrophil count (119 [38.8%]) and decreased WBC count (70 [22.8%]). Interstitial lung disease occurred in only eight (2.6%) patients. Serious AEs and deaths occurred in 70 (22.8%) and 13 (4.2%) patients, respectively. SHR-A1811 led to objective responses in 59.9% (184/307) of all patients, 76.3% (90/118) of HER2-positive breast cancer, 60.4% (55/91) of HER2 low-expressing breast cancer, and 45.9% (39/85 with evaluable tumor responses) of the 98 nonbreast tumors., Conclusion: SHR-A1811 exhibited acceptable tolerability, promising antitumor activity, and a favorable pharmacokinetic profile in heavily pretreated advanced solid tumors. The recommended phase II dose of 4.8 or 6.4 mg/kg was selected for various tumor types.

Humans are endowed with a motor system that resonates to speech sounds, but whether concurrent visual information from lip movements can improve speech perception at a motor level through multisensory integration mechanisms remains unknown. Therefore, the aim of the study was to explore behavioral and neurophysiological correlates of multisensory influences on motor resonance in speech perception. Motor-evoked potentials (MEPs), by single pulse transcranial magnetic stimulation (TMS) applied over the left lip muscle (orbicularis oris) representation in the primary motor cortex, were recorded in healthy participants during the presentation of syllables in unimodal (visual or auditory) or multisensory (audio-visual) congruent or incongruent conditions. At the behavioral level, subjects showed better syllable identification in the congruent audio-visual condition as compared to the unimodal conditions, hence showing a multisensory enhancement effect. Accordingly, at the neurophysiological level, increased MEPs amplitudes were found in the congruent audio-visual condition, as compared to the unimodal ones. Incongruent audio-visual syllables resulting in illusory percepts did not increase corticospinal excitability, which in fact was comparable to that induced by the real perception of the same syllable. In conclusion, seeing and hearing congruent bilabial syllables increases the excitability of the lip representation in the primary motor cortex, hence documenting that multisensory integration can facilitate speech processing by influencing motor resonance. These findings highlight the modulation role of multisensory processing showing that it can boost speech perception and that multisensory interactions occur not only within higher-order regions, but also within primary motor areas, as shown by corticospinal excitability changes., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Lay Abstract: A vast majority of individuals with autism spectrum disorder experience impairments in motor skills. Those are often labelled as additional developmental coordination disorder despite the lack of studies comparing both disorders. Consequently, motor skills rehabilitation programmes in autism are often not specific but rather consist in standard programmes for developmental coordination disorder. Here, we compared motor performance in three groups of children: a control group, an autism spectrum disorder group and a developmental coordination disorder group. Despite similar level of motor skills evaluated by the standard movement assessment battery for children, in a Reach-to-Displace Task, children with autism spectrum disorder and developmental coordination disorder showed specific motor control deficits. Children with autism spectrum disorder failed to anticipate the object properties, but could correct their movement as well as typically developing children. In contrast, children with developmental coordination disorder were atypically slow, but showed a spared anticipation. Our study has important clinical implications as motor skills rehabilitations are crucial to both populations. Specifically, our findings suggest that individuals with autism spectrum disorder would benefit from therapies aiming at improving their anticipation, maybe through the support of their preserved representations and use of sensory information. Conversely, individuals with developmental coordination disorder would benefit from a focus on the use of sensory information in a timely fashion.

Cancerous cells display metabolic engineering through enhanced utilization of nutrients to support their increased requirements for proliferation, bioenergetics, biosynthesis, redox homeostasis, and cell signaling. To investigate the extent to which malignant cells rely on glycolysis and glutaminolysis, the effects of differential deprivation of nutrients such as d-glucose, l-glutamine, and pyruvate on proliferation, morphology, cell cycle, oxidative stress, mitochondrial function, autophagic vacuole formation, and migration in MDA-MB-231, HepG2, and HeLa cells were investigated in this study. Cell viability assay,  cell morphology, and ATP assay showed higher dependence of MDA-MB-231 and HepG2 cells on glucose and glutamine, respectively, for cell survival, growth, ATP production, and proliferation, while HeLa cells were equally dependent on both. However, the combination of all three nutrients displayed maximum proliferation. Differential deprivation of glucose in the absence of glutamine resulted in G0/G1 plus G2/M arrest in MDA-MB-231, whereas G0/G1 arrest in HepG2 and S-phase arrest in HeLa cells occurred at 48 h. Although the differential withdrawal of nutrients revealed a varying degree of effect dependent on cell type, nutrient type, nutrient concentrations, and deprivation time, a general trend of increased oxidative stress, loss of mitochondrial membrane potential, and ATP and antioxidant (GSH) depletion led to mitochondrial dysfunction in all three cell lines and inhibition of cell migration in MDA-MB-231 and HeLa cells at 48 h. Extreme deprivation of nutrients formed autophagic vacuoles. Importantly, normal cells (HEK293) remained unaffected under most of the nutrient-deprived conditions examined. This study enhances our understanding of the impact of differential nutrient deprivation on critical characteristics of cancer cells, contributing to the development of metabolism-based effective anticancer strategies., Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03759-w., Competing Interests: Conflict of interestThe authors declare no competing interests., (© King Abdulaziz City for Science and Technology 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Background: Colorectal cancer with synchronous liver-only metastasis is managed with a multimodal approach, however, optimal sequencing of modalities remains unclear., Methods: A retrospective review of all consecutive rectal or colon cancer cases with synchronous liver-only metastasis was conducted from the South Australian Colorectal Cancer Registry from 2006 to 2021. This study aimed to investigate how order and type of treatment modality affects overall survival., Results: Data of over 5000 cases were analysed (n = 5244), 1420 cases had liver-only metastasis. There were a greater number of colon than rectal primaries (N = 1056 versus 364). Colonic resection was the preferred initial treatment for the colon cohort (60%). In the rectal cohort, 30% had upfront resection followed by 27% that had chemo-radiotherapy as 1st line therapy. For the colon cohort, there was an improved 5-year survival with surgical resection as initial treatment compared to chemotherapy (25% versus 9%, P < 0.001). In the rectal cohort, chemo-radiotherapy as the initial treatment was associated with an improved 5-year survival compared to surgery or chemotherapy (40% versus 26% versus 19%, P = 0.0015). Patients who were able to have liver resection had improved survival, with 50% surviving over 5 years compared to 12 months in the non-resected group (P < 0.001). Primary rectal KRAS wildtype patients who underwent liver resection and received Cetuximab had significantly worse outcomes compared to KRAS wildtype patients who did not (P = 0.0007)., Conclusions: Where surgery is possible, resection of liver metastasis and primary tumour improved overall survival. Further research is required on the use of targeted treatments in patients undergoing liver resection., (© 2023 Royal Australasian College of Surgeons.)

