Cytotoxicity of Pyrazine-Based Cyclometalated (C^Npz^C)Au(III) Carbene Complexes: Impact of the Nature of the Ancillary Ligand on the Biological Properties

The synthesis of a series of cyclometalated gold(III) complexes supported by pyrazine-based (C^N^C)-type pincer ligands is reported, including the crystal structure of a cationic example. The compounds provide a new platform for the study of antiproliferative properties of gold(III) complexes. Seven complexes were tested: the neutral series (C^Npz^C)AuX [X = Cl (1), 6-thioguanine (4), C≡CPh (5), SPh (6)] and an ionic series that included the N-methyl complex [(C^NpzMe^C)AuCl]BF4 (7) and the N-heterocyclic carbene complexes [(C^Npz^C)AuL]+ with L = 1,3-dimethylbenzimidazol-2-ylidene (2) or 1,3,7,9-tetramethylxanthin-8-ylidene (3). Tests against human leukemia cells identified 1, 2, 3, and 4 as particularly promising, whereas protecting the noncoordinated N atom on the pyrazine ring by methylation (as in 7) reduced the cytotoxicity. Complex 2 proved to be the most effective of the entire series against the HL60 leukemia, MCF-7 breast cancer, and A549 lung cancer cell lines, with IC50 values down to submicromolar levels, associated with a lower toxicity toward healthy human lung fibroblast cells. The benzimidazolylidene complex 2 accumulated more effectively in human lung cancer cells than its caffeine-based analogue 3 and the gold(III) chloride 1. Compound 2 proved to be unaffected by glutathione under physiological conditions for periods of up to 6 days and stabilizes the DNA G-quadruplex and i-motif structures; the latter is the first such report for gold compounds. We also show the first evidence of inhibition of MDM2–p53 protein–protein interactions by a gold-based compound and identified the binding mode of the compound with MDM2 using saturation transfer difference NMR spectroscopy combined with docking calculations

The Effect of Volitional Preemptive Abdominal Contraction on Biomechanical Measures During A Front Versus Back Loaded Barbell Squat

# Background Weightlifting is growing in popularity among recreational and competitive athletes. The barbell back squat (BackS) is commonly included in these training programs, while the barbell front squat (FrontS) is commonly performed as a component of other lifts such as the power clean or clean and jerk, it is less commonly practiced in isolation. # Hypothesis/Purpose The purpose of this study was to examine the effects of VPAC performance on trunk muscle and LE biomechanical responses during loaded BackS versus FrontS in healthy subjects. # Study Design Controlled Laboratory Study # Methods Healthy male subjects with the ability to perform a sub-maximal loaded barbell squat lift were recruited. Subjects completed informed consent, demographic/medical history questionnaires and an instructional video. Subjects practiced VPAC and received feedback. Surface electromyography (sEMG) electrodes and kinematic markers were applied. Muscles included were the internal oblique (IO), external oblique (EO), rectus abdominis, iliocostalis lumborum (ICL), superficial multifidi, rectus femoris, vastus lateralis, biceps femoris, and gluteus maximus. Maximal voluntary isometric contractions established reference sEMG values. A squat one-rep-max (1RM) was predicted by researchers using a three to five repetition maximum (3RM, 5RM) load protocol. Subjects performed BackS trials at 75% 1RM while FrontS trials were performed at 75% BackS weight, both with and without VPAC. Subjects performed three repetitions of each condition with feet positioned on two adjacent force plates. Significant interactions and main effects were tested using a 2(VPAC strategy) x 2(squat variation) and 2(VPAC strategy) x 2(direction) within-subject repeated measures ANOVAs. Tukey's Post-Hoc tests identified the location of significant differences. # Results Trunk muscle activity was significantly higher during FrontS versus BackS regardless of VPAC condition. (IO: p=0.018, EO: p\<0.001, ICL: p\<0.001) VPAC increased performance time for both squat variations (p=.0011), which may be associated with decreased detrimental force potential on the lumbar spine and knees. VPAC led to improved ability to maintain a neutral lumbar spine during both squat variations. This finding is associated with decreased detrimental force potential on the lumbar spine. # Conclusions Findings could help guide practitioners and coaches to choose squat variations and incorporate VPAC strategies during their treatments and/or training programs. # Level of Evidence Level 3 ©The Author(s

A translational synthetic biology platform for rapid access to gram-scale quantities of novel drug-like molecules

