First Observation of Multiple Transverse Wobbling Bands of Different Kinds in

We report the first observation of two wobbling bands in ^{183}Au, both of which were interpreted as the transverse wobbling (TW) band but with different behavior of their wobbling energies as a function of spin. It increases (decreases) with spin for the positive (negative) parity configuration. The crucial evidence for the wobbling nature of the bands, dominance of the E2 component in the ΔI=1 transitions between the partner bands, is provided by the simultaneous measurements of directional correlation from the oriented states ratio and the linear polarization of the γ rays. Particle rotor model calculations with triaxial deformation reproduce the experimental data well. A value of spin, I_{m}, has been determined for the observed TW bands below which the wobbling energy increases and above which it decreases with spin. The nucleus ^{183}Au is, so far, the only nucleus in which both the increasing and the decreasing parts are observed and thus gives the experimental evidence of the complete transverse wobbling phenomenon.

Shape Coexistence at Zero Spin in

The low-spin structure of the semimagic ^{64}Ni nucleus has been considerably expanded: combining four experiments, several 0^{+} and 2^{+} excited states were identified below 4.5 MeV, and their properties established. The Monte Carlo shell model accounts for the results and unveils an unexpectedly complex landscape of coexisting shapes: a prolate 0^{+} excitation is located at a surprisingly high energy (3463 keV), with a collective 2^{+} state 286 keV above it, the first such observation in Ni isotopes. The evolution in excitation energy of the prolate minimum across the neutron N=40 subshell gap highlights the impact of the monopole interaction and its variation in strength with N.

Evidence for Rigid Triaxial Deformation in

An extensive, model-independent analysis of the nature of triaxial deformation in ^{76}Ge, a candidate for neutrinoless double-beta (0νßß) decay, was carried out following multistep Coulomb excitation. Shape parameters deduced on the basis of a rotational-invariant sum-rule analysis provided considerable insight into the underlying collectivity of the ground-state and γ bands. Both sequences were determined to be characterized by the same ß and γ deformation parameter values. In addition, compelling evidence for low-spin, rigid triaxial deformation in ^{76}Ge was obtained for the first time from the analysis of the statistical fluctuations of the quadrupole asymmetry deduced from the measured E2 matrix elements. These newly determined shape parameters are important input and constraints for calculations aimed at providing, with suitable accuracy, the nuclear matrix elements relevant to 0νßß.

Combination therapy strategies for improving PD-1 blockade efficacy: a new era in cancer immunotherapy.

Programmed death 1 (PD-1) is an immune checkpoint molecule that negatively regulates T-cell immune function through the interaction with its ligand PD-L1. Blockage of this interaction unleashes the immune system to fight cancer. Immunotherapy using PD-1 blockade has led to a paradigm shift in the field of cancer drug discovery, owing to its durable effect against a wide variety of cancers with limited adverse effects. A brief history and development of PD-1 blockade, from the initial discovery of PD-1 to the recent clinical output of this therapy, have been summarized here. Despite its tremendous clinical success rate over other cancer treatments, PD-1 blockade has its own pitfall; a significant fraction of patients remains unresponsive to this therapy. The key to improve the PD-1 blockade therapy is the development of combination therapies. As this approach has garnered worldwide interest, here, we have summarized the recent trends in the development of PD-1 blockade-based combination therapies and the ongoing clinical trials. These include combinations with checkpoint inhibitors, radiation therapy, chemotherapy and several other existing cancer treatments. Importantly, FDA has approved PD-1 blockade agent to be used in combination with either CTLA-4 blockade or chemotherapy. Responsiveness to the PD-1 blockade therapy is affected by tumour and immune system-related factors. The role of the immune system, especially T cells, in determining the responsiveness has been poorly studied compared with those factors related to the tumour side. Energy metabolism has emerged as one of the important regulatory mechanisms for the function and differentiation of T cells. We have documented here the recent results regarding the augmentation of PD-1 blockade efficacy by augmenting mitochondrial energy metabolism of T cell.

Fission barrier of superheavy nuclei and persistence of shell effects at high spin: cases of 254No and 220Th.

We report on the first measurement of the fission barrier height in a heavy shell-stabilized nucleus. The fission barrier height of 254No is measured to be Bf=6.0±0.5 MeV at spin 15ℏ and, by extrapolation, Bf=6.6±0.9 MeV at spin 0ℏ. This information is deduced from the measured distribution of entry points in the excitation energy versus spin plane. The same measurement is performed for 220Th and only a lower limit of the fission barrier height can be determined: Bf(I)>8 MeV. Comparisons with theoretical fission barriers test theories that predict properties of superheavy elements.

