Role of carnitine in cancer chemotherapy-induced multiple organ toxicity.
In the last few years, cancer chemotherapy has been successfully employed in the treatment of different types of human tumours. Unfortunately, the optimal clinical usefulness of this important treatment modality is usually limited secondary to the development of life-threatening multiple organ toxicity. Cancer chemotherapy may cause these toxic effects by mechanisms not involved in their anticancer activity that can severely affect the life of patients and represent a direct cause of death. Several experimental and clinical studies have demonstrated that some important anticancer drugs interfere with the absorption, synthesis, and excretion of carnitine in non-tumour tissues, resulting in a secondary carnitine deficiency which is reversed by carnitine treatment without affecting anticancer therapeutic efficacy. Prototypes of anticancer drugs that alter carnitine system are doxorubicin, cisplatin, carboplatin, oxaliplatin, cyclophosphamide and ifosfamide. Furthermore, cachectic cancer patients are especially at risk for carnitine deficiency due to decreased oral intake and/or increased renal losses. Altered serum and urine carnitine levels have been reported in cancer patients with various forms of malignant diseases. Recent studies in our laboratory have demonstrated that carnitine deficiency constitute a risk factor and should be viewed as a mechanism during development of oxazaphosphorines-induced cardiotoxicity in rats. Similarly, inhibition of gene expression of heart fatty acid-binding protein and organic cation/carnitine transporter in doxorubicin cardiomyopathic rat model has been reported. In view of these facts and in view of irreplaceability of these important anticancer drugs, this review aimed to highlight the role of carnitine depletion and supplementation during development of chemotherapy-induced multiple organ toxicity.


Disrupted long-range gene regulations elucidate shared tissue-specific mechanisms of neuropsychiatric disorders.
Neurological and psychiatric disorders have overlapped phenotypic profiles, but the underlying tissue-specific functional processes remain largely unknown. In this study, we explore the shared tissue-specificity among 14 neuropsychiatric disorders through the disrupted long-range gene regulations by GWAS-identified regulatory SNPs. Through Hi-C interactions, averagely 38.0% and 17.2% of the intergenic regulatory SNPs can be linked to target protein-coding genes in brain and non-brain tissues, respectively. Interestingly, while the regulatory target genes in the brain tend to enrich in nervous system development related processes, those in the non-brain tissues are inclined to interfere with synapse and neuroinflammation related processes. Compared to psychiatric disorders, neurological disorders present more prominently the neuroinflammatory processes in both brain and non-brain tissues, indicating an intrinsic difference in mechanisms. Through tissue-specific gene regulatory networks, we then constructed disorder similarity networks in two brain and three non-brain tissues, highlighting both known disorder clusters (e.g. the neurodevelopmental disorders) and unexpected disorder clusters (e.g. Parkinson's disease is consistently grouped with psychiatric disorders). We showcase the potential pharmaceutical applications of the small bowel and its disorder clusters, illustrated by the known drug targets NR1I3 and NFACT1, and their small bowel-specific regulatory modules. In conclusion, disrupted long-range gene regulations in both brain and non-brain tissues contribute to the similarity among distinct clusters of neuropsychiatric disorders, and the tissue-specifically shared functions and regulators for disease clusters may provide insights for future therapeutic investigations.


The representation of noise vocoded speech in the auditory nerve of the chinchilla: physiological correlates of the perception of spectrally reduced speech.
This study investigated the neural representation of naturally produced and noise vocoded speech signals in the auditory nerve of the chinchilla. The syllables [see text] produced by male speakers were used to synthesize noise vocoded speech stimuli containing one, two, three and four bands of envelope modulated noise. The ensemble response of the auditory nerve, computed by pooling the PST histograms across many auditory nerve fibers, revealed temporal patterns in the responses to the natural tokens that uniquely identified the stop consonants. The responses to the 3- and 4-band noise vocoded tokens contained temporal patterns that were nearly identical to those observed for the natural tokens, while the responses to the 1- and 2-band tokens were significantly different (p<0.0001). The ALSR, ALIR and autocorrelation of the pooled PST histograms represented the detail of the frequency spectrum for a naturally produced vowel, while the driven rate was unreliable. Each of these spectral analyses failed to reveal significant information about the noise vocoded vowels. These results suggest that temporal patterns in the responses of the auditory nerve can provide the cues necessary for the recognition of noise vocoded stop consonants.


Impact of splenectomy on outcomes of hematopoietic stem cell transplantation in pediatric patients with transfusion-dependent thalassemia.
The role of splenectomy prior to hematopoietic stem cell transplantation (HSCT) is controversial. Only few studies compared the outcomes of splenectomized and nonsplenectomized children with transfusion-dependent thalassemia (TDT) undergoing allogeneic HSCTs. A retrospective analysis was undertaken on a transplantation cohort of TDT patients; August 1987-December 2014 to compare transplant outcomes between splenectomized and nonsplenectomized groups. Ninety-six transplants in 86 TDT patients were analyzed. Sixteen patients were splenectomized before HSCTs. The splenectomized patients were significantly older (8.0 ± 1.9 vs 4.7 ± 0.6 years; P = 0.001), had larger livers and spleens (P = 0.001), and had a significantly shorter neutrophil engraftment time (absolute neutrophil count > 500/mm3 ; 15.0 ± 2.3 vs 19.2 ± 1.3 days; P = 0.004). Graft rejection occurred in 13.8% of the nonsplenectomized group, but not among the splenectomized patients. Though the splenectomized group's mortality rate was higher (25.0% vs 8.8%), this was not statistically significant (P = 0.491). The main causes of death in both groups were severe infections. The five-year overall survival (OS) rate was better for the nonsplenectomized group (91.78% vs 75.00%; P = 0.06). Although splenectomies prior to HSCT for the TDT patients in our cohort were associated with faster neutrophil engraftments and lower rejection rates, they did not produce significantly better OS or affect the mortality. As the splenectomies did not provide any distinct advantages, this procedure should not be routinely performed as a pre-HSCT regimen for TDT patients with splenomegaly. Better pre-HSCT preparation for TDT patients, including early and adequate blood transfusions to avoid splenomegaly, is recommended.


Rhein augments ATRA-induced differentiation of acute promyelocytic leukemia cells.
Rhein (4, 5-dihydroxyanthraquinone-2-carboxylic acid), a natural anthraquinone derivative, is a traditional Chinese herb that has been used as a medication in many Asian countries. It has been used as a laxative and stomach drug for a long time in both China and Korea. It is well-known to have many pharmacological activities, such as anti-cancer, anti-bacterial, anti-fungal, anti-oxidant, anti-atherogenic, anti-angiogenic, anti-fibrosis, anti-inflammatory, hepatoprotective, and nephroprotective properties. However, little is known about how rhein may affect the differentiation activities in acute promyelocytic leukemia (APL) cells. The present study was designed to examine the anti-leukemic effects of rhein against APL cells and to explore the underlying mechanism. Cell viability was investigated by MTS assay. To examine the differentiation activities in APL cells, the cell surface molecules (CD11b, CD14, CCR1 and CCR2), phagocytosis, reactive oxygen species (ROS) were determined by flow cytometry. Also, induction of caspase-3 activity and reduction of mitochondrial membrane potential (MMP) were determined by flow cytometry. RNA and protein expressions were determined by qRT-PCR and western blotting, respectively. In this study we assessed the role of rhein in treating APL. Interestingly, rhein potentiated all-trans retinoic acid (ATRA)-induced macrophage differentiation in NB4 cells by inducing changes in morphology, expression of the differentiation markers CD11b and CD14, ROS production, phagocytic activity, and expression of CCR1 and CCR2. Signaling through CD11b was found to be dependent on ERK activation. Additionally, rhein induced APL cell death by activating apoptosis and suppressing the mTOR pathway. Therefore, we suggest that a combination of rhein and ATRA carries strong therapeutic potential through the beneficial differentiation of APL cells. Moreover, rhein causes cell death via the activation of apoptosis and suppression of survival signals in APL cells. In combination with the ability of rhein to promote functional macrophage differentiation in APL, these properties suggest that a combined treatment of rhein and ATRA has great potential as an anti-leukemic therapy for APL.


Reactivity of lymphocytes to a progesterone receptor-specific monoclonal antibody.
In this study we present evidence for reactivity of pregnancy lymphocytes, but not nonpregnancy lymphocytes, with the progesterone receptor-specific monoclonal antibody mPRI. Using an avidin-biotin peroxidase detection system, we found a nuclear staining in 14.6 +/- 3.7% (mean +/- SEM, N = 27) of pregnancy lymphocytes, while only 0.47 +/- 0.33% (mean +/- SEM, N = 15) of nonpregnancy lymphocytes reacted with the antibody. To characterize the receptor-bearing subset, CD8+ and CD4+ cells were depleted by complement-dependent lysis. Depletion of CD8+ cells was accompanied by 62 +/- 18% loss of progesterone receptor-bearing cells, while depletion of CD4+ cells resulted in a twofold increase in the number of positively staining lymphocytes. In nonpregnancy lymphocytes a 3-day PHA treatment, as well as allogeneic stimulation, resulted in a significant increase in the number of receptor-containing cells. These results suggest that pregnancy, but not nonpregnancy, lymphocytes contain progesterone binding structures, and that these are inducible by mitogenic or alloantigenic stimuli.


Beta-elimination of a phosphonate group from an alkoxy radical: an intramolecular acylation approach using an acylphosphonate as a carbonyl group acceptor.
On the basis of facile beta-elimination of a phosphonate group from an alkoxy radical, intramolecular acylation reaction has been developed, in which an acylphosphonate is used as an excellent carbonyl group radical acceptor.


Racial disparities in functional outcomes following mechanical thrombectomy in a cohort of patients with ischemic stroke.
Non-Hispanic Black (NHB) patients experience increased prevalence of stroke risk factors and stroke incidence compared with non-Hispanic White (NHW) patients. However, little is known about >90-day post-stroke functional outcomes following mechanical thrombectomy. To describe patient characteristics, evaluate stroke risk factors, and analyze the adjusted impact of race on long-term functional outcomes to better identify and limit sources of disparity in post-stroke care. We retrospectively reviewed 326 patients with ischemic stroke who underwent thrombectomy at two centers between 2019 and 2022. Race was self-reported as NHB, NHW, or non-Hispanic Other. Stroke risk factors, insurance status, procedural parameters, and post-stroke functional outcomes were collected. Good outcomes were defined as modified Rankin Scale score ≤2 and/or discharge disposition to home/self-care. To assess the impact of race on outcomes at 3-, 6-, and 12-months' follow-up, we performed univariate and multivariate logistic regression. Patients self-identified as NHB (42%), NHW (53%), or Other (5%). 177 (54.3%) patients were female; the median (IQR) age was 67.5 (59-77) years. The median (IQR) National Institutes of Health Stroke Scale score was 15 (10-20). On univariate analysis, NHB patients were more likely to have poor short- and long-term functional outcomes, which persisted on multivariate analysis as significant at 3 and 6 months but not at 12 months (3 months: OR=2.115, P=0.04; 6 months: OR=2.423, P=0.048; 12 months: OR=2.187, P=0.15). NHB patients were also more likely to be discharged to rehabilitation or hospice/death than NHW patients after adjusting for confounders (OR=1.940, P=0.04). NHB patients undergoing thrombectomy for ischemic stroke experience worse 3- and 6-month functional outcomes than NHW patients after adjusting for confounders. Interestingly, this disparity was not detected at 12 months. Future research should focus on identifying social determinants in the short-term post-stroke recovery period to improve parity in stroke care.


