Intra-articular injection of the cyclooxygenase-2 inhibitor parecoxib attenuates osteoarthritis progression in anterior cruciate ligament-transected knee in rats: role of excitatory amino acids

SummaryObjectiveOur present study examined the effect of intra-articular cyclooxygenase-2 (COX-2) inhibitor parecoxib on osteoarthritis (OA) progression and the concomitant changes in excitatory amino acids' (EAAs) levels of the anterior cruciate ligament-transected (ACLT) knee joint dialysates.MethodsOA was induced in Wistar rats by anterior cruciate ligament transection of the knee of one hindlimb, the other was left unoperated and untreated. Rats were placed into four groups: Group ACLT/P received intra-articular parecoxib injection (100μg) in the ACLT knee once a week for 5 consecutive weeks starting at 8 weeks after surgery. Group ACLT/S received the same procedure as group ACLT/P with saline injection instead. Naïve (Naïve/P) rats received only intra-articular parecoxib injection in one knee once a week for 5 consecutive weeks without surgery. The sham-operated rats underwent arthrotomy only without treatment. Twenty weeks after surgery, knee joint dialysates were collected and EAAs' concentration was assayed by high-performance liquid chromatography, and gross morphology and histopathology (Mankin and synovitis grading) were examined on the medial femoral condyles and synovia.ResultsParecoxib alone had no effect on cartilage and synovium of normal knees in Naïve/P rats. In ACLT/P rats, parecoxib treatment showed a significant inhibition of cartilage degeneration of the medial femoral condyle at both the macroscopic level (1.15±0.17 vs 2.55±0.12, P<0.05) and the Mankin scores (3.03±0.28 vs 8.82±0.43, P<0.05). Intra-articular parecoxib injection also suppressed the synovial inflammation of ACLT joint compared to the ACLT/S group (3.92±0.41 vs 9.25±0.32, P<0.05). Moreover, glutamate and aspartate levels were also significantly reduced in the ACLT/P group compared to the ACLT/S group by parecoxib treatment (91.2±9.4% vs 189.5±17.0%, P<0.05 and 98.2±11.6% vs 175.3±12.4%, P<0.05, respectively).ConclusionThis study shows that intra-articular injection of COX-2 inhibitor parecoxib inhibits the ACLT-induced OA progression; it was accompanied by a reduction of glutamate and aspartate concentration in the ACLT joint dialysates. From our present results, we suggested that intra-articular parecoxib injection, in addition to the anti-inflammatory effect, inhibiting the EAAs' release, may also play a role in inhibiting the traumatic knee injury induced OA progression

Submillimeter ALMA Observations of the Dense Gas in the Low-Luminosity Type-1 Active Nucleus of NGC 1097

We present the first 100 pc scale view of the dense molecular gas in the central ~ 1.3 kpc region of the type-1 Seyfert NGC 1097 traced by HCN (J=4-3) and HCO+ (J=4-3) lines afforded with ALMA band 7. This galaxy shows significant HCN enhancement with respect to HCO+ and CO in the low-J transitions, which seems to be a common characteristic in AGN environments. Using the ALMA data, we study the characteristics of the dense gas around this AGN and search for the mechanism of HCN enhancement. We find a high HCN (J=4-3) to HCO+ (J=4-3) line ratio in the nucleus. The upper limit of the brightness temperature ratio of HCN (v2=1^{1f}, J=4-3) to HCN (J=4-3) is 0.08, which indicates that IR pumping does not significantly affect the pure rotational population in this nucleus. We also find a higher HCN (J=4-3) to CS (J=7-6) line ratio in NGC 1097 than in starburst galaxies, which is more than 12.7 on the brightness temperature scale. Combined from similar observations from other galaxies, we tentatively suggest that this ratio appears to be higher in AGN-host galaxies than in pure starburst ones similar to the widely used HCN to HCO+ ratio. LTE and non-LTE modeling of the observed HCN and HCO+ lines using J=4-3 and 1-0 data from ALMA, and J=3-2 data from SMA, reveals a high HCN to HCO+ abundance ratio (5 < [HCN]/[HCO+] < 20: non-LTE analysis) in the nucleus, and that the high-J lines (J=4-3 and 3-2) are emitted from dense (10^{4.5} < n_H2 [/cc] < 10^6), hot (70 < Tkin [K] < 550) regions. Finally we propose that the high temperature chemistry is more plausible to explain the observed enhanced HCN emission in NGC 1097 than the pure gas phase PDR/XDR chemistry.Comment: 28 pages, 17 figures, 10 tables. Accepted to PAS

Chemoenzymatic Probes for Detecting and Imaging Fucose-α(1-2)-galactose Glycan Biomarkers

The disaccharide motif fucose-α(1-2)-galactose (Fucα(1-2)Gal) is involved in many important physiological processes, such as learning and memory, inflammation, asthma, and tumorigenesis. However, the size and structural complexity of Fucα(1-2)Gal-containing glycans have posed a significant challenge to their detection. We report a new chemoenzymatic strategy for the rapid, sensitive detection of Fucα(1-2)Gal glycans. We demonstrate that the approach is highly selective for the Fucα(1-2)Gal motif, detects a variety of complex glycans and glycoproteins, and can be used to profile the relative abundance of the motif on live cells, discriminating malignant from normal cells. This approach represents a new potential strategy for biomarker detection and expands the technologies available for understanding the roles of this important class of carbohydrates in physiology and disease

ALMA Observations of the Submillimeter Dense Molecular Gas Tracers in the Luminous Type-1 Active Nucleus of NGC 7469

We present ALMA Cycle 1 observations of the central kpc region of the luminous type-1 Seyfert galaxy NGC 7469 with unprecedented high resolution (0.5$"$ $\times$ 0.4$"$ = 165 pc $\times$ 132 pc) at submillimeter wavelengths. Utilizing the wide-bandwidth of ALMA, we simultaneously obtained HCN(4-3), HCO$^+$(4-3), CS(7-6), and partially CO(3-2) line maps, as well as the 860 $\mu$m continuum. The region consists of the central $\sim$ 1$"$ component and the surrounding starburst ring with a radius of $\sim$ 1.5$"$-2.5$"$. Several structures connect these components. Except for CO(3-2), these dense gas tracers are significantly concentrated towards the central $\sim$ 1$"$, suggesting their suitability to probe the nuclear regions of galaxies. Their spatial distribution resembles well those of centimeter and mid-infrared continuum emissions, but it is anti-correlated with the optical one, indicating the existence of dust obscured star formation. The integrated intensity ratios of HCN(4-3)/HCO$^+$(4-3) and HCN(4-3)/CS(7-6) are higher at the AGN position than at the starburst ring, which is consistent to our previous findings (submm-HCN enhancement). However, the HCN(4-3)/HCO$^+$(4-3) ratio at the AGN position of NGC 7469 (1.11$\pm$0.06) is almost half of the corresponding value of the low-luminosity type-1 Seyfert galaxy NGC 1097 (2.0$\pm$0.2), despite the more than two orders of magnitude higher X-ray luminosity of NGC 7469. But the ratio is comparable to that of the close vicinity of the AGN of NGC 1068 ($\sim$ 1.5). Based on these results, we speculate that some other heating mechanisms than X-ray (e.g., mechanical heating due to AGN jet) can contribute significantly for shaping the chemical composition in NGC 1097.Comment: Fixed typos in the title. 15 pages, 8 figures, 4 tables: accepted for publication in ApJ. Comments welcom

ALMA Observations of Multiple-CO and C Lines Toward the Active Galactic Nucleus of NGC 7469: X-Ray-dominated Region Caught in the Act

We used the Atacama Large Millimeter/submillimeter Array (ALMA) to map $^{12}$CO($J$ = 1-0), $^{12}$CO($J$ = 2-1), $^{12}$CO($J$ = 3-2), $^{13}$CO($J$ = 2-1), and [CI]($^3P_1$-$^3P_0$) emission lines around the type 1 active galactic nucleus (AGN) of NGC 7469 ($z = 0.0164$) at $\sim 100$ pc resolutions. The CO lines are bright both in the circumnuclear disk (central $\sim 300$ pc) and the surrounding starburst (SB) ring ($\sim 1$ kpc diameter), with two bright peaks on either side of the AGN. By contrast, the [CI]($^3P_1$-$^3P_0$) line is strongly peaked on the AGN. Consequently, the brightness temperature ratio of [CI]($^3P_1$-$^3P_0$) to $^{13}$CO(2-1) is $\sim 20$ at the AGN, as compared to $\sim 2$ in the SB ring. Our local thermodynamic equilibrium (LTE) and non-LTE models indicate that the enhanced line ratios (or CI enhancement) are due to an elevated C$^0$/CO abundance ratio ($\sim 3-10$) and temperature ($\sim 100-500$ K) around the AGN as compared to the SB ring (abundance ratio $\sim 1$, temperature $\lesssim 100$ K), which accords with the picture of the X-ray-dominated Region (XDR). Based on dynamical modelings, we also provide CO(1-0)-to- and [CI]($^3P_1$-$^3P_0$)-to-molecular mass conversion factors at the central $\sim 100$ pc of this AGN as $\alpha_{\rm CO} = 4.1$ and $\alpha_{\rm CI} = 4.4~M_\odot$ (K km s$^{-1}$ pc$^2$)$^{-1}$, respectively. Our results suggest that the CI enhancement is potentially a good marker of AGNs that could be used in a new submillimeter diagnostic method toward dusty environments.Comment: 25 pages, 12 figures, 8 tables. Accepted for publication in ApJ. Minor updates in a replacemen

Experience with telemedicine among rheumatology clinicians during the COVID-19 pandemic: an international survey

Objective: The aim was to assess rheumatology clinicians' perceptions of telemedicine and their experiences before and during the coronavirus disease 2019 (COVID-19) pandemic. Methods: We conducted a cross-sectional online survey and collected responses from rheumatology clinicians worldwide, between November 2020 and February 2021, regarding use and perceptions of telemedicine in rheumatology. We summarized data with descriptive statistics and qualitative analysis for free-text responses. Results: The survey was completed by 349 rheumatology clinicians from 49 countries; 59% were female and about two-thirds were in the 30-50 years age group. Academic affiliations were held by 55% of participants, and 44% were from North America. Before the pandemic, 24% of participants had experience with telemedicine, whereas about three-quarters used telemedicine for the first time during the pandemic. Overall, 56% thought they provided less adequate care with telemedicine. More than half of clinicians felt that telemedicine was adequate for evaluating crystalline arthritis, inflammatory arthritis and lupus flares. Telemedicine was felt to be inadequate for flares of myositis, vasculitis and scleroderma. Technical problems were reported in 29% of telemedicine encounters and were most commonly related to patient-encountered difficulties. Conclusion: Most rheumatology clinicians used telemedicine for the first time during the pandemic. The quality of care provided was thought to be inferior to that provided in person for specific clinical situations. Additional efforts are needed to address barriers to effective telemedicine, such as patient-related technology issues, challenges with building rapport and performing a physical examination, and to define the appropriate scope of clinical scenarios conducive to telemedicine

The RIP140 Gene Is a Transcriptional Target of E2F1

RIP140 is a transcriptional coregulator involved in energy homeostasis and ovulation which is controlled at the transcriptional level by several nuclear receptors. We demonstrate here that RIP140 is a novel target gene of the E2F1 transcription factor. Bioinformatics analysis, gel shift assay, and chromatin immunoprecipitation demonstrate that the RIP140 promoter contains bona fide E2F response elements. In transiently transfected MCF-7 breast cancer cells, the RIP140 promoter is transactivated by overexpression of E2F1/DP1. Interestingly, RIP140 mRNA is finely regulated during cell cycle progression (5-fold increase at the G1/S and G2/M transitions). The positive regulation by E2F1 requires sequences located in the proximal region of the promoter (−73/+167), involves Sp1 transcription factors, and undergoes a negative feedback control by RIP140. Finally, we show that E2F1 participates in the induction of RIP140 expression during adipocyte differentiation. Altogether, this work identifies the RIP140 gene as a new transcriptional target of E2F1 which may explain some of the effect of E2F1 in both cancer and metabolic diseases

Role of 20-Hydroxyeicosatetraenoic Acid in Mediating Hypertension in Response to Chronic Renal Medullary Endothelin Type B Receptor Blockade

BACKGROUND: The renal medullary endothelin (ET-1) system plays an important role in the control of sodium excretion and arterial pressure (AP) through the activation of renal medullary ET-B receptors. We have previously shown that blockade of endothelin type B receptors (ET-B) leads to salt-sensitive hypertension through mechanisms that are not fully understood. One possible mechanism is through a reduction in renal medullary production of 20-hydroxyeicosatetraenoic acid (20-HETE). 20-HETE, a metabolite of arachidonic acid, has natriuretic properties similar to ET-B activation. While these findings suggest a possible interaction between ET-B receptor activation and 20-HETE production, it is unknown whether blockade of medullary ET-B receptors in rats maintained on a high sodium intake leads to reductions in 20-HETE production. METHODOLOGY/PRINCIPAL FINDINGS: The effect of increasing sodium intake from low (NS = .8%) to high (HS = 8%) on renal medullary production of 20-HETE in the presence and absence of renal medullary ET-B receptor antagonism was examined. Renal medullary blockade of ET-B receptors resulted in salt sensitive hypertension. In control rats, blood pressure rose from 112.8±2.4 mmHg (NS) to 120.7±9.3 mmHg (HS). In contrast, when treated with an ET-B receptor blocker, blood pressure was significantly elevated from 123.7±3.2 (NS) to 164.2±7.1 (HS). Furthermore, increasing sodium intake was associated with elevated medullary 20-HETE (5.6±.8 in NS vs. 14.3±3.7 pg/mg in HS), an effect that was completely abolished by renal medullary ET-B receptor blockade (4.9±.8 for NS and 4.5±.6 pg/mg for HS). Finally, the hypertensive response to intramedullary ET-B receptor blockade was blunted in rats pretreated with a specific 20-HETE synthesis inhibitor. CONCLUSION: These data suggest that increases in renal medullary production of 20-HETE associated with elevating salt intake may be, in part, due to ET-B receptor activation within the renal medulla

Prostaglandins, masculinization and its disorders:effects of fetal exposure of the rat to the cyclooxygenase inhibitor- indomethacin

Recent studies have established that masculinization of the male reproductive tract is programmed by androgens in a critical fetal ‘masculinization programming window’ (MPW). What is peculiar to androgen action during this period is, however, unknown. Studies from 20 years ago in mice implicated prostaglandin (PG)-mediation of androgen-induced masculinization, but this has never been followed up. We therefore investigated if PGs might mediate androgen effects in the MPW by exposing pregnant rats to indomethacin (which blocks PG production by inhibiting cyclooxygenase activity) during this period and then examining if androgen production or action (masculinization) was affected. Pregnant rats were treated with indomethacin (0.8 mg/kg/day; e15.5–e18.5) to encompass the MPW. Indomethacin exposure decreased fetal bodyweight (e21.5), testis weight (e21.5) and testicular PGE2 (e17.5, e21.5), but had no effect on intratesticular testosterone (ITT; e17.5) or anogenital index (AGI; e21.5). Postnatally, AGI, testis weight and blood testosterone were unaffected by indomethacin exposure and no cryptorchidism or hypospadias occurred. Penis length was normal in indomethacin-exposed animals at Pnd25 but was reduced by 26% (p&lt;0.001) in adulthood, an effect that is unexplained. Our results demonstrate that indomethacin can effectively decrease intra-testicular PGE2 level. However, the resulting male phenotype does not support a role for PGs in mediating androgen-induced masculinization during the MPW in rats. The contrast with previous mouse studies is unexplained but may reflect a species difference