Tupistra nutans Wall. ex Lindl. is a medicinal plant found in the Eastern Himalayan region. Besides being used as a folk medicine for pain and high blood sugar, its inflorescence is consumed as a vegetable. However, its medicinal properties have not been proven in vitro and in vivo till now. Therefore, in this study, we reported the phytochemicals present in the methanolic extract of Tupistra nutans Wall. ex Lindl. inflorescence (METNI) and its comparative effect in liver carcinoma HepG2 cells against non-cancerous murine fibroblast F111 cells. Phytochemical profiling by gas chromatography-mass spectrometry (GC-MS) analysis showed that METNI was rich in unsaturated fatty acids, vitamin E, and anticancer compounds like diosgenin, linoleic acid, and palmitoleic acid. METNI was found to have in vitro antioxidant property as determined by DPPH and pyrogallol methods, and UV protection property as investigated by fluorescence-based and spectrophotometric methods. MTT assay revealed METNI caused significantly more cell proliferation inhibition in HepG2 (IC 50  = 138 µg/ml) compared to F111 (IC 50  = 347 µg/ml) cells. Although in both HepG2 and F111 cells METNI showed significant antioxidant activity, it led to intracellular ROS generation and cell cycle alteration at higher exposure. The obtained results suggest that Tupistra nutans can be a promising application for anticancer drug and skin care product development, but can be harmful if overconsumed., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The risk of recurrence after completion of curative-intent treatment of colorectal cancer (CRC) is hard to predict. Post-treatment assaying for circulating tumor DNA (ctDNA) is an encouraging approach for stratifying patients for therapy, but the prognostic value of this approach is less explored. This study aimed to determine if detection of methylated BCAT1 and IKZF1 following completion of initial treatment identified patients with a poorer recurrence-free survival (RFS)., Methods: 142 CRC stage I-III cases with at least 2 years of follow up (unless recurrence was evident sooner) and a methylated BCAT1/IKZF1 test result between 2 weeks and 12 months after completion of initial treatment were eligible for study inclusion. The association between BCAT1/IKZF1 and RFS was assessed by the log-rank (Mantel-Cox) method. Cox proportional hazard regression analysis was used for multivariable survival analysis., Results: Thirty-three (23.2%) had recurrence at a median 1.6y (interquartile range: 0.8-2.4). Methylated BCAT1/IKZF1 was detected in 19 of the 142 patients (13.4%) and was associated with a significant risk of recurrence (hazard ratio [HR] 5.7, 95%CI: 1.9-17.3, p = 0.002). Three-year RFS for patients with or without detectable methylated BCAT1/IKZF1 was 56.5% and 83.3%, respectively. Multivariable analysis showed that detection of methylated BCAT1/IKZF1 (HR = 2.6, p = 0.049) and site of the primary tumor (HR = 4.2, p = 0.002) were the only significant prognostic indicators of poor RFS., Conclusions: BCAT1/IKZF1 methylation testing after curative-intent treatment is an independent prognostic indicator for RFS and identifies a subgroup at high risk. Personalized surveillance is warranted for patients with these ctDNA biomarkers detectable after curative-intent treatment., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Soft electronic skin (soft-e-skin) capable of sensing touch and pressure similar to human skin is essential in many applications, including robotics, healthcare, and augmented reality. However, most of the research effort on soft-e-skin was confined to the lab-scale demonstration. Several hurdles remain challenging, such as highly complex and expensive fabrication processes, instability in long-term use, and difficulty producing large areas and mass production. Here, we present a robust 3D printable large-area electronic skin made of a soft and resilient polymer capable of detecting touch and load, and bending with extreme sensitivity (up to 150 kPa -1 ) to touch and load, 750 times higher than earlier work. The soft-e-skin shows excellent long-term stability and consistent performance up to almost a year. In addition, we describe a fabrication process capable of producing large areas and in large numbers, yet is cost-effective. The soft-e-skin consists of a uniquely designed optical waveguide and a layer of a soft membrane with an array of soft structures which work as passive sensing nodes. The use of a soft structure gives the liberty of stretching to the soft-e-skin without considering the disjoints among the sensing nodes. We have shown the functioning of the soft-e-skin under various conditions.

The present study investigated the anti-inflammatory effects and potential mechanisms of sodium butyrate (SB) in bovine embryo tracheal cells (EBTr) stimulated with lipopolysaccharide (LPS). EBTr were exposed to either 1 mmol/L SB for 18 h for the SB group (SB) or to 0.4 μg/mL LPS for 6 h for the LPS group (LPS). PBS was added to EBTr for a control group (CON). EBTr were pretreated with SB for 18 h followed by 6 h of LPS stimulation for the LSB group (LSB). Results showed that with LPS stimulation, the gene expression of TLR4, NF-κB, IL6, and IL8, as well as cytokine production of IL6 and TNF-α, were significantly increased compared with the CON group. In contrast, protein expression of IL10 was decreased. However, these inflammatory effects induced by LPS were reversed in the LSB group. Compared with the CON group, protein expression of TLR4, phospho-NF-κB p65, phospho-IκBα, and IL1α were increased in the LPS group and these were decreased in the LSB group. Similarly, increased nuclear translocation of phospho-NF-κB p65 in the LPS group was suppressed with SB pretreatment. In conclusion, SB can reduce inflammation induced by LPS in EBTr, and this positive effect is mediated through the TLR4 and NF-κB signaling pathway.

High concentrate (HC) diet feeding leads to the lysis of rumen microbes and the release of hazardous metabolites, which can trigger inflammatory responses, thereby impairing dairy cow health and production. γ -D-glutamyl- meso -diaminopimelic acid (iE-DAP), which constitutes the peptidoglycan (PGN) layer of bacteria, is the minimum PGN structure capable of activating inflammatory signaling pathways. This research paper aimed to determine the iE-DAP concentration and investigate the effects of an HC diet on the concentration of iE-DAP in the rumen fluid of dairy cows. However, there are limited studies on the determination of iE-DAP concentration. Hence, we established a high-performance liquid chromatography (HPLC) method combined with pre-column chiral derivatization to detect the concentration of iE-DAP in rumen fluid. Moreover, we conducted an animal experiment that included 12 lactating Holstein cows, which were randomly divided into a low-concentrate (LC) group and an HC group. The results showed that the linear range of iE-DAP was 5-500 µg/mL and that the intra- and inter-day RSDs were lower than 7%. Meanwhile, this method was successfully applied to the analysis of iE-DAP in rumen fluid, and the results revealed that long-term feeding with an HC diet elevated the concentration of iE-DAP in rumen fluid of dairy cows.