Solubility, (micro)structure, and in vitro digestion of pea protein dispersions as affected by high pressure homogenization and environmental conditions.

In this work, dispersions were prepared with commercial pea protein isolate (PPI) and subjected to different (i) high pressure homogenization (HPH) intensities (0 - 200 MPa) (room temperature, pH 7) or (ii) environmental conditions (60 °C, pH 7 or pH 12) to generate dispersions with distinct protein molecular and microstructural characteristics, impacting protein solubility. Besides, protein digestion was analyzed following the static INFOGEST in vitro digestion protocol. Generally, increasing pressure of the homogenization treatment was linked with decreasing particle sizes and enhanced protein digestion. More specifically, the dispersion that did not undergo HPH (0 MPa) as well as the dispersion treated at 60 °C, pH 7, had highly similar microstructures, consisting of large irregular particles (10 - 500 µm) with shell-like structures, and exhibited low solubility (around 15 % and 28 %, respectively), which resulted in limited proteolysis (35 % and 42 %, respectively). In contrast, the dispersion subjected to HPH at 100 MPa and the dispersion treated at 60 °C, pH 12 also had similar microstructures with small and homogeneous particles (<1 µm), and exhibited relatively good solubility (54 % and 31 %, respectively), which led to enhanced protein digestion levels (87 % and 74 %, respectively). This study highlights the potential of food processing on macronutrient (micro)structure and further gastrointestinal stability and functionality.

Descriptive epidemiology of smothering in Australian commercial free-range layer hen farms.

Since the early 2000 s the practice of free-range egg production has increased in developed countries, partly driven by consumer perception that free-range housing is better for hen welfare. While poultry in free-range systems have more behavioural opportunities compared with poultry in caged systems, free-range systems are associated with greater frequencies of infectious disease, predation and 'smothering', a condition where birds pile on top of one another with death occurring due to suffocation. Although the frequency of smothering deaths in Australian free-range layer poultry is anecdotally high, there is a lack of empirical evidence quantifying smothering cause-specific mortality rates and identifying factors that place birds at higher risk of death from smothering. This was a prospective cohort study of poultry flocks managed by three commercial free-range layer organisations in Eastern Australia. Flocks were enrolled into the study from 1 January 2019 to 29 March 2021 and were followed until the end of lay or until the end of the study on 31 March 2022, whichever occurred first. Throughout the follow-up period flock managers provided production details for each flock and details of smothering events using custom-designed logbooks.A total of 84 flocks were enrolled in the study: 32 from Organisation 1, 35 from Organisation 2 and 17 from Organisation 3. The number of birds per flock ranged from 16,000 to 45,000. The total mortality rate was 1131 deaths per 10,000 bird-years. Smothering mortality rate across the three organisations was 183 (minimum 133, maximum 223) deaths per 10,000 bird-years at risk. Smothering accounted for around 16% (minimum 9%, maximum 22%) of all deaths.We identified no distinctive temporal pattern in daily smothering risk as a function of either the number of days since placement or calendar date. The locations of smothering events in sheds and in the outdoor range were not consistent, with relatively large numbers of smothering events occurring in specific locations for some sheds but not others. To the best of our knowledge, this study is the largest prospective study of smothering mortality in commercial free-range layer flocks conducted to date. Estimates of smothering incidence rate and how that varies within and between flocks and organisations over time provides a critically important benchmark for further investigations into this substantial area of productivity loss.

Fine-grained lower limit of entropic uncertainty in the presence of quantum memory.

The limitation on obtaining precise outcomes of measurements performed on two noncommuting observables of a particle as set by the uncertainty principle in its entropic form can be reduced in the presence of quantum memory. We derive a new entropic uncertainty relation based on fine graining, which leads to an ultimate limit on the precision achievable in measurements performed on two incompatible observables in the presence of quantum memory. We show that our derived uncertainty relation tightens the lower bound set by entropic uncertainty for members of the class of two-qubit states with maximally mixed marginals, while accounting for the recent experimental results using maximally entangled pure states and mixed Bell-diagonal states. An implication of our uncertainty relation on the security of quantum key generation protocols is pointed out.

Complete Genome Sequence of Pasteurella multocida Sequence Type 394, Isolated from a Case of Bovine Respiratory Disease in Australia.

Here, we present the completely closed genome sequence of Pasteurella multocida 17BRD-035, a bovine respiratory disease (BRD) pathogen from Queensland, Australia, with genes that confer resistance to ß-lactams, tilmicosin, and tetracycline. It consists of a single 2,624,884-bp chromosome and an average GC content of 40.23% and belongs to the newly described Rural Industries Research and Development Corporation (RIRDC) sequence type 394.

The evolution and distribution of phage ST160 within Salmonella enterica serotype Typhimurium.

Salmonellosis is an internationally important disease of mammals and birds. Unique epidemics in New Zealand in the recent past include two Salmonella serovars: Salmonella enterica subsp. enterica serovar Typhimurium definitive type (DT) 160 (S. Typhimurium DT160) and S. Brandenburg. Although not a major threat internationally, in New Zealand S. Typhimurium DT160 has been the most common serovar isolated from humans, and continues to cause significant losses in wildlife. We have identified DNA differences between the first New Zealand isolate of S. Typhimurium DT160 and the genome-sequenced strain, S. Typhimurium LT2. All the differences could be accounted for in one cryptic phage ST64B, and one novel P22-like phage, ST160. The majority of the ST160 genome is almost identical to phage SE1 but has two regions not found in SE1 which are identical to the P22-like phage ST64T, suggesting that ST160 evolved from SE1 via two recombination events with ST64T. All of the New Zealand isolates of DT160 were identical indicating the clonal spread of this particular Salmonella. Some overseas isolates of S. Typhimurium DT160 differed from the New Zealand strain and contained SE1 phage rather than ST160. ST160 was also identified in New Zealand isolates of S. Typhimurium DT74 and S. Typhimurium RDNC-April06 and in S. Typhimurium DT160 isolates from the USA. The emergence of S. Typhimurium DT160 as a significant pathogen in New Zealand is postulated to have occurred due to the sensitivity of the Salmonella strains to the ST160 phage when S. Typhimurium DT160 first arrived.

Influence of cadmium and other trace metals on human alpha1-antitrypsin: an in vitro study.

The effect of trace metals on plasma alpha1-antitrypsin was studied in vitro by adding known concentrations of trace metals, either alone or in combination, to plasma. Cadmium was the only trace metal that reduced the concentration of alpha1-antitrypsin and depressed the trypsin inhibitory capacity. No such effects were found with divalent lead, mercury, nickel, iron, and zinc ions. The present study appears to offer a plausible explanation for the emphysema that occurs in industrial workers exposed to cadmium.

Single Sitting Surgery for Concomitant Hydatid Cyst of Lung and Liver: A Case Report.

Hydatid disease is one of the diseases that have been discovered in the ancient times. Liver and lung are the most commonly affected organs, though it can involve any organs. Hydatid disease involving both the liver and the lung is reported about 10% of the cases. Here we report a case of 34 year old male presented with upper abdominal pain and intermittent fever for 3 months admitted in October 2016. His chest radiograph and computed tomography scan revealed large cystic lesion at right lung and another similar large lesion in the right lobe of liver. Echinococcus antibody was found positive. We treated him surgically. Histopathology reports confirmed concomitant hydatid cyst of both the lung and the liver.

Solid Pseudopapillary Tumor of the Pancreas: A Case Report.

Solid pseudopapillary tumors (SPT) of the pancreas are rare neoplasms of the pancreas accounting for only 1-2% of all pancreatic neoplasms, often detected initially on imaging. Its histogenesis is still uncertain and it has a low-grade malignant potential but excellent post-surgical curative rates and rare metastasis. Pathological and/or cytological evaluation still remains the gold standard in reaching a definitive diagnosis. It occurs most commonly in young females. We report a case of solid pseudopapillary tumor in the head of the pancreas in a 20 years old female admitted in Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh on 5th December 2015. Whipple's operation was done as a definitive treatment.

A class 1 integron present in a human commensal has a hybrid transposition module compared to Tn402: evidence of interaction with mobile DNA from natural environments.

In a survey of class 1 integrons from human stools, an unusual class 1 integron from a strain of Enterobacter cloacae was isolated and characterized in detail. Sequence analysis of a fosmid containing the class 1 integron revealed a complex set of transposons which included two Tn402-like transposons. One of these transposons, Tn6007, included a class 1 integron with two non-antibiotic-resistance-type gene cassettes and a complete transposition module. This tni module is a hybrid with a boundary within the res site compared to Tn402, implying that a site-specific recombination event generated either Tn6007 or Tn402. The second Tn402-like transposon, Tn6008, possesses neither a mer operon nor an integron, and most of its tni module has been deleted. Tn6007, Tn6008, and the 2,478 bases between them, collectively designated Tn6006, have transposed into a Tn5036/Tn3926-like transposon as a single unit. Tn6006, Tn6007, and Tn6008 could all transpose as discrete entities. Database analysis also revealed that a version of Tn6008 was present in the genome of Xanthomonas campestris pv. vesicatoria. Overall, the E. cloacae isolate further demonstrated that functional class 1 integrons/transposons are probably common in bacterial communities and have the potential to add substantially to the problem of multidrug-resistant nosocomial infections.

Acute intermittent porphyria and chronic renal failure.

Despite the little known association between renal damage and the acute porphyrias, limited information is available on the characteristics and pathogenesis of renal disease in this patient group. Previous reports have focused on hypertension as the principal etiological factor. We have studied a series of 9 patients with acute intermittent porphyria (AIP) attending the Porphyria Clinic at King's College Hospital, London, UK, who were referred to the Renal Unit for investigation and treatment of their renal disease. No evidence of a glomerular lesion was found in any of the patients. In contrast, renal histology showed features of a tubulointerstitial disease, and there was evidence of impaired erythropoietin production. Hypertension and nonsteroidal antiinflammatory drug use were present in about a half of the patients. It is postulated that the nephrotoxic effects of porphyrin precursors may contribute to the etiology of this clinical syndrome.

Incidence of contamination of live bird markets in Bangladesh with influenza A virus and subtypes H5, H7 and H9.

In the absence of robust active surveillance of avian influenza viruses (AIV) affecting poultry in South Asian countries, monitoring of live bird markets (LBMs) can be an alternative. In a longitudinal study of 32 LBM, five environments were sampled as follows: market floor, stall floor, slaughter area, poultry holding cage and water used for meat processing. Samples were taken monthly for 5 months, September 2013-January 2014. Incidence rates (IRs) of LBM contamination with AIV and its subtypes H5, H7 and H9 were assessed. In 10 of the LBM selected, biosecurity measures had been implemented through FAO interventions: the other 22 were non-intervened. Standard procedures were applied to detect AIV and three subtypes in pooled samples (1:5). An LBM was considered positive for AIV or a subtype if at least one of the pooled samples tested positive. The incidence rates of LBM contamination with AIV, H5, H7 and H9 were 0.194 (95% confidence interval (CI) 0.136-0.276), 0.031 (95% CI 0.013-0.075), 0 and 0.175 (95% CI 0.12-0.253) per LBM-month at risk, respectively. The log IR ratio between the FAO-intervened and non-intervened LBM for contamination with AIV was -0.329 (95% CI -1.052 to -0.394, p = .372), 0.598 (95% CI -1.593 to 2.789, p = .593) with subtype H5 and -0.500 (95% CI -1.249 to 0.248, p = .190) with subtype H9, indicating no significant difference. The results obtained suggest that both H5 and H9 were circulating in LBM in Bangladesh in the second half of 2013. The incidence of contamination with H9 was much higher than with H5.

Nicotine-induced proliferation of isolated rat pancreatic acinar cells: effect on cell signalling and function.

OBJECTIVES: The aim of the current study was to investigate whether nicotine treatment would induce the proliferation of isolated rat primary pancreatic acinar cells in culture by activating mitogen-activated protein kinase (MAPK) signalling and exocrine secretion. MATERIALS AND METHODS: A nicotine dose- and time-response curve was initially developed to determine the optimal dose and time used for all subsequent studies. Proliferation studies were conducted by cell counting and confirmed further by bromodeoxyuridine (BrdU) incorporation and flow cytometry assays. MAPK signalling studies were conducted by Western blot analysis. Localization of ERK1/2 signals, with or without nicotine and the MAPK inhibitor, was visualized by immunofluorescence. RESULTS: Nicotine treatment caused dose-dependent activation of extracellular signal-regulated kinases (ERK1/2), the maxima occurring at 100 micro m and at 3 min after treatment; the response was suppressed by the ERK1/2 inhibitor. Maximal nicotine-induced cell proliferation occurred at 24 h, and UO126-treatment significantly reduced this response. Exposure of cells to 100 microm nicotine for 6 min significantly enhanced both baseline and cholecystokinin-stimulated cell function, and these effects were not affected by treatment with the inhibitor of ERK1/2 but were suppressed by mecamylamine, a nicotinic receptor antagonist. CONCLUSIONS: Our results suggest that nicotine treatment induced cell proliferation of isolated pancreatic acinar cells and that this is coupled with the activation of MAPK signalling with no effect on its function. Hence, in primary cells, the mechanism of induction and regulation of these two processes, cell proliferation and cell function, by nicotine treatment are independent of each other.

Improving antibody affinity by mimicking somatic hypermutation in vitro.

In vivo affinity maturation of antibodies involves mutation of hot spots in the DNA encoding the variable regions. We have used this information to develop a strategy to improve antibody affinity in vitro using phage display technology. In our experiment with the antimesothelin scFv, SS(scFv), we identified DNA sequences in the variable regions that are naturally prone to hypermutations, selected a few hot spots encoding nonconserved amino acids, and introduced random mutations to make libraries with a size requirement between 10(3) and 10(4) independent clones. Panning of the hot spot libraries yielded several mutants with a 15- to 55-fold increase in affinity compared with a single clone with a fourfold increased affinity from a library in which mutagenesis was done outside the hot spots. The strategy should be generally applicable for the rapid isolation of higher-affinity mutants of Fvs, Fabs, and other recombinant antibodies from antibody phage libraries that are small in size.

Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL.

The hypoxia-regulated tumor-suppressor von Hippel-Lindau (VHL) is an E3 ligase that recognizes its substrates as part of an oxygen-dependent prolyl hydroxylase (PHD) reaction, with hypoxia-inducible factor α (HIFα) being its most notable substrate. Here we report that VHL has an equally important function distinct from its hypoxia-regulated activity. We find that Aurora kinase A (AURKA) is a novel, hypoxia-independent target for VHL ubiquitination. In contrast to its hypoxia-regulated activity, VHL mono-, rather than poly-ubiquitinates AURKA, in a PHD-independent reaction targeting AURKA for degradation in quiescent cells, where degradation of AURKA is required to maintain the primary cilium. Tumor-associated variants of VHL differentiate between these two functions, as a pathogenic VHL mutant that retains intrinsic ability to ubiquitinate HIFα is unable to ubiquitinate AURKA. Together, these data identify VHL as an E3 ligase with important cellular functions under both normoxic and hypoxic conditions.

Targeting Alpha Toxin and ClfA with a Multimechanistic Monoclonal-Antibody-Based Approach for Prophylaxis of Serious Staphylococcus aureus Disease.

UNLABELLED: Staphylococcus aureus produces numerous virulence factors, each contributing different mechanisms to bacterial pathogenesis in a spectrum of diseases. Alpha toxin (AT), a cytolytic pore-forming toxin, plays a key role in skin and soft tissue infections and pneumonia, and a human anti-AT monoclonal antibody (MAb), MEDI4893*, has been shown to reduce disease severity in dermonecrosis and pneumonia infection models. However, interstrain diversity and the complex pathogenesis of S. aureus bloodstream infections suggests that MEDI4893* alone may not provide adequate protection against S. aureus sepsis. Clumping factor A (ClfA), a fibrinogen binding protein, is an important virulence factor facilitating S. aureus bloodstream infections. Herein, we report on the identification of a high-affinity anti-ClfA MAb, 11H10, that inhibits ClfA binding to fibrinogen, prevents bacterial agglutination in human plasma, and promotes opsonophagocytic bacterial killing (OPK). 11H10 prophylaxis reduced disease severity in a mouse bacteremia model and was dependent on Fc effector function and OPK. Additionally, prophylaxis with 11H10 in combination with MEDI4893* provided enhanced strain coverage in this model and increased survival compared to that obtained with the individual MAbs. The MAb combination also reduced disease severity in murine dermonecrosis and pneumonia models, with activity similar to that of MEDI4893* alone. These results indicate that an MAb combination targeting multiple virulence factors provides benefit over a single MAb neutralizing one virulence mechanism by providing improved efficacy, broader strain coverage, and protection against multiple infection pathologies. IMPORTANCE: Alternative strategies to broad-spectrum antibiotics are required to combat the antibiotic resistance epidemic. Previous attempts at active or passive immunization against Staphylococcus aureus targeting single antigens have failed in clinical trials despite positive preclinical data. To provide broad disease and isolate coverage, an effective immunization strategy likely must target multiple virulence mechanisms of the pathogen. Herein, we tested a multimechanistic MAb combination targeting alpha toxin (AT) and clumping factor A (ClfA) that neutralizes AT-mediated cytotoxicity, blocks fibrinogen binding by ClfA, prevents bacterial agglutination, targets the bacteria for opsonophagocytic killing, and provides broad isolate coverage in a lethal-bacteremia model. Although each MAb alone was effective in bacteremia against some individual isolates, the MAb combination provided improved protection against other isolates. These results illustrate the importance of targeting multiple virulence mechanisms and highlight the potential for an MAb combination targeting AT and ClfA to effectively prevent S. aureus disease.