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Squamous mobile or portable carcinoma associated with uterine cervix metastatic towards the axillary lymph node.

Qc anxiety analyze pertaining to serious learning-based analysis product in digital camera pathology.

The long-term contribution of global forest restoration to support multiple dimensions of biodiversity and ecosystem function remains largely illusive across contrasting climates and forest types. This hampers the capacity to predict the future of forest rewilding under changing global climates. Here, 120 studies are synthesized across five continents, and it is found that forest restoration promotes multiple dimensions of biodiversity and ecosystem function such as soil fertility, plant biomass, microbial habitat, and carbon sequestration across contrasting climates and forest types. Based on global relationship between stand age and soil organic carbon stock, planting 350 million hectares of forest under the UN Bonn Challenge can sequester >30 Gt soil C in the surface 20 cm over the next century. However, these findings also indicate that predicted increases in temperature and reductions in precipitation can constrain the positive effects of forest rewilding on biodiversity and ecosystem function. Further, important tradeoffs are found in very old forests, with considerable disconnection between biodiversity and ecosystem function. Together, these findings provide evidence of the importance of the multidimensional rewilding of forests, suggesting that on-going climatic changes may dampen the expectations of the positive effects of forest restoration on biodiversity and ecosystem function.Organic ferroelectrics, as a type of crystalline compound, are generally solution processing. However, for most crystalline compounds, the changing of solvent would not influence the crystalline phase, let alone their physical performance. Here, the solvent selective effect occurs in the iodinated adamantanone ferroelectrics. By changing the solvent with different polarities, the ferroelectric crystals can be induced in two different phases, which is unprecedented to the knowledge. More strikingly, this solvent-induced transformation could realize the physical performance optimization in the orthorhombic phase (orth-I-OA, obtained from ethanol) with a stronger second harmonic generation (SHG) response, greater piezoelectric coefficient d33 of 5 pC N-1 , and larger spontaneous polarization (Ps ) of 3.43 µC cm-2 than those of monoclinic one (mono-I-OA, obtained from ethyl acetate). Such an intriguing phenomenon might be closely related to solvent polarity. Based on the quantitative and qualitative analyses, the similar interaction energies of these two phases suggest that their transformation could be easily realized via changing the solvent. This work provides new insights into the chemical design and performance optimization of organic ferroelectrics.Cross bred species such as switchgrass may benefit from advantageous breeding strategies requiring inbred lines. Doubled haploid production methods offer several ways that these lines can be produced that often involve uniparental genome elimination as the rate limiting step. We have used a centromere-mediated genome elimination strategy in which modified CENH3 is expressed to induce the process. Transgenic tetraploid switchgrass lines coexpressed Cas9, a poly-cistronic tRNA-gRNA tandem array containing eight guide RNAs that target two CENH3 genes, and different chimeric versions of CENH3 with alterations to the N-terminal tail region. Genotyping of CENH3 genes in transgenics identified edits including frameshift mutations and deletions in one or both copies of the two CENH3 genes. Flow cytometry of T1 seedlings identified two T0 lines that produced five haploid individuals representing an induction rate of 0.5% and 1.4%. Eight different T0 lines produced aneuploids at rates ranging from 2.1 to 14.6%. A sample of aneuploid lines were sequenced at low coverage and aligned to the reference genome, revealing missing chromosomes and chromosome arms.

Several investigations were carried out during the pandemic, demonstrating a number of neurological symptoms linked to coronavirus disease 2019 (COVID-19) infection.

The goal of this review is to discuss COVID-19 disease's neurological signs and squeals.

From December 2019 to May 2020, data were retrieved from PubMed, Scopus, and ScienceDirect, as well as a manual search using Google Scholar. COVID-19, neurological symptoms, cranial nerves, motor system were among the key phrases utilized in the search.

The intensity of respiratory involvement increases the likelihood of neurological symptoms and consequences. According to some research, it might range from 34% to 80%. The central and peripheral neural systems are both affected, resulting in cranial nerve palsies and limb paralysis.

COVID-19 neurologic complications are key drivers of patient severity and mortality. Headache, convulsions, mental and psychic disorders, delirium, and insomnia are just some of the symptoms that the virus can cause. The olfactory nerve is the most commonly damaged cranial nerve, resulting in anosmia. Stroke (mostly infarction), encephalitis, meningitis, Guillain-Barre syndrome, relapse of multiple sclerosis, and transverse myelitis are all symptoms and squeals.

