[Planned dairy herd health. I: General philosophy].
A dairy herd health programme may be defined as a planned and co-ordinated approach which aims at achieving and maintaining optimal herd health, production and reproduction, the implementation of which is governed by sound economic principles. The object of this article is to present and discuss some facets of the background philosophy of the concept of herd health, and look at some of the pitfalls and shortcomings of their application in practice. In terms of production levels achieved in other developed countries, South Africa lags behind. While factors such as climate, environment, feed quality, and basic livestock potential may play a role in this difference, the single most important factor is undoubtedly the managemental approach. Modern livestock production requires a shift in emphasis of veterinary involvement towards a herd approach which promotes increased cost-effective production. The veterinarian forms part of a production team which, apart from himself, includes the farmer, farm labour and the animal scientist. The veterinarian has a key role in this endeavour. Through his basic training he is well equipped to serve as a co-ordinator of the massive flow of information being generated. To do this effectively he must be able to work with, advise and communicate with people at various levels of management as well as with the labour force. While optimal co-operation of each team member is cardinal to the success of such a programme, no progress will be made unless the farmer is convinced of the viability of the undertaking, and indeed has the managerial skills to implement any directive or recommendation.(ABSTRACT TRUNCATED AT 250 WORDS)


PGC-1α and exercise intensity dependent adaptations in mouse skeletal muscle.
The aim of the present study was to examine the role of PGC-1α in intensity dependent exercise and exercise training-induced metabolic adaptations in mouse skeletal muscle. Whole body PGC-1α knockout (KO) and littermate wildtype (WT) mice performed a single treadmill running bout at either low intensity (LI) for 40 min or moderate intensity (MI) for 20 min. Blood and quadriceps muscles were removed either immediately after exercise or at 3h or 6h into recovery from exercise and from resting controls. In addition PGC-1α KO and littermate WT mice were exercise trained at either low intensity (LIT) for 40 min or at moderate intensity (MIT) for 20 min 2 times pr. day for 5 weeks. In the first and the last week of the intervention period, mice performed a graded running endurance test. Quadriceps muscles were removed before and after the training period for analyses. The acute exercise bout elicited intensity dependent increases in LC3I and LC3II protein and intensity independent decrease in p62 protein in skeletal muscle late in recovery and increased LC3II with exercise training independent of exercise intensity and volume in WT mice. Furthermore, acute exercise and exercise training did not increase LC3I and LC3II protein in PGC-1α KO. In addition, exercise-induced mRNA responses of PGC-1α isoforms were intensity dependent. In conclusion, these findings indicate that exercise intensity affected autophagy markers differently in skeletal muscle and suggest that PGC-1α regulates both acute and exercise training-induced autophagy in skeletal muscle potentially in a PGC-1α isoform specific manner.


Some like it hot: Repeat migration and residency of whale sharks within an extreme natural environment.
The Arabian Gulf is the warmest sea in the world and is host to a globally significant population of the whale shark Rhincodon typus. To investigate regional whale shark behaviour and movements, 59 satellite-linked tags were deployed on whale sharks in the Al Shaheen area off Qatar from 2011-14. Four different models of tag were used throughout the study, each model able to collect differing data or quantities of data. Retention varied from one to 227 days. While all tagged sharks crossed international maritime boundaries, they typically stayed within the Arabian Gulf. Only nine sharks dispersed through the narrow Strait of Hormuz into the Gulf of Oman. Most sharks stayed close to known or suspected feeding aggregation sites over summer months, but dispersed throughout the Arabian Gulf in winter. Sharks rarely ventured into shallow areas (<40 m depth). A single, presumably pregnant female shark was the sole animal to disperse a long distance, crossing five international maritime boundaries in 37 days before the tag detached at a distance of approximately 2644 km from the tagging site, close to the Yemeni-Somali border. No clear space-use differentiation was evident between years, for sharks of different sizes, or between sexes. Whale sharks spent the most time (~66%) in temperatures of 24-30°C and in shallow waters <100 m depth (~60%). Sharks spent relatively more time in cooler (X2 = 121.692; p<0.05) and deeper (X2 = 46.402; p<0.05) water at night. Sharks rarely made dives deeper than 100 m, reflecting the bathymetric constraints of the Gulf environment. Kernel density analysis demonstrated that the tagging site at Al Shaheen was the regional hotspot for these sharks, and revealed a probable secondary aggregation site for whale sharks in nearby Saudi Arabian waters. Analysis of visual re-sightings data of tagged sharks revealed that 58% of tagged individuals were re-sighted back in Al Shaheen over the course of this study, with 40% recorded back at Al Shaheen in the year following their initial identification. Two sharks were confirmed to return to Al Shaheen in each of the five years of study.


Co-expression of IGF-1 family members with myogenic regulatory factors following acute damaging muscle-lengthening contractions in humans.
Muscle regeneration following injury is dependent on the ability of muscle satellite cells to activate, proliferate and fuse with damaged fibres. This process is controlled by the myogenic regulatory factors (MRF). Little is known about the temporal relation of the MRF with the expression of known myogenic growth factors (i.e. IGF-1) in humans following muscle damage. Eight subjects (20.6 +/- 2.1 years; 81.4 +/- 9.8 kg) performed 300 lengthening contractions (180 deg s(-1)) of their knee extensors in one leg on a dynamometer. Blood and muscle samples were collected before and at 4 (T4), 24 (T24), 72 (T72) and 120 h (T120) post-exercise. Mechano growth factor (MGF), IGF-1Ea and IGF-1Eb mRNA were quantified. Serum IGF-1 did not change over the post-exercise time course. IGF-1Ea and IGF-1Eb mRNA increased approximately 4- to 6-fold by T72 (P < 0.01) and MGF mRNA expression peaked at T24 (P = 0.005). MyoD mRNA expression increased approximately 2-fold at T4 (P < 0.05). Myf5 expression peaked at T24 (P < 0.05), while MRF4 and myogenin mRNA expression peaked at T72 (P < 0.05). Myf5 expression strongly correlated with the increase in MGF mRNA (r(2) = 0.83; P = 0.03), while MRF4 was correlated with both IGF-1Ea and -Eb (r(2) = 0.90; r(2) = 0.81, respectively; P < 0.05). Immunofluorescence analysis showed IGF-1 protein expression localized to satellite cells at T24, and to satellite cells and the myofibre at T72 and T120; IGF-1 was not detected at T0 or T4. These results suggest that the temporal response of MGF is probably related to the activation/proliferation phase of the myogenic programme as marked by an increase in both Myf5 and MyoD, while IGF-1Ea and -Eb may be temporally related to differentiation as marked by an increase in MRF4 and myogenin expression following acute muscle damage.


ConBind: motif-aware cross-species alignment for the identification of functional transcription factor binding sites.
Eukaryotic gene expression is regulated by transcription factors (TFs) binding to promoter as well as distal enhancers. TFs recognize short, but specific binding sites (TFBSs) that are located within the promoter and enhancer regions. Functionally relevant TFBSs are often highly conserved during evolution leaving a strong phylogenetic signal. While multiple sequence alignment (MSA) is a potent tool to detect the phylogenetic signal, the current MSA implementations are optimized to align the maximum number of identical nucleotides. This approach might result in the omission of conserved motifs that contain interchangeable nucleotides such as the ETS motif (IUPAC code: GGAW). Here, we introduce ConBind, a novel method to enhance alignment of short motifs, even if their mutual sequence similarity is only partial. ConBind improves the identification of conserved TFBSs by improving the alignment accuracy of TFBS families within orthologous DNA sequences. Functional validation of the Gfi1b + 13 enhancer reveals that ConBind identifies additional functionally important ETS binding sites that were missed by all other tested alignment tools. In addition to the analysis of known regulatory regions, our web tool is useful for the analysis of TFBSs on so far unknown DNA regions identified through ChIP-sequencing.


First rib resection and scalenectomy for chronically occluded subclavian veins: what does it really do?
First rib resection and scalenectomy is an acceptable therapy for those with axillosubclavian vein thrombosis who have responded to lytic therapy and demonstrated subclavian vein patency. However, the treatment for those patients who present with a chronically occluded subclavian vein is controversial. We present four such patients who underwent first rib resection and scalenectomy and whose subclavian vein spontaneously opened within the first year following surgery while anticoagulated, as well as the ultrasound protocol we employ at our institution to identify such reopening. The average age of these patients was 20 (range 17-23) years; three were male and one was female. The average time interval prior to surgery when the initial thrombosis occurred was 25 (12-34) weeks. All patients were symptomatic and underwent a transaxillary first rib resection and scalenectomy with attention to incise the subclavius tendon. All were maintained on warfarin postoperatively and surveilled by duplex scan. In all four patients the subclavian vein subsequently opened after an average of 7 (2-11) months and anticoagulation was stopped. The resultant patent subclavian vein correlated with improvement in symptoms in all four patients. All patients were asymptomatic in the postoperative follow-up period at an average of 14 (2-33 months). In conclusion, selective symptomatic patients with subclavian vein occlusion can be aggressively treated with first rib resection and scalenectomy along with anticoagulation that will lead to recanalization and opening of vein over time. This treatment correlates with improvement of their symptoms.


Quercetin alleviates cadmium-induced BRL-3A cell apoptosis by inhibiting oxidative stress and the PERK/IRE1α/ATF6 signaling pathway.
Cadmium (Cd) is a highly toxic environmental pollutant. The liver is an important metabolic organ in the body and is susceptible to Cd toxicity attacks. Quercetin (Que) is a flavonoid compound with pharmacological activities of scavenging free radicals and antioxidant activity. Previous studies have shown that Que can alleviate Cd caused hepatocyte apoptosis in rats, but the specific mechanism remains unclear. To explore the specific mechanism, we established a model of Cd toxicity and Que rescue in BRL-3A cells and used 4-phenylbutyrate (4-PBA), an endoplasmic reticulum stress (ERS) inhibitor, as positive control. Set up a control group, Cd treatment group, Cd and Que co treatment group, Que treatment group, Cd and 4-PBA co treatment group, and 4-PBA treatment group. Cell Counting Kit-8 (CCK-8) method was employed to measure cell viability. Fluorescence staining was applied to observe cell apoptosis. Flow cytometry was performed to detect reactive oxygen species levels. Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot method was adopted to detect the mRNA and protein expression levels of ERS and apoptosis-related genes. The results showed that compared with the control group, the Cd treated group showed a significant decrease in cell viability (P < 0.01), an increase in intracellular ROS levels, and apoptosis. The mRNA and protein expression levels of ERS and apoptosis related factors such as GRP78, IRE1α, XBP1, ATF6, Caspase-12, Caspase-3 and Bax in the cells were significantly increased (P < 0.01), while the mRNA and protein expression levels of Bcl-2 were significantly reduced (P < 0.01). Compared with the Cd treatment group, the Cd and Que co treatment group and the Cd and 4-PBA co treatment group showed a significant increase in cell viability (P < 0.01), a decrease in intracellular ROS levels, a decrease in cell apoptosis, and a significant decrease in the expression levels of ERS and apoptosis related factors mRNA and protein (P < 0.01), as well as a significant increase in Bcl-2 mRNA and protein expression (P < 0.01). We confirmed that Que could alleviate the apoptosis caused by Cd in BRL-3A cells, and the effects of Que were similar to those of ERS inhibitor.


Stem cells in hepatocarcinogenesis: evidence from genomic data.
Increasing evidence suggests that many, perhaps all solid tumors contain a subset of cells that possess functional properties similar to the normal tissue stem cells, including self-renewal, unlimited proliferative capacity, and pluripotency. The hierarchical cancer model that places a cancer stem cell (CSC) population at the apex of tumor formation is based on this notion. The cancer stem cell hypothesis posits that CSCs are responsible not only for tumor initiation, but also generation of metastasis and local recurrence after therapy. Current definitions of the CSC are based only on functional properties regardless of potential cellular origin. Histopathology investigations of chronic liver diseases and experimental studies support the existence of CSCs in liver cancer. In particular, recent advances in microarray technologies utilizing integrative comparative genomic analysis of human hepatocellular carcinoma specimens, cancer cell lines, and transgenic models establish the molecular similarities between CSC and normal tissue stem cells and highlight the importance of CSC for the prognosis of liver cancer patients. The results have also uncovered the key "stemness" and oncogenic pathways frequently disrupted during hepatocarcinogenesis providing the basis for identifying novel therapeutic targets against CSC.


Determinants of survival in pediatric continuous hemofiltration.
Continuous hemofiltration (CH) is being used in increasing numbers of pediatric intensive care unit patients. Experience with 114 CH treatments in 98 critically ill children from March 1988 to March 1993 is presented in this study. Ages ranged from 1 day to 23 yr (mean +/- SE = 7.1 +/- 0.7 yr), and 54% of patients were male. Seventeen percent of all treatments were performed in neonates under 1 month of age. The most common primary diagnoses were sepsis and adult respiratory distress syndrome (11 patients each), liver transplantation and hypoplastic left heart syndrome (10 patients each), and hemolytic uremic syndrome (9 patients). The most frequent indications for CH were fluid overload and acute renal failure (42% each). Choices for CH included: continuous arteriovenous hemofiltration (CAVH, 50%), continuous arteriovenous hemodiafiltration (CAVH, 23%), continuous venovenous hemofiltration (CVVH, 18%), and continuous venovenous hemodiafiltration (CVVH-D, 9%). Choices for anticoagulation included: none (47%), regional (49%), and systemic (4%). Treatment duration ranged from 1 to 25 days (mean = 5.3 +/- 0.4 days). Mean filter life span for 363 filters was 0.94 +/- 0.1 filters/patient per day. Despite an overall survival rate of 43%, survival to discharge varied greatly (0 to 100%) among the 24 diagnostic groups: tumor lysis syndrome and systemic lupus erythematosus (3/3 patients each, 100%), hemolytic uremic syndrome (8/9 patients, 89%). This compares with: bone marrow transplantation (0/6 patients, 0%), hypoplastic left heart syndrome (2/10 patients, 20%), and leukemia (1/4 patients, 25%). Survival to hospital discharge was better in patients who did not receive pressors (P < 0.005) and in patients treated with combined ultrafiltration and dialysis (CAVH-D, CVVH-D) compared with ultrafiltration alone (CAVH, CVVH) (P < 0.005), but was not notably affected by patient age, sex, use of anticoagulation, filter life span, blood pump-assisted versus spontaneous CH, or duration of therapy. Filter life span was not affected by use of anticoagulation, but was remarkably longer in patients with arteriovenous versus venovenous CH (P < 0.004). It was concluded that: (1) empirical anticoagulation of patients treated with CH is not necessary; (2) children with a minority of underlying diseases and those requiring pressor support at initiation of CH appear to have relatively poor survival rates despite the technically effective use of CH; and (3) the addition of countercurrent dialysis to routine CH may enhance patient survival to hospital discharge.


Acceptability of older adults as living kidney donors.
Kidney transplantation from a living kidney donor (LKD) is associated with better long-term survival and quality of life for a patient with end-stage renal disease (ESRD) than dialysis. We reviewed recent literature on the acceptability and outcomes of older adults as LKDs, which may be misunderstood in routine care. Studies report that receiving a kidney from an older LKD is associated with worse recipient and graft survival compared with receiving a kidney from a younger LKD, but similar recipient and graft survival to receiving a kidney from a standard criteria deceased donor. A kidney from a younger vs. older LKD results in better graft survival in younger recipients, whereas the graft survival is similar in older recipients. Compared with healthy matched nondonors, older LKDs have a similar risk of death and cardiovascular disease and the absolute risk of ESRD after 15 years remains less than 1%. The estimated predonation and postdonation lifetime risk of ESRD varies by age, sex and race with lower incidences in individuals who are older, female and white (vs. African-American). Donor and recipient outcomes from several studies support the acceptability of older adults as LKDs.


Alteration of endometrial receptivity in rats with ovarian hyperstimulation syndrome.
It is unclear if the higher pregnancy rate in patients who experience ovarian hyperstimulation syndrome (OHSS) indicates that OHSS is favourable for embryo implantation, or if patients should be maintained in a hyperstimulation state in order to increase the success rate of embryo transplantation. We developed an animal model to determine the endometrial receptivity in rats with OHSS. Endometrial mRNA levels of ER, PR, HOXA10 and LIF were determined by semi-quantitative PCR and ER, PR, HOXA10, LIF and integrin α(v) β(3) protein levels were determined by Western blotting. Development of pinopodes in the hyperstimulation group was slightly delayed, while in the regular stimulation group, development was significantly inhibited. mRNA transcription in the regular stimulation group was lower, while transcription in the hyperstimulation group was not different from controls. Protein expressions were lowest in the regular stimulation. We conclude that OHSS is associated with favourable endometrial receptivity, similar to that seen in a normal cycle, and receptivity that is increased relative to that seen with a routine stimulation protocol.


Spontaneous resolution of vitreomacular traction: a case series.
Three patients had unilateral vitreomacular traction (VMT) syndrome and the diagnosis was confirmed by spectral domain-type optical coherence tomography (OCT). All patients were female aged 51, 55 and 62 years. All denied surgical intervention. In one patient, rapid spontaneous resolution of the vitreomacular traction with a complete posterior vitreous detachment (PVD) and a normal foveal contour was achieved within 15 days. In the remaining two cases a complete PVD could be detected as late as seven months after the initial presentation. In one, though the vitreomacular adhesion released spontaneously, there was a minimal residual epiretinal membrane. In all three eyes, visual acuity was considerably improved. Spontaneous, uneventful resolution has been rarely reported in the natural course of VMT but several recent studies with the aid of OCT have shown that spontaneous resolution might be more common than previously known. In light of our cases, we believe that there is still room to search for OCT clues in eyes with VMT to predict eyes with higher likelihood of spontaneous resolution, thereby avoiding unnecessary pharmacologic and/or surgical intervention.


The Regulation of Behavioral Plasticity by Performance-Based Feedback and an Experimental Test with Avian Egg Production.
Optimizing plasticity in behavioral performances requires the abilities to regulate physiological effort and to estimate the effects of the environment. To describe how performance-based feedback could play a role in regulating recursive or continuous behavioral performances, I developed two models, one (environmental feedback) that assumes an initial ability to regulate effort but not to predict the effects of the environment and the other (effort feedback) that assumes an initial ability to predict the effects of the environment but not to regulate effort. I tested them by manipulating feedback on egg production, using an egg-substitution experiment in wild, free-ranging Lincoln's sparrows (Melospiza lincolnii). I discovered that females adjusted the size of their clutches' third laid eggs in response to the size of an experimentally substituted first laid egg, such that the size of the third laid egg increased with the size of the substitute. Results were largely consistent with the environmental feedback model, though small portions of the response surface were consistent with the effort feedback model or with neither. Regardless, such feedback-based regulation predicted by either model may help females maximize net benefits of egg production and may be a basis for mechanisms regulating a wide range of other behavioral performances, as well.


Isolation and analysis of restriction endonuclease digestive patterns of chromosomal DNA from Mycobacterium paratuberculosis and other Mycobacterium species.
A relatively rapid and efficient method for the extraction of chromosomal DNA from Mycobacterium paratuberculosis and other mycobacteria was developed. Approximately 25 to 50 micrograms of DNA could be extracted from 100 mg (wet weight) of cells, which was sufficient to perform several restriction endonuclease analyses from a single preparation. The DNA from five Mycobacterium species, including four strains of M. paratuberculosis and four strains of M. avium, was analyzed by this method. Digestion with the restriction endonucleases BstEII and PstI yielded the most definitive restriction patterns. For some strains, the restriction endonuclease analysis results were in agreement with the current identification of these organisms. The two strains of M. avium serotype 2 had identical fragment patterns. Similarly, the two strains of M. avium complex serotype 6 had identical fragment patterns. The three mycobactin-dependent M. paratuberculosis strains were very similar, whereas the mycobactin-independent M. paratuberculosis strain was more similar to the M. avium serotype 2 strains. Although many more cultures would need to be evaluated to determine correct groupings, the results of this study demonstrated the potential of restriction enzyme analysis for the differentiation of slowly growing mycobacteria.


Management of crush syndrome casualties after disasters.
After direct impact of the trauma, crush syndrome is the second most frequent cause of death after mass disasters. However, since crush syndrome is quite rare in daily practice, mistakes are frequent in the treatment of these cases. This paper summarizes the etiopathogenesis of traumatic rhabdomyolysis and of crush syndrome-based acute kidney injury. The clinical and laboratory features, prophylaxis, and treatment of crush cases are described as well. The importance of early and energetic fluid resuscitation is underlined for prophylaxis of acute kidney injury. Since there is chaos, and an overwhelming number of victims, logistic drawbacks create a specific problem in the treatment of crush victims after mass disasters. Potential solutions for logistic hurdles and disaster preparedness scenarios have also been provided in this review article.


Elevated expression of tumour necrosis factor-α-induced protein 8 (TNFAIP8)-like 2 mRNA in peripheral blood mononuclear cells is associated with disease progression of acute-on-chronic hepatitis B liver failure.
Aberrant immunity response contributes to the pathogenesis of acute-on-chronic hepatitis B liver failure. Tumour necrosis factor-α-induced protein-8 like-2 (TIPE2) is a recently identified molecular to maintain immune homoeostasis, but its role in acute-on-chronic hepatitis B liver failure (ACHBLF) is unknown. We detected TIPE2 mRNA levels in peripheral blood mononuclear cells (PBMCs) from 56 patients with ACHBLF, 60 chronic hepatitis B patients, 24 healthy controls and analysed its role in disease severity and prognosis. TIPE2 mRNA expression in patients with ACHBLF was higher than that of patients with chronic infection or healthy controls. In patients with ACHBLF, TIPE2 mRNA level was positively correlated with serum total bilirubin, international normalized ratio and model for end-stage liver disease scores. Furthermore, the level of TIPE2 mRNA was significantly higher in nonsurvivors than survivors in patients with ACHBLF. The mRNA level of TIPE2 gradually decreased week by week in survivors accompanied by recovery from patients with ACHBLF, while its expression sustained at high levels in nonsurvivors. TIPE2 mRNA level after lipopolysaccharide (LPS) stimulation ex vivo in patients with ACHBLF was higher compared with controls and patients with chronic infection. Meanwhile, cytokines ex vivo secreted were measured as a marker of immune activation. After LPS stimulation, interleukin (IL)-6 and tumour necrosis factor (TNF)-α mRNA expression were reduced in patients with ACHBLF, and a significantly negative correlation was found between TIPE2 and TNF-α mRNA levels. In conclusion, our results identified the potential role of TIPE2 in predicting disease progression and prognosis in patients with ACHBLF by negative regulating of cell-mediated immunity.


Ketogenic diets cause opposing changes in synaptic morphology in CA1 hippocampus and dentate gyrus of late-adult rats.
Ketogenic diets (KDs) have beneficial effects on several diseases, such as epilepsy, mitochondriopathies, cancer, and neurodegeneration. However, little is known about their effects on aging individuals. In the present study, late-adult (19-month-old) rats were fed for 8 weeks with two medium chain triglycerides (MCT)-KDs, and the following morphologic parameters reflecting synaptic plasticity were evaluated in stratum moleculare of hippocampal CA1 region (SM CA1) and outer molecular layer of hippocampal dentate gyrus (OML DG): average area (S), numeric density (Nv(s)), and surface density (Sv) of synapses, and average volume (V), numeric density (Nv(m)), and volume density (Vv) of synaptic mitochondria. In SM CA1, MCT-KDs induced the early appearance of the morphologic patterns typical of old animals (higher S and V, and lower Nv(s) and Nv(m)). On the contrary, in OML DG, Sv and Vv of MCT-KDs-fed rats were higher (as a result of higher Nv(s) and Nv(m)) versus controls; these modifications are known to improve synaptic function and metabolic supply. The opposite effects of MCT-KDs might reflect the different susceptibility to aging processes: OML DG is less vulnerable than SM CA1, and the reactivation of ketone bodies uptake and catabolism might occur more efficiently in this region, allowing the exploitation of their peculiar metabolic properties. Present findings provide the first evidence that MCT-KDs may cause opposite morphologic modifications, being potentially harmful for SM CA1 and potentially advantageous for OML DG. This implies risks but also promising potentialities for their therapeutic use during aging.


Epstein-Barr virus EB2 protein exports unspliced RNA via a Crm-1-independent pathway.
Human herpesviruses encode posttranscriptional activators that are believed to up-regulate viral replication by facilitating early and late gene expression. We have reported previously that the Epstein-Barr virus protein EB2 (also called M or SM) promotes nuclear export of RNAs that are poor substrates for spliceosome assembly, an effect that closely resembles the human immunodeficiency virus type 1 Rev-dependent nuclear export of unspliced viral RNA. Here we present experimental data showing that EB2 efficiently promotes the nuclear export of unspliced RNA expressed from a Rev reporter construct. Site-directed mutagenesis as well as domain swapping experiments indicate that a leucine-rich region found in the EB2 protein, which matches the consensus sequence for the leucine-rich nuclear export signal, is not a nuclear export signal per se. Accordingly, leptomycin B (LMB), a specific Crm-1 inhibitor, impairs Rev- but not EB2-dependent nuclear export of unspliced RNA. Moreover, EB2 nucleocytoplasmic shuttling visualized by a heterokaryon assay is, unlike Rev shuttling, not affected by LMB. We also show that overexpression of an N-terminal deletion mutant of Nup214/can, a major nucleoporin of the nuclear pore complex involved in several aspects of nuclear transport, blocks both Rev- and EB2-dependent nuclear export of RNA. These results strongly suggest that EB2 nuclear export of unspliced RNA is mediated by a Crm-1-independent pathway.


RCN1 deficiency inhibits oral squamous cell carcinoma progression and THP-1 macrophage M2 polarization.
Reticulocalbin 1 (RCN1), a calcium-binding protein located in the endoplasmic reticulum (ER) lumen, contains six conserved regions. Its main functions include maintaining intracellular homeostasis and regulating cell proliferation and apoptosis, and it plays an important role in the development of various tumours. However, the exact function of RCN1 in oral squamous cell carcinoma (OSCC) is not fully understood. Therefore, the aim of this study was to investigate the effects of RCN1 on the biological behaviour of OSCC and the regulation of tumour-associated macrophage (TAM) polarization. The expression of RCN1 in OSCC and normal oral mucosa was evaluated through bioinformatics analysis and immunohistochemical staining. The growth, migration, and invasion of OSCC cells were observed after knockdown of RCN1 using CCK-8 and Transwell assays. Apoptosis was detected by flow cytometry. The effect of tumour cell-derived RCN1 on the polarization of THP-1 macrophages was investigated by establishing a coculture model of THP-1 macrophages and OSCC cells. Additionally, changes in the expression levels of relevant proteins were detected using Western blotting. The upregulation of RCN1 in tumour tissues compared to normal oral mucosal tissues is associated with a poor prognosis and can be utilized as a prognostic indicator for OSCC. Knockdown of RCN1 inhibited the proliferation, migration, and invasion of OSCC cells. Additionally, knockdown of RCN1 in Cal-27 and SCC-25 cells resulted in inhibition of the M2 polarization of THP-1 macrophages. RCN1 knockdown inhibits OSCC progression and M2 macrophage polarization. Targeting RCN1 may be a promising approach for OSCC treatment.


C4b-binding protein and a 60,000-Dalton plasma protein share antigenic determinants with membrane cofactor protein of complement.
Membrane cofactor protein (MCP) of the C system is a widely distributed regulatory molecule with C3b/C4b binding and factor I-dependent cofactor activity. A rabbit polyclonal antibody was raised against purified human MCP, and it was found to also immunoprecipitate C4b-binding protein (C4bp). Other related complement regulatory proteins, factor H, C3b/C4b receptor, and decay-accelerating factor, were not recognized by this polyclonal antibody to MCP. The cross-reactive epitope was sensitive to reduction with 2-ME and about 3% of the anti-MCP antibody reacted with C4bp. The amino-terminal 48,000-Da, chymotryptic fragment of C4bp was recognized by the antibody to MCP. This fragment of C4bp contains a seven-amino acid peptide that is identical, in its sequence and its location in the third short consensus repeat, to one found in MCP. Two polyclonal antibodies to C4bp, one raised to native and the other to reduced C4bp, did not cross-react with MCP. In addition to this one-way cross-reaction with C4bp, a protein with a m.w. of approximately 60,000 (p60) was found in two of three C4bp preparations that also cross-reacted with antiserum to MCP. p60 was present in trace quantities in the C4bp preparation and was successfully isolated from plasma by C3b affinity chromatography. Its Mr was distinct from that of MCP and other known C3b/C4b binding proteins. Furthermore, p60 was isolated by two different procedures and such material possessed no detectable cofactor activity. Based on these results, p60 is a plasma C3b-binding protein that shares epitopes with C4bp and MCP, and is probably not a soluble form of MCP.


Respite care models and practices for persons with intellectual disability: A scoping review.
Families are the primary caregivers for persons with intellectual disability (ID), offering informal support to ensure community living. Ensuring families are adequately supported is key to reduce the financial, physical, mental and social toll which long-standing inadequately supported care giving may evoke. Respite care is such a support service offered to caregivers and care-recipients with ID. Part of a larger study aimed at developing a respite care service framework for persons with ID for South Africa, the review aimed to elucidate what principles and practices inform current respite care services for this population globally. The Joanna Briggs Institute (JBI) scoping review framework guided the review. Databases were searched using key and surrogate terms for relevant literature published from 2006 to 2021. Thirty-one sources met the inclusion criteria from 417 screened sources of evidence. These were published between 2006 and 2020, and included grey and peer-reviewed articles, the latter mostly mixed design. Information on respite care service characteristics, principles, practices, guidelines, evaluations and impacts were found for high- but not low-and-middle-income countries (LMICs). There is an existing knowledge base that can be drawn on to inform the development of quality respite care. The lack of published information on respite care in LMICs necessitates further research to ensure contextually appropriate respite care developments in these settings. This study contributes to the knowledge base on respite care for persons with ID and points out the research gap in LMICs.


The Conserved Colletotrichum spp. Effector Candidate CEC3 Induces Nuclear Expansion and Cell Death in Plants.
Plant pathogens secrete proteins, known as effectors, that promote infection by manipulating host cells. Members of the phytopathogenic fungal genus Colletotrichum collectively have a broad host range and generally adopt a hemibiotrophic lifestyle that includes an initial biotrophic phase and a later necrotrophic phase. We hypothesized that Colletotrichum fungi use a set of conserved effectors during infection to support the two phases of their hemibiotrophic lifestyle. This study aimed to examine this hypothesis by identifying and characterizing conserved effectors among Colletotrichum fungi. Comparative genomic analyses using genomes of ascomycete fungi with different lifestyles identified seven effector candidates that are conserved across the genus Colletotrichum. Transient expression assays showed that one of these putative conserved effectors, CEC3, induces nuclear expansion and cell death in Nicotiana benthamiana, suggesting that CEC3 is involved in promoting host cell death during infection. Nuclear expansion and cell death induction were commonly observed in CEC3 homologs from four different Colletotrichum species that vary in host specificity. Thus, CEC3 proteins could represent a novel class of core effectors with functional conservation in the genus Colletotrichum.


Towards Semantic Smart Cities: A Study on the Conceptualization and Implementation of Semantic Context Inference Systems.
Smart cities provide integrated management and operation of urban data emerging within a city, supplying the infrastructure for smart city services and resolving various urban challenges. Nevertheless, cities continue to grapple with substantial issues, such as contagious diseases and terrorism, that pose severe financial and human risks. These problems sporadically arise in various locales, and current smart city frameworks lack the capability to autonomously identify and address these issues. The challenge intensifies especially when trying to recognize and respond to unprecedented problems. The primary objective of this research is to predict potential urban issues and support their resolution proactively. To achieve this, our system makes use of semantic reasoning to understand the ongoing situations within the city. In this process, the 5W1H principles serve as inference rules, guiding the extraction and consolidation of context. Firstly, utilizing domain-specific annotation templates, we craft a semantic graph by amalgamating information from various sources available in the city, such as municipal public data and IoT platforms. Subsequently, the system autonomously infers and accumulates contexts of situations occurring in the city using 5W1H-based reasoning. As a result, the accumulated contexts allow for inferring potential urban problems by identifying repeated disruptions in city services at specific times or locations and establishing connections among them. The main contribution of this paper lies in proposing a comprehensive conceptual model for the suggested system and presenting actual implementation cases and applicable use cases. These contributions facilitate awareness among city administrators and citizens within a smart city regarding potential problem-prone areas or times, thereby aiding in the preemptive identification and mitigation of urban challenges.


Importance of frailty in patients with cardiovascular disease.
Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality. With the ageing population, the prognostic determinants among others include frailty, health status, disability, and cognition. These constructs are seldom measured and factored into clinical decision-making or evaluation of the prognosis of these at-risk older adults, especially as it relates to high-risk interventions. Addressing this need effectively requires increased awareness and their recognition by the treating cardiologists, their incorporation into risk prediction models when treating an elderly patient with underlying complex CVD, and timely referral for comprehensive geriatric management. Simple measures such as gait speed, the Fried score, or the Rockwood Clinical Frailty Scale can be used to assess frailty as part of routine care of elderly patients with CVD. This review examines the prevalence and outcomes associated with frailty with special emphasis in patients with CVD.


[Hand reconstruction and prosthesis].
An experience of the work has shown that of 36 patients with severe defects of the hand after amputations who had been completely informed and free to decide, plastic operations were made on the majority (25) of the patients, microsurgical transplantations of toes (15) included. However 11 patients were satisfied with the prostheses alone. A complex method of rehabilitation was worked out including surgical plasty of one of the two clutch branches and the prosthezing of the other (11 patients).


Pits and CtBP Control Tissue Growth in Drosophila melanogaster with the Hippo Pathway Transcription Repressor Tgi.
The Hippo pathway is an evolutionarily conserved signaling network that regulates organ size, cell fate, and tumorigenesis. In the context of organ size control, the pathway incorporates a large variety of cellular cues, such as cell polarity and adhesion, into an integrated transcriptional response. The central Hippo signaling effector is the transcriptional coactivator Yorkie, which controls gene expression in partnership with different transcription factors, most notably Scalloped. When it is not activated by Yorkie, Scalloped can act as a repressor of transcription, at least in part due to its interaction with the corepressor protein Tgi. The mechanism by which Tgi represses transcription is incompletely understood, and therefore we sought to identify proteins that potentially operate together with Tgi. Using an affinity purification and mass-spectrometry approach we identified Pits and CtBP as Tgi-interacting proteins, both of which have been linked to transcriptional repression. Both Pits and CtBP were required for Tgi to suppress the growth of the Drosophila melanogaster eye and CtBP loss suppressed the undergrowth of yorkie mutant eye tissue. Furthermore, as reported previously for Tgi, overexpression of Pits repressed transcription of Hippo pathway target genes. These findings suggest that Tgi might operate together with Pits and CtBP to repress transcription of genes that normally promote tissue growth. The human orthologs of Tgi, CtBP, and Pits (VGLL4, CTBP2, and IRF2BP2) have previously been shown to physically and functionally interact to control transcription, implying that the mechanism by which these proteins control transcriptional repression is conserved throughout evolution.


Viruses in the treatment of brain tumors.
The grave outlook for malignant glioma patients in spite of improvements to current modalities has ushered in new approaches to therapy. Viruses have emerged on the scene and gained attention for their ability to play essentially two roles: first, as vectors for therapeutic gene delivery and second, as engineered infectious agents capable of selectively lysing tumor cells. To date, clinical brain tumor trials using viruses for gene delivery have employed retroviral or adenoviral vectors to introduce ganciclovir susceptibility to tumors in the form of the HSV1-TK gene. Clinical oncolytic studies, on the other hand, have evaluated a conditionally replicating HSV as an antineoplastic agent. Despite some promise afforded by these trials, further studies are warranted; the investigation of additional viruses to play these roles is inevitable and is now precedented.


Sonographic assessment of tumor response: from in vivo models to clinical applications.
The advent of antiangiogenic drugs in cancer therapy necessitates an imaging modality that can longitudinally assess posttreatment changes in tumor vasculature. In this regard, microbubble contrast-enhanced ultrasonography (CEUS) offers several advantages over conventional imaging modalities. The small size of microbubbles (approximately 2-3 mum) permits their retention in the intravascular compartment and travel through the tortuous tumor vasculature. Mathematical models applied to signal intensity versus time depicting the kinetics of microbubble flow through the tumor are used to characterize tumor vascular density, blood flow velocity, and perfusion. In vivo studies using CEUS have demonstrated its comparability to dynamic contrast-enhanced magnetic resonance imaging and fluorodeoxyglucose positron emission tomography in distinguishing between diseased or malignant tissue and normal tissue. Moreover, CEUS has great potential for other novel clinical applications such as improved cancer diagnosis, enhanced medication delivery, and early antiangiogenic cancer treatment response evaluation. This review discusses the principles and potential clinical applications of CEUS in determining tumor response and its promising role in enhancing medication delivery in certain tumors.


Differential oxidative damage and expression of stress defence regulons in culturable and non-culturable Escherichia coli cells.
Potentially pathogenic bacteria, such as Escherichia coli and Vibrio cholerae, become non-culturable during stasis. The analysis of such cells has been hampered by difficulties in studying bacterial population heterogeneity. Using in situ detection of protein oxidation in single E. coli cells, and using a density-gradient centrifugation technique to separate culturable and non-culturable cells, we show that the proteins in non-culturable cells show increased and irreversible oxidative damage, which affects various bacterial compartments and proteins. The levels of expression of specific stress regulons are higher in non-culturable cells, confirming increased defects relating to oxidative damage and the occurrence of aberrant, such as by amino-acid misincorporation, proteins. Our data suggest that non-culturable cells are produced due to stochastic deterioration, rather than an adaptive programme, and pinpoint oxidation management as the 'Achilles heel' of these cells.


Temporal changes of diffusion patterns in mild traumatic brain injury via group-based semi-blind source separation.
Despite the emerging applications of diffusion tensor imaging (DTI) to mild traumatic brain injury (mTBI), very few investigations have been reported related to temporal changes in quantitative diffusion patterns, which may help to assess recovery from head injury and the long term impact associated with cognitive and behavioral impairments caused by mTBI. Most existing methods are focused on detection of mTBI affected regions rather than quantification of temporal changes following head injury. Furthermore, most methods rely on large data samples as required for statistical analysis and, thus, are less suitable for individual case studies. In this paper, we introduce an approach based on spatial group independent component analysis (GICA), in which the diffusion scalar maps from an individual mTBI subject and the average of a group of controls are arranged according to their data collection time points. In addition, we propose a constrained GICA (CGICA) model by introducing the prior information into the GICA decomposition process, thus taking available knowledge of mTBI into account. The proposed method is evaluated based on DTI data collected from American football players including eight controls and three mTBI subjects (at three time points post injury). The results show that common spatial patterns within the diffusion maps were extracted as spatially independent components (ICs) by GICA. The temporal change of diffusion patterns during recovery is revealed by the time course of the selected IC. The results also demonstrate that the temporal change can be further influenced by incorporating the prior knowledge of mTBI (if available) based on the proposed CGICA model. Although a small sample of mTBI subjects is studied, as a proof of concept, the preliminary results provide promising insight for applications of DTI to study recovery from mTBI and may have potential for individual case studies in practice.


Transcriptomic and anatomic parcellation of 5-HT3AR expressing cortical interneuron subtypes revealed by single-cell RNA sequencing.
Cortical GABAergic interneurons constitute a highly diverse population of inhibitory neurons that are key regulators of cortical microcircuit function. An important and heterogeneous group of cortical interneurons specifically expresses the serotonin receptor 3A (5-HT3AR) but how this diversity emerges during development is poorly understood. Here we use single-cell transcriptomics to identify gene expression patterns operating in Htr3a-GFP+ interneurons during early steps of cortical circuit assembly. We identify three main molecular types of Htr3a-GFP+ interneurons, each displaying distinct developmental dynamics of gene expression. The transcription factor Meis2 is specifically enriched in a type of Htr3a-GFP+ interneurons largely confined to the cortical white matter. These MEIS2-expressing interneurons appear to originate from a restricted region located at the embryonic pallial-subpallial boundary. Overall, this study identifies MEIS2 as a subclass-specific marker for 5-HT3AR-containing interstitial interneurons and demonstrates that the transcriptional and anatomical parcellation of cortical interneurons is developmentally coupled.


Concept abstractness and the representation of noun-noun combinations.
Research on noun-noun combinations has been largely focusing on concrete concepts. Three experiments examined the role of concept abstractness in the representation of noun-noun combinations. In Experiment 1, participants provided written interpretations for phrases constituted by nouns of varying degrees of abstractness. Interpretive focus (the modifier, the head noun, or both) for each noun-noun phrase was evaluated. In Experiment 2, a different group of participants directly indicated which noun, the modifier or the head noun, was the focus of the meaning of each noun-noun phrase. Finally, participants in Experiment 3 assessed similarity of noun-noun phrases with overlapping modifiers. If abstractness of constituent nouns affects information distribution between modifier and head noun, it would accordingly affect similarity ratings for noun-noun phrases with overlapping modifiers. Results showed that the pattern of information distribution within a noun-noun phrase differed between phrases with abstract head nouns and phrases with concrete head nouns. Specifically, the center of representation was more on the head noun side for phrases with concrete head nouns, whereas the center seemed to shift to the direction of the modifier for phrases with abstract head nouns. Some issues related to effects of concept abstractness on noun-noun combinations are discussed.


Influence of lignans depletion on murine mammary gland morphology.
Different studies have focused on the effects of phytoestrogens-supplemented diets on mammary gland morphogenesis and breast cancer risk; however, particular dieting behaviors and food choices may result in a reduction of the natural source of phytoestrogens. The evaluation of a reduced phytoestrogens intake effect by depletion without modifying other dietary ingredients is hard. Since lignans, the largest contributors to phytoestrogens intake in Western diets, are metabolized into bioactive compounds by gut bacteria, long-term antibiotic treatments, inducing intestinal microflora disruption, may reduce enterolactone availability. To elucidate the effect of phytoestrogens lack on mammary tissue morphogenesis, female FVB mice were treated with gentamicin or metronidazole/ciprofloxacin from the age of 6 to 7 wk. After 21 wk, enterolactone urine levels were 120.07 +/- 20.5 ng/ml in untreated mice, 30.4 +/- 24.46 ng/ml in metronidazole/ciprofloxacin-treated mice, and 3.29 +/- 4.38 ng/ml in gentamicin-treated mice. Histological analysis revealed no significant alterations of mammary morphology in metronidazole/ciprofloxacin-treated mice, whereas gentamicin-treated mice showed increase of ducts number and duct-tree branching vs. controls. These findings indicate that normal mammary tissue size and shape are maintained even in the presence of low levels of lignans and suggest that only a complete depletion of these compounds induced significant alterations of mammary gland structure.


Genome skimming reveals the origin of the Jerusalem Artichoke tuber crop species: neither from Jerusalem nor an artichoke.
The perennial sunflower Helianthus tuberosus, known as Jerusalem Artichoke or Sunchoke, was cultivated in eastern North America before European contact. As such, it represents one of the few taxa that can support an independent origin of domestication in this region. Its tubers were adopted as a source of food and forage when the species was transferred to the Old World in the early 1600s, and are still used today. Despite the cultural and economic importance of this tuber crop species, its origin is debated. Competing hypotheses implicate the occurrence of polyploidization with or without hybridization, and list the annual sunflower H. annuus and five distantly related perennial sunflower species as potential parents. Here, we test these scenarios by skimming the genomes of diverse populations of Jerusalem Artichoke and its putative progenitors. We identify relationships among Helianthus taxa using complete plastomes (151 551 bp), partial mitochondrial genomes (196 853 bp) and 35S (8196 bp) and 5S (514 bp) ribosomal DNA. Our results refute the possibility that Jerusalem Artichoke is of H. annuus ancestry. We provide the first genetic evidence that this species originated recursively from perennial sunflowers of central-eastern North America via hybridization between tetraploid Hairy Sunflower and diploid Sawtooth Sunflower.


Translating quantitative theories of behavior into improved clinical treatments for problem behavior.
The most important advancement in the treatment of destructive behavior has been the development of the functional analysis, which is used to prescribe effective treatments like functional communication training. Although this approach can be highly effective, extinction bursts and forms of treatment relapse commonly occur when function-based treatments are implemented by caregivers in natural community settings. In recent years, researchers have increasingly applied quantitative theories of behavior like behavioral momentum theory (BMT) and the temporally weighted matching law (TWML) to understand, prevent, or mitigate extinction bursts and treatment relapse. In this paper, we describe BMT and TWML and selectively review the basic, translational, and applied research supporting and opposing each theory. Then, we describe how function-based treatments may be refined based on these theories to improve the effectiveness, generality, and durability of function-based treatments for individuals with autism spectrum and related disorders who display problem behavior.


Creating an outcomes framework.
Four constructs used to build a framework for outcomes management for a large midwestern tertiary hospital are described in this article. A system framework outlining a model of clinical integration and population management based in Steven Shortell's work is discussed. This framework includes key definitions of high-risk patients, target groups, populations and community. Roles for each level of population management and how they were implemented in the health care system are described. A point of service framework centered on seven dimensions of care is the next construct applied on each nursing unit. The third construct outlines the framework for role development. Three roles for nursing were created to implement strategies for target groups that are strategic disease categories; two of those roles are described in depth. The philosophy of nursing practice is centered on caring and existential advocacy. The final construct is the modification of the Dartmouth model as a common framework for outcomes. System applications of the scorecard and lessons learned in the 2-year process of implementation are shared


Toxicity of aflatoxin B1 to penaeid shrimp.
Single intramuscular injections of aflatoxin B1 into the tail muscle of Penaeus stylirostris produced 24- and 96-h median lethal doses of 100.5 (78.3 to 129.0) and 49.5 (29.8 to 82.3) mg/kg, respectively. A toxicity curve showed no threshold at the levels tested. The mortality response in a feeding study with P. vannamei was not dose dependent, but tissue and organ damage were similar to that seen in injected animals.


The tissue-engineered vascular graft using bone marrow without culture.
To overcome the shortcomings of current vascular grafts, tissue-engineering methods have been applied to cardiovascular regions. We previously reported the creation of a tissue-engineered vascular graft by using vascular mixed cells. However, the cost and manpower for harvesting and culturing the cells was too burdensome. To overcome these drawbacks, we have developed a new method for creating a tissue-engineered vascular graft by using bone marrow cells, which can be obtained easily and used immediately, without cell culture. Biodegradable polymers seeded with different types of cells (group V, cultured venous cells; group B, bone marrow cells without culture; and group C, non-cell-seeded graft [as control]) were implanted into the inferior venae cavae of dogs. The grafts were explanted at 4 weeks and assessed histologically and biochemically. In the histologic examination, a regular layer of Masson-staining collagen fiber and a layer of factor VII-stained endothelial and ant-alpha-smooth muscle cell antigen-immunoreactive cells stained in groups V and B like native vascular tissue, whereas no such stained regular lining was detected in group C. A 4-hydroxyproline assay in group C showed significantly lower levels than in groups V and B or native tissue ( P < .05). The DNA content of the tissue-engineered vascular graft tended to be higher in group C than in groups V and B or in native tissue. In the creation of tissue-engineered vascular grafts, the method of using bone marrow cells seems to be useful and superior to that of using vascular cells because bone marrow cells can be used directly, without culture.


Prevalence of the Bifid Mandibular Condyle and Its Relationship with Pathologies of the Temporomandibular Joint: A Systematic Review and Meta-Analysis.
The aim of this study was to describe the prevalence of anatomical variants in the bifid mandibular condyle (BMC) and report its association with temporomandibular joint (TMJ) pathology. We searched the Medline, Scopus, Web of Science, Google Scholar, CINAHL, and LILACS databases from their inception up to September 2023. Two authors independently performed the search, study selection, and data extraction, and they also assessed the methodological quality with an assurance tool for anatomical studies (AQUA). Finally, the pooled prevalence was estimated using a random effects model. A total of 50 studies met the eligibility criteria. Twenty studies, with a total of 88,625 subjects, were included in the meta-analysis. The overall prevalence of the bifid mandibular condyle (BMC) variant was 1% (95% CI = 1% to 2%). The correlation between the BMC and TMJ pathologies has a relatively low prevalence in studies that present a considerable number of subjects. From a clinical point of view, a direct association cannot be made between the presence of the BMC and TMJ pathologies or symptoms.


The Ndr/LATS Kinase Cbk1 Regulates a Specific Subset of Ace2 Functions and Suppresses the Hypha-to-Yeast Transition in Candida albicans.
The regulation of Ace2 and morphogenesis (RAM) pathway is an important regulatory network in the human fungal pathogen Candida albicans The RAM pathway's two most well-studied components, the NDR/Lats kinase Cbk1 and its putative substrate, the transcription factor Ace2, have a wide range of phenotypes and functions. It is not clear, however, which of these functions are specifically due to the phosphorylation of Ace2 by Cbk1. To address this question, we first compared the transcriptional profiles of CBK1 and ACE2 deletion mutants. This analysis indicates that, of the large number of genes whose expression is affected by deletion of CBK1 and ACE2, only 5.5% of those genes are concordantly regulated. Our data also suggest that Ace2 directly or indirectly represses a large set of genes during hyphal morphogenesis. Second, we generated strains containing ACE2 alleles with alanine mutations at the Cbk1 phosphorylation sites. Phenotypic and transcriptional analysis of these ace2 mutants indicates that, as in Saccharomyces cerevisiae, Cbk1 regulation is important for daughter cell localization of Ace2 and cell separation during yeast-phase growth. In contrast, Cbk1 phosphorylation of Ace2 plays a minor role in C. albicans yeast-to-hypha transition. We have, however, discovered a new function for the Cbk1-Ace2 axis. Specifically, Cbk1 phosphorylation of Ace2 prevents the hypha-to-yeast transition. To our knowledge, this is one of the first regulators of the C. albicans hypha-to-yeast transition to be described. Finally, we present an integrated model for the role of Cbk1 in the regulation of hyphal morphogenesis in C. albicansIMPORTANCE The regulation of Ace2 and morphogenesis (RAM) pathway is a key regulatory network that plays a role in many aspects of C. albicans pathobiology. In addition to characterizing the transcriptional effects of this pathway, we discovered that Cbk1 and Ace2, a key RAM pathway regulator-effector pair, mediate a specific set of the overall functions of the RAM pathway. We have also discovered a new function for the Cbk1-Ace2 axis: suppression of the hypha-to-yeast transition. Very few regulators of this transition have been described, and our data indicate that maintenance of hyphal morphogenesis requires suppression of yeast phase growth by Cbk1-regulated Ace2.


A new duck genome reveals conserved and convergently evolved chromosome architectures of birds and mammals.
Ducks have a typical avian karyotype that consists of macro- and microchromosomes, but a pair of much less differentiated ZW sex chromosomes compared to chickens. To elucidate the evolution of chromosome architectures between ducks and chickens, and between birds and mammals, we produced a nearly complete chromosomal assembly of a female Pekin duck by combining long-read sequencing and multiplatform scaffolding techniques. A major improvement of genome assembly and annotation quality resulted from the successful resolution of lineage-specific propagated repeats that fragmented the previous Illumina-based assembly. We found that the duck topologically associated domains (TAD) are demarcated by putative binding sites of the insulator protein CTCF, housekeeping genes, or transitions of active/inactive chromatin compartments, indicating conserved mechanisms of spatial chromosome folding with mammals. There are extensive overlaps of TAD boundaries between duck and chicken, and also between the TAD boundaries and chromosome inversion breakpoints. This suggests strong natural selection pressure on maintaining regulatory domain integrity, or vulnerability of TAD boundaries to DNA double-strand breaks. The duck W chromosome retains 2.5-fold more genes relative to chicken. Similar to the independently evolved human Y chromosome, the duck W evolved massive dispersed palindromic structures, and a pattern of sequence divergence with the Z chromosome that reflects stepwise suppression of homologous recombination. Our results provide novel insights into the conserved and convergently evolved chromosome features of birds and mammals, and also importantly add to the genomic resources for poultry studies.


Inhibitory effects of docosyl p-coumarate on DNA topoisomerase activity and human cancer cell growth.
We previously found six compounds of alkyl p-coumarates from a composite plant Artemisia annua L., and chemically synthesized these compounds (cis-isomer of C20, C22 and C24, and trans-isomer of C20, C22 and C24 of p-coumarates are compounds 1-6, respectively). This report describes the inhibitory activities of these alkyl p-coumarates against DNA polymerase (pol), DNA topoisomerase (topo), and human cancer cell growth. Among the compounds tested, compounds 1 and 4 weakly inhibited repair-related pol beta activity, but no compound influenced the activity of replicative pol alpha. Compounds 4-6 and compounds 2 and 5 were potent inhibitors of human topos I and II, respectively. Compounds 2, 4, 5 and 6 also suppressed the growth of human colon carcinoma cell line, HCT116, with or without p53, suggesting that cell growth inhibition had the same tendency as the inhibition of topos rather than pols. Compound 5 (docosyl p-coumarate), which was the strongest inhibitor of topo II and cancer cell growth in the compounds tested, halted HCT116 p53(+/+) cells in G2/M phases, and induced apoptosis, although this compound did not affect the cell cycle of HCT116 p53(-/-) cells. These results suggest that the effect of p53-dependent cell cycle arrest may be effective for topo inhibition by com-pound 5. From these findings, the action mode of alkyl p-coumarates as an anti-cancer agent is discussed.


Effect of bisphenol A on the neurological system: a review update.
Bisphenol A (BPA) is an endocrine-disrupting chemical (EDC) and one of the most produced synthetic compounds worldwide. BPA can be found in epoxy resins and polycarbonate plastics, which are frequently used in food storage and baby bottles. However, BPA can bind mainly to estrogen receptors, interfering with various neurologic functions, its use is a topic of significant concern. Nonetheless, the neurotoxicity of BPA has not been fully understood despite numerous investigations on its disruptive effects. Therefore, this review aims to highlight the most recent studies on the implications of BPA on the neurologic system. Our findings suggest that BPA exposure impairs various structural and molecular brain changes, promoting oxidative stress, changing expression levels of several crucial genes and proteins, destructive effects on neurotransmitters, excitotoxicity and neuroinflammation, damaged blood-brain barrier function, neuronal damage, apoptosis effects, disruption of intracellular Ca2+ homeostasis, increase in reactive oxygen species, promoted apoptosis and intracellular lactate dehydrogenase release, a decrease of axon length, microglial DNA damage, astrogliosis, and significantly reduced myelination. Moreover, BPA exposure increases the risk of developing neurologic diseases, including neurovascular (e.g. stroke) and neurodegenerative (e.g. Alzheimer's and Parkinson's) diseases. Furthermore, epidemiological studies showed that the adverse effects of BPA on neurodevelopment in children contributed to the emergence of serious neurological diseases like attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), depression, emotional problems, anxiety, and cognitive disorders. In summary, BPA exposure compromises human health, promoting the development and progression of neurologic disorders. More research is required to fully understand how BPA-induced neurotoxicity affects human health.


'Oh Rose, thou art sick!' Anti-individuation forces in the film American Beauty.
The film American Beauty is used as a vehicle to explore difficulties in the individuation process, to look at a particular aspect of couple relationships in which mourning is avoided, and to make a general comment about the relationship between film and psychological experience. The thesis of the paper is that the individuation process is both an intra-psychic experience and an inter-psychic one which relies on relationships with external figures to enable development. The adult couple relationship is taken as one of the key areas of emotional life for the individuation process and as an area that can best show up false starts, successes, or even retreats in psychological development. Using the poetry of William Blake and the work of Michael Fordham, I show a process of anti-individuation going on in the relationship between the characters of Lester and Carolyn Burnham in the film.


CANet: Context Aware Network for Brain Glioma Segmentation.
Automated segmentation of brain glioma plays an active role in diagnosis decision, progression monitoring and surgery planning. Based on deep neural networks, previous studies have shown promising technologies for brain glioma segmentation. However, these approaches lack powerful strategies to incorporate contextual information of tumor cells and their surrounding, which has been proven as a fundamental cue to deal with local ambiguity. In this work, we propose a novel approach named Context-Aware Network (CANet) for brain glioma segmentation. CANet captures high dimensional and discriminative features with contexts from both the convolutional space and feature interaction graphs. We further propose context guided attentive conditional random fields which can selectively aggregate features. We evaluate our method using publicly accessible brain glioma segmentation datasets BRATS2017, BRATS2018 and BRATS2019. The experimental results show that the proposed algorithm has better or competitive performance against several State-of-The-Art approaches under different segmentation metrics on the training and validation sets.


Measuring coronary calcium on CT images adjusted for attenuation differences.
To quantify scanner and participant variability in attenuation values for computed tomographic (CT) images assessed for coronary calcium and define a method for standardizing attenuation values and calibrating calcium measurements. Institutional review board approval and participant informed consent were obtained at all study sites. An image attenuation adjustment method involving the use of available calibration phantom data to define standard attenuation values was developed. The method was applied to images from two population-based multicenter studies: the Coronary Artery Risk Development in Young Adults study (3041 participants) and the Multi-Ethnic Study of Atherosclerosis (6814 participants). To quantify the variability in attenuation, analysis of variance techniques were used to compare the CT numbers of standardized torso phantom regions across study sites, and multivariate linear regression models of participant-specific calibration phantom attenuation values that included participant age, race, sex, body mass index (BMI), smoking status, and site as covariates were developed. To assess the effect of the calibration method on calcium measurements, Pearson correlation coefficients between unadjusted and attenuation-adjusted calcium measurements were computed. Multivariate models were used to examine the effect of sex, race, BMI, smoking status, unadjusted score, and site on Agatston score adjustments. Mean attenuation values (CT numbers) of a standard calibration phantom scanned beneath participants varied significantly according to scanner and participant BMI (P < .001 for both). Values were lowest for Siemens multi-detector row CT scanners (110.0 HU), followed by GE-Imatron electron-beam (116.0 HU) and GE LightSpeed multi-detector row scanners (121.5 HU). Values were also lower for morbidly obese (BMI, > or =40.0 kg/m(2)) participants (108.9 HU), followed by obese (BMI, 30.0-39.9 kg/m(2)) (114.8 HU), overweight (BMI, 25.0-29.9 kg/m(2)) (118.5 HU), and normal-weight or underweight (BMI, <25.0 kg/m(2)) (120.1 HU) participants. Agatston score calibration adjustments ranged from -650 to 1071 (mean, -8 +/- 50 [standard deviation]) and increased with Agatston score (P < .001). The direction and magnitude of adjustment varied significantly according to scanner and BMI (P < .001 for both) and were consistent with phantom attenuation results in that calibration resulted in score decreases for images with higher phantom attenuation values. Image attenuation values vary by scanner and participant body size, producing calcium score differences that are not due to true calcium burden disparities. Use of calibration phantoms to adjust attenuation values and calibrate calcium measurements in research studies and clinical practice may improve the comparability of such measurements between persons scanned with different scanners and within persons over time.


Outcomes are Worse in US Patients Undergoing Surgery on Weekends Compared With Weekdays.
Increasing surgical access to previously underserved populations in the United States may require a major expansion of the use of operating rooms on weekends to take advantage of unused capacity. Although the so-called weekend effect for surgery has been described in other countries, it is unknown whether US patients undergoing moderate-to-high risk surgery on weekends are more likely to experience worse outcomes than patients undergoing surgery on weekdays. The aim of this study was to determine whether patients undergoing surgery on weekends are more likely to die or experience a major complication compared with patients undergoing surgery on a weekday. Using all-payer data, we conducted a retrospective cohort study of 305,853 patients undergoing isolated coronary artery bypass graft surgery, colorectal surgery, open repair of abdominal aortic aneurysm, endovascular repair of abdominal aortic aneurysm, and lower extremity revascularization. We compared in-hospital mortality and major complications for weekday versus weekend surgery using multivariable logistic regression analysis. After controlling for patient risk and surgery type, weekend elective surgery [adjusted odds ratio (AOR)=3.18; 95% confidence interval (CI), 2.26-4.49; P<0.001] and weekend urgent surgery (AOR=2.11; 95% CI, 1.68-2.66; P<0.001) were associated with a higher risk of death compared with weekday surgery. Weekend elective (AOR=1.58; 95% CI, 1.29-1.93; P<0.001) and weekend urgent surgery (AOR=1.61; 95% CI, 1.42-1.82; P<0.001) were also associated with a higher risk of major complications compared with weekday surgery. Patients undergoing nonemergent major cardiac and noncardiac surgery on the weekends have a clinically significantly increased risk of death and major complications compared with patients undergoing surgery on weekdays. These findings should prompt decision makers to seek to better understand factors, such physician and nurse staffing, which may contribute to the weekend effect.


Changes in protein kinase C during vitellogenesis in the crayfish Cherax quadricarinatus--possible activation by methyl farnesoate.
During ovarian maturation in the crayfish Cherax quadricarinatus, changes in ovarian protein kinase C (PKC) isoenzymes take place in parallel to yolk accumulation (as shown by immunoblot analysis). Significant changes were recorded in the amounts of specific isoenzymes and in their distribution between the cytosol and the membranes. Ovarian maturation was accompanied by the appearance of high- and low-molecular-weight immunoreactive PKC isoenzyme species. Among the isoenzymes tested, PKC alpha was the most clearly activated during ovarian maturation, as shown by significant translocation from the cytosol to the particulate fraction and the appearance of high-molecular-weight species. Moreover, a similar picture was obtained in the ovaries of intersex individuals upon induction of secondary vitellogenesis by androgenic gland ablation. Immunohistological staining showed PKC alpha to be localized mainly in the cytosol of premature oocytes, whereas in later maturation stages, it was concentrated around the nucleus in a vesicular structure and in the oocyte membrane. In secondary vitellogenic stages, PKC was localized in the plasma membrane and apparently in follicular cells. In addition, its activity was demonstrated by in vitro phosphorylation assays of a crayfish ovarian homogenate. Activation of total PKC phosphorylation of histone, an external substrate, was induced by phosphatidylserine plus 12-O-tetradecanoylphorbol-13-acetate (TPA) or methyl farnesoate. Both TPA and methyl farnesoate stimulated activation of PKC alpha in organ culture, causing its translocation from the cytosol to the membranes and inducing autophosphorylation of threonine residues. The changes in PKC isoenzymes during ovarian maturation in the crayfish suggest their involvement in this process as well as a possible regulatory role for methyl farnesoate through a direct effect on some PKC isoenzymes.


COVID-19 in Pediatric Cancer Patients and Hematopoietic Stem Cell Transplant Recipients in a Tertiary Care Hospital in Argentina.
The outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in cancer pediatric patients was initially uncertain. The objective of this study was to describe the characteristics and outcome of cancer patients and hematopoietic stem cell transplant recipients from 0 to 19 years with detectable SARS-CoV-2 from April 23, 2020, to April 30, 2022, treated in a tertiary-level hospital in Argentina. A total of 348 cases were registered in 339 patients. The median age was 89.5 (3 to 224) months. The sex was predominantly male: 193 (55.5%). The most common malignant disease was leukemia (42.8%). One hundred four cases (29.9%) had comorbidities. Of the 346 cases with an available blood count, 17.6% had a lymphocyte count <300/mm 3 . Fever was the most common symptom. In most cases (93.1%) presented asymptomatic or mild disease. Twenty-one cases (6%) presented severe or critical status. Eleven of 24 admissions to the intensive care unit were due to COVID-19 (coronavirus disease 2019). Eight patients (2.3%) died. Two deaths were attributable to SARS-CoV-2 (0.6%). Being older, having fever, lymphopenia at diagnosis, and having received hematopoietic stem cell transplant were associated with a more severe disease. Around 90% of the children continued their cancer treatment without any change.


Mouse metallothionein-1 and metallothionein-2 are not biologically interchangeable in an animal model of multiple sclerosis, EAE.
Mouse metallothionein-1 and 2 (MT1 and MT2) are often considered physiologically equivalent, because they are normally regulated coordinately by a wide range of stimuli, and it is assumed that in vivo they will be normally fully loaded with zinc(ii) (Zn7-MT1/2), although other metal ions, such as copper(i), may be eventually found as well. However, mouse MT2, in contrast to MT1, exhibits a preference for Zn(ii) coordination in comparison to that for Cu(i), which might underlie putatively different biological functions for these two mammalian isoforms. We have characterized the effects of exogenously administered mouse MT1 and MT2, and of transgenic Mt1 overexpression, in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), by active immunization with MOG35-55 peptide. Mice treated daily with MT2 showed a significant amelioration of the clinical course, with decreased peak and cumulative scores and delayed onset of EAE. In contrast, treatment with MT1 or its transgenic overexpression only caused a non-significant trend. MT2 treatment preserved better the myelin of the spinal cord, and the pattern of leukocyte infiltrates and gene expression are compatible with an inhibitory effect on neuroinflammation. Splenocytes from these animals in culture responded adequately to MOG35-55 peptide, but a bias for a Th2 profile seemed to be present in the MT2-treated mice. Interestingly, MT1 but not MT2 decreased the number of cytokines in the serum. The present results indicate that mouse MT1 and MT2 are not biologically interchangeable in the EAE model.


[The pentose phosphate pathway and NADP-dependent glycerol-3-phosphate dehydrogenase activity in some tissues of albino rat].
The NADP-dependent glycerol-3-phosphate dehydrogenase activity in liver, heart and skeletal muscle of rat was studied. The activity is found when glyceraldehyde-3-phosphate or ribose-5-phosphate in the presence of ATP are taken as substrates. The data obtained confirm that NADP-dependent glycerol-3-phosphate dehydrogenase exists in skeletal muscle and demonstrate that it is found in heart muscle as well.


Optimization of reflux conditions for total flavonoid and total phenolic extraction and enhanced antioxidant capacity in Pandan (Pandanus amaryllifolius Roxb.) using response surface methodology.
Response surface methodology was applied to optimization of the conditions for reflux extraction of Pandan (Pandanus amaryllifolius Roxb.) in order to achieve a high content of total flavonoids (TF), total phenolics (TP), and high antioxidant capacity (AC) in the extracts. Central composite experimental design with three factors and three levels was employed to consider the effects of the operation parameters, including the methanol concentration (MC, 40%-80%), extraction temperature (ET, 40-70°C), and liquid-to-solid ratio (LS ratio, 20-40 mL/g) on the properties of the extracts. Response surface plots showed that increasing these operation parameters induced the responses significantly. The TF content and AC could be maximized when the extraction conditions (MC, ET, and LS ratio) were 78.8%, 69.5°C, and 32.4 mL/g, respectively, whereas the TP content was optimal when these variables were 75.1%, 70°C, and 31.8 mL/g, respectively. Under these optimum conditions, the experimental TF and TP content and AC were 1.78, 6.601 mg/g DW, and 87.38%, respectively. The optimized model was validated by a comparison of the predicted and experimental values. The experimental values were found to be in agreement with the predicted values, indicating the suitability of the model for optimizing the conditions for the reflux extraction of Pandan.


Characteristics of hypertension in obstructive sleep apnea: An Asian experience.
Obstructive sleep apnea (OSA) is a risk of hypertension and is associated with cardiovascular disease (CVD) incidence. In Asian countries, the prevalence of OSA is high, as in Western countries. When blood pressure (BP) is evaluated in OSA individuals using ambulatory BP monitoring (ABPM), the BP phenotype often indicates abnormal BP variability, such as increased nighttime BP or abnormal diurnal BP variation, that is, non-dipper pattern, riser pattern, and morning BP surge, and all these conditions have been associated with increased CVD events. Asians have a higher prevalence of increased nighttime BP or morning BP surge than Westerners. Therefore, this review paper focused on OSA and hypertension from an Asian perspective to investigate the importance of the association between OSA and hypertension in the Asian population. Such abnormal BP variability has been shown to be associated with progression of arterial stiffness, and this association could provoke a vicious cycle between abnormal BP phenotypes and arterial stiffness, a phenomenon recognized as systemic hemodynamic atherothrombotic syndrome (SHATS). OSA may be one of the background factors that augment SHATS. An oxygen-triggered nocturnal oscillometric BP measurement device combined with a pulse oximeter for continuous SpO2 monitoring could detect BP variability caused by OSA. In addition to treating the OSA, accurate and reliable detection and treatment of any residual BP elevation and BP variability caused by OSA would be necessary to prevent CVD events. However, more detailed detection of BP variability, such as beat-by-beat BP monitoring, would further help to reduce CV events.


Hydrogel micropost-based qPCR for multiplex detection of miRNAs associated with Alzheimer's disease.
Quantitative polymerase chain reaction (qPCR) renders profiling of genes of interest less time-consuming and cost-effective. Recently, multiplex profiling of miRNAs has enabled identifying or investigating predominant miRNAs for various diseases such as cancers and neurodegenerative diseases. Conventional multiplex qPCR technologies mostly use colorimetric measurements in solution phase, yet not only suffer from limited multiplexing capacity but also require target-screening processes due to non-specific binding between targets and primers. Here, we present hydrogel micropost-based qPCR for multiplex detection of miRNAs associated with Alzheimer's disease (AD). Our methodology promises two key advantages compared with the conventional solution-based PCR: 1) nearly no non-specific crosstalks between targets and primers, and 2) practically valuable multiplexing by spatial encoding within a single microchamber. Specifically, we immobilized hydrogel microposts (~ 400µm in diameter) within commercially available polycarbonate PCR chips by multi-step ultraviolet (UV, 365nm) exposure. We optimized this photoimmobilization for thermal cycles of PCR as well. Acrylated forward primers incorporated in polyethylene glycol diacrylate (PEGDA) posts played a crucial role to confine fluorescent signal of cDNA amplification within the PEGDA hydrogel. To demonstrate the potential of our platform, we successfully verified multiplex detection of five miRNAs, which were reported to be highly correlated with AD, from a complex buffer of human plasma.


First-principles method for calculating the rate constants of internal-conversion and intersystem-crossing transitions.
A method for calculating the rate constants for internal-conversion (kIC) and intersystem-crossing (kISC) processes within the adiabatic and Franck-Condon (FC) approximations is proposed. The applicability of the method is demonstrated by calculation of kIC and kISC for a set of organic and organometallic compounds with experimentally known spectroscopic properties. The studied molecules were pyrromethene-567 dye, psoralene, hetero[8]circulenes, free-base porphyrin, naphthalene, and larger polyacenes. We also studied fac-Alq3 and fac-Ir(ppy)3, which are important molecules in organic light emitting diodes (OLEDs). The excitation energies were calculated at the multi-configuration quasi-degenerate second-order perturbation theory (XMC-QDPT2) level, which is found to yield excitation energies in good agreement with experimental data. Spin-orbit coupling matrix elements, non-adiabatic coupling matrix elements, Huang-Rhys factors, and vibrational energies were calculated at the time-dependent density functional theory (TDDFT) and complete active space self-consistent field (CASSCF) levels. The computed fluorescence quantum yields for the pyrromethene-567 dye, psoralene, hetero[8]circulenes, fac-Alq3 and fac-Ir(ppy)3 agree well with experimental data, whereas for the free-base porphyrin, naphthalene, and the polyacenes, the obtained quantum yields significantly differ from the experimental values, because the FC and adiabatic approximations are not accurate for these molecules.


Emotional processing of personally familiar faces in the vegetative state.
The Vegetative State (VS) is a severe disorder of consciousness in which patients are awake but display no signs of awareness. Yet, recent functional magnetic resonance imaging (fMRI) studies have demonstrated evidence for covert awareness in VS patients by recording specific brain activations during a cognitive task. However, the possible existence of incommunicable subjective emotional experiences in VS patients remains largely unexplored. This study aimed to probe the question of whether VS patients retain a brain ability to selectively process external stimuli according to their emotional value and look for evidence of covert emotional awareness in patients. In order to explore these questions we employed the emotive impact of observing personally familiar faces, known to provoke specific perceptual as well as emotional brain activations. Four VS patients and thirteen healthy controls first underwent an fMRI scan while viewing pictures of non-familiar faces, personally familiar faces and pictures of themselves. In a subsequent imagery task participants were asked to actively imagine one of their parent's faces. Analyses focused on face and familiarity selective regional brain activations and inter-regional functional connectivity. Similar to controls, all patients displayed face selective brain responses with further limbic and cortical activations elicited by familiar faces. In patients as well as controls, Connectivity was observed between emotional, visual and face specific areas, suggesting aware emotional perception. This connectivity was strongest in the two patients who later recovered. Notably, these two patients also displayed selective amygdala activation during familiar face imagery, with one further exhibiting face selective activations, indistinguishable from healthy controls. Taken together, these results show that selective emotional processing can be elicited in VS patients both by external emotionally salient stimuli and by internal cognitive processes, suggesting the ability for covert emotional awareness of self and the environment in VS patients.


Restoration of T Cell function in multi-drug resistant bacterial sepsis after interleukin-7, anti-PD-L1, and OX-40 administration.
Multidrug resistant (MDR) bacterial pathogens are a serious problem of increasing importance facing the medical community. MDR bacteria typically infect the most immunologically vulnerable: patients in intensive care units, patients with extensive comorbidities, oncology patients, hemodialysis patients, and other immune suppressed individuals are likely to fall victim to these pathogens. One promising novel approach to treatment of MDR bacteria is immuno-adjuvant therapy to boost patient immunity. Success with this strategy would have the major benefit of providing protection against a number of MDR pathogens. This study had two main objectives. First, immunophenotyping of peripheral blood mononuclear cells from patients with sepsis associated with MDR bacteria was performed to examine for findings indicative of immunosuppression. Second, the ability of three immuno-adjuvants with distinct mechanisms of action to reverse CD4 and CD8 T cell dysfunction, a pathophysiological hallmark of sepsis, was evaluated. Septic patients with MDR bacteria had increased expression of the inhibitory receptor PD-1 and its ligand PD-L1 and decreased monocyte HLA-DR expression compared to non-septic patients. All three immuno-adjuvants, IL-7, anti-PD-L1, and OX-40L, increased T cell production of IFN-γ in a subset of septic patients with MDR bacteria: IL-7 was most efficacious. There was a strong trend toward increased mortality in patients whose T cells failed to increase IFN-γ production in response to the three treatments. Immuno-adjuvant therapy reversed T cell dysfunction, a key pathophysiological mechanism in septic patients with MDR bacteria.


Pre- and intra-operative mediastinal staging in non-small-cell lung cancer.
Primary mediastinal lymph node staging is important to select properly patients who can benefit from an induction treatment. The accuracy of CT scan in the evaluation of mediastinal lymph nodes is low. Further staging can be omitted in patients with negative mediastinal PET in most of the cases. PET positive findings should always be histologically or cytologically confirmed. Endoscopic techniques are accurate minimally invasive techniques mostly used to confirm a PET-positive finding but not for complete mediastinal staging. Mediastinoscopy is an invasive technique which provides a complete statging of the upper mediastinum. At least one ipsilateral, one contralateral and the subcarinal nodes should be routinely biopsied. Restaging of the mediastinum after induction treatment is necessary to select the patients who can benefit from surgery. There are no imaging techniques which can accurately determine the biological response of the tumour to the induction treatment. Neither CT, PET or PET-CT seem good enough to make further therapeutic decisions, based on their results. The accuracy of PET in mediastinal restaging is not optimal, mainly due to its low sensitivity. Fusion images with PET-CT seem to improve the results with a very favourable sensitivity, specificity and accuracy. An invasive technique providing cytohistological information is necessary. For restaging techniques, endoscopic techniques or surgical invasive techniques can be used. If they yield a positive result, definitive nonsurgical treatment seems to be indicated in most patients. Remediastinoscopy has proven to be feasible but due to adhesions and fibrosis, the intervention is technically challenging. The technique of lymph-node assessment during surgery for non-small-cell lung cancer (NSCLC) is not standardised to date. Accurate intra-operative staging is necessary to compare the results from different institutions and to conduct multi-institutional trials. Systematic mediastinal lymph-node dissection is recommended in all cases for complete resection of NSCLC and improves pathologic staging and the prospect for adjuvant therapy. The role of mediastinal lymphadenectomy regarding overall survival and local control remains controversial but systematic lymph-node dissection might be associated with a better outcome in stage I NSCLC. Lobe-specific systematic nodal dissection is acceptable for peripheral squamous T1 tumours, if hilar and interlobar nodes are negative on frozen section studies.


[Effect of the combined use of rifampicin and a low-molecular immunomodulator of natural origin on the primary immune response to the antigens of a tularemia vaccinal strain].
The effect of rifampicin combination with a natural low molecular immunomodulator on the primary immune response to the antigens of tularemia vaccine was studied with the methods of multifactor designing of the experiment. The dependence of the delayed hypersensitivity and antibody titer on doses of the antibiotic and immunomodulator and the time of the immunomodulator administration was manifested by the second order equation. Nomographs for precise quantitative estimation of the doses and regimens providing the maximal delayed type hypersensitivity and antibody titers were plotted.


Multicenter Clinical Evaluation of a Novel Multiplex Real-Time PCR (qPCR) Assay for Detection of Fluoroquinolone Resistance in Mycoplasma genitalium.
Mycoplasma genitalium causes a common sexually transmitted infection with a marked propensity to develop antimicrobial resistance. As few treatment options exist, this poses significant challenges to clinicians. Recent diagnostic advances have resulted in tests that report the simultaneous detection of M. genitalium and any resistance to macrolides, the first-line treatment. This allows for therapy to be tailored to the individual, thereby optimizing treatment outcomes. However, resistance to fluoroquinolones, the second-line treatment, is increasing in M. genitalium In this study, we describe a new assay, MG+parC (beta), which simultaneously reports the detection of M. genitalium and five parC mutations that have been associated with resistance to fluoroquinolones. These mutations affect the amino acid sequence of ParC at residues S83R (A247C), S83I (G248T), D87N (G259A), D87Y (G259T), and D87H (G259C). The study tested the MG+parC (beta) assay with 202 M. genitalium-positive clinical samples from Australia (n = 141) and Spain (n = 61). Compared to Sanger sequencing, the assay performed with a kappa value of 0.985 (95% confidence interval [CI], 0.955 to 1.000), with a mutation detection sensitivity of 97.6% (95% CI, 87.4 to 99.9), and specificity of 100.0% (95% CI, 97.7 to 100.0). Fluoroquinolone resistance-associated mutations in parC targeted by the assay were more prevalent among the Australian cohort (23.4% [95% CI,16.3 to 31.8]) compared to the Spanish population (8.8% [95% CI, 2.9% to 19.3%]) (P = 0.019). The MG+parC (beta) kit is a simple and reliable method for simultaneous detection of M. genitalium and fluoroquinolone resistance-associated mutations in clinical settings. This novel diagnostic tool may extend the utility of the second line of antimicrobial therapies in M. genitalium infection.


RISK FACTORS FOR EARLY POSTOPERATIVE COMPLICATIONS IN ACUTE COLITIS IN THE ERA OF BIOLOGIC THERAPY.
Despite major advances in the clinical treatment of inflammatory bowel disease, some patients still present with acute colitis and require emergency surgery. To evaluate the risk factors for early postoperative complications in patients undergoing surgery for acute colitis in the era of biologic therapy. Patients with inflammatory bowel disease admitted for acute colitis who underwent total colectomy at a single tertiary hospital from 2012 to 2022 were evaluated. Postoperative complications were graded according to Clavien-Dindo classification (CDC). Patients with more severe complications (CDC≥2) were compared with those with less severe complications (CDC<2). A total of 46 patients underwent surgery. The indications were: failure of clinical treatment (n=34), patients' or surgeon's preference (n=5), hemorrhage (n=3), toxic megacolon (n=2), and bowel perforation (n=2). There were eight reoperations, 60.9% of postoperative complications classified as CDC≥2, and three deaths. In univariate analyses, preoperative antibiotics use, ulcerative colitis diagnosis, lower albumin levels at admission, and preoperative hospital stay longer than seven days were associated with more severe postoperative complications. Emergency surgery for acute colitis was associated with a high incidence of postoperative complications. Preoperative use of antibiotics, ulcerative colitis, lower albumin levels at admission, and delaying surgery for more than seven days were associated with more severe early postoperative complications. The use of biologics was not associated with worse outcomes.


Anti-nucleolin Aptamer as a Boom in Rehabilitation of Breast Cancer.
Breast cancer is the second leading cause of cancer-related deaths. It is important to target the complex pathways using a suitable targeted delivery system. Targeted delivery systems can effectively act on cancer cells and lead to the annihilation of tumor proliferation. They mainly employ targeting agents like aptamers linked to the formulation. Based on the expression of the receptors on the surface of the cancer cells, suitable aptamers can be developed. AS1411 is one such aptamer that has the ability to bind to the over-expressed nucleolin present in breast cancer cells. Nucleolin is a phosphoprotein that is involved in various aspects, like cell growth, differentiation and survival. Mostly they are found in the nucleolus, nucleus, cytoplasm and cell surface. The shuttling effect of the nucleolin between the nucleus and cytoplasm serves as a bonus for the AS1411 aptamer. Because of the shutting effect, the internalization of the drug compound or chemotherapeutic drug inside the cell can be achieved. In this article, we have discussed nucleolin, anti-nucleolin aptamer, namely, AS1411, and its application in exhibiting various anticancer activities, including apoptosis, anti-angiogenesis, anti-metastasis, stimulation of tumor suppressor (i.e., P53), and inhibition of tumor inducer. Further, the ways of internalization, namely macropinocytosis, are also discussed. Additionally, we have also discussed the superiority of the aptamer compared to the antibodies as well as the limitations of the aptamers. By considering all the above parameters, we hope this aptamer will be effective in the management and eradication of breast cancer cells.