When describing motion along both the horizontal and vertical axes, languages from different families express the elements encoding verticality before those coding for horizontality (e.g., going up right instead of right up ). In light of the motor grounding of language, the present study investigated whether the prevalence of verticality in Path expression also governs the trajectory of arm biological movements. Using a 3D virtual-reality setting, we tracked the kinematics of hand pointing movements in five spatial directions, two of which implied the vertical and horizontal vectors equally (i.e., up right +45° and bottom right -45°). Movement onset could be prompted by visual or auditory verbal cues, the latter being canonical in French ("en haut à droite"/up right) or not ("à droite en haut"/right up). In two experiments, analyses of the index finger kinematics revealed a significant effect of gravity, with earlier acceleration, velocity, and deceleration peaks for upward (+45°) than downward (-45°) movements, irrespective of the instructions. Remarkably, confirming the linguistic observations, we found that vertical kinematic parameters occurred earlier than horizontal ones for upward movements, both for visual and congruent verbal cues. Non-canonical verbal instructions significantly affected this temporal dynamic: for upward movements, the horizontal and vertical components temporally aligned, while they reversed for downward movements where the kinematics of the vertical axis was delayed with respect to that of the horizontal one. This temporal dynamic is so deeply anchored that non-canonical verbal instructions allowed for horizontality to precede verticality only for movements that do not fight against gravity. Altogether, our findings provide new insights into the embodiment of language by revealing that linguistic path may reflect the organization of biological movements, giving priority to the vertical axis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Boulenger, Finos, Koun, Salemme, Desoche and Roy.)

Aims: Gastric cancer with peritoneal involvement has a poor prognosis. Intraperitoneal (IP) paclitaxel has shown promising results in these patients. However, this approach has only been studied in the Asian population, and in combination with S-1. We investigated the maximum tolerated dose of IP paclitaxel, with a standard chemotherapy combination, in the Australian population., Methods: The study of the population included metastatic human epidermal growth factor receptor 2 (HER2) negative gastric adenocarcinoma with peritoneal involvement. Treatment included six 21-day cycles of cisplatin (80 mg/m 2 IV, day 1) plus capecitabine (1000 mg/m 2 PO BD, days 1-14) plus IP paclitaxel (days 1 and 8). IP paclitaxel doses for cohort 1-3 were 10, 20, and 30 mg/m 2 , respectively, in a 3 + 3 standard dose-escalation design., Results: Fifteen patients were enrolled of which 6 were female and the median age was 63. Two patients developed dose-limiting toxicities. No grade 4/5 toxicities were recorded. The maximum tolerated dose was not reached. Therefore, as defined by the study protocol, the recommended phase-2 dose for IP paclitaxel was determined to be 30 mg/m 2 . The 12-month survival rate was 46.7%, and the median survival was 11.5 months (interquartile range [IQR]: 15.3-6.9)., Conclusions: IP paclitaxel is safe in combination with cisplatin and capecitabine and the recommended phase-2 dose is 30 mg/m 2 ., (© 2021 John Wiley & Sons Australia, Ltd.)

Objectives: Nab-paclitaxel has radiosensitizing antitumor efficacy in pancreatic cancer. We aimed to establish maximum tolerated dose (MTD) of nab-paclitaxel with radiotherapy in unresectable locally advanced pancreatic cancer., Methods: In a phase I dose escalation trial patients received weekly nab-paclitaxel for 6 weeks with external beam radiotherapy (EBRT). 3 + 3 design was used with nab-paclitaxel doses: 25 mg/m 2 (cohort 1), 50 mg/m 2 (cohort 2), 75 mg/m 2 (cohort 3), and 100 mg/m 2 (cohort 4). Primary endpoint was MTD. Secondary objectives were progression-free survival and overall survival., Results: Fourteen patients were recruited. Median age was 69 years (range, 40-86). Grade 1/2 toxicities were nausea (93%), vomiting (54%), diarrhea (57%), and fatigue (69%). There were no dose limiting toxicities (DLT) in cohorts 1 to 3. In cohort 4, DLTs of febrile neutropenia and enterocolitis were observed in patient 1. Subsequent DLT of febrile neutropenia and enterocolitis occurred in patient 5 in the expanded cohort. Following chemoradiotherapy median progression-free survival was 4.7 months (95% confidence interval, 2.5-27.5) and median overall survival was 10.8 months (95% confidence interval, 6.37-25.2)., Conclusions: Nab-paclitaxel and EBRT was well-tolerated at doses below 100 mg/m 2 . The MTD and recommended phase II study dose for nab-paclitaxel with EBRT is 75 mg/m 2 in this disease., Competing Interests: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs., (© 2022. Crown.)

Background: Nivolumab improves disease control and survival in advanced NSCLC in patients with good performance status (PS), but there is limited data on its efficacy in patients with poor PS., Aim: Primary objective of the study was to evaluate the efficacy and safety of nivolumab and examine the influence of PS on outcomes., Methods and Results: Retrospective analysis of patients treated with single-agent nivolumab for advanced NSCLC at a single institution was performed. Sixty-six patients treated with nivolumab were identified (33 male) with a median age of 68.5 years. Fifty-six (85%) patients were current or former smokers and 17 (26%) had brain metastasis. All patients had received prior chemotherapy, 39 (59%) patients received one and 27 (41%) had ≥2 prior lines of therapy. Median overall survival (OS) was 7.1 months (95%CI 3.61-11.3) in the overall study population. OS of patients with PS ≥2 at the start of treatment was 3.04 months (95%CI 1.64-7.36) as compared to 10.23 months (95%CI 7.06-18.9) with PS ≤1. The overall response rate was 7% (four patients had a partial response), 23 (40%) patients had stable disease; the overall disease control rate (partial response and stable disease) was 47%. Twenty-six (40%) patients had PS ≥2 at the start of treatment and 2 (8%) of these patients developed a partial response, 4 (15%) had stable disease; the overall disease control rate was 23%. Fourteen (58%) patients with PS ≥2 had disease progression at the time of first disease response evaluation. In the overall population, 20% of patients experienced grade ≥3 treatment-related adverse events (TRAEs), most commonly pneumonitis, hepatitis, and colitis. Fourteen TRAEs led to treatment discontinuation, 9 (23%) adverse events (AEs) in patients with PS ≤1 and 5 (19%) with PS ≥2. Fourteen (21%) patients died within 30 days of the last nivolumab treatment., Conclusion: There was no significant difference in toxicity leading to treatment discontinuation between the poor and good PS groups, but survival was shorter with poorer PS. PS appears to be an important prognostic factor and remains a relevant discriminator in the selection of treatment with immunotherapy for lung cancer., (© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Developmental Coordination Disorder (DCD) is a pathological condition characterized by impaired motor skills. Current theories advance that a deficit of the internal models is mainly responsible for DCD children's altered behavior. Yet, accurate movement execution requires not only correct movement planning, but also integration of sensory feedback into body representation for action (Body Schema) to update the state of the body. Here we advance and test the hypothesis that the plasticity of this body representation is altered in DCD. To probe Body Schema (BS) plasticity, we submitted a well-established tool-use paradigm to seventeen DCD children, required to reach for an object with their hand before and after tool use, and compared their movement kinematics to that of a control group of Typically Developing (TD) peers. We also asked both groups to provide explicit estimates of their arm length to probe plasticity of their Body Image (BI). Results revealed that DCD children explicitly judged their arm shorter after tool use, showing changes in their BI comparable to their TD peers. Unlike them, though, DCD did not update their implicit BS estimate: kinematics showed that tool use affected their peak amplitudes, but not their latencies. Remarkably, the kinematics of tool use showed that the motor control of the tool was comparable between groups, both improving with practice, confirming that motor learning abilities are preserved in DCD. This study thus brings evidence in favor of an alternative theoretical account of the DCD etiology. Our findings point to a deficit in the plasticity of the body representation used to plan and execute movements. Though not mutually exclusive, this widens the theoretical perspective under which DCD should be considered: DCD may not be limited to a problem affecting the internal models and their motor functions, but may concern the state of the effector they have to use., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Effective targeting of RAS mutations has proven elusive until recently. Novel agents directly targeting KRAS G12C have shown promise in early-phase clinical trials that included patients with metastatic colorectal cancer. Prior reports have suggested that G12C mutation may be predictive of poor outcome., Objective: Assessment of the specific characteristics and prognostic implications of individual RAS mutation subtypes in patients with metastatic colorectal cancer., Patients and Methods: Retrospective review of individual RAS mutation types from the South Australian Metastatic Colorectal Registry between 2006 and 2020., Results: Of the 5165 patients entered onto the registry, 2305 (45%) had RAS mutation results available. 772 (33%) had a RAS mutation. The nature of the RAS mutation was available in 668 (87% of those with RAS mutation). Rare mutations (outside codons 12 and 13) made up 12.6% of the total. There were numerical differences in survival between the specific RAS mutation subgroups, with the longest median overall survival (30 months) observed in those with G12S mutations. However, there was no statistical difference in survival when comparing the various RAS mutations, including the comparison of G12C to G12S (p = 0.38). Patients with cancer harbouring rare RAS mutations had a median survival of 30 months., Conclusions: Whilst the G12S mutation was associated with the longest survival numerically, the observed survival for patients with the most common RAS mutations (G12C, G12V, G12A, G12D and G13D) did not significantly differ., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Pancreatic cancer remains a challenging malignancy due to the high proportion of patients diagnosed at advanced stages and the limited treatment options. This article discusses recent evidence in the management of both localized and advanced pancreatic cancer and offers an expert opinion on current best practice., Areas Covered: For patients with localized disease, the evidence for adjuvant chemotherapy is discussed as well as emerging neoadjuvant approaches for resectable, borderline resectable, and locally advanced disease. Advances in metastatic disease are discussed including cytotoxic chemotherapy, targeted therapies, and the role of genomic testing to identify patients with molecular alterations. Reviewed literature included journal publications, abstracts presented at major international oncology meetings, and ongoing clinical trials databases., Expert Opinion: Pancreatic cancer is a devastating diagnosis and despite recent advances has a very poor prognosis. Only a minority of patients, 20%, are diagnosed with potentially curable disease. The shifting paradigm toward neoadjuvant therapy may improve resectability and survival rates; however, robust evidence is required. Thus far, there has only been limited progress in advanced stage disease. Genomic testing may potentially identify more treatment targets although limited to small subgroups.