COVID-19 neurologic complications are key drivers of patient severity and mortality. Headache, convulsions, mental and psychic disorders, delirium, and insomnia are just some of the symptoms that the virus can cause. The olfactory nerve is the most commonly damaged cranial nerve, resulting in anosmia. Stroke (mostly infarction), encephalitis, meningitis, Guillain-Barre syndrome, relapse of multiple sclerosis, and transverse myelitis are all symptoms and squeals.Amaranth species (Amaranthus spp.) serve as pseudo cereals and also as traditional leafy vegetables worldwide. In addition to high vigor and richness in nutrients, drought and salinity tolerance makes amaranth a promising vegetable to acclimatize to the effects of global climate change. The World Vegetable Center gene bank conserves ∼1,000 amaranth accessions, and various agronomic properties of these accessions were recorded during seed regeneration over decades. In this study, we verified the taxonomic annotation of the germplasm based on a 15K single-nucleotide polymorphism (SNP) set. Given that the yield components of grain amaranth are different from those of leaf amaranth, we observed that grain amaranth species presented larger inflorescences and earlier flowering than leaf amaranth species. Dual-purpose amaranth showed larger leaves than leaf amaranth and later flowering than grain amaranth, which seemed reasonable because farmers can harvest more leaves during the prolonged vegetable stage, which also provides recovery time to enrich grain production. Considering frequent interspecific hybridization among species of the grain amaranth complex, we performed an interspecific genome-wide association study (GWAS) for days to flowering, identifying a AGL20/SOC1 homolog. Another GWAS using only A. tricolor L. accessions revealed six candidate genes homologous to lba1, bri1, sgs1, and fca. These homologous genes were involved in the regulation of flowering time in Arabidopsis thaliana (L.) Heynh. This study revealed the usefulness of genotypic data for species demarcation in the genus Amaranthus and the potential of interspecific GWAS to detect quantitative trait loci (QTL) across different species, opening up the possibility of targeted introduction of specific genetic variants into different Amaranthus species.Plant metabolites are important traits for plant breeders seeking to improve nutrition and agronomic performance yet integrating selection for metabolomic traits can be limited by phenotyping expense and degree of genetic characterization, especially of uncommon metabolites. As such, developing generalizable genomic selection methods based on biochemical pathway biology for metabolites that are transferable across plant populations would benefit plant breeding programs. We tested genomic prediction accuracy for >600 metabolites measured by gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) in oat (Avena sativa L.) seed. Using a discovery germplasm panel, we conducted metabolite genome-wide association study (mGWAS) and selected loci to use in multikernel models that encompassed metabolome-wide mGWAS results or mGWAS from specific metabolite structures or biosynthetic pathways. Bcl-2 pathway Metabolite kernels developed from LC-MS metabolites in the discovery panel improved prediction accuracy of LC-MS metabolite traits in the validation panel consisting of more advanced breeding lines. No approach, however, improved prediction accuracy for GC-MS metabolites. We ranked model performance by metabolite and found that metabolites with similar polarity had consistent rankings of models. Overall, testing biological rationales for developing kernels for genomic prediction across populations contributes to developing frameworks for plant breeding for metabolite traits.

This study profiles ceramides extracted from visceral and subcutaneous adipose tissue of human subjects by liquid chromatography-mass spectrometry to determine a correlation with status of diabetes and gender.

Samples of visceral and abdominal wall subcutaneous adipose tissue (n=36 and n=31, respectively) were taken during laparoscopic surgery from 36 patients (14 nondiabetic, 22 diabetic and prediabetic) undergoing bariatric surgery with a body mass index (BMI) >35 kg/m

with ≥1 existing comorbidity or BMI ≥40 kg/m

. Sphingolipids were extracted and analyzed using liquid chromatography-mass spectrometry.

After logarithm 2 conversion, paired analysis of visceral to subcutaneous tissue showed differential accumulation of Cer(d181/160), Cer(d181/180), and Cer(d181/241) in visceral tissue of prediabetic/diabetic female subjects, but not in males. Within-tissue analysis showed higher mean levels of ceramide species linked to insulin resistance, such as Cer(d181/180) and Cer(d181/160), in visceral tisst on the prelipolytic state that leads the lipotoxic phase of insulin resistance and may shed light on the predisposition to insulin resistance by gender.Interstitial cystitis/bladder pain syndrome (IC/BPS) has a significant impact on quality of life, but the etiopathogenesis remains largely unknown. The bladder microenvironment of patients with IC/BPS to obtain biological evidence supporting diagnosis and novel therapy is systematically characterized. Single-cell RNA sequencing (scRNA-seq) and image mass cytometry (IMC) are applied to bladder biopsies of the IC/BPS cohort. A total of 42 distinct cell clusters are identified from different groups. The increased hyperactivated Th1-biased response, but not Th2-biased response, and decreased immunosuppressive Treg are elucidated in the bladder microenvironment of non-Hunner-type IC (NHIC)/Hunner-type IC (HIC). M2/M2-like macrophage extends in the HIC and M1-like macrophage extends in NHIC, all of which secrete a range of chemokines with different pattern. The pro-inflammatory mediators, TNF-α, produced by tissue-resident macrophages and IL6, by the inflammatory fibroblasts are identified as key mediators of IC/BPS pathogenesis. Additionally, a regulatory network between different cell types is observed as a shift from structural cell communication in unaffected normal bladder to a Macrophage-Endothelial-dominated interactome in NHIC/HIC. The results demonstrate the high heterogeneity in NHIC/HIC, and provide an essential resource for diagnosis, and treatment of IC/BPS in the future by highlighting the importance of the microenvironment of bladder mucosa.

The bone mineral density in patients with type 1 diabetes mellitus is reduced due to impaired insulin secretion. However, it is unclear whether the rate of bone mineral density reduction is affected by the type 1 diabetes mellitus subtype. This study aimed to clarify the difference in bone mineral density across type 1 diabetes mellitus subtypes slowly progressive (SP), acute-onset (AO), and fulminant (F).

This was a retrospective, single-center, cross-sectional study conducted on 98 adult type 1 diabetes mellitus patients. The main outcome included the bone mineral density Z-score (BMD-Z) measured at the lumbar spine and femoral neck.

The lumbar spine BMD-Z was lower in the acute-onset than in the slowly progressive subtype (P = 0.03). No differences were observed when compared with the fulminant subtype. The femoral neck BMD-Z tended to be higher in the slowly progressive than in the acute-onset and fulminant subtypes. Multiple regression analyses showed that the lumbar spine BMD-Z was associated withal density decline follows the impaired insulin secretion. These results provide novel insights into the association between the low insulin exposure duration and bone mineral density.

To evaluate the mechanical stability and clinical efficacy of minimally invasive percutaneous TightRope® systems applied via gun-shaped reduction forceps for unstable posterior pelvic ring fractures.

This study consists of two parts a clinical retrospective study and a randomized controlled biomechanical test. For the clinical study, a retrospective analysis of posterior pelvic ring fractures was performed between June 2015 and May 2020. Eighteen patients underwent surgery using two TightRope® systems to fix a broken posterior pelvic ring because of unstable AO type C1 and C2 pelvic ring fractures. The patients were followed up for at least 2 years, and all patients were evaluated using the Majeed scoring system and vertical displacement. In the biomechanical tests, six embalmed adult pelvic specimens were used. The fractures were subjected to TightRope®, IS screw, and TBP fixation in a randomized block design. The specimens were placed in a biomechanical testing machine in a standing neutral posture. A cup (1798 ± 83.53 N) was significantly greater than that in the TBP group (1352 ± 74.41 N) (t=9.78, P <0.0001) and the TightRope® group (1347 ± 54.28 N) (t=11.11, P < 0.0001). However, no significant difference was observed between the TightRope® and TBP groups (t=0.13, P=0.90).

Percutaneous posterior TightRope® system shows strong stability in mechanical experiments and shows good results in clinical follow-up while this system has certain advantages in lower surgical requirements and lower risk of related nerve and vascular structural damage.

Percutaneous posterior TightRope® system shows strong stability in mechanical experiments and shows good results in clinical follow-up while this system has certain advantages in lower surgical requirements and lower risk of related nerve and vascular structural damage.HgTe film is widely used for quantum Hall well studies and devices, as it has unique properties, like band gap inversion, carrier-type switch, and topological evolution depending on the film thickness modulation near the so-called critical thickness (63.5 Å), while its counterpart bulk materials do not hold these nontrivial properties at ambient pressure. Here, much richer transport properties emerging in bulk HgTe crystal through pressure-tuning are reported. Not only the above-mentioned abnormal properties can be realized in a 400 nm thick bulk HgTe single crystal, but superconductivity is also discovered in a series of high-pressure phases. Combining crystal structure, electrical transport, and Hall coefficient measurements, a p-n carrier type switching is observed in the first high-pressure cinnabar phase. Superconductivity emerges after the semiconductor-to-metal transition at 3.9 GPa and persists up to 54 GPa, crossing four high-pressure phases with an increased upper critical field. Density functional theory calculations confirm that a surface-dominated topologic band structure contributes these exotic properties under high pressure. This discovery presents broad and efficient tuning effects by pressure on the lattice structure and electronic modulations compared to the thickness-dependent critical properties in 2D and 3D topologic insulators and semimetals.Topological field-effect transistor is a revolutionary concept that physical fields are used to switch on and off quantum topological states of the condensed matter. Although this emerging concept has been explored in electronics, how to realize it in the acoustic realm remains elusive. In this work, a class of magnetoactive acoustic topological transistors capable of on-demand switching on and off topological states and reconfiguring topological edges with external magnetic fields is presented. The key mechanism is to harness magnetic fields to tune air-cavity volumes within acoustic chambers, thus breaking or preserving the inversion symmetry to manifest or conceal the quantum valley Hall effect. To switch the topological transport beyond the in-plane routes, a magneto-tuned non-topological band gap to allow or forbid the wave transport out-of-plane is harnessed. With the reversible magnetic control, on-demand switching of topological routes to realize topological field-effect waveguides and wave regulators is demonstrated. Analogous to the impact of semiconductor transistors on modern electronics, this work may expand the scope of topological acoustics by achieving unprecedented functions in acoustic modulation.

To investigate the changes in proinflammatory cytokines and chemokines, namely, C-C motif ligand (CCL) 2 and CCL7, in postmenopausal osteoporosis (PMOP) and to develop a new drug, bindarit (Bnd), for PMOP in an ovariectomized (OVX) mouse model.

Bone marrow macrophages (BMMs) from the femurs of five women with PMOP and five premenopausal women without osteoporosis were detected by RNA sequencing. BMMs from mice were differentiated into osteoclasts and treated with a synthetic inhibitor of CCL2 and CCL7, Bnd, or 17 beta estradiol (E

). Mouse BMMs were differentiated into osteoclasts with or without Bnd for 7 days and analyzed by RNA sequencing. Osteoblasts of mice were induced to undergo osteoblastogenesis and treated with Bnd. OVX mice were treated with E

or Bnd after surgery. The protein and mRNA expression of CCL2 and CCL7 was detected using immunostaining and qPCR, respectively, in OVX and aged mice and in cells cultured in vitro. Osteoclast formation was detected using a tartrate-resistant acid phod bone turnover in vivo. p-IKKα/β and p-NFκB p65 levels were increased in BMMs of mice after differentiation into osteoclasts but were significantly decreased by Bnd.

The proinflammatory cytokines and chemokines CCL2, CCL7 and CCR2 were correlated with PMOP. Bnd attenuated the increases in CCL2 and CCL7 levels to affect osteoporosis in OVX mice via the NFκB signaling pathway. Thus, Bnd may be useful as a new therapeutic for the prevention of PMOP.