Plants are an excellent source of drug leads. However availability is limited by access to source species, low abundance and recalcitrance to chemical synthesis. Although plant genomics is yielding a wealth of genes for natural product biosynthesis, the translation of this genetic information into small molecules for evaluation as drug leads represents a major bottleneck. For example, the yeast platform for artemisinic acid production is estimated to have taken >150 person years to develop. Here we demonstrate the power of plant transient transfection technology for rapid, scalable biosynthesis and isolation of triterpenes, one of the largest and most structurally diverse families of plant natural products. Using pathway engineering and improved agro-infiltration methodology we are able to generate gram-scale quantities of purified triterpene in just a few weeks. In contrast to heterologous expression in microbes, this system does not depend on re-engineering of the host. We next exploit agro-infection for quick and easy combinatorial biosynthesis without the need for generation of multi-gene constructs, so affording an easy entrée to suites of molecules, some new-to-nature, that are recalcitrant to chemical synthesis. We use this platform to purify a suite of bespoke triterpene analogs and demonstrate differences in anti-proliferative and anti-inflammatory activity in bioassays, providing proof of concept of this system for accessing and evaluating medicinally important bioactives. Together with new genome mining algorithms for plant pathway discovery and advances in plant synthetic biology, this advance provides new routes to synthesize and access previously inaccessible natural products and analogs and has the potential to reinvigorate drug discovery pipelines

Genealogies of Slavery

This chapter addresses the concept of slavery, exploring its character and significance as a dark page in history, but also as a specifically criminological and zemiological problem, in the context of international law and human rights. By tracing the ambiguities of slavery in international law and international development, the harms associated with slavery are considered. Harms include both those statutorily proscribed, and those that are not, but that can still be regarded as socially destructive. Traditionally, antislavery has been considered within the parameters of abolition and criminalization. In this context recently, anti-trafficking has emerged as a key issue in contemporary anti-slavery work. While valuable, anti-trafficking is shown to have significant limitations. It advances criminalization and stigmatization of the most vulnerable and further perpetuates harm. At the same time, it identifies structural conditions like poverty, vulnerability, and “unfreedom” of movement only to put them aside. Linked to exploitation, violence and zemia, the chapter brings to the fore some crucial questions concerning the prospects of systemic theory in the investigation of slavery, that highlight the root causes of slavery, primarily poverty and inequality. Therefore, the chapter counterposes an alternative approach in which the orienting target is not abolition of slavery but advancing structural changes against social harm

Current practice in the removal of benign endometrial polyps: a Dutch survey

The purpose of this study is to evaluate the current practice of Dutch gynecologists in the removal of benign endometrial polyps and compare these results with the results of a previous study from 2003. In 2009 Dutch gynecologists were surveyed by a mailed questionnaire about polypectomy. Gynecologists answered questions about their individual performance of polypectomy: setting, form of anesthesia, method, and instrument use. The results were compared with the results from the previous survey. The response rate was 70% (585 of 837 gynecologists). Among the respondents, 455 (78%) stated to remove endometrial polyps themselves. Polyps were mostly removed in an inpatient setting (337; 74%) under general or regional anesthesia (247; 54%) and under direct hysteroscopic vision (411; 91%). Gynecologists working in a teaching hospital removed polyps more often in an outpatient setting compared with gynecologists working in a nonteaching hospital [118 (43%) vs. 35 (19%) p < 0.001]. These results are in accordance with the results from 2003. Compared to 2003 there was an increase in the number of gynecologists performing polypectomies with local or no anesthesia [211 (46%) vs. 98 (22%), p < 0.001]. An increase was also noted in the number of gynecologists using direct hysteroscopic vision [411 (91%) vs. 290 (64%), p < 0.001] and 5 Fr electrosurgical instruments [181 (44%) vs. 56 (19%), p < 0.001]. Compared to the situation in 2003, there is an increase in removal under direct hysteroscopic vision, with 5 Fr electrosurgical instruments, using local or no anesthesia. This implies there is progress in outpatient hysteroscopic polypectomy in the Netherlands

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Longitudinal observation and decline of neutralizing antibody responses in the three months following SARS-CoV-2 infection in humans

