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Foam diversion acidizing can effectively solve the problem of acid distribution with severe heterogeneity between and within layers. Based on the foam diversion principle, the gas trap theory, and volume conservation principle, the foam slug diversion acidizing model was established and solved considering the change of bottomhole temperature and deviation factor of foam. The simulation results show that the change of temperature has a great influence on the diversion effect at the initial stage of injection, but a small influence at the middle and late stage. The effect of temperature on the highly permeable layer is greater than that of temperature on the low permeability layer. The deviation factor of foam is mainly controlled by temperature at the initial stage, and by pressure at the middle and late stage, and the whole process shows a downward trend, which has little influence on the diversion effect. The quasi-skin factor of gas trap is the most important parameter that influences the effect of foam diversion. The water saturation of the low permeability layer rises faster than that of the high permeability layer, and the effect of diversion is obvious. The research results have a strong guiding significance for foam diversion acidizing.

On the Ground • We explored private landowner perceptions about the invasive Kentucky bluegrass in the US northern Great Plains. • Landowner responses to a mail survey indicated little to no preventative action. • We also employed a scenario approach to assess landowner perceptions based on changes to ecosystem services. • Scenario results indicated that the early stage of invasion was considered slightly acceptable. At the late stage, when negative impacts are most severe for landowner livelihoods, bluegrass was rated as slightly unacceptable. • Cascading impacts will become more evident and incentivizing early action to prevent further invasion is key to maintaining these working landscapes.

This fifth paper on Scottish mineral Geological Conservation Review (GCR) sites describes five sites of highest conservation value that reflect a wide range of mineral occurrences and formative systems. Host rocks are predominantly basalts of different ages and varying compositions, although in one site the host rocks are mostly basalts and basaltic andesites. The geology and mineralogy of each site differs considerably. Many zeolites have been identified from Skye, Mull and inland localities, their formation resulted from percolating aqueous surface waters or magmatic fluids in amygdales or veins. At some localities geodes and amygdales have been filled with agates some of which are of exquisite quality. Studies of agates reveal that their origin is complex.

This study evaluated and compared the expression of secreted protein acidic and rich in cysteine (SPARC) in epithelial cells and fibroblasts of oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC) using normal oral mucosa as a control.The expression of SPARC was determined in samples of normal oral mucosa (n = 12), OL without dysplasia (n = 31), OL with dysplasia (n = 54), and OSCC (n = 69) using immunohistochemistry. The percentage of positive cells in epithelial cells and fibroblasts was independently evaluated.Epithelial SPARC was found in 33.3%, 35.5%, 25.9%, and 66.7% of normal oral mucosa, OL without dysplasia, OL with dysplasia, and OSCC, respectively. Fibroblast SPARC was found in 50.0%, 29.0%, 46.3%, and 84.1% of normal oral mucosa, OL without dysplasia, OL with dysplasia, and OSCC, respectively. OSCC had higher epithelial and fibroblast SPARC expression than normal oral mucosa, OL without dysplasia, and OL with dysplasia (P.05). No significant differences were observed in epithelial and fibroblast SPARC among normal oral mucosa or OL with and without dysplasia.Overexpression of epithelial and fibroblast SPARC was observed in OSCC but not in OL, suggesting that SPARC is involved in the late stage of oral carcinogenesis.

Our emotional response to people is discordant with their emotional experience in competitive situations; this phenomenon is termed "counterempathy." Using event-related potentials, this study investigated the neural underpinnings of the effect of forgiveness on counterempathy. Twenty-seven female university students participated in a two phase-interpersonal competitive game with two other players whose smiles and frowns indicated the participant's losing and winning, respectively. In the "passive" phase, participants were passively punished with a high- or low-intensity noise chosen by the opponent each time they lost a trial (i.e., the opponent smiles). During the break, participants received a negative or friendly message from each opponent. Participants were more likely to forgive the opponent who had sent a friendly message. In the "active" phase, participants could punish both opponents when they won a trial (i.e., the opponent frowns). Behavioral data showed that participants' empathic responses were inconsistent with the opponents' expressions, and that forgiveness could weaken this effect. The electrophysiological data revealed that both very early emotional sharing (reflected in the N170) and late elaborative cognitive evaluation stage (reflected in the P300) of counterempathy were affected by forgiveness, whereas the early automatic cognitive evaluation stage (reflected in the feedback-related negativity [FRN]) was not. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A unified protecting group-free approach to two stemarene and two betaerene diterpenoids through a bioinspired two-phase strategy has been developed, and three of them were obtained for the first t...

Introduction Adolescent pregnancy is associated to school desertion, violence, termination of pregnancy under suboptimal conditions, obstetric complications and other consequences that can put the woman's quality of life at risk and of those that surround her. The purpose of this study is to describe the situation and tendencies of adolescent pregnancies, abortions and maternal deaths between 2013 and 2016 in Ecuador. Methods This cross-sectional study uses secondary data from national Ecuadorian vital statistics reports of adolescents between 10 and 19 years old. The data sources used register all the births, deaths and hospital discharges in the country at both public and private health establishments. We performed a descriptive analysis of qualitative and quantitative variables. Results Ecuador has approximately 1.5 million female adolescents that gave birth to 256,561 newborns between 2013 and 2016, resulting in an average annual birth rate in early adolescence of 13.9 live births per 1000 and in late adolescence of 86.6 per 1000 live births. The number of registered abortions among adolescents between 2013 and 2016 was of 19,214. The estimated annual abortion rate in late stage adolescents is 6.3 abortions per 1000 women between 15 and 19. The estimated abortion ratio for this same age group is 72.9 per 1000 live births. Of all the adolescents that gave birth, 84.9% self-identified as mestiza, while 71.9% of Ecuador's general population identifies as such. Only 7% of the general population in Ecuador self-identifies as indigenous, while 21.6% of pregnancies come from this population. Out of all adolescents that gave birth, 57.4% of those aged 17 and over; 43% of those between 14 and 16 and 96.7% of adolescents from 10 to 13, completed the level of education for their age. There were 81 maternal deaths among this group. The maternal mortality rate for late stage adolescents is of 7.72 per 100,000.