The proinflammatory cytokines and chemokines CCL2, CCL7 and CCR2 were correlated with PMOP. Bnd attenuated the increases in CCL2 and CCL7 levels to affect osteoporosis in OVX mice via the NFκB signaling pathway. Thus, Bnd may be useful as a new therapeutic for the prevention of PMOP.Although rifampin drug-drug interaction (DDI) studies are routinely conducted, there have been instances of liver function test (LFT) elevations, warranting further evaluation. A literature review was conducted to identify studies in which combination with rifampin resulted in hepatic events and evaluate any similarities. Bcl-2 pathway Over 600 abstracts and manuscripts describing rifampin DDI studies were first evaluated, of which 30 clinical studies reported LFT elevations. Out of these, 11 studies included ritonavir in combination with other drug(s) in the rifampin DDI study. The number of subjects that were discontinued from treatment on these studies ranged from 0 to 71 (0-100% of subjects in each study). The number of subjects hospitalized for adverse events in these studies ranged from 0 to 41 (0-83.67% of subjects in each study). LFT elevations in greater than 50% of subjects were noted during the concomitant administration of rifampin with ritonavir-boosted protease inhibitors and with lorlatinib; with labeled contraindication due to observed hepatotoxicity related safety findings only for saquinavir/ritonavir and lorlatinib. In the lorlatinib and ritonavir DDI studies, considerable LFT elevations were observed rapidly, typically within 24-72 h following co-administration. A possible sequence effect has been speculated, where rifampin induction prior to administration of the combination may be associated with increased severity of the LFT elevations. The potential role of rifampin in the metabolic activation of certain drugs into metabolites with hepatic effects needs to be taken into consideration when conducting rifampin DDI studies, particularly those for which the metabolic profiles are not fully elucidated.

To estimate the quality of life, anxiety, depression, and illness perception in patients with medically treated cerebral cavernous malformation (CCM) and associated epilepsy.

Nonsurgically treated patients with CCM-related epilepsy (CRE) were included. Demographic, radiographic, and clinical features were assessed. All participants received established questionnaires (short-form 36 health survey, SF-36; hospital anxiety and depression score, HADS-A/D; visual analogue scale score, VAS) assessing the functional and psychosocial burden of disease. To some extent, calculated values were compared with reference values from population-based studies. Test results were related to seizure control.

A total of 37 patients were included. Mean age was 45.8 ± 14.4 years, and 54.1% were female. Diagnosis of CRE was significantly associated with attenuated quality of life and increased level of anxiety, affecting physical and psychosocial dimensions. The assessment of illness perception identified considerable burden. HADS was significantly associated with VAS and SF-36 component scores. Efficacy of antiepileptic medication had no restoring impact on quality of life, anxiety, depression, or illness perception.

CRE negatively influences quality of life and mood, independent of seizure control due to antiepileptic medication. Screening for functional and psychosocial deficits in clinical practice might be useful for assessing individual burden and allocating surgical or drug treatment.

CRE negatively influences quality of life and mood, independent of seizure control due to antiepileptic medication. Screening for functional and psychosocial deficits in clinical practice might be useful for assessing individual burden and allocating surgical or drug treatment.

Video game addiction (VGA) is associated with physical and mental disorders, one of which is problem in executive function, particularly inhibitory control. The present study aimed to investigate reactive and proactive inhibitory controls by event-related potential (ERP).

Thirty video game (action video games)-addicted subjects and 30 matched healthy controls participated in the study, who were tested by the selective stop-signal task.

The main results revealed that the VGA group had significantly more problems in preparatory processes and proactive stop trials, showing that VGA has a negative effect on proactive inhibition.

Finding the problem in proactive inhibitory control might be helpful in developing new treatments and rehabilitation methods in these fields.

Finding the problem in proactive inhibitory control might be helpful in developing new treatments and rehabilitation methods in these fields.New rhenium bipyridyl complexes with dipyrromethene-BF2 chromophores (A-ReBDP-CZ, A-ReBDP2 , ReBDP-CZ, and ReBDP2 ) were developed for highly efficient photocatalytic carbon dioxide (CO2 ) reduction to carbon monoxide (CO). These catalysts consisted of two moderate electron-deficient groups (dipyrromethene-BF2 , BDP) as the visible-light-harvesting antenna as well as both electron donor (N-phenylcarbazole, CZ) and acceptor (BDP) on Re bipyridyl framework. Among ReBDP-CZ and ReBDP2 complexes, the ReBDP2 incorporating two electron-deficient BDP chromophores had a longer-lived photoexcited state (182.4 μs) and a twofold enhanced molar absorption coefficient (ϵ=157000 m-1  cm-1 ) compared with ReBDP-CZ. Thus, ReBDP2 achieved the superior photocatalytic reactivity and stability with a CO turnover number (TONCO ) value as high as 1323 and quantum yield (ΦCO ) up to 55 %, which was the most excellent photocatalysis efficiency among the single-active-site Re catalysts without additional photosensitizer. Furthermore, the acetylene-bridged linker was detrimental to the photoactivity and durability of the catalyst. In brief, two BDP-based Re bipyridyl systems with outstanding catalytic performance and significant visible-light-harvesting capabilities in the solar spectrum offer a promising strategy for solar-to-fuel conversion schemes.

Transaxillary endoscopic thyroidectomy has been introduced to achieve better cosmetic outcomes. However, the benefits of this technology on the patients' health-related quality of life (HRQoL) remain unclear. We aimed to investigate whether transaxillary endoscopic lobectomy is comparable to conventional open lobectomy in terms of QOL and cosmetic results in order to provide more evidence for establishing appropriate clinical decisions.

Between August 2019 and May 2020, transaxillary endoscopic lobectomy and conventional open lobectomy were performed in 73 and 99 patients with papillary thyroid microcarcinoma, respectively. HRQoL was assessed at 1, 3, 6, and 12months after surgery using the Thyroid Cancer-Specific Quality of Life Questionnaire. The cosmetic outcomes were assessed 12months after surgery using the Patient and Observer Scar Assessment Scale (POSAS).

No significant difference was observed in the surgical results between the two groups. However, the data showed that the average operative time and postoperative hospital stay of the transaxillary group were longer than those of the open group (p < 0.001). Both groups showed similar changes in the QOL scores over time. However, the transaxillary group had fewer complaints of the throat or oral problems at 1 month postoperatively than the open group (p < 0.001). During the follow-up, the cosmetic results of scars in the transaxillary group were significantly better than those in the open group (p < 0.05). Patients who underwent transaxillary endoscopic lobectomy had higher overall satisfaction with their scar appearance, determined using POSAS, at 12months postoperatively.

The current findings suggest that transaxillary endoscopic lobectomy may offer better cosmetic and HRQoL outcomes.

The current findings suggest that transaxillary endoscopic lobectomy may offer better cosmetic and HRQoL outcomes.

Long-acting anticoagulant rodenticide (LAAR) poisoning remains a serious public health problem. The aim of this study was to explore the clinical characteristics of different LAARs and a method of making a decision on the VK1 treatment course and the time to stop VK1 treatment safely.

This retrospective study compared the clinical characteristics of two LAARs poisoning patients and used multivariate regression method to explore the relationship between blood LAAR concentration and vitamin K1 dose/treatment time.

A total of 115 patients with LAAR poisoning were included in this study after screening. Of these, 50 patients attempted to commit suicide. The median LAAR concentration of the patients at admission was 409 (157-1174)ng/mL, and the VK1 treatment duration was 14 (8-34)days. The total VK1 treatment time in patients with LAAR poisoning was positively correlated with admission LAAR concentration. During the maintenance treatment period, the VK1 dosage was positively correlated with blood LAAR concentration.

Low dose of VK1 during the maintenance period is indicative of the blood LAAR concentration being relatively low. This provides a basis for judging the LAAR content in the body during the maintenance treatment period.

Low dose of VK1 during the maintenance period is indicative of the blood LAAR concentration being relatively low. This provides a basis for judging the LAAR content in the body during the maintenance treatment period.

Palbociclib was the only available cyclin-dependent kinase 4/6 inhibitor in China until very recently, and its effect has not been systemically evaluated among Chinese patients. This study aims to assess the efficacy, safety and patient-reported outcomes (PROs) of palbociclib plus endocrine therapy (ET) in real-world China.

An ambispective cohort study was conducted on patients with advanced HR+HER2- breast cancer who received palbociclib between July 2018, and November 2020 and were enrolled from 12 hospitals. Treatment patterns, survival outcomes, and safety events were documented, and PROs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items [EORTC QLQ-C30] and EuroQoL 5 dimensions [EQ-5D]) were analyzed. The Kaplan-Meier method was used to visualize and estimate the median progression-free survival (mPFS). Log-rank tests, Cox regressions, t tests, and chi-square tests were performed for comparison.

A total of 190 patients (median follow-up of 18.0 mive patients in real-world China and is generally well tolerated. The prevalence of AEs in the Chinese population is different from that reported in the PALOMA-2/3 trials.

Palbociclib is effective for front-line use and for treating endocrine-sensitive patients in real-world China and is generally well tolerated. The prevalence of AEs in the Chinese population is different from that reported in the PALOMA-2/3 trials.3D printing of optics has gained significant attention in optical industry, but most of the research has been focused on organic polymers. In spite of recent progress in 3D printing glass, 3D printing of precision glass optics for imaging applications still faces challenges from shrinkage during printing and thermal processing, and from inadequate surface shape and quality to meet the requirements for imaging applications. This paper reports a new liquid silica resin (LSR) with higher curing speed, better mechanical properties, lower sintering temperature, and reduced shrinkage, as well as the printing process for high-precision glass optics for imaging applications. It is demonstrated that the proposed material and printing process can print almost all types of optical surfaces, including flat, spherical, aspherical, freeform, and discontinuous surfaces, with accurate surface shape and high surface quality for imaging applications. It is also demonstrated that the proposed method can print complex optical systems with multiple optical elements, completely removing the time-consuming and error-prone alignment process. Most importantly, the proposed printing method is able to print optical systems with active moving elements, significantly improving system flexibility and functionality. The printing method will enable the much-needed transformational manufacturing of complex freeform glass optics that are currently inaccessible with conventional processes.Protein arginine methyltransferases 1 and 5 (PRMT1 and PRMT5) are frequently overexpressed in diverse types of cancers and correlate with poor prognosis, thus making these enzymes potential therapeutic targets. The aim of this study was to assess and elucidate the anti-tumour effect and epigenetic regulatory mechanism of ribavirin in soft tissue sarcomas (STS). We showed that ribavirin inhibited growth and metastasis and prolonged survival in animals bearing STS cells by downregulating the mRNA and protein levels of PRMT1/PRMT5 and attenuating the accumulation of asymmetric and symmetric di-methylation of arginine (ADMA and SDMA). link= Bcl-2 pathway Furthermore, ribavirin lowered the permeability of the peritoneum in KM mice bearing S180 ascites via decreasing the level of vascular endothelial growth factor (VEGF). Ribavirin was a potent inhibitor of cell proliferation and metastasis in STS cells through downregulation of both type I PRMT1 and type II PRMT5. Ribavirin could be used to enhance the efficacy of doxorubicin in STS allograft tumour models.Surgical management of post-esophagojejunostomy aortoesophageal fistula (AEF) has been scarcely reported, but is universally fatal. This report described a case of AEF after total gastrectomy with Roux-en-Y esophagojejunostomy and adjuvant chemoradiotherapy for gastric cardiac cancer. A three-stage hybrid approach was used to successfully manage this complication. First, thoracic endovascular aortic repair curbed bleeding. Second, radical fistula resection eradicated infected areas and adjacent structures. Third, esophageal reconstruction using an ileocolonic conduit restored gastrointestinal continuity. This strategy could be safely feasible for managing post-esophagojejunostomy AEF.Automation and microfluidic tools potentially enable efficient, fast, and focused reaction development of complex chemistries, while minimizing resource- and material consumption. link2 The introduction of automation-assisted workflows will contribute to the more sustainable development and scale-up of new and improved catalytic technologies. Herein, the application of automation and microfluidics to the development of a complex asymmetric hydrogenation reaction is described. Screening and optimization experiments were performed using an automated microfluidic platform, which enabled a drastic reduction in the material consumption compared to conventional laboratory practices. A suitable catalytic system was identified from a library of RuII -diamino precatalysts. In situ precatalyst activation was studied with 1 H/31 P nuclear magnetic resonance (NMR), and the reaction was scaled up to multigram quantities in a batch autoclave. These reactions were monitored using an automated liquid-phase sampling system. Ultimately, in less than a week of total experimental time, multigram quantities of the target enantiopure alcohol product were provided by this automation-assisted approach.A series of digermylenes R(EGeL)2 (L=CH[C(Me)N(Ar)]2 , Ar=2,6-iPr2 C6 H3 ; E=O, R=1,3-C6 H4 (1), 1,4-C6 H4 (2), Me2 C(CH2 )2 (3); E=NH, R=1,4-C6 H4 (4), 1,4-C6 H10 (5); E=C(O)O, R=1,3-C6 H4 (6)) were synthesized by the reactions of L'Ge (L'=HC[C(CH2 )N(Ar)]C(Me)N(Ar), Ar=2,6-iPr2 C6 H3 ) with selected diphenols, diol, diamines, and o-/m-phthalic acids, respectively. Treatment of digermylene 1,3-C6 H4 (OGeL)2 (1) with sulfur, selenium and CuX (X=Cl, Br, I) led to the formation of 1,3-C6 H4 [OGe(S)L]2 (8), 1,3-C6 H4 [OGe(Se)L]2 (9), and (CuX)2 [1,3-C6 H4 (OGeL)2 ]2 (X=Cl (10), Br (11), I (12)), respectively. The obtained products were characterized by melting point, elemental analysis, FT-IR, 1 H and 13 C NMR spectroscopy, and single-crystal X-ray diffraction.People with Methamphetamine Use Disorder (PwMUD) spend substantial time and resources on substance use, which hinders their ability to explore alternate reinforcers. Gold-standard behavioural treatments attempt to remedy this by encouraging action towards non-drug reinforcers, but substance use often persists. We aimed to unravel the mechanistic drivers of this behaviour by applying a computational model of explore/exploit behaviour to decision-making data (Iowa Gambling Task) from 106 PwMUD and 48 controls. We then examined the longitudinal link between explore/exploit mechanisms and changes in methamphetamine use 6 weeks later. Exploitation parameters included reinforcement sensitivity and inverse decay (i.e., number of past outcomes used to guide choices). Exploration parameters included maximum directed exploration value (i.e., value of trying novel actions). The Timeline Follow Back measured changes in methamphetamine use. Compared to controls, PwMUD showed deficits in exploitative decision-making, characterised by reduced reinforcement sensitivity, U = 3065, p = 0.009, and less use of previous choice outcomes, U = 3062, p = 0.010. This was accompanied by a behavioural pattern of frequent shifting between choices, which appeared consistent with random exploration. Furthermore, PwMUD with greater reductions of methamphetamine use at 6 weeks had increased directed exploration (β = 0.22, p = 0.045); greater use of past choice outcomes (β = -0.39, p = 0.002) and greater choice consistency (β = -0.39, p = 0.002). Therefore, limited computational exploitation and increased behavioural exploration characterise PwMUD's presentation to treatment, while increased directed exploration, use of past choice outcomes and choice consistency predict greater reductions of methamphetamine use.2-Fluorodeschloroketamine (2-FDCK) as a substitute for ketamine has emerged among drug abusers in recent years. However, 2-FDCK has not been controlled or regulated in many countries, which may be partly related to the lack of evidence on its abuse potential. In this study, we evaluated the abuse potential of 2-FDCK via the tests of the conditioned place preference (CPP), locomotor sensitization, drug self-administration and drug discrimination using ketamine as a reference. 