A Gravitational Theory of the Quantum

The synthesis of quantum and gravitational physics is sought through a finite, realistic, locally causal theory where gravity plays a vital role not only during decoherent measurement but also during non-decoherent unitary evolution. Invariant set theory is built on geometric properties of a compact fractal-like subset $I_U$ of cosmological state space on which the universe is assumed to evolve and from which the laws of physics are assumed to derive. Consistent with the primacy of $I_U$, a non-Euclidean (and hence non-classical) state-space metric $g_p$ is defined, related to the $p$-adic metric of number theory where $p$ is a large but finite Pythagorean prime. Uncertain states on $I_U$ are described using complex Hilbert states, but only if their squared amplitudes are rational and corresponding complex phase angles are rational multiples of $2 \pi$. Such Hilbert states are necessarily $g_p$-distant from states with either irrational squared amplitudes or irrational phase angles. The gappy fractal nature of $I_U$ accounts for quantum complementarity and is characterised numerically by a generic number-theoretic incommensurateness between rational angles and rational cosines of angles. The Bell inequality, whose violation would be inconsistent with local realism, is shown to be $g_p$-distant from all forms of the inequality that are violated in any finite-precision experiment. The delayed-choice paradox is resolved through the computational irreducibility of $I_U$. The Schr\"odinger and Dirac equations describe evolution on $I_U$ in the singular limit at $p=\infty$. By contrast, an extension of the Einstein field equations on $I_U$ is proposed which reduces smoothly to general relativity as $p \rightarrow \infty$. Novel proposals for the dark universe and the elimination of classical space-time singularities are given and experimental implications outlined

SYCE2 is required for synaptonemal complex assembly, double strand break repair, and homologous recombination

Synapsis is the process by which paired chromosome homologues closely associate in meiosis before crossover. In the synaptonemal complex (SC), axial elements of each homologue connect through molecules of SYCP1 to the central element, which contains the proteins SYCE1 and -2. We have derived mice lacking SYCE2 protein, producing males and females in which meiotic chromosomes align and axes form but do not synapse. Sex chromosomes are unaligned, not forming a sex body. Additionally, markers of DNA breakage and repair are retained on the axes, and crossover is impaired, culminating in both males and females failing to produce gametes. We show that SC formation can initiate at sites of SYCE1/SYCP1 localization but that these points of initiation cannot be extended in the absence of SYCE2. SC assembly is thus dependent on SYCP1, SYCE1, and SYCE2. We provide a model to explain this based on protein–protein interactions

Mutation of the Mouse Syce1 Gene Disrupts Synapsis and Suggests a Link between Synaptonemal Complex Structural Components and DNA Repair

In mammals, the synaptonemal complex is a structure required to complete crossover recombination. Although suggested by cytological work, in vivo links between the structural proteins of the synaptonemal complex and the proteins of the recombination process have not previously been made. The central element of the synaptonemal complex is traversed by DNA at sites of recombination and presents a logical place to look for interactions between these components. There are four known central element proteins, three of which have previously been mutated. Here, we complete the set by creating a null mutation in the Syce1 gene in mouse. The resulting disruption of synapsis in these animals has allowed us to demonstrate a biochemical interaction between the structural protein SYCE2 and the repair protein RAD51. In normal meiosis, this interaction may be responsible for promoting homologous synapsis from sites of recombination

A national quality incentive scheme to reduce antibiotic overuse in hospitals; evaluation of perceptions and impact

In 2016/2017, a financially-linked antibiotic prescribing quality improvement initiative (AMR-CQUIN) was introduced across acute hospitals in England. This aimed for >1% reductions in Defined Daily Doses / 1000 admissions of total antibiotics, piperacillin/tazobactam and carbapenems compared with 2013/2014 and improved review of empiric antibiotic prescriptions

p53 Dependent Centrosome Clustering Prevents Multipolar Mitosis in Tetraploid Cells

BACKGROUND: p53 abnormality and aneuploidy often coexist in human tumors, and tetraploidy is considered as an intermediate between normal diploidy and aneuploidy. The purpose of this study was to investigate whether and how p53 influences the transformation from tetraploidy to aneuploidy. PRINCIPAL FINDINGS: Live cell imaging was performed to determine the fates and mitotic behaviors of several human and mouse tetraploid cells with different p53 status, and centrosome and spindle immunostaining was used to investigate centrosome behaviors. We found that p53 dominant-negative mutation, point mutation, or knockout led to a 2∼ 33-fold increase of multipolar mitosis in N/TERT1, 3T3 and mouse embryonic fibroblasts (MEFs), while mitotic entry and cell death were not significantly affected. In p53-/- tetraploid MEFs, the ability of centrosome clustering was compromised, while centrosome inactivation was not affected. Suppression of RhoA/ROCK activity by specific inhibitors in p53-/- tetraploid MEFs enhanced centrosome clustering, decreased multipolar mitosis from 38% to 20% and 16% for RhoA and ROCK, respectively, while expression of constitutively active RhoA in p53+/+ tetraploid 3T3 cells increased the frequency of multipolar mitosis from 15% to 35%. CONCLUSIONS: p53 could not prevent tetraploid cells entering mitosis or induce tetraploid cell death. However, p53 abnormality impaired centrosome clustering and lead to multipolar mitosis in tetraploid cells by modulating the RhoA/ROCK signaling pathway

Dual Mechanisms of LYN Kinase Dysregulation Drive Aggressive Behavior in Breast Cancer Cells