Lipopolysaccharide (LPS) is the dominating endotoxin of Gram-negative bacteria, which can cause mastitis. Bovine mammary epithelial cells (BMECs), as major components of the mammary gland, usually suffer LPS challenge. Cis-9, trans-11 conjugated linoleic acid (CLA) has been reported to have anti-inflammatory characteristics, while its anti-oxidative ability to maintain cellular homeostasis in BMECs under LPS challenge is limited. Therefore, we studied whether cis-9, trans-11 CLA can restore the disturbance of cellular homeostasis indicated by the redox status and autophagy level caused by LPS and have an effect on cellular function- milk fat metabolism. For oxidative stress, LPS challenge promoted the formation of reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS) and decreased the concentration of glutathione. Anti-oxidative signaling regulated by transcription factor nuclear factor, erythroid 2 like 2 (Nrf2) was also depressed by LPS at the mRNA and protein level. However, cis-9, trans-11 CLA pretreatment downregulated the formation of ROS and TBARS and upregulated the expression of antioxidative enzymes. As a part of innate immunity, autophagy was also motivated by LPS challenge, while CLA decreased the autophagy level. LPS and H 2 O 2 inhibited milk fat synthesis-related transcription factor sterol regulatory element binding protein (SREBP1), peroxisome proliferator activated receptor gamma (PPARG) and their downstream enzymes. Furthermore, 50 uM cis-9, trans-11 CLA promoted the mRNA and protein abundance of milk fat synthesis-related genes and lipid droplet formation in BMECs. In conclusion, LPS challenge disturbed the cellular homeostasis and depressed milk fat synthesis in BMECs; while cis-9, trans-11 CLA alleviated oxidative stress and decreased autophagy level, thus promoting milk fat synthesis, which offers a natural therapeutic strategy for mastitis.

Bacterial infection is one of the main causes of bovine respiratory disease (BRD), which can cause tremendous losses for the herd farming industry worldwide. L-Glutamine (GLN), a neutral amino acid, has been reported to have anti-inflammatory properties. This study aims to explore the potential protective effects and mechanisms of GLN on acute lung injury (ALI) induced by lipopolysaccharide (LPS) in mice. Forty ICR mice were randomly divided into four groups (n = 10): a PBS intratracheal instillation group, a LPS intratracheal instillation group, a GLN gavage group, and a LPS+GLN group (GLN was given 1 h before the LPS stimulation). Twelve hours after LPS administration, the lung tissue and blood were collected. The results showed that the concentrations of IL-6, IL-8, and IL-1β; the protein abundance of the toll-like receptor 4 (TLR4), phosphorylated p38 (p-p38), phosphorylated ERK1/2 (p-ERK1/2), and phosphorylated JNK (p-JNK); and the expression level of genes associated with inflammation, such as IL-1β, IL-8, TNF-α, IL-6, TLR4, p38, ERK1/2, and JNK, were significantly increased in the LPS group compared with those in the PBS group. However, these increases were attenuated by GLN pretreatment in the LPS+GLN group. Furthermore, the pathological change of the structure of lung tissue from the LPS group was obvious compared to that from the PBS group; however, with GLN administration, these pathological changes were alleviated. Additionally, the secretion level of mucus and the percentage of positive MUC5AC staining on the epithelial surface area of the airway increased dramatically in the LPS group; however, GLN pretreatment in the LPS+GLN group markedly decreased these phenomena compared with that of the LPS group. These results indicate that GLN supplementation ameliorates LPS-induced ALI in mice and this effect may be mediated by the TLR4/MAPK signaling pathway., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Does tool use share syntactic processes with language? Acting with a tool is thought to add a hierarchical level into the motor plan. In the linguistic domain, syntax is the cognitive function handling interdependent elements. Using functional magnetic resonance imaging, we detected common neurofunctional substrates in the basal ganglia subserving both tool use and syntax in language. The two abilities elicited similar patterns of neural activity, indicating the existence of shared functional resources. Manual actions and verbal working memory did not contribute to this common network. Consistent with the existence of shared neural resources, we observed bidirectional behavioral enhancement of tool use and syntactic skills in language so that training one function improves performance in the other. This reveals supramodal syntactic processes for tool use and language.