Hepatocellular carcinoma (HCC) continues to have a dismal prognosis, with 5-year survival below 20%. This poor prognosis can be in part attributed to failures along the cancer screening process continuum such as underuse of screening in at risk patients and appropriate treatments for patients with HCC. Better understanding these process failures, and how they compare to those seen in other cancer types, can help inform potential intervention targets and strategies to reduce HCC-related mortality. Herein, we outline a conceptual model with several discrete steps in the HCC screening process continuum including risk assessment, screening initiation, follow-up of screening results, diagnostic evaluation, and treatment evaluation. The conceptual model illustrates how each step in the screening process is prone to delays or failure, resulting in worse outcomes such as late stage diagnosis or poor survival, and how factors at the patient, provider, and health care system levels can contribute to these failures. We compare cancer screening processes for HCC with those employed in breast and colorectal cancer screening to identify opportunities for improvement. The Translational Liver Cancer consortium was recently established by the National Cancer Institute with the goal of improving early detection of HCC. Studies designed to address failures in the HCC screening process continuum will help accomplish this goal.

Glyco-polypeptides (Comosain, Bromelain) induced leucocyte binding ability to tumor surface antigens, such as interleukin 2, 6, 8, and TNFs, is known as an immuno-target therapy. Using different concentration of Bromelain proteinases in 6 types of cancer cell, it resulted in hydrolysis, fibrinolysis, necrosis, and anti-metastatic effects in tumor cells. Anti-cancer effects were achieved in carcinoma of lung, breast, colon, ovary, cervix, and uterus. Investigation of anti-metastatic effects in Bromelain were carried out in a double-blind study: low dose cohort was on 10 mg/kg/day and a high dose cohort which was on 50 mg/kg/day for a period of over six months. A total of 83 patients with 3rd and 4th stage of refractory solid tumors were enrolled, whom at least previously failed on two regimens of chemotherapy and/or failed on radiation therapy. The rates of Complete Response (CR) and Partial Responses (PR) in high dose cohort are astonishing with 52% and 27% respectively. The Progress Disease (PD) was 10%, and the Stable Disease (SD) was 11%. The implications and results of the findings are discussed with in view of the reported anti-metastatic activity of orally administrated Bromelain.

INTRODUCTION The estrogen receptor (ER) is a clinically validated oncology target with a pivotal role in hormonally driven breast cancer, the most prevalent form of female cancer. Current treatments which directly modulate ER include antagonists (SERMs), such as tamoxifen, and degraders (SERDs), such as fulvestrant which is administered by intramuscular injection. AREAS COVERED This review covers patent applications that claim estrogen receptor degraders (SERDs) and covalent antagonists (SERCAs) between the period January 2015 to June 2021. A total of 114 patent applications from 23 different applicants are evaluated with stratification into acidic SERDs, basic SERDs and SERCAs. EXPERT OPINION The clinical success of fulvestrant in the treatment of ER+ breast cancer has spurred research over the last decade into the discovery and development of novel SERDs, with a particular focus on the discovery of orally bioavailable drugs. This has resulted in a diverse range of candidates entering clinical trials. Although some have faltered in development, a cohort of oral SERDs has generated encouraging efficacy and safety data that has allowed advancement into late stage clinical trials. Data from these trials is eagerly awaited, with these molecules having the potential to offer significant benefits in the treatment of ER+ breast cancer.

Background: The study involved a female patient diagnosed with late-stage dementia, with chronic daytime somnolence (CDS) as a prominent symptom. Objective: To explore whether her dementia resulted from Type 3 diabetes, and whether it could be reversed through ketosis therapy. Methods: A ketogenic diet (KD) generating low-dose 100 μM Blood Ketone Levels (BKL) enhanced by a brief Ketone Mono Ester (KME) regimen with high-dose 2–4 mM BKLs was used. Results: Three sets of data describe relief (assessed by % days awake) from CDS: 1) incremental, slow, time-dependent KD plus KME-induced sigmoid curve responses which resulted in partial wakefulness (0–40% in 255 days) and complete wakefulness (40–85% in 50 days); 2) both levels of wakefulness were shown to be permanent; 3) initial permanent relief from CDS with low-dose ketosis from 6.7% to 40% took 87 days. Subsequent low-dose recovery from illness-induced CDS (6.9% to 40%) took 10 days. We deduce that the first restoration involved permanent repair, and the second energized the repaired circuits. Conclusion: The results suggest a role for ketosis in the elimination of CDS with the permanent functional restoration of the awake neural circuits of the Sleep-Wake cycle. We discuss whether available evidence supports ketosis-induced bioenergetics alone or whether other mechanisms of functional renewal were the basis for the elimination of CDS. Given evidence for permanent repair, two direct links between ketosis and neurogenesis in the adult mammalian brain are discussed: Ketosis-induced 1) brain-derived neurotrophic factor, resulting in neural progenitor/stem cell proliferation, and 2) mitochondrial bioenergetics-induced stem cell biogenesis.

Mg-6Gd-3Y-0.5Zr (VW63K) alloy is widely used in the aerospace field because of its excellent mechanical properties not only at room temperature but also under high service temperature. In this study, the effect of minor changes to the Y alloying levels on the hot tearing behavior of VW63K alloys was researched by using a "T" mold, with pouring temperature of 720 °C and mold temperature of 150 °C. The results show that the hot tearing susceptibility of the alloy decreases gradually with the increase of Y content from 2.8 to 3.4 wt%. The reason for this phenomenon is that high content of Y element narrows the susceptible freezing range and increases the eutectic liquid fraction of the alloy, which is helpful for the alloy to have a better compensation at the late stage of solidification and, thereby decreasing the hot tearing susceptibility.