Molecular characterization of Cryptosporidium isolates from human and bovine using 18s rRNA gene in Shahriar county of Tehran, Iran.
Cryptosporidiosis is a widespread cause of diarrheal diseases of humans, young calves, and many mammals. Although in recent years molecular investigations on Cryptosporidium have increased, no data are available on Iran in this regard. Two species of Cryptosporidium are known to infect human beings; Cryptosporidium hominis which shows anthroponotic transmission among humans and Cryptosporidium parvum which shows zoonotic transmission between animals and humans. Cryptosporidium oocysts, morphologically identified as C. parvum, were isolated from 24 human and 35 bovine cases in Shahriar (suburb of Tehran, Iran), and genotyped by means of a Nested-polymerase chain reaction/restriction fragment length polymorphism analysis of the 18s rRNA gene. The isolates from bovine samples gave zoonotic or 2 genotype (C. parvum), and DNA profiles of human isolates gave two distinct genotypes, namely an anthroponotic or 1 (C. hominis) and zoonotic genotype or 2 (C. parvum).


Cannabinoid modulation of wide dynamic range neurons in the lumbar dorsal horn of the rat by spinally administered WIN55,212-2.
The effects of spinally administered cannabinoids on nociceptive responses of wide dynamic range (WDR) neurons in the lumbar spinal cord were investigated in urethane-anesthetized rats. Noxious thermal stimulation was applied with a Peltier device to regions of the ipsilateral hindpaw corresponding to the receptive fields of isolated neurons. WIN55,212-2 (100 microg, i.t.), applied topically on the dorsal spinal surface, suppressed noxious heat-evoked activity in spinal WDR neurons. By contrast, responsiveness was unchanged following administration of either vehicle or WIN55,212-3, the receptor-inactive enantiomer. WIN55,212-2, administered intrathecally to separate rats, produced antinociceptive effects in the tail-flick test with a time course and efficacy that paralleled the suppression of noxious heat-evoked activity. These results suggest that cannabinoid modulation of spinal nociceptive processing involves direct actions in the spinal dorsal horn and is related to the antinociceptive effects of intrathecally administered cannabinoids.


The clinical performance of human papillomavirus genotyping using PANArray HPV chip: Comparison to ThinPrep cytology alone and co-testing.
Recently, a high-risk human papillomavirus (HR-HPV) detecting assay alone could be used as a first-line screening tool for cervical cancer, although the test system has been limited to the Cobas 4800 HPV test. However, the screening efficiency of the HPV chip, which is widely used in Eastern Asia because of the high prevalence of non16/18 HR-HPV genotypes, has not been well elucidated. After selecting 300 women who were co-tested using the PANArray HPV chip and the ThinPrep assay and had confirmed histological diagnoses, we evaluated the diagnostic accuracy of the PANArray HPV test based on direct sequencing and clinical performance compared to the ThinPrep alone and co-testing. HR-HPVs were identified in 212 (70.7 %) patients by the PANArray HPV test. The results of the PANArray HPV test and direct sequencing for detecting HR-HPVs were in almost perfect agreement, consistent in 95.3 % of the cases (k = 0.89). HR-HPVs were more commonly detected by the PANArray HPV assay in patients with high-grade squamous intraepithelial lesions (HSILs) or worse (p < 0.001, both) by cytological and histological examinations. The PANArray HPV test had higher sensitivity (91.7 %) than the ThinPrep (52.6 %) but co-testing increased the sensitivity for predicting HSIL or worse cervical lesions to 99.2 %. In conclusion, the PANArray HPV test accurately detected HR-HPVs determined by cytological and histological examinations to be HSIL or worse cervical lesions. The PANArray HPV assay alone was more sensitive than the ThinPrep alone for detecting HSIL or worse cervical lesions, however, co-testing enhanced the sensitivity. Co-testing is more useful for screening HSIL or worse lesions than use of either the ThinPrep or PANArray HPV genotyping alone.


Ugly aesthetic perception associated with emotional changes in experience of art by behavioural variant of frontotemporal dementia patients.
The aesthetic experience through art is a window into the study of emotions. Patients with behavioural variant of frontotemporal dementia (bvFTD) have early alteration of emotional processing. A new appreciation of art has been reported in some of these patients. We designed a computerized task using 32 abstract paintings that allowed us to investigate the integrity of patients' emotions when viewing the artwork. We evaluated both conscious and explicit appraisal of emotions [aesthetic judgment (beautiful/ugly), emotional relevance (affected or not by the painting), emotional valence (pleasant/unpleasant), emotional reaction (adjective choice) and arousal] and unconscious processing. Fifteen bvFTD patients and 15 healthy controls were included. BvFTD patients reported that they were "little touched" by the paintings. Aesthetic judgment was very different between the two groups: the paintings were considered ugly (negative aesthetic bias) and unpleasant (negative emotional bias) more often by the patients than by controls. Valence and aesthetic judgments correlated in both groups. In addition, there was a positive bias in the implicit task and for explicit emotional responses. Patients frequently chose the word "sad" and rarely expressed themselves with such adjectives as "happy". Our results suggest that bvFTD patients can give an aesthetic judgment, but present abstraction difficulties, as spectators, resulting from impairments in the cognitive processes involved. They also have difficulties in terms of emotional processes with the loss of the ability to feel the emotion per se (i.e., to feel an emotion faced with art) linked to behaviour assessment. This cognitive approach allows us to better understand which spectators are bvFTD patients and to show interactions between emotions and behavioural disorders.


Gamma-glutamyl transpeptidase level is a novel adverse prognostic indicator in human metastatic colorectal cancer.
Biomarkers have been utilized for prognosis in colorectal cancer; however, relatively few have been identified. We compared the prognostic value of serum alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and gamma-glutamyl transpeptidase (GGT) with carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) in patients with metastatic colorectal cancer (mCRC). Blood samples were collected from 239 patients with mCRC presenting between 2005 and 2010 in the Sun Yat-sen University Cancer Center. CEA (P < 0.001), CA19-9 (P < 0.001), GGT (P < 0.001), ALP (P < 0.001) and LDH (P = 0.001) were statistically significant prognostic factors of overall survival (OS). CEA (P = 0.002) and GGT (P = 0.021) were validated as independent predictors. On univariate analysis, CEA (P = 0.003), CA19-9 (P = 0.006), GGT (P < 0.001) and ALP (P = 0.001) were statistically significant predictive factors of progression-free survival (PFS) in patients having first-line chemotherapy. CEA (P = 0.011) and GGT (P = 0.027) were independent predictors. GGT (P = 0.001), ALP (P = 0.016) and LDH (P = 0.039) levels were correlated with the tumour response rate assessed by CT, whilst CEA (P = 0.724) and CA19-9 (P = 0.822) were not. There was a statistically significant difference in OS (P < 0.001) and PFS (P < 0.001) among patients who had elevations of both CEA and GGT compared with those in whom only one or neither was elevated. Among GGT, LDH and ALP, only GGT plays an independent role with CEA in predicting OS and PFS in mCRC. When coupled with CEA, GGT may lead to improved prognostic predictors.


In vivo fascicle length measurements via B-mode ultrasound imaging with single vs dual transducer arrangements.
Ultrasonography is a useful technique to study muscle contractions in vivo, however larger muscles like vastus lateralis may be difficult to visualise with smaller, commonly used transducers. Fascicle length is often estimated using linear trigonometry to extrapolate fascicle length to regions where the fascicle is not visible. However, this approach has not been compared to measurements made with a larger field of view for dynamic muscle contractions. Here we compared two different single-transducer extrapolation methods to measure VL muscle fascicle length to a direct measurement made using two synchronised, in-series transducers. The first method used pennation angle and muscle thickness to extrapolate fascicle length outside the image (extrapolate method). The second method determined fascicle length based on the extrapolated intercept between a fascicle and the aponeurosis (intercept method). Nine participants performed maximal effort, isometric, knee extension contractions on a dynamometer at 10° increments from 50 to 100° of knee flexion. Fascicle length and torque were simultaneously recorded for offline analysis. The dual transducer method showed similar patterns of fascicle length change (overall mean coefficient of multiple correlation was 0.76 and 0.71 compared to extrapolate and intercept methods respectively), but reached different absolute lengths during the contractions. This had the effect of producing force-length curves of the same shape, but each curve was shifted in terms of absolute length. We concluded that dual transducers are beneficial for studies that examine absolute fascicle lengths, whereas either of the single transducer methods may produce similar results for normalised length changes, and repeated measures experimental designs.


Müllerian remnant malignancy.
Mixed gonadal dysgenesis is a disorder of sexual differentiation, characterized by mosaicism, ambiguous external genitalia, and both Wolffian and Müllerian internal genitalia. These patients are at a known increased risk of germ cell cancer, specifically gonadoblastoma; however, in this report we describe a case of adenocarcinoma of a remnant Müllerian structure.


Change in weight category among youth early in the COVID-19 pandemic.
Remote learning and shelter-in-place orders during the COVID-19 pandemic are associated with obesity risk factors such as decreased physical activity, altered routines and sleep schedules, increased screen time, and non-nutritious food choices. The objective of this brief report is to describe change in weight category 3-6 months after the onset of the pandemic in a cohort of 4509 low-income youth. Inclusion criteria were youth aged 2-17 years with weight and height measure in a large primary care network between 1 January and 30 March 2020 (Q1), designated as pre-COVID period; and 1 June-30 September 2020, (Q3), as early-COVID period. Change in weight category was assessed between Q1 and Q3. Adjusting for visit type and time lapse, logistic regression was conducted to examine the association between weight category change and age, sex, and race/ethnicity. The proportion of youth with overweight or obesity increased from 37.8% to 44.6%; and declined by 5.6% in the healthy weight category. Over the 3-6 month period, 23.1% of youth gained ≥5 kg, 4.3% gained ≥10 kg, and 17.8% increased their BMI by ≥2 units. Among underweight youth, 45.3% switched to the healthy weight category, with a median weight gain of 2.1 kg (interquartile range [IQR] = 2.1 kg). Median weight gain was highest among those youth with severe obesity (5.8 kg, IQR = 5.2 kg). Younger age (2-9 years), female and ethnic-minority youth were more likely to change to a higher/worse weight category. Significant weight gain occurred in the first 3-6 months of the pandemic among low-income youth, reflecting the short-term effects of the pandemic.