Autophagy is a crucial cellular homeostatic process and an important part of the host defense system. Dysfunction in autophagy enhances tissue susceptibility to infection and multiple diseases. However, the role of nucleotide oligomerization domain 1 (NOD1) in autophagy in bovine hepatocytes is not well known. Therefore, our aim was to study the contribution of NOD1 to autophagy during inflammation in response to a specific ligand γ-d-glutamyl-meso-diaminopimelic acid (iE-DAP). To achieve this aim, hepatocytes separated from cows at ∼160 days in milk (DIM) were divided into six groups: the nontreated control (CON) group, the rapamycin-treated (RAP) group as a positive control, the iE-DAP-treated (DAP) group, the 3-MA-treated (MA) group, the rapamycin with 3-MA (RM) group, and the iE-DAP with 3-MA (DM) group. iE-DAP administration significantly increased the mRNA expression of NOD1, ATG16L1, RIPK2, ULK1, AMBRA1, DFCP1, WIPI1, ATG5, ATG7, ATG10, ATG4A, IκBα, NF-κB, CXCL1, IL-8, and STAT6 and significantly decreased PIK3C3. The protein expression of NOD1, p-IκBα, p-NF-κB/p-p65, LC3-II, ATG5, and beclin 1 were significantly upregulated and that of SQSTM1/p62, p-mTOR, and FOXA2 were significantly downregulated in response to iE-DAP. iE-DAP also induced the formation of LC3-GFP autophagic puncta in bovine hepatocytes. We also knocked down the NOD1 with siRNA. NOD1 silencing suppressed the autophagy and inflammation-related genes and proteins. The application of the autophagy inhibitor increased the expression of inflammatory molecules and alleviated autophagy-associated molecules. Taken together, these findings suggest that NOD1 is a key player for regulating both ATG16L1 and RIPK2-ULK1 directed autophagy during inflammation in response to iE-DAP in bovine hepatocytes., (© 2020 Wiley Periodicals LLC.)

Aim: To assess the prevalence of elementary visuospatial perception (EVSP) deficit in children with neurodevelopmental disorders., Method: Using a screening test designed and validated to measure dorsal EVSP ability, 168 children (122 males, 46 females; mean age 10y [SD 1y 10mo], range 4y 8mo-16y 4mo) diagnosed with developmental coordination disorder (DCD), specific learning disorder (SLD), attention-deficit/hyperactivity disorder (ADHD), and/or oral language disorder were compared with a group of 184 typically developing children. We also tested 14 children with binocular vision dysfunction and no neurodevelopmental disorder., Results: Children with SLD scored below the interquartile range of typically developing children as frequently (59%) as children with DCD, but only 5% were severely impaired (i.e. scored as outliers). Children with DCD were the most severely impaired (22% of outliers), even more so when they exhibited a co-occuring disorder. Children with language disorder and those with binocular vision dysfunction scored similarly to the group of typically developing children., Interpretation: These results confirm the importance of assessing EVSP in the clinical evaluation of children with neurodevelopmental disorders, in particular those presenting with DCD or SLD. What this paper adds More than half of children with developmental coordination disorder (DCD) scored below the normal interquartile range on the elementary visuospatial perception (EVSP) test. More than half of children with specific learning disorder (SLD) scored below the normal interquartile range on the EVSP test. Twenty-two percent of children with DCD performed as outliers on the EVSP test. Children with language disorder and those with binocular vision dysfunction scored similarly to typically developing children., (© 2020 Mac Keith Press.)

Background: Long-term high-concentrate (HC) diet feeding increased bacterial endotoxins, which translocated into the mammary glands of dairy goats and induced inflammatory response. γ-d-Glutamyl-meso-diaminopimelic acid (iE-DAP), bacterial peptidoglycan component, triggered inflammatory response through activating nucleotide oligomerization domain protein 1 (NOD1) signaling pathway. While dietary supplemented with sodium butyrate (SB) relieved inflammatory response and improved animal health and production. To investigate the effects and the mechanisms of action of SB on the inflammatory response in the mammary glands of dairy goats fed HC diet, 12 Saanen dairy goats were randomly assigned into HC group and SB regulated (BHC) group., Results: The results showed that SB supplementation attenuated ruminal pH decrease caused by HC diet in dairy goats resulting in a decrease of proinflammatory cytokines and iE-DAP plasma concentration and the mRNA expression of NOD1 and other inflammation-related genes. The protein levels of NOD1, NF-κB p65 and NF-κB pp65 were decreased by the SB supplementation. The expression of histone deacetylase 3 (HDAC3) was also inhibited by the SB supplementation. Meanwhile, the chromatin compaction ratios and DNA methylation levels of NOD1 and receptor-interacting protein 2 (RIP2) of BHC group were upregulated., Conclusion: Collectively, the SB supplementation mitigated the inflammatory response in the mammary glands of dairy goats during HC-induced subacute ruminal acidosis (SARA) by inhibiting the activation of the NOD1/NF-κB signaling pathway through the decrease of the iE-DAP concentration in the rumen fluid and plasma and HDAC3 expression. DNA methylation and chromatin remodeling also contributed to the anti-inflammatory effect of SB. © 2020 Society of Chemical Industry., (© 2020 Society of Chemical Industry.)

A tool can function as a body part yet not feel like one: Putting down a fork after dinner does not feel like losing a hand. However, studies show fake body-parts are embodied and experienced as parts of oneself. Typically, embodiment illusions have only been reported when the fake body-part visually resembles the real one. Here we reveal that participants can experience an illusion that a mechanical grabber, which looks scarcely like a hand, is part of their body. We found changes in three signatures of embodiment: the real hand's perceived location, the feeling that the grabber belonged to the body, and autonomic responses to visible threats to the grabber. These findings show that artificial objects can become embodied even though they bear little visual resemblance to the hand.

Humans evolution is distinctly characterized by their exquisite mastery of tools, allowing them to shape their environment in more elaborate ways compared to other species. This ability is present ever since infancy and most theories indicate that children become proficient with tool use very early. In adults, tool use has been shown to plastically modify metric aspects of the arm representation, as indexed by changes in movement kinematics. To date, whether and when the plastic capability of updating the body representation develops during childhood remains unknown. This question is particularly important since body representation plasticity could be impacted by the fact that the human body takes years to achieve a stable metric configuration. Here we assessed the kinematics of 90 young participants (8-21 years old) required to reach for an object before and after tool use, as a function of their pubertal development. Results revealed that tool incorporation, as indexed by the adult typical kinematic pattern, develops very slowly and displays a u-shaped developmental trajectory. From early to mid puberty, the changes in kinematics following tool use seem to reflect a shortened arm representation, opposite to what was previously reported in adults. This pattern starts reversing after mid puberty, which is characterized by the lack of any kinematics change following tool use. The typical adult-like pattern emerges only at late puberty, when body size is stable. These findings reveal the complex dynamics of tool incorporation across development, possibly indexing the transition from a vision-based to a proprioception-based body representation plasticity.