The auricular cartilage is considered to develop from a funnel-like arrangement of six embryonic hillocks. However, there is little information as to when and how the initial cartilage plate differentiates into the major three hollows or caves: the concha, the scapha and the triangular fossa. We examined semiserial histological sections from 42 human fetuses as well as from seven cadavers of elderly individuals. Tangential sections from adults suggested that three ring-like cartilages were combined to provide a single auricular cartilage and that the external auditory meatus was attached to the lowest ring or concha. All of the fetuses studied carried the three major hollows delineated by skin folds. These skin folds often contained a cartilage loop as a core in place of a thickening or tubercle. Conversely, some of the skin folds corresponded to a highly wavy cartilage plate without looping. According to whether the cartilage loop was present or absent in horizontal sections from 35 fetuses, we classified the cartilage morphology into four patterns, the most frequent of which was absence of the triangular fossa loop (27 fetuses), followed by absence of the scapha loop (11 fetuses). Each pattern was evenly distributed among small and large fetuses. This suggested that some form of cartilage correction or reconstruction was likely to occur after birth, especially at the triangular fossa and/or scapha. Infants appear to show significant region-specific variation in the postnatal growth of the auricular cartilages, especially at the triangular fossa and/or scapha. This article is protected by copyright. All rights reserved.

Some studies suggest that thyroid hormones and disorders can influence breast (BC) and ovarian (OC) cancers risks. However, studies regarding their effect on these tumors progression are limited. Thyroid-stimulating hormone (TSH), T4, free T4 (FT4), T3, and free T3 (FT3) were detected in patients with BC, OC, benign breast and ovary diseases, and healthy controls using highly sensitive chemiluminescence assay. In contrast to OC, hypothyroidism prevalence was associated with BC late stage (11/24 vs. 2/46), high grade (11/23 vs. 4/47), lymph node invasion (11/42 vs. 0/28), positive distant metastasis (11/25 vs. 1/45), and large tumor size (14/25 vs. 1/45) compared to tumor early stages, low grades, negative lymph node, and distant metastasis and small size, respectively. Patients with late stage, high grade, large tumor size, positive lymph nodes, or positive distant metastasis were significantly (P < 0.05) associated with elevated levels of TSH and decreased levels of T4, FT4, T3, and FT3. There were both significant positive correlation of serum TSH and significant inverse correlation of T4, FT4, T3, and FT3 with these tumor worse outcomes. In conclusion, our results identify hypothyroidism as potentially important prognostic factor in BC not in OC that is associated with poor outcomes of BC patients.

Tidal creeks are the main channels of land-sea ecosystem interactions, and their high dynamics are an important factor affecting the hydrological connectivity of tidal flats. Taking the Yellow River Delta as the research area, we selected remote sensing images obtained during five periods from 1998 to 2018 as the data sources. Based on the spatial analysis function in GIS, the typical morphological characteristics of tidal creeks, such as the level, length, density, curvature, bifurcation ratio, and overmarsh path length (OPL), were extracted to characterize the degree of development of the tidal creeks in the Yellow River Delta wetlands. The spatio-temporal evolution of the tidal creeks was studied, and the development process and the characteristics of the tidal creeks during the different stages of development were investigated. The results revealed that (1) The number, density, and bifurcation ratio of tidal creeks exhibit an increasing trend, but the growth of the trend is slowing. The number of tidal creeks increased by 44.9% from the initial stage of the Yellow River diversion to the late stage of the wetland restoration, but it only increased by 26.2% from the late stage of the wetland restoration to the slow expansion of the Spartina alterniflora. (2) The curvature of the tidal creeks on the landward side is greater than that on the seaward side. (3) The development degree of tidal creek has spatial heterogenetiy, which is Area III > Area II > Area I. (4) The drainage efficiency is significantly correlated with the tidal creak density and bifurcation ratio. Based on the analysis of the various morphological parameters and the drainage efficiency, it was found that after the rapid change in the tidal creek system in the early stage, the tidal creeks entered a state of slow change, and the development state of the tidal creeks tends to be in dynamic balance. The results of this study are expected to provide scientific support for the sustainable development and utilization of coastal tidal flats.

The structural evolution of lotus starch (LS)-chlorogenic acid (CA) complexes was investigated after microwave-heating treatment, to reveal the relationship between the interactions of lotus starch and chlorogenic acid molecules, and the digestive properties of the starch, after microwave gelatinization. During the early stage of microwave gelatinization (65, 70 °C), CA was mainly participating in the rearrangement of starch molecules in a weakly-bound form, and at that stage, the LS-CA complex acted as an inhibitor of digestion, under small intestine conditions, mainly through the release of CA, which inhibited amylase. However, during the late stage of microwave gelatinization (85 °C), many chlorogenic acid molecules entered the hydrophobic helical cavity of the starch, promoting formation of the V-type starch helical structure in the LS-CA complex, which made a major contribution to inhibiting digestion under oral digestion conditions.

The use of F-based decorations in drug discovery started from the development of fluorocorticoids and fluorochinolones (1950s and 1980s respectively) and it resulted in about 20% of approved drugs on the Market containing fluorine. From a medicinal chemistry perspective, the installation of F-based small groups (e.g. -CF3, -CF2H, -OCF3, -OCF2H, -SCF3, - SCF2H) necessarily impacts on physicochemical, pharmacokinetics, pharmacodynamics and toxicological properties of small molecules. Accordingly, a huge interest on this topic is constantly arising in the medicinal chemistry community. Focusing on heteroarenes, the synthetic access to these substitutions is guaranteed by a number of effective reactions, such as Miniscitype reaction, photochemistry or electrochemistry C-H activation. The aim of this work is to analyze the rational in using these groups in medicinal chemistry and to highlight the current available synthetic toolbox of C-H activation for their introduction on heteroarenes of pharmaceutical interest. A particular focus has been given to those procedures amenable at late-stage functionalisation process.

Prostate-Specific Membrane Antigen (PSMA) is a credentialed imaging and therapy (theranostic) target for the detection and treatment of prostate cancer. PSMA-targeted positron emission tomography (PET) imaging and molecular radiotherapy (MRT) are promising evolving technologies that will improve the outcomes of prostate cancer patients. In anticipation of this new era in prostate cancer theranostics, this article will review the history of PSMA from discovery, through early and late stage clinical trials. Since 1993, the Prostate Cancer Foundation (PCF) has funded critical and foundational PSMA research that established this theranostic revolution. The history and role of PCF funding in this field will be discussed.

Interest in therapeutic discovery typically drives the preparation of natural product analogs, but these undertakings contribute significant advances for synthetic chemistry as well. The need for a highly efficient and scalable synthetic route to a complex molecular scaffold for diversification frequently inspires new methodological development or unique application of existing methods on structurally intricate systems. Additionally, synthetic planning with an aim toward late-stage diversification can provide access to otherwise unavailable compounds or facilitate preparation of complex molecules with diverse patterns of substitution around a shared carbon framework. For these reasons among others, programs dedicated to the diversification of natural product frameworks and other complex molecular scaffolds have been increasing in popularity, a trend likely to continue given their fruitfulness and breadth of impact. In this Perspective, we discuss our experience using late-stage diversification as a guiding principle for the synthesis of natural product analogs and reflect on the impact such efforts have on the future of complex molecule synthesis.

Surveillance of hepatocellular carcinoma (HCC) is beneficial for detecting early-stage HCC. The factors that influence adherence to HCC surveillance and late-stage detection have never been evaluated. We investigated the predictive factors that contribute to patients accessing regular HCC surveillance and their association with the detection of late-stage HCC at the time of diagnosis.We conducted a prospective observational study at Hatyai Hospital (Songkhla, Thailand) between 2014 and 2016. HCC surveillance includes performing hepatic ultrasonography with/without serum alpha-fetoprotein 6-12 months before the detection of HCC. Logistic regression analyses were conducted separately to examine the relationship between the variables and each endpoint.One hundred ninety-nine HCC patients were enrolled in the study; most patients were of low socioeconomic status, 90.5% had less than a bachelor's degree, and 69.3% of patients had a monthly income of10,000 baths (US $312.50). Nearly all (93.5%) patients had cirrhosis, 39.7% had hepatitis B virus (HBV) infection, 24.6% had hepatitis C virus infection, and 24.6% had alcohol-related liver disease. The risk of HCC was recognized in 51.8% of patients, and regular HCC surveillance was achieved in 36.2% of patients. Multivariate logistic regression analysis revealed that a monthly income10,000 baths (US $312.50) (odds ratio [OR], 4.566; p = 0.013), HBV infection (OR, 0.188; p = 0.001), and recognition of patients at risk of HCC (OR, 130.396; p0.001) were independent predictive factors for adherence to HCC surveillance. Regular HCC surveillance (OR, 0.215; p = 0.003) and recognition of HBV infection (OR, 0.356; p = 0.040) were independent preventive factors for the detection of late-stage HCC at the time of diagnosis.In Thailand, awareness of patients at risk of developing HCC and the rate of regular HCC surveillance are low. Greater awareness will enable physicians to surveil and detect HCC.

Epidemiological data show that the incidence rate of cholangiocarcinoma (CCA) has been increasing over the past 20 years. Due to its concealment of clinical manifestations, most patients are diagnosed with CCA at a late stage. On this premise, this review not only discusses the research progress related to CCA diagnosis, but also focuses on the concept of circulating tumor cell (CTC), its evaluation value, application, and prospects for the early diagnosis of extrahepatic cholangiocarcinoma.

The first total synthesis of the recently isolated natural product thiocladospolide A, along with its C2-epimer, is achieved in nine straightforward linear steps and 12% overall yield. The key feature of the synthesis is the construction of the macrocyclic ring via a late-stage ring-closing metathesis reaction followed by alkene reduction.

This study investigated childhood cancer disparities in the state of Texas based on data from 1995 to 2014 from the perspective of race/ethnicity, geographic location, and social factors. The enhan...

The C–H arylation of indoles holds the promise to shorten synthetic routes in the production of pharmaceuticals. However, late-stage C–H activation reactions often rely on the presence of protecting groups or stoichiometric metal additives. The regiospecific C–H arylation of a highly functionalized azepino[5,3,4-cd]indole scaffold lacking directing groups via Pd(II) and Cu(II) co-catalysis is reported. The direct C–H coupling was demonstrated in the convergent synthesis of rucaparib, an FDA approved anticancer drug.

The indolo[2,3-a]quinolizines, canthines, and arborescidines natural products exhibit a wide range of bioactivities including anticancer, antiviral, antibacterial, and anti-inflammatory, among others. Therefore, the development of modular and efficient strategies to access the core scaffolds of these classes of natural products is a remarkable achievement. The Complexity-to-Diversity (CtD) strategy has become a powerful tool that transforms natural products into skeletal and stereochemical diversity. However, many of the reactions that could be utilized in this process are limited by the type of functional groups present in the starting material, which restrict transformations into a variety of products to achieve the desired diversity. In the course of employing a (CtD) strategy en route to the synthesis of nature-inspired compounds, unexpected stereoelectronic-driven rearrangement reactions have been discovered. These reactions provided a rapid access to indolo[2,3-a]quinolizines-, canthines-, and arborescidines-inspired alkaloids in a modular and diastereoselective manner. The disclosed strategies will be widely applicable to other late-stage natural product transformation programs and drug discovery initiatives.

J.R. and G.A.B. thank GlaxoSmithKline (GSK) and the Engineering and Physical Sciences Research Council (EPSRC) for an industrial CASE studentship. MMA is supported by a studentship from the government of Libya, and MAU by a studentship from the Petroleum Technology Development Fund (PTDF), Abuja, Nigeria. A selective mono-N-arylation strategy of amidines under Chan-Lam conditions is described. During the reaction optimization phase, the isolation of a mononuclear Cu(II) complex provided unique mechanistic insight into the operation of Chan-Lam mono-N-arylation. The scope of the process is demonstrated, and then applied to access the first mono-N-arylated analogues of pentamidine. Sub-micromolar activity against kinetoplastid parasites was observed for several analogues with no cross-resistance in pentamidine and diminazene-resistant trypanosome strains and against Leishmania mexicana. A fluorescent mono-N-arylated pentamidine analogue revealed rapid cellular uptake, accumulating in parasite nuclei and the kinetoplasts. The DNA binding capability of the mono-N-arylated pentamidine series was confirmed by UV-melt measurements using AT-rich DNA. This work highlights the potential to use Chan-Lam mono-N-arylation to develop therapeutic leads against diamidine-resistant trypanosomiasis and leishmaniasis. Publisher PDF

Aim: In the late stage of atherosclerosis, the endothelial barrier of plaque is destroyed. The rapid deposition of oxidized lipids in the circulation leads to migration of numerous smooth muscle cells and macrophages, as well as foaming necrosis. The plaque progresses rapidly, and vulnerable plaques can easily induce adverse cardiovascular events. Here, we take the principle of gene editing to transfer the liver to express the LOX-1 receptor which is more sensitive to Ox-LDL by using AAV8 containing a liver-specific promoter. In this way, we want to explore whether the progress of advanced atherosclerosis and the stability of advanced plaque can be improved when the liver continues to clear Ox-LDL from the circulation. Methods and Results: In order to explore the effect of the physiological and continuous elimination of Ox-LDL through the liver on advanced atherosclerosis, we chose ApoE-/- mice in high-fat diet for 20 weeks. After 16 weeks of high-fat diet, the baseline group was sacrificed and the specimens were collected. The virus group and the control group were injected with the same amount of virus dilution and normal saline through the tail vein, and continued to feed until 20 weeks of high-fat diet, and then sacrificed to collect specimens. The results showed that LOX-1 was ectopically and functionally expressed in the liver as an Ox-LDL receptor, reducing the content of it in circulation. Compared with the control group, the degree of plaque progression in the virus group was significantly reduced, similar to the baseline group, the plaque necrosis core decreased, and the collagen fiber content increased. In addition, there are more contractile smooth muscle cells in the plaques of the virus group instead of synthetic ones, and the content of macrophages was also reduced. These data suggested that the virus group mice have greatly increased advanced plaque stability compared with the control group mice. Conclusions: Due to the destruction of endothelial barrier in advanced plaques, rapid deposition of Ox-LDL can result in fast plaque progression, increased necrotic cores, and decreased stability. Our research shows that the use of AAV8 through gene editing allows the liver to express LOX-1 receptors that are more sensitive to Ox-LDL, so that it can continue to bind Ox-LDL in the circulation and exploit the liver's strong lipid metabolism ability to physiologically clear Ox-LDL, which can inhibit the rapid progress of advanced plaque and increase the stability of plaque.

Background: The incidence of anterior cruciate ligament (ACL) injuries have been consistently increasing in adolescents, with those who return to competitive sport having up to a 32% risk of a secondary ACL injury. There is limited evidence regarding knee strength outcomes in young adolescents following ACL reconstruction during late-stage rehabilitation when compared to older patient groups. Purpose: The purpose of this study was to 1) establish normative knee strength values according to age group in adolescent female and male patients during late-stage rehabilitation following ACLR and 2) determine whether strength differences exist between age groups. Methods: A retrospective review of adolescent patients who underwent primary ACL reconstruction was performed. Patients completed a standardized isokinetic (60°/sec) knee extension and flexion strength assessment during late-stage rehabilitation. Peak torque was normalized to the patient’s body mass (Nm/kg) and used to calculate Limb Symmetry Index (LSI). Analyses were conducted separately for female and male cohorts and grouped by early (11-14 years) and middle (15-17 years) adolescence. An independent samples t-test examined strength differences between age groups. Results: 130 females (age=15.4 ± 1.4 years; days since surgery=239.0 ± 84.4) and 112 males (age=15.4 ± 1.5 years; days since surgery= 232.6 ± 91.2) were included. Normalized knee extension peak torque on the involved limb was reported for female (1.5 Nm/kg) and male (1.8 Nm/kg) cohorts. Differences between age groups in knee extension peak torque were found on the surgical and nonsurgical limbs in female (p = 0.02 – 0.05) and male (pConclusion: Early adolescents produced less knee extension and flexion peak torque compared to middle adolescents after ACLR, but no differences were found between age groups when normalized to body mass for female or male cohorts. Normalized knee extension strength in young adolescents may differ from older patients and should be considered in the rehabilitation process. [Table: see text][Table: see text][Table: see text][Table: see text]

The “bullseye” sign has been exclusively reported in patients suffering from coronavirus disease 2019 (COVID-19) pneumonia. It is theorized that this newly recognized computed tomography (CT) feature represents a sign of organizing pneumonia. Well established signs of organizing pneumonia also reported in COVID-19 patients include linear opacities, the “reversed halo” sign (or “atoll” sign), and a perilobular distribution of abnormalities. These findings are usually present on imaging in the intermediate and late stage of the disease. This is a case of simultaneous presence of the “bullseye” and the “reversed halo” sign on chest CT images of a COVID-19 patient examined 22 days after symptom onset.

Late-stage functionalization of the periphery of oligophenylene dendrimers was efficiently achieved via site-selective C-H activation of a preconstructed, readily accessible dendron. By fourfold iridium-catalyzed C-H borylation followed by Suzuki-Miyaura cross-coupling, various arene units were introduced into the end points of the 1,3,5-phenylene-based hydrocarbon dendron. Coupling of the modified dendrons with a core unit, such as 2,6-dibromobenzoic acid derivatives, afforded the periphery-functionalized dendrimers that also have an endohedral functionality at the core position.

Cancer has risen up to be a major cause of mortality worldwide over the past decades. Despite advancements in cancer screening and diagnostics, a significant number of cancers are still diagnosed at a late stage with poor prognosis. Hence, the discovery of reliable and accurate methods to diagnose cancer early would be of great help in reducing cancer mortality. Extracellular vesicles (EVs) are phospholipid vesicles found in many biofluids and are released by almost all types of cells. In recent years, using EVs as cancer biomarkers has garnered attention as a novel technique of cancer diagnosis. Compared with traditional tissue biopsy, there are many advantages that this novel diagnostic tool presents - it is less invasive, detects early-stage asymptomatic cancers, and allows for monitoring of tumour progression. As such, EV biomarkers have great potential in improving the diagnostic accuracy of cancers and guiding subsequent therapeutic decisions. Efficient isolation and accurate characterization of EVs are essential for reliable outcomes of clinical application. However, these are complicated by the size and biomolecular diversity of EVs. In this review, we present an analysis and evaluation of the current techniques of EV isolation and characterization, as well as discuss the potential EV biomarkers for specific types of cancer. Taken together, EV biomarkers have a lot of potential as a novel method in cancer diagnostics and diagnosis. However, more work is still needed to streamline the purification, characterization and biomarker identification process to ensure optimal outcomes for patients.

Summary Polyarteritis nodosa is a necrotizing systemic vasculitis of medium caliber arteries whose cause, most often unknown, may be hepatitis B virus. It is a serious condition diagnosed on the basis of well-defined criteria. Clinically, it is manifested by signs of kidney, skin, digestive, cardiac, joint or even vascular damage. The neurological manifestations of polyarteritis nodosa are frequent and make the disease serious. Peripheral neuropathy is the most frequent and earliest symptom. Central nervous system manifestations are less frequent and usually occur at a late stage. The objective of this review article is to describe the clinical manifestations of polyarteritis nodosa with a focus on damage to the central and peripheral nervous system.

This study was conducted to investigate the effect of different fattening periods on the growth performance, carcass characteristics, and economic traits of Holstein steers. Sixty Holstein steers (8.0 ± 0.28 months old) with an average body weight (BW) of 231.88 ± 2.61 kg, were randomly allocated to five different fattening period treatments: 20, 21, 22, 23, and 24 months (n = 12 in each treatment group). Final BW and average daily gain (ADG) did not differ among the treatment groups during the early fattening period. At the late stage of the fattening period, the final BW of steers in the 24-month treatment group (812.84 kg) was greater (p < 0.05) than that of steers in the 20-month treatment group (750.39 kg). During the same period, steers in the 20- and 21-month treatment groups had a significantly higher (p < 0.05) ADG than those in the 22-month treatment group. The highest ADG (1.36 kg/day) was found in the 20-month treatment group (1.36), followed by the 21- (1.33 kg/day), 22- (1.22 kg/day), 23- (1.21 kg/day), and 24- (1.14 kg/day) month treatment groups. The feed conversion ratio (FCR) increased as the fattening period increased, and the FCR was 12.88% lower in the 20-month treatment group than in the 24-month treatment group. However, no significant differences were detected in back-fat thickness, loin area, marbling score, and chemical characteristics (water, crude protein, and crude fat content) among the treatment groups. The composition of fatty acids including C18:0, C18:1, saturated fatty acids, unsaturated fatty acids, and poly-unsaturated fatty acids did not differ among the experimental groups. As the fattening period increased, production costs increased, resulting in a decrease in gross income. The gross income for steers in the 24-month treatment group was 35.8% and 23.5% lower than that for steers in the 20- and 21-month treatment groups, respectively. Taken together, the best performance, including the ADG, FCR, and gross income, was obtained when the fattening program of the Holstein steers lasted 20 months.

The scapholunate ligament is made of 3 portions: proximal, volar, and dorsal. The latter is the major stabilizer of the scapholunar pair, and its lesion is bound to cause a destabilization of the carpus, as well as scapholunar diastasis, dorsal intercalated segment instability, then eventually SLAC (i.e., scapholunate advanced collapse) wrist. The healing process of this ligament, either spontaneous or after primary repair with direct suture, is rarely observed and a significant number of patients are diagnosed only at a late stage, thus making an illusion of a maintained stability of the carpus first range. Management then consists of ligamentoplasty. Several open techniques are described to restore stability, but at the cost of a frequent and significant tightening of the wrist. We will introduce here an arthroscopic ligamentoplasty technique completed by a posterior capsulodesis., Technique Video Video 1 The patient is in the decubitus position, upper limb lies in pronation on an arm table with a pneumatic tourniquet at the basis of the limb, wrist on an arthroscopic tower, right wrist. 00’05: Introduction. 00’22: Ligament check-up and testing. 00’40: Articular check-up. 00’58: Debridement. 01’31: Setting the guide pins. 02’07: Drilling the tunnels. 02’38: Fixation of the SutureTape in the proximal pole of the scaphoid. 03’03: Fixation of the SutureTape in the posterior cornea of the lunate. 03’48: Ligamentoplasty testing through radiocarpal joint. 04’09: Ligamentoplasty testing through midcarpal joint. 04’19: Dorsal capsulodesis.

In the United Arab Emirates (UAE), lung cancer (LC) was the third leading cause of deaths due to cancer in 2017. Around 80% of the patients in the UAE are diagnosed at a late stage, rendering the treatment less effective in improving survival outcomes. Lack of awareness of disease symptomatology, deficient screening initiatives, misdiagnosis, and delayed referral to the specialist are contributing factors for delayed diagnosis. Effective screening at a primary care setting can be crucial for early diagnosis, referral to specialists, and enhancing patient outcomes. It is important to establish screening and referral guidelines through which each suspected case can be identified and provided timely intervention. Although the international screening and referral pathway framework are comprehensive, several regional barriers need to be addressed before they can be adapted at the national level. A group of LC experts from the UAE deliberated on issues like delayed diagnosis of LC and strategic recommendations for overcoming the challenges. The discussion was based on the review of the published evidence, international and regional guidelines for screening and early diagnosis of LC. Herein, we present a guideline, endorsed by the esteemed panel of experts, for aiding early diagnosis and optimizing the management of LC in the UAE.

Herein, we report the total synthesis of the phosphorylated zwitterionic trisaccharide repeating unit of Photorhabdus temperata subsp. cinerea 3240. The efficient route involves regio- and stereoselective assembly of trisaccharide with rare deoxyamino sugar AAT at the nonreducing end, late stage oxidation, and installation of a phosphate linker on the trisaccharide. The total synthesis was completed via a longest linear sequence of 24 steps in 6.5% overall yield.

Purpose The exact nature of sex and gender differences in knee osteoarthritis (OA) among patient candidates for total knee arthroplasty (TKA) remains unclear and requires better elucidation to guide clinical practice. The purpose of this investigation was to survey physician practices and perceptions about the influence of sex and gender on knee OA presentation, care, and outcomes after TKA. Methods The survey questions were elaborated by a multidisciplinary scientific board composed of 1 pain specialist, 4 orthopedic specialists, 2 physiatrists, and 1 expert in gender medicine. The survey included 5 demographic questions and 20 topic questions. Eligible physician respondents were those who treat patients during all phases of care (pain specialists, orthopedic specialists, and physiatrists). All survey responses were anonymized and handled via remote dispersed geographic participation. Results Fifty-six physicians (71% male) accepted the invitation to complete the survey. In general, healthcare professionals expressed that women presented worse symptomology, higher pain intensity, and lower pain tolerance and necessitated a different pharmacological approach compared to men. Pain and orthopedic specialists were more likely to indicate sex and gender differences in knee OA than physiatrists. Physicians expressed that the absence of sex and gender-specific instruments and indications is an important limitation on available studies. Conclusions Healthcare professionals perceive multiple sex and gender-related differences in patients with knee OA, especially in the pre- and perioperative phases of TKA. Sex and gender bias sensitivity training for physicians can potentially improve the objectivity of care for knee OA among TKA candidates.

Alzheimer's disease (AD) has become a global threat to the elderly health with a short survival time after diagnosis. Due to the asymptomatic stage during the early development, patients are usually diagnosed at the middle or late stage. Therefore, an efficient tool for AD early diagnosis deserves considerable attention, which could make a significant contribution to the treatment intervention. A fluorescent probe has been widely applied for detecting and visualizing species of interest in vitro and in vivo, and the proper reaction between the probe and analytes is responsible for the fluorescence change to provide a lighting-on or ratiometric responsive pattern with satisfactory sensing behavior. In this work, we report the first attempt to build up an AND-logic probe P2 for AD accuracy diagnosis taking butyrylcholinesterase (BChE) and reactive oxygen species (ROSs) as dual targets. Upon the co-stimulation by these two factors through enzymatic hydrolysis and redox reaction, the NIR emission could be readily turned on. This AND sensing pattern avoided the false-positive response effectively, and other diseases sharing one biomarker could hardly induce a NIR fluorescence response. The sensing assay has also been confirmed to be feasible in vitro and in vivo with good sensibility and selectivity. It is worth mentioning that the probe structure has been optimized in terms of the linkage length. This study shows that probe P2 with a connecting arm of medium length (one methylene, n = 1) has superior sensing performance, promising to provide a reference for the relative structure design.

The effect of Ge modification on the oxidation of NbSi2 was performed by using the first-principles method based on Density Functional Theory (DFT). The O2 molecule absorption configurations on the ideal NbSi2 (001) surface with and without Ge substitution was constructed to study the initial oxidation behavior as well as oxygen diffusion in the bulk NbSi2 cell in the late oxidation stage. Ge substitution was found to decrease the absorption energy of O2 molecule on the NbSi2 (001) surface and therefore reduce the oxidation rate in the initial oxidation stage. The further linear synchronous transit (LST) calculation revealed that Ge substitution increased the energy barrier of O atom diffusion in the bulk NbSi2 cell and decreased the oxidation rate in the late stage.

Based on the spontaneous imbibition phenomenon and seepage mechanism of the tight core, a spontaneous imbibition model of the tight reservoir was established. The imbibition experiment was used to verify the reliability of the model and reverse the parameters. The relative error between the experimental and model recovery is within 5%. The model is used to calculate the oil recovery and oil saturation distribution characteristics of spontaneous imbibition in tight reservoirs under different boundary conditions. The model results show that the imbibition area and imbibition recovery are different under different boundary conditions [one-end-open, two-end-open, two-end-close (TEC), and all-face-open (AFO)]. If the imbibition area increases, imbibition recovery increases. If the side is closed, the spontaneous imbibition occurring at two end faces does not interfere with each other in the initial stage. When the imbibition process under TEC conditions is advanced to the middle and late stage, the superimposed effect occurs between the two imbibition leading edges. Under the AFO condition, the imbibition process has a superimposed effect at the corner between the end face and the side face. The superimposed effect of the end face is more obvious than that of the side face. The superimposed effect not only improves the oil washing efficiency but also inhibits the imbibition area.

The enzymatic generation of carbon–halogen bonds is a powerful strategy used by both nature and synthetic chemists to tune the bioactivity, bioavailability and reactivity of compounds, opening up the opportunity for selective C–H functionalisation. Genes encoding halogenase enzymes have recently been shown to transcend all kingdoms of life. These enzymes install halogen atoms into aromatic and less activated aliphatic substrates, achieving selectivities that are often challenging to accomplish using synthetic methodologies. Significant advances in both halogenase discovery and engineering have provided a toolbox of enzymes, enabling the ready use of these catalysts in biotransformations, synthetic biology, and in combination with chemical catalysis to enable late stage C–H functionalisation. With a focus on substrate scope, this review outlines the mechanisms employed by the major classes of halogenases, while in parallel, it highlights key advances in the utilisation of the combination of enzymatic halogenation and chemical catalysis for C–H activation and diversification., An overview of enzymatic tools for generation of carbon–halogen bonds and their use in enabling selective C–H functionalisation through combination of enzyme and chemo catalysis.

Carboxylic acids are highly abundant in bioactive molecules. In this study, we describe the late-stage β-C(sp3)-H deuteration of free carboxylic acids. On the basis of the finding that C-H activation with our catalysts is reversible, the de-deuteration process was first optimized. The resulting method uses ethylenediamine-based ligands and can be used to achieve the desired deuteration when using a deuterated solvent. The reported method allows for the functionalization of a wide range of free carboxylic acids with diverse substitution patterns, as well as the late-stage deuteration of bioactive molecules and related frameworks and enables the functionalization of nonactivated methylene β-C(sp3)-H bonds for the first time.

Over the past decade, the landscape of molecular synthesis has gained major impetus by the introduction of late-stage functionalization (LSF) methodologies. C–H functionalization approaches, particularly, set the stage for new retrosynthetic disconnections, while leading to improvements in resource economy. A variety of innovative techniques have been successfully applied to the C–H diversification of pharmaceuticals, and these key developments have enabled medicinal chemists to integrate LSF strategies in their drug discovery programmes. This Review highlights the significant advances achieved in the late-stage C–H functionalization of drugs and drug-like compounds, and showcases how the implementation of these modern strategies allows increased efficiency in the drug discovery process. Representative examples are examined and classified by mechanistic patterns involving directed or innate C–H functionalization, as well as emerging reaction manifolds, such as electrosynthesis and biocatalysis, among others. Structurally complex bioactive entities beyond small molecules are also covered, including diversification in the new modalities sphere. The challenges and limitations of current LSF methods are critically assessed, and avenues for future improvements of this rapidly expanding field are discussed. We, hereby, aim to provide a toolbox for chemists in academia as well as industrial practitioners, and introduce guiding principles for the application of LSF strategies to access new molecules of interest. Late-stage C–H functionalization of complex molecules has emerged as a powerful tool in drug discovery. This Review classifies significant examples by reaction manifold and assesses the benefits and challenges of each approach. Avenues for future improvements of this fast-expanding field are proposed.

This article is a maiden attempt at exploring determinants of stage-specific investment choices of Indian venture capital and private equity (VCPE) firms. Analysis of 5,782 VCPE investment deals during 1998–2016 shows that firms’ preferences to invest in various stages (early vs. late) are significantly affected by the characteristics of the VCPE firms, features of the deal, and characteristics of the investee firms. More specifically, experience and ownership (foreign vs. domestic) of VCPE firm, type of deal (syndicated or otherwise), investment size of the deal, and location and industry of the investee firm influence the stage of investment. Detailed empirical analysis shows that younger VCPE firms and those with domestic investors prefer to invest in early stages, presumably because they wish to build a reputation and also leverage their proximity with investee firms to manage high market and technological risks associated with early-stage investments. Syndication is another mechanism used to manage the risks associated with early-stage deals. Investee firms in industries that have lower investment requirements or shorter gestation periods and those located in regions with a mature entrepreneurial ecosystems are more likely to attract early-stage investments. JEL Classification: G24, L26, D81

This is an article that draws on the institutional work literature about provisional institutions. To date, nearly every U.S. sector has been impacted by COVID-19. To sustain their core missions, highly institutionalized organizations such as universities have had to rethink foundational structures and policies. Using a historical ethnographic approach to investigate records from faculty senate deliberations at “Rural State University” (RSU), the authors examine the implementation of a temporary grading policy to supplement traditional, qualitative grades spring 2020 during the outbreak. The authors find that RSU implemented a temporary, supplemental grading policy as a provisional institution to momentarily supersede traditional grading as a means to—as soon as possible—return to it. This finding contrasts with the common understanding that provisional institutions operate primarily as a temporary solution to a social problem that leads to more stable and enduring, ostensibly nonprovisional institutions. The temporary grading policy, the authors argue, constitutes a “late-stage” provisional institution and, with this new lens, subsequently characterize the more commonplace understanding of provisional institutions as “early-stage.” This contribution has theoretical implications for studies of institutions and empirical implications for research on shared governance and disruption in higher education.

Tumor recurrence after surgery is the main cause of treatment failure. However, the initial stage of recurrence is not easy to detect, and it is difficult to cure in the late stage. In order to improve the life quality of postoperative patients, an efficient synergistic immunotherapy was developed to achieve early diagnosis and treatment of post-surgical tumor recurrence, simultaneously. In this paper, two kinds of theranostic agents based on gold nanorods (AuNRs) platform were prepared. AuNRs and quantum dots (QDs) in one agent was used for the detection of carcinoembryonic antigen (CEA), using fluorescence resonance energy transfer (FRET) technology to indicate the occurrence of in situ recurrence, while AuNRs in the other agent was used for photothermal therapy (PTT), together with anti-PDL1 mediated immunotherapy to alleviate the process of tumor metastasis. A series of assays indicated that this synergistic immunotherapy could induce tumor cell death and the increased generation of CD3+/CD4+ T-lymphocytes and CD3+/CD8+ T-lymphocytes. Besides, more immune factors (IL-2, IL-6, and IFN-γ) produced by synergistic immunotherapy were secreted than mono-immunotherapy. This cooperative immunotherapy strategy could be utilized for diagnosis and treatment of postoperative tumor recurrence at the same time, providing a new perspective for basic and clinical research., Graphical abstract This efficient synergistic immunotherapy was developed to achieve early diagnosis and treatment of post-surgical tumor recurrence, simultaneously.Image 1

Brassica napus L. (rapeseed) is one of the most important oil crops with large cultivated area in China. Seed size and seed weight play crucial roles for yield and harvest. In this study, a type of 15 bp-deletion in BnaGRF7.C02 coding region was identified through sequence alignment of BnaGRF7.C02 in 42 rapeseed varieties, and association analysis indicated that the 15 bp-deletion was related to the rapeseed Thousand-Seed Weight (TSW) phenotype. Furthermore, we developed two InDel markers to identify this 15 bp InDel. The tissue-specific expression patterns showed that BnaGRF7.C02 prominently expressed in the late stage of seed development. These findings may assist in InDel markers-based breeding efforts to select higher TWS varieties and improve the crop yield of B. napus.