2-FDCK induced significant CPP at a minimum dose of 3 mg/kg in mice, an effect comparable with that of ketamine (3 mg/kg). Acute injections of 2-FDCK or ketamine at 30 mg/kg enhanced locomotor activity. Repeated treatments with this dose of 2-FDCK and ketamine induced locomotor sensitization after withdrawal. 2-FDCK readily induced self-administration with 0.5 mg/kg/infusion, the same dose for ketamine, and induced the highest seeking response at 1 mg/kg. Drug discrimination test showed that 2-FDCK dose-dependently substitute for ketamine with comparable ED50 to ketamine in substitution testing. Taken together, these results strongly suggested that 2-FDCK has an abuse potential comparable with ketamine.Opioid use disorder (OUD) and opioid-related deaths remain a significant public health crisis having reached epidemic status globally. OUDs are defined as chronic, relapsing conditions often characterized by compulsive drug seeking despite the deleterious consequences of drug taking. The use of nicotine-containing products has been linked to increased likelihood of prescription opioid misuse, and there exists a significant comorbidity between habitual nicotine use and opioid dependence. In rodent models, nicotine administration nearly doubles the amount of opioids taken in intravenous self-administration paradigms. Here, we examined the effect of acute systemic nicotine administration in male rats on responding for the synthetic opioid remifentanil (RMF) in a contextual punishment paradigm using either an exteroceptive punisher (foot-shock) or an interoceptive punisher (histamine). Nicotine administration, relative to saline, increased RMF intake in both unpunished and punished contexts, regardless of form of punishment, and resulted in significantly higher motivation to obtain RMF in the previously punished context, as measured by progressive ratio breakpoint. Additionally, regardless of context, nicotine-treated rats were slower to extinguish RMF responding following drug removal and displayed higher levels of cue-induced reinstatement than saline-treated controls. Furthermore, these data support that, compared with histamine adulteration, contingent foot-shock is a more potent form of punishment, as histamine punishment failed to support contextual discrimination between the unpunished and punished contexts. In contrast to RMF administration, augmentation of responding for an audiovisual cue by nicotine pretreatment was lost following contextual punishment. In conclusion, acute nicotine administration in adult male rats significantly enhances compulsive-like responding for RMF that persists despite contingent punishment of drug-directed responding.There is growing evidence that immune signalling may be involved in both the causes and consequences of alcohol abuse. Toll-like receptor (TLR) expression is increased by alcohol consumption and is implicated in AUD, and specifically TLR7 may play an important role in ethanol consumption. We administered the TLR7-specific agonist imiquimod in male and female Long-Evans rats to determine (1) gene expression changes in brain regions involved in alcohol reinforcement, the nucleus accumbens core and anterior insular cortex, in rats with and without an alcohol history, and (2) whether TLR7 activation could modulate operant alcohol self-administration. Interferon regulatory factor 7 (IRF7) was dramatically increased in both sexes at both 2- and 24-h post-injection regardless of alcohol history and TLR3 and 7 gene expression was increased as well. The proinflammatory cytokine TNFα was increased 24-h post-injection in rats with an alcohol self-administration history, but this effect did not persist after four injections, suggesting molecular tolerance. Ethanol consumption was increased 24 h after imiquimod injections but did not occur until the third injection, suggesting adaptation to repeated TLR7 activation is necessary for increased drinking to occur. link2 Notably, imiquimod reliably induced weight loss, indicating that sickness behaviour persisted across repeated injections. These findings show that TLR7 activation can modulate alcohol drinking in an operant self-administration paradigm and suggest that TLR7 and IRF7 signalling pathways may be a viable druggable target for treatment of AUD.This study investigated the potential therapeutic effects of the FDA-approved drug metformin on cue-induced reinstatement of cocaine seeking. Metformin (dimethyl-biguanide) is a first-line treatment for type II diabetes that, among other mechanisms, is involved in the activation of adenosine monophosphate activated protein kinase (AMPK). link3 Cocaine self-administration and extinction is associated with decreased levels of phosphorylated AMPK within the nucleus accumbens core (NAcore). Previously, it was shown that increasing AMPK activity in the NAcore decreased cue-induced reinstatement of cocaine seeking. Decreasing AMPK activity produced the opposite effect. The goal of the present study was to determine if metformin in the NAcore reduces cue-induced cocaine seeking in adult male and female Sprague Dawley rats. Rats were trained to self-administer cocaine followed by extinction prior to cue-induced reinstatement trials. Metformin microinjected in the NAcore attenuated cue-induced reinstatement in male and female rats. Importantly, metformin's effects on cocaine seeking were not due to a general depression of spontaneous locomotor activity. In female rats, metformin's effects did generalize to a reduction in cue-induced reinstatement of sucrose seeking. These data support a potential role for metformin as a pharmacotherapy for cocaine use disorder but warrant caution given the potential for metformin's effects to generalize to a natural reward in female rats.Childhood trauma (CT) is frequent in patients with alcohol use disorder (AUD) and may impact on adult drinking behaviour and treatment outcome. This study aimed to investigate the structural correlates of CT in AUD, focusing on the amygdala, which plays a crucial role in the neurobiology of trauma. We hypothesized reduced amygdala volume and reduced structural connectivity as quantified by fractional anisotropy (FA) and by number of streamlines in those AUD patients with a history of moderate to severe CT (AUD-CT). T1-weighted MP2RAGE and diffusion-weighted imaging (DWI) 3-Tesla MRI-scans were acquired in 41 recently abstinent patients with AUD. We compared bilateral amygdala volume and structural connectivity (FA and number of streamlines) of pathways emanating from the amygdala between AUD-CT (n = 20) and AUD without CT (AUD-NT, n = 21) using a mixed model multivariate analysis of variance (MANCOVA) controlling for age and gender. AUD-CT displayed reduced FA and reduced number of streamlines of amygdalar tracts. There were no differences regarding amygdala volume. The severity of physical abuse, a subscale of the childhood trauma questionnaire, was negatively correlated with FA and with number of streamlines. AUD-CT and AUD-NT differ regarding structural connectivity of pathways projecting to and from the amygdala, but not regarding amygdala volume. Those alterations of structural connectivity in AUD-CT may represent a distinguishable neurobiological subtype of AUD, which might be associated with the complex clinical picture and poorer outcome that patients with CT and AUD often present.Paternal methamphetamine (METH) exposure results in long-term behavioural deficits in the sub-generations with a sex difference. Here, we aim to investigate the sex-specific neurobehavioural outcomes in the first-generation offspring mice (F1 mice) paternally exposed to METH prior to conception and explore the underlying brain mechanisms. We found that paternal METH exposure increased anxiety-like behaviours and spatial memory deficits only in female F1 mice and caused depression-like behaviours in the offspring without sex-specific differences. In parallel, METH-sired F1 mice exhibited sex-specific brain activity pattern in response to mild stimulus (in water at room temperature for 3 min). Overall, paternal METH exposure caused a blunting phenomenon of prelimbic cortex (PrL), infralimbic cortex (IL) and nucleus accumbens (NAc) core in both male and female F1 mice, as indicated by the decreased c-Fos levels under mild stimulus. Of note, the activity of central nucleus of the amygdala (CeA) by mild stimulus was triggered in male but suppressed in female F1 mice, whereas the neurons of orbitofrontal cortex (OFC), cingulate cortex (Cg1), NAc shell, medial habenula (mHb), dorsal hippocampal CA1 (dCA1) and ventral hippocampal CA1 (vCA1) were only blunted in female F1 mice. Taken together, the distinct brain stimulation patterns between male and female F1 mice might contribute to the sex-specific behavioural outcomes by paternal METH exposure, which indicate that sex differences should be considered in the treatment of offspring paternally exposed drugs.It is widely held that the central monoamine neurotransmitters modulate alcohol intake. Few studies, however, directly assess the relationship between baseline and alcohol-induced monoamine turnover, as well as the change from baseline, as predictors of alcohol intake. Using a nonhuman primate model, this study investigates baseline, alcohol-induced and alcohol-induced change in monoamine activity and their relationship with alcohol intake. Alcohol-naïve, adolescent rhesus macaques (Macaca mulatta, N = 114) were administered a standardized intravenous bolus of alcohol solution (16.8%, v/v) on two occasions, approximately 1 month apart. One month prior to and 1 h following each alcohol infusion, cisternal cerebrospinal fluid (CSF) was obtained and assayed for monoamine metabolite concentrations. Approximately 6-7 months later, subjects were allowed unfettered access to an aspartame-sweetened alcohol solution (8.4%, v/v) for 1 h/day, 5 days/week, over 5-7 weeks. Results showed strong positive correlations between baseline and post-infusion CSF monoamine metabolite concentrations, indicating a trait-like response. Low baseline and post-infusion serotonin and dopamine metabolite concentrations and a smaller change in serotonin and dopamine metabolites from one infusion to the next were associated with higher alcohol intake. Low baseline and post-infusion norepinephrine metabolite concentrations predicted high alcohol intake, but unlike the other monoamines, a greater change in norepinephrine metabolite concentrations from one infusion to the next was associated with higher alcohol intake. These findings suggest that individual differences in naturally occurring and alcohol-induced monoamine activity, as well as the change between exposures, are important modulators of initial alcohol consumption and may play a role in the risk for excessive alcohol intake.Previous studies have indicated a role for molecular chaperone heat shock protein 70 (Hsp70) in the development of behavioural sensitization to morphine in rodents, suggesting that Hsp70 expression following morphine exposure is involved in molecular changes that may underlie addiction vulnerability. The current study was carried out to investigate the role of Hsp70 in the positive reinforcing properties of morphine using conditioned place preference (CPP) in male rats. An unbiased CPP procedure of three phases (pre-conditioning d1-d3; conditioning d4-d6; and testing d7) was used. During the conditioning phase, morphine injections (5 mg/kg, subcutaneously) were administered to induce significant place preference. To explore the effect of Hsp70 on the development and expression of morphine CPP, Hsp70 inhibitors (PES, KNK437 and methylene blue) were administered into the lateral ventricle prior to either morphine conditioning sessions or a morphine challenge on the test day. Furthermore, Hsp70 expression within the mesocorticolimbic system was measured after the treatment with KNK437, a transcriptional inhibitor. We found that PES and KNK437, respectively, injected intracerebroventricularly dose-dependently attenuated both the development and expression of morphine CPP. Methylene blue treatment demonstrated an attenuation of the development, but had no effect on the expression of morphine CPP. Following KNK437 treatment, Hsp70 expression was significantly inhibited in the shell of nucleus accumbens (NAc) during both the development and expression of morphine CPP. The findings suggest that Hsp70 in the NAc shell plays an important role in the reinforcing effects of morphine and may be involved in the development of morphine dependence.Alcohol use disorder is characterised by disrupted reward learning, underpinned by dysfunctional cortico-striatal reward pathways, although relatively little is known about the biology of reward processing in populations who engage in risky alcohol use. Cues that trigger reward anticipation can be categorized according to their learnt valence (i.e., positive vs. negative outcomes) and motivational salience (i.e., incentive vs. neutral cues). link3 Separating EEG signals associated with these dimensions is challenging because of their inherent collinearity, but the recent application of machine learning methods to single EEG trials affords a solution. Here, the Alcohol Use Disorders Identification Test (AUDIT) was used to quantify risky alcohol use, with participants split into high alcohol (HA) (n = 22, mean AUDIT score 13.82) and low alcohol (LA) (n = 22, mean AUDIT score 5.77) groups. We applied machine learning multivariate single-trial classification to the electroencephalography (EEG) data collected during reward anticipation. The LA group demonstrated significant valence discrimination in the early stages of reward anticipation within the cue-P3 time window (400-550 ms), whereas the HA group was insensitive to valence within this time window. Notably, the LA, but not the HA group demonstrated a relationship between single-trial variability in the early valence component and reaction times for gain and loss trials. This study evidences disrupted hypoactive valence sensitivity in the HA group, revealing potential neurophysiological markers for risky drinking behaviours which place individuals at-risk of adverse health events.