Background: Studies have reported significant differences in baseline characteristics and outcomes of metastatic colorectal cancer (mCRC) patients when managed in private versus public hospitals., Aims: To compare disease, treatment and survival outcomes of patients with mCRC in public versus private hospitals in South Australia (SA)., Methods: Analysis of prospectively collected data from the SA mCRC Registry. Patterns of care and outcome data according to location of care and socioeconomic status based on Index of Relative Socio-Economic Advantage and Disadvantage were analysed., Results: A total of 3470 patients' data was analysed during February 2006-January 2015. The majority (70%) of patients received treatment in public hospitals. Patients in the upper 50% for Index of Relative Socio-Economic Advantage and Disadvantage score were more likely to receive treatment at a private hospital (41.2% vs 21.56%) compared to <50%. Public patients had higher burden of disease (10.49% vs 7.41%, P = 0.005). Public patients received less treatment compared to the private patients (odds ratio = 0.48 (0.38-0.61), P = 0.01) and rates of surgical resections were lower in public patients. After adjusting for the covariates, public patients survive 1.33 months (P = 0.025) shorter than private patients with follow-up time of 5 years. Patients receiving metastasectomy and more than three lines of treatment were shown to have the greatest survival benefit., Conclusion: Public patients have a higher burden of disease and in comparison are less likely to receive systemic therapy and have lower survival than patients treated in private hospitals., (© 2020 Royal Australasian College of Physicians.)

Following tool-use, the kinematics of free-hand movements are altered. This modified kinematic pattern has been taken as a behavioral hallmark of the modification induced by tool-use on the effector representation. Proprioceptive inputs appear central in updating the estimated effector state. Here we questioned whether online proprioceptive modality that is accessed in real time, or offline, memory-based, proprioception is responsible for this update. Since normal aging affects offline proprioception only, we examined a group of 60 year-old adults for proprioceptive acuity and movement's kinematics when grasping an object before and after tool-use. As a control, participants performed the same movements with a weight-equivalent to the tool-weight-attached to their wrist. Despite hampered offline proprioceptive acuity, 60 year-old participants exhibited the typical kinematic signature of tool incorporation: Namely, the latency of transport components peaks was longer and their amplitude reduced after tool-use. Instead, we observed no kinematic modifications in the control condition. In addition, online proprioception acuity correlated with tool incorporation, as indexed by the amount of kinematics changes observed after tool-use. Altogether, these findings point to the prominent role played by online proprioception in updating the body estimate for the motor control of tools.

Objective: The reliability and validity of a screening test for a deficit in elementary visuo-spatial perception (EVSP) were evaluated., Method: This prospective study collected performance from 210 typically developing individuals and evaluated the internal consistency of the EVSP screening test. Test-retest reliability was examined with 25 individuals. Validity also involved retrospective clinical data collected from 223 non-typically developing children coming to the hospital for outpatient consultation. Since EVSP matures through childhood, we standardized the EVSP screening test scores by age category and performed Pearson correlations with standardized clinical tests scores., Results: Test-retest reliability (intraclass correlation coefficient=0.76) and internal consistency (Cronbach's alpha=0.76) were satisfactory. Construct validity included correlation with the subtests of the Wechsler Intelligence Scale IV (WISC-IV) involving visuo-spatial analysis (Matrix Reasoning and Block Design, P<0.01; Symbol Search and Coding, P<0.05) and was reinforced by the expected non-correlation between the Verbal Comprehension Index and EVSP scoring class. The EVSP scoring class was correlated with Manual dexterity of the M-ABC (P<0.05) and the Working Memory Index (P<0.05) of the WISC-IV including the subtest Arithmetic (P<0.01)., Conclusion: This screening test is reliable and valid to evaluate EVSP before more complex cognitive or motor assessment., (Copyright © 2019. Published by Elsevier Masson SAS.)

Embodiment of action-related language into the motor system has been extensively documented. Yet the case of sensory words, especially referring to touch, remains overlooked. We investigated the influence of verbs denoting tactile sensations on tactile perception. In Experiment 1, participants detected tactile stimulations on their forearm, preceded by tactile or non-tactile verbs by one of three delays (170, 350, 500 ms) reflecting different word processing stages. Results revealed shorter reaction times to tactile stimulations following tactile than non-tactile verbs, irrespective of delay. To ensure that priming pertained to tactile, and not motor, verb properties, Experiment 2 compared the impact of tactile verbs to both action and non-tactile verbs, while stimulations were delivered on the index finger. No priming emerged following action verbs, therefore not supporting the motor-grounded interpretation. Facilitation by tactile verbs was however not observed, possibly owing to methodological changes. Experiment 3, identical to Experiment 2 except that stimulation was delivered to participants' forearm, replicated the priming effect. Importantly, tactile stimulations were detected faster after tactile than after both non-tactile and action verbs, indicating that verbs' tactile properties engaged resources shared with sensory perception. Our findings suggest that language conveying tactile information can activate somatosensory representations and subsequently promote tactile detection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The anti-inflammatory effects of sodium valproate (VPA) in vivo and in vitro have been demonstrated in recent studies. The aim of this study was to evaluate whether VPA can suppress inflammation in bovine mammary epithelial cells (BMECs) stimulated by γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP). First, the concentration and treatment points of iE-DAP and VPA were optimized. Then, BMECs were cultured in complete media and separated into four groups: untreated control cells (CON group), cells stimulated by 10 μg/mL iE-DAP for 6 h (DAP group), cells stimulated by 0.5 mmol/L VPA for 6 h (VPA group), and cells pretreated with VPA (0.5 mmol/L) for 6 h followed by 10 μg/mL of iE-DAP for 6 h (VD group). The results showed that the level of  interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the culture medium increased in the iE-DAP-treated cells and that pretreatment with VPA reversed this increase. iE-DAP increased both mRNA and protein expression levels of nucleotide-binding oligomerization domain-containing protein 1 (NOD1) and receptor-interacting protein kinas (RIPK2) and activated inhibitor of NF-κB (IκB) and nuclear factor-kappa B p65 (NF-κB p65) through phosphorylation. Upon activation of the NF-κB pathway, the expression of the pro-inflammatory cytokines IL-6, interleukin-8 (IL-8) and interleukin-1β (IL-1β), the acute phase protein serum amyloid A 3 (SAA3) and the lingual antimicrobial peptide (LAP) but not  haptoglobi (HP) or bovine neutrophil beta defensing 5 (BNBD5) were increased in the DAP group. The VPA pretreatment induced the acetylation of signal transducers and activators of transcription(STAT1) and histone 3 (H3) by inhibiting histone deacetylase (HDAC) and then suppressed the NF-κB pathway. Moreover, VPA induced autophagy and reduced apoptosis in BMECs in the VD group. These results suggested that VPA treatment can attenuate the inflammatory response induced by iE-DAP., Competing Interests: Declaration of Competing Interest We declare no conflicts of interest involved in the present study., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction : A multimodal approach in operable early-stage oesophago-gastric (OG) cancer has evolved in the last decade, leading to improvement in overall outcomes. Areas covered : A review of the published literature and conference abstracts was undertaken on the topic of optimal adjunctive chemotherapy or chemoradiotherapy in early-stage OG cancers. This review article focuses on the current evidence pertaining to neoadjuvant and perioperative strategies in curable OG cancers including the evolving landscape of immunotherapy and targeted drugs in this setting. Expert commentary : Adjunctive therapies in the form of preoperative chemo-radiotherapy (CRT) or chemotherapy and perioperative chemotherapy over surgery alone improve outcomes in patients with operable OG cancer. Although there are variations in practice around the world, a multi-disciplinary approach to patient care is of paramount importance. Immunotherapy and on treatment functional imaging are two examples of emerging strategies to improve the outcome for early-stage patients. A better understanding of the molecular biology of this disease may help overcome the problem of tumor heterogeneity and enable more rationally designed and targeted therapeutic interventions in the future.

The development of safe and cost-effective methods for the treatment of dye polluted wastewater has been a great concern among researchers. Herein, we developed a nanocomposite (M3D-PAA-CCN) based on polyacrylic acid (PAA) crosslinked with magnetic 3D crosslinkers (M3D) and carboxylated cellulose nanocrystals (CCN), for the removal of cationic dyes from aqueous solutions. Acrylic-functionalized Fe 3 O 4 nanoparticles were covalently linked to the polymer chains via the form of the 3D crosslinker to introduce magnetic properties into the as-synthesized nanocomposite. The addition of highly dispersive CCN reduced the gel-like properties of the nanocomposite and instead incorporated a diffusive nature, which was more desirable for adsorbents. The surface morphology of the nanocomposite was analyzed by FESEM and the size of the nanocomposite particles was found to be in the range of 60-90 nm. The chemical functionalities and compositions were determined by XPS, FTIR, and EDX analyses whereas TGA confirmed the thermal stability of M3D-PAA-CCN. The maximum adsorption capacity of the M3D-PAA-CCN (332 mg g -1 ) was measured higher than that of M3D-PAA (114 mg g -1 ) to a cationic methylene blue (MB) dye indicating the significant contribution of CCN. The adsorption capacity of the as-synthesized M3D-PAA-CCN was found to be highly pH-dependent and the adsorption capacity increased with the increase of pH owing to the greater negative charge as indicated by the higher zeta potential. The adsorption kinetics of MB on the composites was found to follow the pseudo-second-order model. The adsorption capacity was also investigated as a function of concentration to figure out the adsorption mechanism using Langmuir and Freundlich isotherm models. The Langmuir model fitted the adsorption process better as suggested by the relatively smaller nonlinear chi-square value obtained from the fitting parameters., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Objective: Reprocessing reusable medical devices is crucial in the healthcare industry. To ensure patient safety, strict standards are dictated to validate thermal disinfection in automated washer-disinfectors. The United States Food and Drug Administration (FDA) has specific recommendations on the vegetative bacterial challenge but comparatively vague guidance on the use of a thermophilic Mycobacterium strain for thermal disinfection studies. This study aims to compare thermal resistance of Mycobacterium hassiacum and Mycobacterium terrae and determine which strain is suitable for medical device thermal disinfection validation testing in automated washer-disinfectors., Results: Thermal resistance was demonstrated in vitro by calculating D-values for each strain at different exposure temperatures, and correlated with actual in situ processing conditions. M. terrae was completely killed (> 7 log reduction) at temperatures above 68 °C, with D-values between 46.6 and 27.8 s at temperatures between 59.5 and 67.2 °C. M. hassiacum was completely killed (> 8 log reduction) at temperatures above 75 °C, with D-values between 82.1 and 21.7 s at temperatures ranging between 69.2 and 73.6 °C. In vitro results were correlated in a washer-disinfector performance validation setup.

(1) Background: The effects of a high-concentrate (HC) diet in inducing mammary epithelial cell apoptosis in dairy cows via the NOD1/Caspase-8 pathway have never been investigated before the current study. (2) Methods: Twelve Holstein Frisian cows at mid-lactation were selected to conduct this research. The animals were randomly allocated to two groups (n = 6), and both groups received one of two diets: a low-concentrate (LC) (forage: concentrate 6:4) or a high-concentrate (HC) (forage: concentrate 4:6) diet. Furthermore, an enzyme activity assay, tunnel cell assay, RT-qPCR, western blotting, and an immunofluorescence antibody (IFA) assay were performed to elucidate the effect of an HC diet in the mammary gland of dairy cows. (3) Results: The tunnel cell assay revealed a significant number of apoptotic cells in HC group, and the concentration of Caspase-3, and Caspase-8 was higher in the HC group than in the LC group. NOD1, Rip-2, Caspase-3, Caspase-8, Caspase-9, and Bax mRNA expressions, and NOD1, Caspase-3, Caspase-8, and Bax protein expressions, in the HC group were markedly higher than those in the LC group. Furthermore, Bcl-2 mRNA and protein expressions were markedly decreased in the HC compared to those in the LC group. (4) Conclusions: A HC diet fed to dairy cows incites subacute ruminal acidosis (SARA), which increases the iE-DAP concentration and induces apoptosis in the mammary gland via the NOD1/Caspase-8 pathway.

Nucleotide oligomerization domain protein-1 (NOD1), a cytosolic pattern recognition receptor for the γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP) is associated with the inflammatory diseases. Very little is known how bovine hepatocytes respond to specific ligands of NOD1 and sodium butyrate (SB). Therefore, the aim of our study was to investigate the role of bovine hepatocytes in NOD1-mediated inflammation during iE-DAP or LPS treatment or SB pretreatment. To achieve this aim, hepatocytes separated from cows at ∼160 days in milk (DIM) were divided into six groups: The nontreated control group (CON), the iE-DAP-treated group (DAP), the lipopolysaccharide-treated group (LPS), iE-DAP with SB group (DSB), LPS with SB group (LSB), and the SB group. Both iE-DAP and LPS highly increased the expression of both NOD1 and RIPK2, the two key factors for the immune response in hepatocytes. IκBα, NF-κB/p65, and MAP kinases (ERK, JNK, and p38) were activated through phosphorylation. The activation of NF-κB and MAPK pathway consequently increased the proinflammatory cytokines, IL-6, TNF-α, IL-8, and IFN-γ and the chemokines CCL5, CCL20, and CXCL-10. Both treatments improved iNOS/NOS2 expression. However, iE-DAP was failed to express acute phase protein SAA3, but HP and LPS HP but SAA3. These ligands also increased LRRK2, TAK1, TAB1, and β-defensins expression. The SB pretreatment at lower dose restored the function of hepatocytes by suppressing these increased molecules, as HDAC3 was inhibited. The activated NOD1 negatively regulated the expression of FOXA2. Altogether these data suggest an important role of bovine hepatocytes to promote immune responses via NOD1 expression during infection in the liver and a key role of SB to attenuate inflammation., (© 2019 Wiley Periodicals, Inc.)