Epidemiology of traumatic spinal cord injury: a large population-based study.
A retrospective population-based study. Describe the incidence of traumatic spinal cord injury (TSCI) and mortality risks, based on the characteristics of the patient, anatomical level of the lesion, setting/cause of the injury, and type of healthcare support received within the regional trauma network (highly specialized trauma center or spoke hospital). Between 2011 and 2020, 1303 patients with incident TSCI were identified in a population of 4.9 million inhabitants. Hospital discharge records and mortality records were used to identify patients and outcomes. Cox regression models were fitted to estimate mortality risks across several subgroups. Over the past decade, age-sex-standardized TSCI incidence rates remained stable with 26.5 cases (95% CI, 25.0-27.9) per 1,000,000 inhabitants (mean age 59.2 years) and most cases were males (68.3%). Incidence was directly associated with age while the male to female ratio was inversely related. Most TSCIs were cervical lesions (52.1%), and the most common cause of injury were traffic crashes (29.9%) followed by occupational accidents (29.8%). Sex, cause of the trauma, or inpatient hospital management were not associated with an increased risk of death. Mortality rates were greater for cervical lesions, and increased with age, remaining stably high among older individuals even 12 months after the accident. One-month mortality risk was significantly higher at ≥75 years compared to <55 years (adjusted HR 9.14 (95% CI, 4.17-20.03)). Public health policies should aim at reducing preventable TSCIs, and special attention should be drawn to long-term management of elderly patients in the attempt to decrease mortality rates.


Several cases of work-related allergic contact dermatitis caused by isocyanates at a company manufacturing heat exchangers.
A 43-year-old woman was referred by her occupational health service with suspected occupational contact dermatitis. In connection with the investigation, a workplace visit was undertaken at her company, which used an adhesive based on pre-polymeric diphenylmethane diisocyanate in one of its units. During the visit, we became aware of six other employees with skin problems who were then referred to our department for investigation. To investigate the seven employees complaining about skin problems. Seven employees were patch tested with a baseline series, an isocyanate series, and a series with work material. Five of seven patients had occupational contact allergy. Four reacted to isocyanate-related test preparations, and one to a cleanser used at the workplace. Workplace visits constitute an important part of an occupational investigation, as they might give a broader picture of the problems at a company. In this case, it was found that 5 of 100 employees currently had or had previously had occupation-related skin problems. Owing to 'healthy worker selection', some of these patients might have been missed if we had not performed a full-scale workplace visit.


Acute phase and opsonin response in cardiac surgery patients: influence of underlying cardiac disease.
Cardiopulmonary bypass (CPB) leads to an activation of plasma cascade systems, complement activation, and an acute phase response. To evaluate the influence of the underlying cardiac disease on the activation pattern of these systems, we compared inflammatory changes in coronary artery bypass grafting (CABG) patients with patients undergoing aortic valve replacement. We investigated changes of the acute phase proteins alpha 1-proteinase inhibitor and fibrinogen, the unspecific opsonin fibronectin, and the complement components C3c and C4 induced by extracorporeal circulation in 12 patients undergoing aortic valve replacement and in 12 patients undergoing CABG. Concentrations of C3c and C4 decreased in both groups after the onset of CPB and C4 concentration remained below post-induction levels up to 24 h after onset of CPB (p = 0.04). Fibronectin levels dropped immediately before the onset of CPB (p = 0.01), reaching the lowest values after 20 min of extracorporeal circulation. Fibrinogen and alpha 1-proteinase inhibitor levels after induction of anaesthesia were significantly higher in the CABG group and remained higher throughout the entire study period (p < 0.001). As an indicator of a postoperative acute phase response, concentrations of both proteins rose in the postoperative period above post-induction levels (p < 0.02).


New PDMP analogues inhibit process outgrowth in an insect cell line.
d-threo-1-Phenyl-2-aminodecanoyl-3-morpholinopropanol (d-threo-PDMP) has previously been shown to inhibit the biosynthesis of glycosphingolipids (GSLs) in mammals and mammalian cell lines by the inhibition of glucosylceramide synthase. New d-threo-PDMP analogues were synthesized from d-serine, and found to suppress neurite extension in an embryonic insect cell line from the moth Manduca sexta, and in explanted neural tissue from insect pupae. Inhibition occurred at lower concentrations than d-threo-PDMP. The observed suppression of neurite formation was found to be reversible after the removal of the compounds. Due to their small size and short life cycle, M. sexta is shown to be an ideal model organism for studies of GSL effects in cellular development, and for drug development studies.


PET in clinical oncology.
Positron Emission Tomography (PET) is an imaging technique that produces cross sectional images based on tissue biochemical and physiological processes. PET complements other anatomic imaging techniques such as x-ray CT and magnetic resonance imaging (MRI). Fundamental processes such as glucose metabolism, oxygen metabolism, and blood flow can be imaged and quantified with PET, in addition to many other processes of both clinical and investigative interest. PET is now emerging as a clinical tool in oncology and is useful in noninvasively grading tumors, in determining tumor activity and recurrence, and in monitoring the effects of a variety of therapeutic interventions with tumors. While most of the applications of PET in oncology to date have been in brain tumors, the technique is now being applied in tumor evaluations outside of the central nervous system.


Early initiation of rivaroxaban after reperfusion therapy for stroke patients with nonvalvular atrial fibrillation.
The optimal timing of initiating oral anticoagulants after reperfusion therapy for ischemic stroke is unknown. Factors related to early initiation of rivaroxaban and differences in clinical outcomes of stroke patients with nonvalvular atrial fibrillation (NVAF) who underwent reperfusion therapy was investigated. From data of 1,333 NVAF patients with ischemic stroke or transient ischemic attack (TIA) in a prospective multicenter study, patients who started rivaroxaban after intravenous thrombolysis and/or mechanical thrombectomy were included. The clinical outcomes included the composite of ischemic events (recurrent ischemic stroke, TIA, or systemic embolism) and major bleeding at 3 months. Among the 424 patients, the median time from index stroke to starting rivaroxaban was 3.2 days. On multivariable logistic regression analysis, infarct size (odds ratio [OR], 0.99; 95%CI, 0.99-1.00) was inversely and successful reperfusion (OR, 2.13; 95%CI, 1.24-3.72) was positively associated with initiation of rivaroxaban within 72 hours. 205 patients were assigned to the early group (< 72 hours) and 219 patients (≥ 72 hours) to the late group. Multivariable Cox regression models showed comparable hazard ratios between the two groups at 3 months for ischemic events (hazard ratio [HR], 0.18; 95%CI, 0.03-1.32) and major bleeding (HR, 1.80; 95%CI, 0.24-13.54). Infarct size and results of reperfusion therapy were associated with the timing of starting rivaroxaban. There were no significant differences in the rates of ischemic events and major bleeding between patients after reperfusion therapy who started rivaroxaban < 72 hours and ≥ 72 hours after the index stroke. Unique identifier: NCT02129920; URL: https://www.clinicaltrials.gov.


Cell determination and transdetermination in Drosophila imaginal discs.
Drosophila imaginal discs, the precursors of the adult fly appendages, are an important system for studying mechanisms of cell determination. How the different imaginal discs acquire and maintain their appendage-specific determined states are problems that have been addressed using experimental embryology as well as genetic and molecular approaches. Here we discuss the concept of cell determination and describe what is known about how determination is established and maintained in imaginal disc cells. The phenomenon of imaginal disc transdetermination, originally discovered in the 1960s, has remained an intriguing problem for understanding imaginal disc cell determination. We review the topic of imaginal disc transdetermination and describe how recent results from molecular genetic approaches have provided new insights into imaginal disc transdetermination and determination. We also discuss how an understanding of imaginal disc transdetermination can aid our understanding of parallel phenomena in other organisms, including human metaplasias.


Correction to: ITR-Seq, a next-generation sequencing assay, identifies genome-wide DNA editing sites in vivo following adeno-associated viral vector-mediated genome editing.
An amendment to this paper has been published and can be accessed via the original article.


K562 chronic myeloid leukemia cells modify osteogenic differentiation and gene expression of bone marrow stromal cells.
Bone marrow (BM) microenvironment plays an important role in normal and malignant hematopoiesis. As a consequence of interaction with the leukemic cells, the stromal cells of the bone marrow become deregulated in their normal function and gene expression. In our study, we found that mesenchymal stem cells (MSC) from BM of chronic myeloid leukemia (CML) patients have defective osteogenic differentiation and on interaction with K562 CML cells, the normal MSC showed reduced osteogenic differentiation. On interaction with K562 cells or its secreted factors, MSC acquired phenotypic abnormalities and secreted high levels of IL6 through NFκB activation. The MSC derived secreted factors provided a survival advantage to CML cells from imatinib induced apoptosis. Thus, a therapy targeting stromal cells in addition to leukemia cells might be more effective in eliminating CML cells.


Avian influenza revisited: concerns and constraints.
Avian influenza (AVI) is being known for its pandemic potential and devastating effects on poultry and birds. The AVI outbreaks in domesticated birds are of concern because the Low pathogenic avian influenza virus (LPAI) tends to evolve into a High pathogenic avian influenza virus (HPAI) resulting in the rapid spread and significant outbreak in poultries. The containment should be rapid and stringent precautions should be taken in handling the infected poultry cases or infected materials. In general, AVI viruses do not replicate efficiently in humans, indicating that transmitting these viruses to humans directly is a very rare preference. However, the HPAI ability to the cross-species barrier and infect humans has been known for H5N1 and H7N9. Recently, the world's first human case of transmission of the H5N8 strain from the avian species to humans has been documented. In this recent scenario, it is worth discussing the strain variations, disease severity, economic loss, and effective controlling strategies for controlling avian influenza.


The effects of antecedent interventions and extinction on toddlers' compliance during transitions.
We compared the effects of two antecedent strategies commonly used in early childhood settings to increase compliance during activity transitions: a warning condition, in which children were informed of the transition 2 min before it began, and a condition in which children were allowed access to a toy during the transition. Both antecedent interventions were ineffective when implemented alone; however, when these strategies were combined with extinction, improvements in compliance were observed for all children.