Antibody responses to SARS-CoV-2 can be detected in most infected individuals 10–15 d after the onset of COVID-19 symptoms. However, due to the recent emergence of SARS-CoV-2 in the human population, it is not known how long antibody responses will be maintained or whether they will provide protection from reinfection. Using sequential serum samples collected up to 94 d post onset of symptoms (POS) from 65 individuals with real-time quantitative PCR-confirmed SARS-CoV-2 infection, we show seroconversion (immunoglobulin (Ig)M, IgA, IgG) in >95% of cases and neutralizing antibody responses when sampled beyond 8 d POS. We show that the kinetics of the neutralizing antibody response is typical of an acute viral infection, with declining neutralizing antibody titres observed after an initial peak, and that the magnitude of this peak is dependent on disease severity. Although some individuals with high peak infective dose (ID50 > 10,000) maintained neutralizing antibody titres >1,000 at >60 d POS, some with lower peak ID50 had neutralizing antibody titres approaching baseline within the follow-up period. A similar decline in neutralizing antibody titres was observed in a cohort of 31 seropositive healthcare workers. The present study has important implications when considering widespread serological testing and antibody protection against reinfection with SARS-CoV-2, and may suggest that vaccine boosters are required to provide long-lasting protection

FasL is more frequently expressed in liver metastases of colorectal cancer than in matched primary carcinomas

Colorectal carcinoma cells have recently been shown to express Fas ligand (FasL). This ligand could allow the tumour cells to evade activated tumour-infiltrating lymphocytes (TILs) by inducing their apoptosis and would thus promote tumour survival and possibly metastasis formation. To test this hypothesis in vivo we analysed the expression of FasL mRNA and protein in paired tissue samples of normal colonic mucosa (N), primary colorectal carcinomas (T) and their metastases (M) from a total of 21 patients by four different methods. Additionally, the presence and activation status of infiltrating lymphocytes, which might contribute to the total amount of FasL in the tissue, was determined by semiquantitative reverse transcription–polymerase chain reaction (RT–PCR) in the same samples. The frequency of FasL detection was 30–40% in T and was 60–100% in M, depending on the sensitivity of the method. Simultaneously, the amount of CD25 mRNA, used as a measure of the number of activated TILs, was in 90% of patients lower in M than in T. The increased frequency of FasL detection in liver metastases was therefore not due to the presence of activated TILs. We conclude that metastasizing subpopulations of colorectal tumour cells express FasL more frequently than the primary carcinomas and may be able to eliminate activated TILs in vivo via Fas/FasL-induced apoptosis or other hitherto unknown mechanisms. © 1999 Cancer Research Campaig

Age and date for early arrival of the Acheulian in Europe (Barranc de la Boella, la Canonja, Spain)

The first arrivals of hominin populations into Eurasia during the Early Pleistocene are currently considered to have occurred as short and poorly dated biological dispersions. Questions as to the tempo and mode of these early prehistoric settlements have given rise to debates concerning the taxonomic significance of the lithic assemblages, as trace fossils, and the geographical distribution of the technological traditions found in the Lower Palaeolithic record. Here, we report on the Barranc de la Boella site which has yielded a lithic assemblage dating to ,1 million years ago that includes large cutting tools (LCT). We argue that distinct technological traditions coexisted in the Iberian archaeological repertoires of the late Early Pleistocene age in a similar way to the earliest sub-Saharan African artefact assemblages. These differences between stone tool assemblages may be attributed to the different chronologies of hominin dispersal events. The archaeological record of Barranc de la Boella completes the geographical distribution of LCT assemblages across southern Eurasia during the EMPT (Early-Middle Pleistocene Transition, circa 942 to 641 kyr). Up to now, chronology of the earliest European LCT assemblages is based on the abundant Palaeolithic record found in terrace river sequences which have been dated to the end of the EMPT and later. However, the findings at Barranc de la Boella suggest that early LCT lithic assemblages appeared in the SW of Europe during earlier hominin dispersal episodes before the definitive colonization of temperate Eurasia took place.The research at Barranc de la Boella has been carried out with the financial support of the Spanish Ministerio de Economı´a y Competitividad (CGL2012- 36682; CGL2012-38358, CGL2012-38434-C03-03 and CGL2010-15326; MICINN project HAR2009-7223/HIST), Generalitat de Catalunya, AGAUR agence (projects 2014SGR-901; 2014SGR-899; 2009SGR-324, 2009PBR-0033 and 2009SGR-188) and Junta de Castilla y Leo´n BU1004A09. Financial support for Barranc de la Boella field work and archaeological excavations is provided by the Ajuntament de la Canonja and Departament de Cultura (Servei d’Arqueologia i Paleontologia) de la Generalitat de Catalunya. A. Carrancho’s research was funded by the International Excellence Programme, Reinforcement subprogramme of the Spanish Ministry of Education. I. Lozano-Ferna´ndez acknowledges the pre-doctoral grant from the Fundacio´n Atapuerca. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript