A review on cullin neddylation and strategies to identify its inhibitors for cancer therapy.

The cullin-RING E3 ligases (CRLs) are the biggest components of the E3 ubiquitin ligase protein family, and they represent an essential role in various diseases that occur because of abnormal activation, particularly in tumors development. Regulation of CRLs needs neddylation, a post-translational modification involving an enzymatic cascade that transfers small, ubiquitin-like NEDD8 protein to CRLs. Many previous studies have confirmed neddylation as an enticing target for anticancer drug discoveries, and few recent studies have also found a significant increase in advancement in protein neddylation, including preclinical and clinical target validation to discover the neddylation inhibitor compound. In the present review, we first presented briefly the essence of CRLs' neddylation and its control, systematic analysis of CRLs, followed by the description of a few recorded chemical inhibitors of CRLs neddylation enzymes with recent examples of preclinical and clinical targets. We have also listed various structure-based pointing of protein-protein dealings in the CRLs' neddylation reaction, and last, the methods available to discover new inhibitors of neddylation are elaborated. This review will offer a concentrated, up-to-date, and detailed description of the discovery of neddylation inhibitors.

Effects of Ferula asafetida, closantel, albendazole, oxfendazole, and ivermectin against Haemonchus contortus in goats and sheep.

BACKGROUND: Haemonchosis is a fatal disease of small ruminants caused by the parasite Haemonchus contortus (H. contortus). The most common drugs used in the treatment of H. contortus include albendazole, oxfendazole, and ivermectin. However, as previously reported in the treatment of haemonchosis, these medicines have acquired drug resistance problems over time. Interestingly, natural plant compounds have demonstrated promising effects in the treatment of H. contortus. Therefore, the current study evaluated the effects of plant extract, Ferula asafetida, against common drugs such as albendazole, oxfendazole, ivermectin, and closantel for the treatment of haemonchosis in small ruminants. METHODOLOGY: The current study was conducted on different small ruminant farms in Kasur District, Punjab, Pakistan. The positive animals (n = 720) after coprological examination were selected in this study and divided into two major groups (n = 360 goats and n = 360 sheep). Further, animals were divided into five treatment groups (A-E) and one control group with no treatment (F). Albendazole, oxfendazole, ivermectin, closantel, and Ferula asafetida were administered orally to groups A-E, respectively. The eggs per gram feces (EPG) were determined through the McMaster technique on days 0, 7th, and 14th of treatment. RESULTS: The results showed a significantly higher efficacy of closantel and Ferula asafetida against H. contortus in both goats (100% and 70%; p < 0.05) and sheep (99% and 87%; p < 0.05), respectively. No correlation was observed between EPG reduction with age and gender in both goats and sheep. CONCLUSION: Allopathic drug closantel and herbal drug, Ferula asafetida, have been proved an effective dewormer against H. contortus in small ruminants.

High Prevalence of Asymptomatic COVID-19 Infection in Hemodialysis Patients Detected Using Serologic Screening.

BACKGROUND: Strategies to minimize the risk of transmission and acquisition of COVID-19 infection in patients with ESKD receiving in-center hemodialysis have been rapidly implemented across the globe. Despite these interventions, confirmed COVID-19 infection rates have been high in the United Kingdom. Prevalence of asymptomatic disease in an adult hemodialysis population has not been reported. Also, to our knowledge, the development of humoral response to SARS-CoV-2 has not been previously reported in this population. Although serologic testing does not provide information on the infectivity of patients, seroprevalence studies may enable investigation of exposure within dialysis units and hence, assessment of current screening strategies. METHODS: To investigate the seroprevalence of SARS-CoV-2 antibodies in a hemodialysis population, we used the Abbott IgG assay with the Architect system to test serum samples from 356 patients receiving in-center hemodialysis for SARS-CoV-2 antibodies. RESULTS: Of 356 patients, 121 had been symptomatic when screened before a dialysis session and received an RT-PCR test; 79 (22.2% of the total study population) tested positive for COVID-19. Serologic testing of all 356 patients found 129 (36.2%) who tested positive for SARS-CoV-2 antibodies. Only two patients with PCR-confirmed infection did not seroconvert. Of the 129 patients with SARS-CoV-2 antibodies, 52 (40.3%) had asymptomatic disease or undetected disease by PCR testing alone. CONCLUSIONS: We found a high seroprevalence of SARS-CoV-2 antibodies in patients receiving in-center hemodialysis. Serologic evidence of previous infection in asymptomatic or PCR-negative patients suggests that current diagnostic screening strategies may be limited in their ability to detect acute infection.

Epidemiology and antibiogram of common mastitis-causing bacteria in Beetal goats.

BACKGROUND AND AIM: Mastitis has been identified as the most prevalent and economically imperative disease among dairy animals. Thus, understanding its common bacterial pathogens and risk factors is necessary to improve udder health at herd, region, or country level. However, scientific research on caprine mastitis, especially on Beetal breed, has remained to be insufficient in Pakistan. Therefore, this study aimed to evaluate the epidemiology and antibiogram assay of common mastitis-causing bacterial agents, that is, Staphylococcus, Streptococcus, and Escherichia coli, in dairy goats. MATERIALS AND METHODS: In total, 500 Beetal goats, irrespective of age and those that were not treated with any kind of antimicrobial agents during the past 120 h, were screened using California Mastitis Test in Pattoki, Kasur District, whereas epidemiological factors were recorded. The milk samples of mastitic goats were then collected and processed using standard methods. Each sample was primarily cultured on nutrient agar. Using a specific medium, each bacterial colony was separated using several streak methods. Six antibiotic disks belonging to different antibiotic groups were used for antibiogram profiling of bacterial isolates. Chi-square test was used to assess the association of baseline characteristics and mastitis occurrence. Meanwhile, multivariable logistic regression (p<0.001) was utilized to determine the risk factors associated with positive and negative dichotomous outcome of mastitis. RESULTS: The results revealed that the overall prevalence of goat mastitis was 309 (61.8%), in which 260 (52%) and 49 (9.8%) cases were positive for subclinical mastitis (SCM) and clinical mastitis (CM), respectively. Streptococcus and E. coli were found to be the predominant isolates causing SCM and CM, respectively (p<0.001). It was observed that amoxicillin+clavulanic acid was highly sensitive to isolates of Staphylococcus and Streptococcus and ceftiofur sodium to isolates of Streptococcus and E. coli., while enrofloxacin was found to be sensitive to isolates of Streptococcus and E. coli. Risk factors such as herd structure, deworming, vaccination, presence of ticks, use of teat dip and mineral supplements, feeding type, age, parity, housing, blood in the milk, milk leakage, milk taste, and milk yield were found to have the strongest association with mastitis occurrence, while ease of milking has moderate association. CONCLUSION: In the area examined, cases of SCM were found to be higher compared with that of CM, and ceftiofur sodium has been identified as the preferred treatment in both clinical and subclinical forms of caprine mastitis in Beetal goats. Risk factors for mastitis that was identified in this study can form the basis for the creation of an udder health control program specific for dairy goats. We hope our findings could raise awareness of the risk factors and treatment approaches for common mastitis-causing bacterial agents.

Levels of serum thyroxine, triidothyronine and thyrotropin in patients with acute myocardial infarction.

OBJECTIVE: To determine the levels of serum thyroxine (T3, T4), triiodothyronine and thyrotropin in patients with acute myocardial infarction (AMI). METHODS: It was an observational prospective study and 60 patients (both males and females) of AMI, (diagnosed by ECG & cardiac enzymes.) were included. Serum thyroid stimulating hormone (TSH), Free T3 and Free T4 were measured and relevant data was entered into a predesigned proforma. RESULTS: FT3 levels were below the reference range in 56.7% cases while both the FT4 and TSH values were found to be the lower limit of normal range. When the decrease in FT3 was correlated with the duration of illness, it was found that significant inverse correlation existed between FT3 value and the duration of illness and linear regression line was obtained. No such correlation existed between FT4 and TSH values. CONCLUSION: Thyroid hormone levels (FT3) decreases in AMI and this change is associated with the duration of illness.