The effects of ozone and acid mist on Scots pine saplings.
It has been suggested that the forest decline ("Neuartige Waldschäden") seen recently in parts of West Germany is due to the direct effects of ozone combined with acid mists, rather than soil-mediated effects of acid deposition. It has been proposed that ozone (a) makes the needles of affected conifers more susceptible to leaching by acid mist and (b) damages the photosynthetic apparatus, giving rise to diminished carbohydrate reserves which reduce the ability of affected trees to replace the leached nutrients. This nutrient deficiency (especially of Ca and Mg) is a characteristic symptom of the Waldschäden, which progresses through growth decline, needle loss, and eventually death. Parts of this hypothesis were tested in a preliminary experiment in which 3-year old Pinus sylvestris (Scots pine) saplings were exposed to 4 different O3 levels, with and without acid mist (pH 3) treatment, for 56 days between July and September, 1983 in outdoor 'solardome' fumigation chambers. The visual symptoms observed at >100 μg m-3 were more characteristic of the chlorotic mottle seen on O3-affected trees in the USA than the general chlorosis of affected stands in Germany. O3 at mean concentrations of >200 μg m-3 for 56 days reduced the fine root biomass and accelerated the senescence of older needles, in keeping with field effects observed in Germany. However, these O3 levels increased, rather than decreased, the concentrations of most elements in the needles. Acid mist had no effect on needle concentrations, and there was no O3-acid mist interaction. O3 up to 300 μg m-3 also had no effect on the amount of ions leached from the needles, whereas acid mist increased the leaching of some ions, and again there was no interaction. The only nutritional effect of O3 was to reduce the foliar uptake of NO -3 from the acid mist solution. An aphid infection part way through the experiment caused a large increase in leaching, particularly of K, and affected the intermediate O3 and watersprayed plants most. Caution is needed in extrapolating these results to the field, as the experiments were of short duration on young trees with fully-formed needles, growing in a soil better supplied with nutrients than field soils. Nevertheless, these preliminary results do not support the hypothesis of an O3-mediated increase in foliar leaching as the major cause of forest decline nor were the symptoms of O3-injury on Scots pine comparable with those reported in the field.


Effects of bradykinin on electrical properties of Madin-Darby canine kidney epithelioid cells.
In the present study we have investigated the influence of bradykinin on the potential difference across the cell membrane (PD) of Madin Darby Canine Kidney (MDCK)-cells. In the absence of bradykinin PD averages -52.6 +/- 0.9 mV (n = 52). Increasing extracellular potassium concentration from 5.4 to 10 and 20 mmol/l depolarizes the cell membrane by +5.2 +/- 0.3 mV (n = 8) and +14.9 +/- 1.0 mV (n = 9), respectively. The application of 0.1 mumol/l bradykinin leads to a transient hyperpolarization of the cell membrane to -70.3 +/- 0.6 mV (n = 30). During this transient hyperpolarization increasing extracellular potassium concentration from 5.4 to 10 and 20 mmol/l depolarizes the cell membrane by +10.4 +/- 0.7 mV (n = 10) and +29.2 +/- 0.8 mV (n = 8) respectively. Application of fragments of bradykinin (0.1 mumol/l) are without significant effect on the potential difference across the cell membrane. 1 mmol/l barium depolarizes the cell membrane by +15.8 +/- 1.2 mV (n = 9) and abolishes the effect of step increase of extracellular potassium concentration from 5.4 to 10 mmol/l. In the presence of barium, bradykinin leads to a transient hyperpolarization by -24.7 +/- 1.3 mV (n = 7). During this transient hyperpolarization, the cell membrane is sensitive to extracellular potassium concentration despite the continued presence of barium. In the nominal absence of extracellular calcium, bradykinin leads to a transient hyperpolarization, which can be elicited only once. The transient hyperpolarization is not affected by the presence of verapamil or indomethacin. In conclusion, bradykinin hyperpolarizes MDCK-cells by increasing the apparent potassium conductance.(ABSTRACT TRUNCATED AT 250 WORDS)


Integrated single-cell and bulk RNA sequencing analysis identifies a prognostic signature related to ferroptosis dependence in colorectal cancer.
Ferroptosis is an iron-dependent form of cell death induced by lipid oxidation with an essential role in diseases, including cancer. Since prognostic value of ferroptosis-dependent related genes (FDRGs) in colorectal cancer (CRC) remains unclear, we explored the significance of FDRGs in CRC through comprehensive single-cell analysis. We downloaded the GSE161277 dataset for single-cell analyses and calculated the ferroptosis-dependent gene score (FerrScore) for each cell type. According to each cell type-specific median FerrScore, we categorized the cells into low- and high-ferroptosis groups. By analyzing differentially-expressed genes across the two groups, we identified FDRGs. We further screened these prognosis-related genes used to develop a prognostic signature and calculated its correlation with immune infiltration. We also compared immune checkpoint gene efficacy among different risk groups, and qRT-PCR was performed in colorectal normal and cancer cell lines to explore whether the signature genes could be used as clinical prognostic indicators. In total, 523 FDRGs were identified. A prognostic signature including five signature genes was constructed, and patients were divided into two risk groups. The high-risk group had poor survival rates and displayed high levels of immune infiltration. Our newly developed ferroptosis-based prognostic signature possessed a high predictive ability for CRC.


Low prevalence of subclinical synovitis in patients with juvenile idiopathic arthritis (JIA) in long-term clinical remission on medication.
Subclinical synovitis is highly prevalent in patients with JIA in clinical remission (CR) with a short duration. The objective was to evaluate its prevalence by ultrasound (US) in patients with JIA in long CR during a one-year follow-up. In this prospective and longitudinal study, we included 76 patients with JIA according to ILAR with CR by the Wallace modified criteria and JADAS27 and compared them with 22 patients with active disease. Clinical and demographic characteristics were recorded. US evaluation was by 10-joint count. Differences in US evaluations were analyzed by the Mann-Whitney U test. There were no differences among the two group with regard to disease duration at enrollment, and age (p = 0.540 and p = 0.080, respectively), but JADAS 27, CHAQ, and acute phase reactants were significantly higher (p < 0.001) in the clinically active group. The prevalence of subclinical synovitis at baseline and the end of the study in the CR group was 18.4% and 11.8%, respectively, while it was 100% and 40.9% in the active disease group. Subclinical synovitis at baseline was significantly more prevalent in the clinically active group (elbow, p = 0.01; wrist, p = 0.001; MCP 2, p = 0.001; knee, p = 0.001 and ankle p = 0.001; and PD only in the ankle, p = 0.002). The concordance of inter-reader reliability in all evaluated joints was excellent (p = 0.001). Although the prevalence of subclinical synovitis is low in patients with JIA with long-term clinical remission on medication, a percentage of patients continue to have subclinical involvement that could predict the risk of relapse and structural damage. Key Points • Subclinical synovitis is less prevalent in JIA in long-term clinical remission compared to patients in short-term remission. • The persistence of imaging signs of inflammation in a significant percentage of patients may indicate the need for ongoing medication.


Assessment of availability and challenges of WHO recommended priority life-saving medicines for under five-year children in primary public health facilities of Amhara region.
The world health organization (WHO) priority lifesaving medicines are medicines recommended for the prevention and treatment of leading causes of under-five morbidity and mortality. They should be available in all health systems and at all times. However, the availability of these medicines and its determinants is not well studied in Ethiopia in general and in primary public health facilities Amhara region in particular. The study aimed to assess the availability and challenges of the WHO-recommended priority lifesaving medicines for under-five children in primary public health facilities of the Amhara region. A cross-sectional study design was conducted from February to December 2020 in 98 health centers and 22 primary hospitals in the Amhara region, Ethiopia. Facilities were selected with a simple random sampling technique. The data were collected through a pretested and structured questionnaire. Binary logistic regression was used to identify predictors associated with availability of WHO-recommended priority lifesaving medicines for under-five children. The availability of oral rehydration salt was high (82.5%) and the availability of vitamin A (47.5%), morphine tablet (13.3%), and artesunate rectal suppository (7.5%) were within low and very low WHO range respectively. Budget adequacy (AOR = 12.9 CI= (2.1-78.2)), periodic review of stock level ((AOR = 13.4,CI=(1.9-92.0)), training on integrated pharmaceutical logistic system ((AOR = 4.5,CI=(1.0-20.5)), inclusion of WHO priority under five children facility specific medicine list (AOR = 12.4,CI=(2.3-66.4)), lead time for EPSA(Ethiopia Pharmaceutical Supply Agency) procurement (AOR = 7.9,CI=(1.3-44.8)) were significantly associated with availability of all WHO priority lifesaving medicines for under- five children. The average availability of WHO-recommended priority lifesaving medicines for under-five children was low. The habit of updating bincard and adoption of the life-saving medicine list were the independent predictors of medication availability.


[Cranio-carpo-tarsal dysplasia syndrome (Freeman-Sheldon syndrome, whistling face syndrome)].
A case of the rare Freeman-Sheldon Syndrome combined with a high luxation of the left hip is reported. The importance of differential diagnosis to arthrogryposis multiplex congenita is explained.


Thrombosed sapheno-varix: an important and unusual differential diagnosis of strangulated femoral hernia.
An incarcerated femoral hernia often requires prompt operative management to decrease the risk of bowel strangulation, perforation and death from peritonitis. We present a case of a 60-year-old man who had a clinically irreducible right femoral hernia, and in whom a Richter's hernia could not be excluded. He was found to have a thrombosed sapheno-varix with no evidence of a femoral hernia. Thrombosed sapheno-varix presenting as a strangulated femoral hernia has never previously been described in the literature.


The development of the tapeworm Diphyllobothrium latum (L. 1756) (Cestoda; Pseudophyllidea) in its definitive hosts, with special references to the growth patterns of D. dendriticum (Nitzsch, 1824) and D. ditremum (Creplin, 1827).
When Diphyllobothrium latum develops from larva to adult in a definitive host, it first sheds the entire larval 'body' before growth of an adult strobila starts. This process of shedding off the entire larval abothrial extremity, piece by piece, takes about 48 h. By this time the larva has usually reached the anterior third of the small intestine of the host. D. dendriticum and D. ditremum develop quite differently, although exhibiting similar anterior migrations. In these two species the larvae develop directly into adults without the larval 'body' first being shed. The implications of the observed differences in growth pattern between these three species of Diphyllobothrium to the classification of diphyllobothriid cestodes is discussed briefly.


A novel nanomagnetic task specific ionic liquid as a selective sorbent for the trace determination of cadmium in water and fruit samples.
A selective sorbent was prepared for the simultaneous separation and preconcentration of cadmium ion from water and fruit samples, prior to determination by flame atomic absorption spectrometry (FAAS). The sorbent was synthesized by combining of Fe3O4 magnetic nanoparticles (MNPs) and Aliquat(®)336 thiosalicylate, [A336][TS], a thiol-containing task specific ionic liquid (TSIL). The high affinity of TSIL toward the target compound as well as the magnetic behavior of Fe3O4 was combined to provide an efficient and simple magnetic sorbent for solid-phase extraction (SPE). The prepared nanoparticles were characterized by Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX) and vibrating sample magnetometer (VSM). The important parameters influencing the extraction efficiency such as pH, sorbent dosage, extraction and desorption conditions were studied and optimized. Under the optimum conditions, the calibration curve was linear in the range of 2.5-260 ng mL(-1) and good linearity (R(2)>0.996) was obtained. The limit of detection (LOD) and enrichment factor (EF) of the method were found to be 0.5 ng mL(-1) and 50, respectively. The relative standard deviations (RSDs %) were less than 3.1 (n=6) for the target analyte. In this method, only small amounts (20mg) of adsorbent were needed to obtain satisfactory extraction recoveries within 20 min. Finally, the proposed method was successfully applied for the trace determination of cadmium ions in fruit (apple, orange and banana) and water samples. Good spike recoveries, varied within the range of 95-109%, confirmed the good performance of the method in real sample analysis.


A comparison of sonographic estimation of fetal weight and obstetrically determined gestational age in the prediction of neonatal outcome for the very low-birth weight fetus.
A comparison of sonographic estimation of fetal weight and obstetrically determined gestational age in the prediction of neonatal outcome for the very low-birth weight fetus was conducted in a study population of 122 fetuses. With stepwise logistic regression, obstetric gestational age was found to be the best predictor of neonatal death, while sonographic estimated fetal weight did not add significantly to this prediction. However, both variables were important in the prediction of adverse neonatal outcome (neonatal death together with major neonatal complications of prematurity.


Tumour induction by transplacental infection with polyoma virus of the F1 generation of Wistar rats.
Intravenous polyoma virus inoculation into pregnant Wistar rats resulted in transplacental infection of the foetus, causing tumours and hydronephroses. Cyclosporin A reduced these effects significantly.


Anemia in the long-term care setting: routine screening and differential diagnosis.
To provide an overview of the epidemiology of anemia in the geriatric patient, to identify common diagnostic issues in this population, and to determine practical strategies for overcoming barriers to the recognition of anemia in older adults. Recent literature, epidemiological studies, and clinical practice guidelines related to the diagnosis and management of anemia in older adults. This clinical review includes data relevant to routine screening and the differential diagnosis of anemia in the long-term care setting. Anemia is often unrecognized and untreated in the long-term care setting. The adverse effects of anemia (morbidity, mortality, and decreases in quality of life) on the geriatric population make its management a high priority. A proactive approach to screening and diagnosis is required in this setting. Anemia is often unrecognized and under-diagnosed in the geriatric population, especially in the long-term care setting. Because anemia has been associated with substantial morbidity and mortality rates and with decline in quality of life, strategies must be implemented for screening and treating geriatric patients for anemia.


Sex Differences in In-hospital Mortality of Patients With Septic Shock: An Observational Study Based on Data Analysis From a Cover Sheet of Medical Records in Beijing.
Background: The goal of our study was to evaluate the association of sex and in-hospital mortality in patients with septic shock in Beijing, China. Materials and Methods: We analyzed 3,643 adult patients with septic shock from January 1, 2019, to Dec 31, 2019, in all secondary and tertiary hospitals in Beijing. Study data were retrospectively extracted from the Quality Control Center of Beijing Municipal Health Commission. Results: There were 2,345 (64.37%) male and 1,298 (35.63%) female patients. Compared to male patients, female patients with septic shock had a higher in-hospital mortality rate (55.54 vs. 49.29%, p < 0.01). The median length of hospitalization stay for male patients was 22.71 days, while that for female patients was 19.72 days (p > 0.01). Male patients had a higher prevalence of pulmonary infection (68.8 vs. 31.2%, p < 0.01). The B values of sex in univariate and multivariate logistic regression were -0.251 and -0.312, respectively. Men had a lower likelihood of hospital mortality than women (OR = 0.732, 95% CI = 0.635-0.844, p = 0.000). Conclusions: Female patients with septic shock had a higher risk of dying in the hospital than male patients.


Optimal foraging: Random movement by pollen collecting bumblebees.
Two bumblebee species, Bombus bifarius and B. flavifrons, forage randomly with respect to direction when gathering pollen on Potentilla gracilis. Bees avoid revisiting flowers by being able to differentiate recently visited from unvisited flowers. This recognition occurs while bees are flying over open flowers and appears to be a response to the amount of available pollen within flowers. Random foraging with respect to direction is the optimal strategy when the probability of flower revisitation is low. Bumblebees appear to be moving preferentially between nearest neighbors, again as predicted by foraging theory. This behavior causes the establishment of pollen patches in the P. gracilis population. Unlike other pollinators studied in similar situations, bumblebees on P. gracilis do not forage utilizing an area-restricted searching behavior. Because floral reward quality can be assessed at low cost by bees foraging on P. gracilis, their tendency to move to nearby flowers even after encountering a poor quality blossom apparently yields a higher rate of net energy intake than does area-restricted searching. The data indicate that bumblebees exhibit great plasticity in foraging behavior and that they are able to forage efficiently under a wide range of environmental conditions.


An Innovative Selective Fluorescence Sensor for Quantification of Hazardous Food Colorant Allura Red in Beverages Using Nitrogen-Doped Carbon Quantum Dots.
An innovative simple, sensitive, and selective method has been developed and validated for quantification of hazardous Allura red (AR, E129) dye in beverages. Allura red (AR) is a synthetic dye that is commonly used in the food industry to give foods a bright and appealing color. The method is based on microwave-assistant nitrogen-doped carbon quantum dots (N@CQDs) from a very cheap source with a high quantum yield equal to (36.60%). The mechanism of the reaction is based on an ion-pair association complex between AR and nitrogen-doped carbon quantum dots (N@CQDs) at pH 3.2. The reaction between AR and N@CQDs led to a quenching effect of the fluorescence intensity of N@CQDs at 445 nm after excitation at 350 nm. Moreover, the quantum method's linearity covered the range between 0.07 and 10.0 µg mL- 1 with a regression coefficient is 0.9992. The presented work has been validated by ICH criteria. High-resolution transmission electron microscopy (HR-TEM), X-ray photon spectroscopy (XPS), Zeta potential measurements, fluorescence, UV-VIS, and FTIR spectroscopy have all been used to fully characterize of the N@CQDs. The N@CQDs were successfully utilized in different applications (beverages) with high accuracy.


Bullous esophageal lesions due to cotrimoxazole: an immune-mediated process?
A 78-yr-old man experienced a generalized bullous eruption of the skin (a Stevens-Johnson variant of erythema multiforme) with simultaneous involvement of the esophagus due to co-trimoxazole. Immunologic tests revealed specific antibodies of the immunoglobulin G class but not of the immunoglobulin E class against sulfamethoxazole, and in particular against trimethoprim. Lymphocyte transformation tests demonstrated sensitized lymphocytes against trimethoprim but not sulfamethoxazole. The esophageal mucosa showed intraepithelial vesicle formation with diffuse cytoplasmic deposits of immunoglobulin G. This adverse drug reaction involving both the skin and the esophagus appears to be immune-mediated.


In situ growth of metal-organic frameworks (MOFs) on the surface of other MOFs: a new strategy for constructing magnetic resonance/optical dual mode imaging materials.
This work presents for the first time the synthesis of a novel nanoscale Fe-MOFs/Eu-MOFs heterostructure, in which spherical Fe-MOFs with a large surface area were introduced as a matrix for the well-dispersed growth of rodlike Eu-MOFs. The obtained Fe-MOFs/Eu-MOFs materials exhibit excellent magnetic resonance/optical imaging capacity and satisfactory drug delivery behavior.


Synthesis and properties on some 2-, 4- and 5-aminopyrimidines. Effect of -NH2 and ortho-C methylation on protolytic equilibria and electronic absorption spectra.
A number of new 2-, 4- and 5-aminopyrimidines with sterical hindrance to the amino group rotation were synthesized. The pKa values and u.v. absorption spectra of the aminopyrimidines were measured in order to elucidate the conformation of the amino group depending on the place of substitution.


T-cell subsets induced in Listeria monocytogenes-immune mice. Ly phenotypes of T cells interacting with macrophages in vitro.
Interactions of peritoneal exudate T lymphocytes from listeria-immune mice with macrophages from normal mice in the presence of heat-killed listeriae result in the induction of interleukins. The data show that Ly 1+, 23- T cells specific for listeria antigens are essential for interleukin induction and make it likely that, in addition, Ly 1+, 23+ T cells are required for optimal responses.


Non-cyclic photoreductive carbon fixation in photosynthesis. Light and dark transients of the glycerate-3-P special pair.
It is demonstrated that carbon fixation in photosynthesis is regulated in two kinetically coupled pathways involving the specialized pair of non-equivalent, enzyme-bound glycerate-3-P (3-PGA) molecules obtained from ribulose 1,5-bisphosphate (RuBP) carboxylation in the light. A non-cyclic pathway is suggested (reaction 2) for the direct biosynthesis of sucrose from the 3-PGA obtained from C-3, C-4 and C-5 of the six-carbon carboxylation adduct. Concomitant to the appearance of sucrose as the principal product, the Mg2+-bound 3-PGA molecule formed from C-1, C-2 and C-2' of the C6 intermediate is released and subsequently reduced in regenerating the RuBP. It is proposed that the nocturnal inhibitor, 2-carboxyarabinitol-1-phosphate (1-PCA) is obtained from a condensation of 3-PGA and glyceraldehyde.


Characterizing and exploiting the many roles of aberrant H2B monoubiquitination in cancer pathogenesis.
Monoubiquitination of histone H2B on lysine 120 (H2Bub1) is implicated in the control of multiple essential processes, including transcription, DNA damage repair and mitotic chromosome segregation. Accordingly, aberrant regulation of H2Bub1 can induce transcriptional reprogramming and genome instability that may promote oncogenesis. Remarkably, alterations of the ubiquitin ligases and deubiquitinating enzymes regulating H2Bub1 are emerging as ubiquitous features in cancer, further supporting the possibility that the misregulation of H2Bub1 is an underlying mechanism contributing to cancer pathogenesis. To date, aberrant H2Bub1 dynamics have been reported in multiple cancer types and are associated with transcriptional changes that promote oncogenesis in a cancer type-specific manner. Owing to the multi-functional nature of H2Bub1, misregulation of its writers and erasers may drive disease initiation and progression through additional synergistic processes. Accordingly, understanding the molecular determinants and pathogenic impacts associated with aberrant H2Bub1 regulation may reveal novel drug targets and therapeutic vulnerabilities that can be exploited to develop innovative precision medicine strategies that better combat cancer. In this review, we present the normal functions of H2Bub1 in the control of DNA-associated processes and describe the pathogenic implications associated with its misregulation in cancer. We further discuss the challenges coupled with the development of therapeutic strategies targeting H2Bub1 misregulation and expose the potential benefits of designing treatments that synergistically exploit the multiple functionalities of H2Bub1 to improve treatment selectivity and efficacy.


Early role of the κ opioid receptor in ethanol-induced reinforcement.
Effects of early ethanol exposure on later ethanol intake emphasize the importance of understanding the neurobiology of ethanol-induced reinforcement early in life. Infant rats exhibit ethanol-induced appetitive conditioning and ethanol-induced locomotor activation, which have been linked in theory and may have mechanisms in common. The appetitive effects of ethanol are significantly modulated by μ and δ opioid receptors, whereas μ but not δ receptors are involved in the motor stimulant effects of ethanol during early development. The involvement of the κ opioid receptor (KOR) system in the motivational effects of ethanol has been much less explored. The present study assessed, in preweanling (infant) rats, the modulatory role of the KOR system in several paradigms sensitive to ethanol-induced reinforcement. Kappa opioid activation and blockade were examined in second-order conditioned place preference with varied timing before conditioning and with varied ethanol doses. The role of KOR on ethanol-induced locomotion and ethanol-induced taste conditioning was also explored. The experiments were based on the assumption that ethanol concurrently induces appetitive and aversive effects and that the latter may be mediated by activation of kappa receptors. The main result was that blockade of kappa function facilitated the expression of appetitive ethanol reinforcement in terms of tactile and taste conditioning. The effects of kappa activation on ethanol conditioning seemed to be independent from ethanol's stimulant effects. Kappa opioid activation potentiated the motor depressing effects of ethanol but enhanced motor activity in control subjects. Overall, the results support the hypothesis that a reduced function of the KOR system in nondependent subjects should attenuate the aversive consequences of ethanol.


Animal-Assisted Intervention and Health Care Workers' Psychological Health: A Systematic Review of the Literature.
Healthcare settings have recently increased the use of companion animals in the workplace to provide emotional support to people with disabilities, but there is limited empirical research on the effects of these programs on healthcare workers. However, it is reasonable to speculate that Animal-Assisted Interventions (AAIs) may have positive effects on health care workers (HCWs) by buffering the negative effects of work-related stress and other occupational psychosocial risk factors. The aim of this review was to examine the beneficial effects of AAIs on the psychological well-being of HCWs. A systematic review was conducted in December 2021 to gain insight into the positive effects of pets on HCWs in the workplace. Searches were conducted in the following databases: Scopus, PubMed/Medline, Web of Science, and Google Scholar, including studies between 2001 and December 2021, and 12 articles were included in the review. The results indicate that implementing the AAI program in a busy clinic is feasible and that the program is accepted by medical professionals because of the immense psychological benefits it provides. However, the healthcare professionals disliked the experimental design that forced them to leave their workplaces at a certain time.


[Study on chromatography-efficacy relation of Zanthoxylum nitidum on gastric cancer cells].
To develop a method for elucidating " chromatography-efficacy" relation of the extract of Zanthoxylum nitidum on the gastric cancer cells. After obtaining the tumor inhibition rate and fingerprint peak data through MTT and HPLC, "chromatography-efficacy" relation was established by an appropriate statistical method. The gastric cancer "chromatography-efficacy" relation of Z. nitidum was established by step-back technique. The "chromatography-efficacy" relation has statistically significant and practical significance, so it has reference value in some way.


Lipid transfer particle catalyzes transfer of carotenoids between lipophorins of Bombyx mori.
The yellow color of Bombyx mori hemolymph is due to the presence of carotenoids, which are primarily associated with lipophorin particles. Carotenoids were extracted from high density lipophorin (HDLp) of B. mori and analyzed by HPLC. HDLp contained 33 micrograms of carotenoids per mg protein. Over 90% of carotenoids were lutein while alpha-carotene and beta-carotene were minor components. When larval hemolymph was subjected to density gradient ultracentrifugation, a second minor yellow band was present, which was identified as B. mori lipid transfer particle (LTP). During other life stages examined however, this second band was not visible. To determine if coloration of LTP may fluctuate during development, we determined its concentration in hemolymph and compared it to that of lipophorin. Both proteins were present during all life stages and their concentrations gradually increased. The ratio of lipophorin: LTP was 10-15:1 during the fourth and fifth instar larval stages, and 20-30:1 during the pupal and adult stages. Thus, there was no correlation between the yellow color attributed to LTP and its hemolymph concentration. It is possible that yellow coloration of the LTP fraction corresponds to developmental stages when the particle is active in carotene transport. To determine if LTP is capable of facilitating carotene transfer, we took advantage of a white hemolymph B. mori strain which, when fed artificial diet containing a low carotene content, gives rise to a lipophorin that is nearly colorless. A spectrophotometric, carotene specific, transfer assay was developed which employed wild type, carotene-rich HDLp as donor particle and colorless low density lipophorin, derived from the white hemolymph strain animals, as acceptor particle. In incubations lacking LTP carotenes remained associated with HDLp while inclusion of LTP induced a redistribution of carotenes between the donor and acceptor in a time and concentration dependent manner. Time course studies suggested the rate of LTP-mediated carotene transfer was relatively slow, requiring up to 4 h to reach equilibrium. By contrast, studies employing 3H-diacylglycerol labeled HDLp as donor particle in lipid transfer assays revealed a rapid equilibration of label between the particles. Thus, it is plausible that the slower rate of LTP-mediated carotene transfer is due to its probable sequestration in the core of HDLp.


Tunneled modified lotus petal flap for surgical reconstruction of severe introital stenosis after radical vulvectomy.
We presented the anatomical, functional and aesthetic results achieved with lotus petal flap in case of introital stenosis as a results of inadequate primary plastic reconstruction. We discussed the potential advantages of lotus petal flap compared to others vulvar reconstructive techniques. We report a case of a 44-years old woman presenting a severe introital stenosis following radical surgery for vulvar cancer. She could not have a normal sexual activity life because the narrow scarred introitus resulting after primary closure of a large vulvar defect. The patient comes to our attention after three years from primary surgery. Once the scar was removed we performed a vulvoperineal reconstruction with bilateral tunneled lotus petal flaps. Lotus petal flap is a safe, easy and quick technique, has a good functional and cosmetic results in this young woman, and represents an optimal alternative solution for plastic reconstruction in case of severe introital stenosis after primary closure of large vulvoperineal defect. Tunneled lotus petal flaps represents a feasible, attractive and versatile surgical reconstructive technique that can be easily performed after surgical treatment of vulvoperineal neoplasms.


Spontaneous Dissociation of Fluocinolone Acetonide Sustained Release Implant (Retisert) with Dislocation into the Anterior Chamber.
To report two cases of spontaneous Retisert implant dissociation with dislocation of the medication reservoir into the anterior chamber. Case reports. Two patients with chronic, noninfectious uveitis following Retisert implantation between 6 and 7 years prior presented with a complaint of a "white spot" in their right eyes. Both patients had previous pars plana vitrectomies. Anterior segment examination revealed a dislocated medication reservoir of the Retisert implant in the inferior portion of anterior chamber with associated reservoir-corneal endothelial touch and stromal edema. The reservoirs were subsequently retrieved via a pars plana approach and removed from the anterior chamber through a corneal incision. Spontaneous dissociation of the Retisert implant with dislocation of the medication reservoir into the anterior chamber can be a late complication of Retisert implantation. Eye care professionals and patients should be aware of this complication, particularly with long-term intraocular retention of this device.


Pyrazine-2(1H)-thione.
The title compound, C4H4N2S, was obtained by the reduction of 2-mercapto-pyrazine (during its crystallization with 2-mercapto-pyrazine and isonicotinic acid N-oxide in ethanol solution. It crystallizes in the monoclinic space group P21/m. In the crystal, the mol-ecules are linked by N-H⋯N and C-H⋯S hydrogen bonds.


Leptocneria vinarskii sp. nov. (Lepidoptera: Erebidae: Lymantriinae), an overlooked Wallacean lineage of the Australian genus.
The tussock moth genus Leptocneria Butler, 1886 (Lepidoptera: Erebidae: Lymantriinae) has been considered an entirely Australian taxon that includes two species: L. reducta (Walker, 1855) and L. binotata Butler, 1886. However, we discovered a divergent lineage of Leptocneria inhabiting Flores Island, Lesser Sundas, Indonesia. Here, we describe this lineage as the third species of the genus, L. vinarskii Bolotov, Kondakov et Spitsyn sp. nov. The new species is sister to L. reducta but differs from it by dark gray marking patterns of the forewing that lack orange or dark yellow marks. The mean COI genetic distance between L. vinarskii sp. nov. and L. reducta sensu lato is 2.9%. Our findings confirm that the Wallacean region was a faunal exchange area between Sundaland and Sahul during the Pleistocene but highlight that the vicariance events may have played a crucial role in origin of the endemic faunas on the islands of East Nusa Tenggara. Additionally, we show that both Australian species most likely represent cryptic species complexes, which are in need of further taxonomic revision.


Pairwise antibiotic interactions in Escherichia coli: triclosan, rifampicin and aztreonam with nine other classes of antibiotics.
Previous investigations have shown that analyzing pairwise interactions between 22 antibiotics in Escherichia coli enable the grouping of drugs into nine functional classes. Our aim is to significantly expand this drug network by adding three clinically relevant antibiotics, two of which have distinct mechanisms of action not previously represented. Here, we examine triclosan, rifampicin and aztreonam, by testing them pairwise against themselves and one antibiotic from each of the nine classes. Network analysis shows that triclosan, rifampicin and aztreonam each form distinct functional groups of their own. This is particularly surprising for aztreonam, which is a cell wall synthesis inhibitor but did not cluster with other cell wall synthesis inhibitors. Furthermore, of the 30 pairs tested, we found several previously unreported synergies that could potentially be used in multidrug therapies. The distinct functional groups suggest that there may be properties of these drugs that are different from other drugs even with similar mechanism of action, and that, when considering drug combinations, aztreonam in particular is not simply interchangeable with other cell wall synthesis inhibitors.


FMixCutMatch for semi-supervised deep learning.
Mixed sample augmentation (MSA) has witnessed great success in the research area of semi-supervised learning (SSL) and is performed by mixing two training samples as an augmentation strategy to effectively smooth the training space. Following the insights on the efficacy of cut-mix in particular, we propose FMixCut, an MSA that combines Fourier space-based data mixing (FMix) and the proposed Fourier space-based data cutting (FCut) for labeled and unlabeled data augmentation. Specifically, for the SSL task, our approach first generates soft pseudo-labels using the model's previous predictions. The model is then trained to penalize the outputs of the FMix-generated samples so that they are consistent with their mixed soft pseudo-labels. In addition, we propose to use FCut, a new Cutout-based data augmentation strategy that adopts the two masked sample pairs from FMix for weighted cross-entropy minimization. Furthermore, by implementing two regularization techniques, namely, batch label distribution entropy maximization and sample confidence entropy minimization, we further boost the training efficiency. Finally, we introduce a dynamic labeled-unlabeled data mixing (DDM) strategy to further accelerate the convergence of the model. Combining the above process, we finally call our SSL approach as "FMixCutMatch", in short FMCmatch. As a result, the proposed FMCmatch achieves state-of-the-art performance on CIFAR-10/100, SVHN and Mini-Imagenet across a variety of SSL conditions with the CNN-13, WRN-28-2 and ResNet-18 networks. In particular, our method achieves a 4.54% test error on CIFAR-10 with 4K labels under the CNN-13 and a 41.25% Top-1 test error on Mini-Imagenet with 10K labels under the ResNet-18. Our codes for reproducing these results are publicly available at https://github.com/biuyq/FMixCutMatch.


The K562 chronic myeloid leukemia cell line undergoes apoptosis in response to interferon-alpha.
The K562 cell line, derived from a chronic myeloid leukemia (CML) patient and expressing B3A2 bcr-abl hybrid gene, is known to be particularly resistant to apoptotic death. IFN-alpha treatment of CML patients impairs malignant cell clone, apparently protecting from progression to terminal blast crisis. The mechanisms underlying this kind of cell deletion are analyzed here by multiple technical approaches. K562 cells, variably treated with IFN-alpha, were examined by agarose gel DNA electrophoresis, light and electron microscopy. The presence of bcr-abl rearrangement was revealed by RT-PCR. At 4 day treatment both DNA ladder and apoptotic nuclear changes were identified, consistently in the presence of bcr-abl expression. Even cells expressing bcr-abl, such as K562, can be triggered to apoptosis. Therefore, this genetic condition, commonly preventing PCD, does not prevent IFN-alpha-mediated apoptosis. PCD seems thus to be the mechanism underlying IFN-alpha-treated K562 cell deletion and it could be the basis of malignant clone reduction in IFN-alpha treated CML patients.


Evaluation of some alternative mechanisms for interface-related stress relaxation in lung.
Lung surfactant might exchange reversibly between the alveolar gas-liquid interface and the liquid lining layer. This solubilization process could then contribute to time-dependent pulmonary mechanical phenomena. Theoretical analysis of a model alveolus shows how solubilization can produce recoil pressure relaxation of the lung. The analysis shows that for most experimental observations reported the solubilization kinetics probably could not have been determined by the actual fitting in, or squeezing out, of surfactant in the surface film. Most data are consistent with a solubilization rate controlled by diffusion in the liquid sublayer. However, in order for a diffusion-controlled mechanism to be significant the diffusing substance should be large, such as a micelle, and the alveolar liquid layer should be at least 1 micrometer thick. These conditions are quite realistic for slightly edematous lungs and thus might apply to many experimental, or pathological, situations.


Olaparib: a promising PARP inhibitor in ovarian cancer therapy.
Ovarian cancer (OC) is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at advanced stage with poor prognosis. Currently, surgical tumor debulking followed by chemotherapy based on platinum and taxane is the standard treatment for advanced OC. However, these patients remain at great risk for recurrence and developing drug resistance. Therefore, new treatment strategies are needed to improve outcomes for patients with advanced and recurrent OC. Olaparib (AZD2281, KU-0059436), as one of the best understood Poly-(ADP-ribose) polymerase (PARP) inhibitor targeting DNA repair mechanisms, caused more and more attention. Clinical trial data of Olaparib had been cumulated, which applied as the single-agent in relapsed OC monotherapy, especially for BRCA mutation associated OC. In this review, we demonstrated the mechanism of PARP inhibitors and summarized clinical trial data and clinical development of Olaparib targeted OC in order to address a new promising therapy strategy for advanced relapsed OC. Given the unprecedented clinical potential of Olaparib, the further research on Olaparib will have great significance in selection of OC patient populations that will respond to treatment.


Metabolomics Reveals the Effects of High Dietary Energy Density on the Metabolism of Transition Angus Cows.
The diet energy level plays a vital role in the energy balance of transition cows. We investigated the effects of high dietary energy density on body metabolism. Twenty multiparous Angus cows were randomly assigned to two treatment groups (10 cows/treatment), one receiving a high-energy (HE) diet (NEm = 1.67 Mcal/kg of DM) and the other administered a control (CON) diet (NEm = 1.53 Mcal/kg of DM). The results indicated that feeding a high-energy diet resulted in higher plasma glucose concentration and lower concentrations of plasma NEFA and BHBA on d 14 relative to calving in the HE-fed cows compared to the CON-fed ones. The postpartum plasma levels of T-AOC were lower in cows that received the CON diet than in cows in the HE group, while the concentration of malondialdehyde (MDA) showed an opposite trend. Among the 51 significantly different metabolites, the concentrations of most identified fatty acids decreased in HE cows. The concentrations of inosine, glutamine, and citric acid were higher in HE-fed cows than in CON-fed cows. Enrichment analysis revealed that linoleic acid metabolism, valine, leucine as well as isoleucine biosynthesis, and glycerophospholipid metabolism were significantly enriched in the two groups.


Impact Excitation of a Seismic Pulse and Vibrational Normal Modes on Asteroid Bennu and Associated Slumping of Regolith.
We consider an impact on an asteroid that is energetic enough to cause resurfacing by seismic reverberation and just below the catastrophic disruption threshold, assuming that seismic waves are not rapidly attenuated. In asteroids with diameter less than 1 km we identify a regime where rare energetic impactors can excite seismic waves with frequencies near those of the asteroid's slowest normal modes. In this regime, the distribution of seismic reverberation is not evenly distributed across the body surface. With mass-spring model elastic simulations, we model impact excitation of seismic waves with a force pulse exerted on the surface and using three different asteroid shape models. The simulations exhibit antipodal focusing and normal mode excitation. If the impulse excited vibrational energy is long lasting, vibrations are highest at impact point, its antipode and at high surface elevations such as an equatorial ridge. A near equatorial impact launches a seismic impulse on a non-spherical body that can be focused on two additional points on an the equatorial ridge. We explore simple flow models for the morphology of vibration induced surface slumping. We find that the initial seismic pulse is unlikely to cause large shape changes. Long lasting seismic reverberation on Bennu caused by a near equatorial impact could have raised the height of its equatorial ridge by a few meters and raised two peaks on it, one near impact site and the other near its antipode.


Functional characterisation of autoantibodies from patients with pediatric opsoclonus-myoclonus-syndrome.
Paraneoplastic opsoclonus-myoclonus-syndrome (OMS) both in children and adults is suspected to be the result of an autoimmune response directed against cross-reactive proteins of tumor and neuronal cells. We here characterised the binding and functional activities of anti-neuroblastoma antibodies in IgG fractions from 11 OMS children with and without neuroblastoma. IgG fractions from neuroblastoma without OMS (NB) and healthy children served as controls. Indirect immunofluorescence and Western blot revealed IgG binding to intracellular autoantigens in all OMS patients, but in only one of the controls (p<0.001). Using flow cytometry, we could demonstrate surface binding of IgG fractions in all OMS patients, but only in one of control (p<0.001). Moreover OMS IgG exhibited a significant anti-proliferative and a cytotoxic effect on neuroblastoma cells compared to control IgG (p<0.001 and p<0.01). TUNEL assay revealed increased apoptotic cell death of the neuroblastoma cells after exposure to OMS IgG, but not to NB or control IgG (p<0.01). Preabsorption of membrane binding abandoned the anti-proliferative effect of OMS IgG. These findings indicate that surface-binding autoantibodies are present in OMS patients and these autoantibodies cause inhibition of cell proliferation and induce apoptosis.


Associations between existing and newly diagnosed chronic health conditions and change in subjective life expectancy: Results from a panel study.
Subjective life expectancy (SLE) is a vital predictor of mortality, health and retirement. Nevertheless, we have sparse knowledge about what drives changes in SLE. Having a chronic health condition (CHC) is probably associated with a change SLE. However, how CHCs are associated with changes in SLE may depend on whether the CHC was newly diagnosed and the type of CHC. We hypothesize that newly diagnosed CHCs will be strongly negatively associated with changes in SLE than existing CHCs. As CHCs vary in their presentation and prognosis, we differentiate associations between five CHCs - arthritis, cardiovascular diseases, sleep disorders, psychological disorders and life-threatening conditions - and changes in SLE. Data from two waves of a Dutch pension panel survey, collected 3 years apart in 2015 and 2018, were used. The analytical sample included 4824 older workers between the ages of 60-65 years at wave 1. Data were analysed longitudinally using a conditional change ordered logistic regression model. In general, newly diagnosed CHCs were strongly negatively associated with changes in SLE, relative to having no CHCs. Existing CHCs were also negatively associated with changes in SLE, but to a weaker strength. Interestingly, associations between CHCs and the change in SLE differed based on the CHC in question. Newly diagnosed life-threatening conditions, psychological disorders and cardiovascular diseases are strongly negatively associated with changes in SLE. These results provide insight into the differences in how older workers with CHCs experience late career work and how these experiences influence their SLE.


A microsomal endopeptidase from liver with substrate specificity for processing proproteins such as the vitamin K-dependent proteins of plasma.
The microsomal fraction of rabbit liver contains an endopeptidase that cleaves synthetic peptides that mimic the amino acid sequences of the processing sites of many proproteins, including the vitamin K-dependent proteins. The endopeptidase (M(r) 69,000) was extracted from liver microsomes with 1% Lubrol and purified about 2,700-fold. The substrate employed for isolation and characterization of the enzyme was the decapeptide acetyl-Ala-Arg-Val-Arg-Arg-Ala-Asn-Ser-Phe-Leu (prothrombin peptide), in which hydrolysis occurred on the carboxyl side of the paired Arg-Arg residues. The purified enzyme, whose activity was enhanced 1.8-fold by 0.1 mM CoCl2, has a Km = 80 microM and Vmax = 21,000 nmol.min-1.mg-1 and a pH optimum of 8.7. Proteolytic cleavage of decapeptide substrates was dependent on an arginine residue at positions P1 and P4. The enzyme was completely inhibited by EDTA and 1,10-phenanthroline as well as by p-chloromercuriphenylsulfonic acid and Hg2+. Inhibitors of serine proteases and cysteine proteases had no effect. Based on the substrate preference, the endopeptidase appears to be a good candidate for the enzyme responsible for the precursor processing of the vitamin K-dependent proteins and a number of other proproteins that are synthesized via the secretory pathway in liver and other tissues.


siRNA depletion of 7SK snRNA induces apoptosis but does not affect expression of the HIV-1 LTR or P-TEFb-dependent cellular genes.
P-TEFb is a general transcriptional elongation factor composed of Cdk9 and either cyclin T1, T2, or K. A substantial portion of P-TEFb is associated with the 7SK small nuclear RNA (7SK) and the HEXIM1 or HEXIM2 proteins; this complex has reduced kinase activity in vitro relative to free P-TEFb. Here we report that 7SK and HEXIM1 levels are induced in activated lymphocytes concomitantly with increased P-TEFb activity and global transcription. We used siRNA-mediated depletion to probe the function of 7SK in HeLa cells. Depletion of 7SK caused a large reduction in the association of HEXIM1 with Cdk9 and cyclin T1, and greatly reduced the amount of the cyclin T1 present in the 7SK/HEXIM1/P-TEFb complex. Similar to previous studies, siRNA-mediated depletion of 7SK resulted in increased expression of several reporter plasmids tested, including a plasmid lacking promoter elements. However, in contrast to previous studies, which did not examine the effects of 7SK depletion on endogenous gene expression, depletion of 7SK did not appear to affect the expression of the corresponding endogenous genes. Moreover, 7SK depletion had no effect on expression from the integrated HIV-1 provirus or the c-myc and MCL-1 genes, three transcription units known to be highly dependent upon P-TEFb. Importantly, depletion of 7SK was found to cause apoptosis by 72 h post-transfection in HeLa cells. These results suggest that 7SK may provide an essential cellular function whose relation to P-TEFb function is unclear.


Mammalian dihydropyrimidine dehydrogenase.
Dihydropyrimidine dehydrogenase (DPD) catalyzes the two-electron reduction of pyrimidine bases uracil and thymine as the first step in pyrimidine catabolism. The enzyme achieves this simple chemistry using a complex cofactor set including two flavins and four Fe4S4 centers. The flavins, FAD and FMN, interact with respective NADPH and pyrimidine substrates and the iron-sulfur centers form an electron transfer wire that links the two active sites that are separated by 56 Å. DPD accepts the common antineoplastic agent 5-fluorouracil as a substrate and so undermines the establishment of efficacious toxicity. Though studied for multiple decades, a precise description of the behavior of the enzyme had remained elusive. It was recently shown that the active form of DPD has the cofactor set of FAD-4(Fe4S4)-FMNH2. This two-electron reduced state is consistent with fewer mechanistic possibilities and data suggests that the instigating and rate determining step in the catalytic cycle is reduction of the pyrimidine substrate that is followed by relatively rapid oxidation of NADPH at the FAD that, via the electron conduit of the 4(Fe4S4) centers, reinstates the FMNH2 cofactor for subsequent catalytic turnover.


Further observations on back-firing in the motor nerve fibres of a muscle during twitch contractions.
1. The tension developed by a muscle in response to a single supramaximal nerve volley is often the sum of two contractions, the second resulting from re-excitation of some nerve terminals during the first contraction. Re-excitation or back-firing can be prevented if the muscle nerve is stimulated twice with the second volley arriving in the muscle at a time when muscle fibres are still refractory following the first volley (Brown & Matthews, 1960). 2. Back-firing has been studied here in the medial gastrocnemius muscle of the spinal cat and responses have been recorded, either representing the summed activity of the muscle's motor supply or discharges of single functional motor axons. 3. When stimulating at a distance from the muscle, the second of two shocks is effective in suppressing back-firing over a narrower range of stimulus intervals than when stimulating close to the muscle. 4. The amount of back-firing can be reduced by stretching the muscle. At a length corresponding to the optimum for a twitch little if any back-firing remains. 5. Measurements of threshold to electrical stimulation of single functional motor axons suggests that low threshold axons are more likely to show back-firing. In the majority of cases, most or all of the motor units in the muscle have to be active before back-firing can be observed.


[Efficacy of tele-rehabilitation in patients with chronic obstructive pulmonary disease: A systematic review].
Since 2020 we have lived an exceptional situation that made us experience a complete lockdown due to SARS-CoV-2, what affected the treatments of different pathologies, such as the chronic obstructive pulmonary disease (COPD). Because of those reasons, it has arisen the idea of implementing the tele-rehabilitation program as a treatment of these pathologies. The search was done between the months of October and November 2020, with the aim of analyzing and updating the efficacy of the tele-rehabilitation in patients who have COPD, finding eight articles which met the inclusion criteria. The pulmonary tele-rehabilitation is able to improve the quality of life and physical state, and decreasing the number of hospitalizations and exacerbations. Furthermore, patients showed a great level of satisfaction and adherence to this treatment program. The pulmonary tele-rehabilitation can achieve similar results as of pulmonary rehabilitation. For this reason, people who have difficulties to go to their outpatients clinic or even in a lockdown can use it. However, it is necessary to investigate which tele-rehabilitation program is better.


MEA Preparation for Direct Formate/Formic Acid Fuel Cell-Comparison of Palladium Black and Palladium Supported on Activated Carbon Performance on Power Generation in Passive Fuel Cell.
Membrane electrode assemblies (MEAs) with palladium catalysts were successfully prepared by using a home-made manual pressing system with Nafion glue application that contributed to a decrease of additional energy consumption. The catalyst coated membranes were prepared with supported palladium on activated carbon (PdC) and unsupported palladium black (PdB) for comparison. The performance of passive, air breathing, functioning under ambient conditions and with low concentration (1 M) formate/formic acid fuel cell was evaluated. Based on polarization curves, the best result was obtained with carbon supported catalyst and HCOOK fuel, achieving 21.01 mW/mgPd. Still, constant current discharge with PdC showed an energy generation efficiency of 14% with HCOOH over 3% with HCOOK caused by lower potassium ion conductivity and its permeability through the proton exchange membrane. The faradic efficiency of conversion in the cell is equal to the overall energy efficiency and makes the cell self-sufficient.


Potential lipid-lowering effects of Ulmus macrocarpa Hance extract in adults with untreated high low-density lipoprotein cholesterol concentrations: A randomized double-blind placebo-controlled trial.
Ulmus macrocarpa Hance extract (UME) has demonstrated an antilipidemic effect via upregulation of the adenosine monophosphate-activated protein kinase pathway and regulation of lipid metabolism in both laboratory and animal studies. Therefore, we examined the effects and safety of UME on plasma lipids in adults with untreated high, low-density lipoprotein cholesterol (LDL-C) concentrations. In the current double-blind placebo-controlled randomized clinical trial, 80 patients with untreated high LDL-C concentrations (130-190 mg/dl) were randomly allocated to either the "UME group" (received 500 mg UME as two capsules per day) or the "Placebo group" (received placebo containing cornstarch as two capsules per day) for 12 weeks. The primary outcome was the change in LDL-C concentration within the 12-week treatment period; secondary outcomes included changes in total cholesterol (TC), triglyceride, high-density lipoprotein cholesterol, apolipoprotein A1, and apolipoprotein B (ApoB) concentrations. UME over 12 weeks led to a greater decrease in LDL-C, TC, and ApoB concentrations than did the placebo as follows: by 18.1 mg/dl (P < 0.001); 23.3 mg/dl (P < 0.001); 9.3 mg/dl (P = 0.018), respectively. When LDL-C, TC, and ApoB concentrations were expressed as a lsmeans percentage of the baseline concentration, they after 12 weeks of UME had greater % differences compared to the placebo as follows: by 11.9% (P < 0.001); 10.0% (P < 0.001); 8.6% (P < 0.05), respectively. However, no significant inter- and intra-group changes in liver enzyme, free fatty acid, anti-inflammatory marker, and fasting glucose concentrations were observed. None of the participants experienced notable adverse events. UME causes a significant improvement in lipid profiles in adults with untreated high LDL-C concentrations. [www.clinicaltrials.gov/], identifier [NCT03773315].


Inpatient Obesity Recognition and Diagnosis in Pediatric Patients.
Despite obesity's effect on pediatric patient health, the role of hospitalizations in recognizing and diagnosing pediatric obesity is poorly explored. We performed a retrospective cohort study of pediatric inpatients aged 2 to 18 years utilizing CERNER Health Facts database to determine the: (1) prevalence of obesity in a large, multicenter inpatient database, (2) appropriate International Classification of Diseases, 10th Revision, obesity diagnosis proportion, and (3) variables associated with appropriate obesity diagnosis. Covariates included patient demographics and hospital descriptors, which were summarized using frequencies, and differences across groups were compared using χ Square testing. Of the hospitalized children with obesity (19.5%), only 13.2% had an appropriate obesity diagnosis. Appropriate obesity diagnosis increased with higher obesity class and was least common in the South census region at only 8.5%. Despite pediatric hospitalizations being a potential area for recognition and intervention of obesity, the majority of hospitalized children do not receive an appropriate obesity diagnosis.


Recognition of stable protein mutants with 3D stochastic average electrostatic potentials.
As more and more proteins are applied to biochemical research there is increasing interest in studying their stability. In this study, a Markov model has been used to calculate molecular descriptors of the protein structure and these are called the average electrostatic potentials (xi(k)). These descriptors were intended to encode indirect electrostatic pair-wise interactions between amino acids located at Euclidean distance k within a given 3D protein backbone. The different xi(k) values could be calculated for the protein as a whole or for specific protein regions (orbits), which include amino acids that lie within a given range of distances from the center of charge of the protein. In this work we calculated the xi(k) values for 657 mutants of different proteins. A Linear Discriminant Analysis model correctly classified a subset of 435 out of 493 proteins according to their thermal stability - a level of predictability of 88.2%. This experiment was repeated with three additional subsets of proteins selected at random from the initial series of 657. More specifically, the model predicted 314/356 (88.2%) of mutants with higher stability than the corresponding wild-type protein and 264/301 (86.7%) of proteins with near wild-type stability. These results illustrate the possibilities for the average stochastic potentials xi(k) in the study of 3D-structure/property relationships for biochemically relevant proteins.