Different disciplines converge to trace language evolution from motor skills. The human ability to use tools has been advocated as a fundamental step toward the emergence of linguistic processes in the brain. Neuropsychological and neuroimaging research has established that linguistic functions and tool-use are mediated by partially overlapping brain networks. Yet, scholars still theoretically debate whether the relationship between tool-use and language is contingent or functionally relevant, since empirical evidence is critically missing. Here, we measured both linguistic production and tool-use abilities in the same participants, as well as manual and linguistic motor skills. A path analysis ruling out unspecific contributions from manual or linguistic motor skills, showed that motor proficiency using a tool lawfully predicts differences in individual linguistic production. In addition, more complex tool-use reveals stronger association between linguistic production and tool mastery. These findings establish the existence of shared cognitive processes between tool-use and language.

During bimanual coordination, that is, manipulating with the dominant hand an object held by the postural hand, anticipatory postural adjustments are required to cancel the perturbations and ensure postural stabilization. Using magnetoencephalography (MEG), we investigated changes mediating the acquisition of anticipatory postural adjustments during a bimanual load-lifting task. Participants lifted a load with their right hand, hence triggering the fall of a second load fixed to their left (postural) forearm. During Acquisition, the onset of load-lifting and the fall of the second load were experimentally delayed after few trials. During Control, load-lifting triggered the fall of the second load without delay. Upward elbow rotation decreased with trial repetition during Acquisition, hence attesting the ongoing acquisition of anticipatory postural adjustments. Bilateral event-related desynchronisation (ERD) of the alpha rhythm (8-12 Hz) was recorded. Generators of the mu rhythm were found within central and associative motor regions. Their spatial distribution within the hemisphere contralateral to the load-lifting arm was less refined and circumscribed during Acquisition compared to Control. Regression analyses emphasized the specific involvement of the precuneus in the right hemisphere contralateral to the postural forearm, and a medial prefrontal region in the left hemisphere. Analyses of the time course power showed that an increase in preunloading activation within the precuneus and a decrease in postunloading inhibition within the medial prefrontal region were associated with the acquisition of anticipatory postural adjustments. The study provides original insights into cortical activations mediating the progressive tuning of anticipatory postural adjustments during the acquisition stage of motor learning., (© 2019 Wiley Periodicals, Inc.)

Streptococcus suis has received increasing attention for its involvement in severe infections in pigs and humans; however, their pathogenesis remains unclear. ClpX and ClpP, two subunits of the ATP-dependent caseinolytic protease Clp, play key roles in bacterial adaptation to various environmental stresses. In this study, a virulent S. suis serotype 2 strain, ZY05719, was employed to construct clpX and clpP deletion mutants (ΔclpX and ΔclpP, respectively) and their complementation strains. Both ΔclpX and ΔclpP displayed significantly reduced adaptability compared with the wild-type strain, evident through several altered phenotypes: formation of long cell chains, tendency to aggregate in culture, and reduced growth under acidic pH and H 2 O 2 -induced oxidative stress. ClpP and ClpX were required for the optimal growth during heat and cold stress, respectively. An in vitro experiment on RAW264.7 macrophage cells showed significantly increased sensitivity of ΔclpX and ΔclpP to phagocytosis compared with the wild-type strain. Mouse infection assays verified the deletion of clpX and clpP led to not only fewer clinical symptoms and lower mortality but also to a marked attenuation in bacterial colonization. These virulence-related phenotypes were restored by genetic complementation. Furthermore, the deletion of clpX or clpP caused a significant decrease in the expression of sodA, tpx, and apuA compared with the wild-type strain, suggesting that these genes may be regulated by ClpX and ClpP as downstream response factors to facilitate the bacterial tolerance against various environmental stresses. Taken together, these results suggest that ClpX and ClpP play important roles in stress tolerance for achieving the full virulence of S. suis serotype 2 during infection., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Introduction: Gastric cancer with peritoneal metastasis has a poor outcome. Only a few studies have specifically investigated this group of patients. Japanese researchers have shown that chemotherapy with intraperitoneal paclitaxel (IPP) and oral S-1 (tegafur/gimeracil/oteracil) is active and well tolerated. These results have been achieved in a specific genetic pool (Japanese population), using regimens that may not be available in other parts of the world. We have designed this phase I trial to investigate IPP in combination with a standard chemotherapy combination in these patients., Methods: We use a 3+3 expanded cohort dose escalation until a predefined number of dose-limiting toxicities are reached. Patients will have an intraperitoneal catheter placed surgically after trial enrolment. Chemotherapy includes a maximum of six cycles (21 days) of capecitabine (X) (1000 mg/m 2 two times a day, days 1-14)+cisplatin (C) (intravenous 80 mg/m 2 day 1) and IPP (days 1 and 8) with the following doses: cohort-1: 10 mg/m 2 , cohort-2: 20 mg/m 2 and cohort-3: 30 mg/m 2 . Primary endpoint is to determine the maximum tolerated dose of IPP. Secondary endpoints include determining the safety and tolerability of IPP in combination with C and X, overall response rates, ascites response rate, progression-free survival, overall survival and effects on quality of life.Important inclusion criteria include age ≥18 years, human epidermal growth factor receptor 2 non-amplified gastric adenocarcinoma with histological or cytology-proven peritoneal involvement and adequate organ function. Exclusion criteria include previous malignancy within 5 years, recent abdominal or pelvic radiation treatment, significant abdominal adhesions or sepsis., Ethics and Dissemination: The study is approved by Southern Adelaide Clinical Human Research Ethics Committee. A manuscript will be prepared for publication on the completion of the trial. This study will be conducted according to the Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) annotated with TGA comments (Therapeutic Goods Administration DSEB July 2000) and in compliance with applicable laws and regulations. The study will be performed in accordance with the NHMRC Statement on Ethical Conduct in Research Involving Humans (© Commonwealth of Australia 2007), and the NHMRC Australian Code for the Responsible Conduct of Research (©Australian Government 2007), and the principles laid down by the World Medical Assembly in the Declaration of Helsinki 2008., Trial Registration Number: ACTRN12614001063606., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tool-use changes both peripersonal space and body representations, with several effects being nowadays termed tool embodiment. Since somatosensation was typically accompanied by vision in most previous tool use studies, whether somatosensation alone is sufficient for tool embodiment remains unknown. Here we address this question via a task assessing arm length representation at an implicit level. Namely, we compared movement's kinematics in blindfolded healthy participants when grasping an object before and after tool-use. Results showed longer latencies and smaller peaks in the arm transport component after tool-use, consistent with an increased length of arm representation. No changes were found in the hand grip component and correlations revealed similar kinematic signatures in naturally long-armed participants. Kinematics changes did not interact with target object position, further corroborating the finding that somatosensory-guided tool use may increase the represented size of the participants' arm. Control experiments ruled out alternative interpretations based upon altered hand position sense. In addition, our findings indicate that tool-use effects are specific for the implicit level of arm representation, as no effect was observed on the explicit estimate of the forearm length. These findings demonstrate for the first time that somatosensation is sufficient for incorporating a tool that has never been seen, nor used before.