The SRC-family kinase LYN is highly expressed in triple-negative/basal-like breast cancer (TNBC) and in the cell of origin of these tumors, c-KIT-positive luminal progenitors. Here, we demonstrate LYN is a downstream effector of c-KIT in normal mammary cells and protective of apoptosis upon genotoxic stress. LYN activity is modulated by PIN1, a prolyl isomerase, and in BRCA1 mutant TNBC PIN1 upregulation activates LYN independently of c-KIT. Furthermore, the full-length LYN splice isoform (as opposed to the Δaa25-45 variant) drives migration and invasion of aggressive TNBC cells, while the ratio of splice variants is informative for breast cancer-specific survival across all breast cancers. Thus, dual mechanisms-uncoupling from upstream signals and splice isoform ratios-drive the activity of LYN in aggressive breast cancers

Chronic digital infection presenting with gross enlargement of the toes: two case reports and review of the literature

There are many conditions ranging from the benign to the malignant, which can present with enlargement of one or more digits. An understanding of the differential diagnosis is important such that the potentially serious aetiologies are not missed and patients can therefore be treated appropriately

The British Services Dhaulagiri Medical Research Expedition 2016 : a unique military and civilian research collaboration

The British Service Dhaulagiri Research Expedition took place in March-May 2016. A total of 129 personnel took part in the expedition and were invited to consent to a variety of study protocols investigating adaptation to high altitudes and diagnosis of altitude illness. The study took place in a remote and inhospitable environment at altitudes up to 7500m. This paper gives an overview of the challenges involved, the research protocols investigated and the execution of the expedition in Nepal

Flexibility within the Heads of Muscle Myosin-2 Molecules

We show that negative-stain electron microscopy and image processing of nucleotide-free (apo) striated muscle myosin-2 subfragment-1 (S1), possessing one light chain or both light chains, is capable of resolving significant amounts of structural detail. The overall appearance of the motor and the lever is similar in rabbit, scallop and chicken S1. Projection matching of class averages of the different S1 types to projection views of two different crystal structures of apo S1 shows that all types most commonly closely resemble the appearance of the scallop S1 structure rather than the methylated chicken S1 structure. Methylation of chicken S1 has no effect on the structure of the molecule at this resolution: it too resembles the scallop S1 crystal structure. The lever is found to vary in its angle of attachment to the motor domain, with a hinge point located in the so-called pliant region between the converter and the essential light chain. The chicken S1 crystal structure lies near one end of the range of flexion observed. The Gaussian spread of angles of flexion suggests that flexibility is driven thermally, from which a torsional spring constant of ~ 23 pN·nm/rad2 is estimated on average for all S1 types, similar to myosin-5. This translates to apparent cantilever-type stiffness at the tip of the lever of 0.37 pN/nm. Because this stiffness is lower than recent estimates from myosin-2 heads attached to actin, we suggest that binding to actin leads to an allosteric stiffening of the motor–lever junction

The relationship between appetite and food preferences in British and Australian children

Background: Appetitive traits and food preferences are key determinants of children’s eating patterns but it is unclear how these behaviours relate to one another. This study explores relationships between appetitive traits and preferences for fruits and vegetables, and energy dense, nutrient poor (noncore) foods in two distinct samples of Australian and British preschool children. Methods: This study reports secondary analyses of data from families participating in the British GEMINI cohort study (n = 1044) and the control arm of the Australian NOURISH RCT (n = 167). Food preferences were assessed by parent-completed questionnaire when children were aged 3–4 years and grouped into three categories; vegetables, fruits and noncore foods. Appetitive traits; enjoyment of food, food responsiveness, satiety responsiveness, slowness in eating, and food fussiness were measured using the Children’s Eating Behaviour Questionnaire when children were 16 months (GEMINI) or 3–4 years (NOURISH). Relationships between appetitive traits and food preferences were explored using adjusted linear regression analyses that controlled for demographic and anthropometric covariates. Results: Vegetable liking was positively associated with enjoyment of food (GEMINI; β = 0.20 ± 0.03, p < 0.001, NOURISH; β = 0.43 ± 0.07, p < 0.001) and negatively related to satiety responsiveness (GEMINI; β = -0.19 ± 0.03, p < 0.001, NOURISH; β = -0.34 ± 0.08, p < 0.001), slowness in eating (GEMINI; β = -0.10 ± 0.03, p = 0.002, NOURISH; β = -0.30 ± 0.08, p < 0.001) and food fussiness (GEMINI; β = −0.30 ± 0.03, p < 0.001, NOURISH; β = -0.60 ± 0.06, p < 0.001). Fruit liking was positively associated with enjoyment of food (GEMINI; β = 0.18 ± 0.03, p < 0.001, NOURISH; β = 0.36 ± 0.08, p < 0.001), and negatively associated with satiety responsiveness (GEMINI; β = −0.13 ± 0.03, p < 0.001, NOURISH; β = −0.24 ± 0.08, p = 0.003), food fussiness (GEMINI; β = -0.26 ± 0.03, p < 0.001, NOURISH; β = −0.51 ± 0.07, p < 0.001) and slowness in eating (GEMINI only; β = -0.09 ± 0.03, p = 0.005). Food responsiveness was unrelated to liking for fruits or vegetables in either sample but was positively associated with noncore food preference (GEMINI; β = 0.10 ± 0.03, p = 0.001, NOURISH; β = 0.21 ± 0.08, p = 0.010). Conclusion: Appetitive traits linked with lower obesity risk were related to lower liking for fruits and vegetables, while food responsiveness, a trait linked with greater risk of overweight, was uniquely associated with higher liking for noncore foods