R-parity Conservation via the Stueckelberg Mechanism: LHC and Dark Matter Signals

We investigate the connection between the conservation of R-parity in supersymmetry and the Stueckelberg mechanism for the mass generation of the B-L vector gauge boson. It is shown that with universal boundary conditions for soft terms of sfermions in each family at the high scale and with the Stueckelberg mechanism for generating mass for the B-L gauge boson present in the theory, electric charge conservation guarantees the conservation of R-parity in the minimal B-L extended supersymmetric standard model. We also discuss non-minimal extensions. This includes extensions where the gauge symmetries arise with an additional U(1)_{B-L} x U(1)_X, where U(1)_X is a hidden sector gauge group. In this case the presence of the additional U(1)_X allows for a Z' gauge boson mass with B-L interactions to lie in the sub-TeV region overcoming the multi-TeV LEP constraints. The possible tests of the models at colliders and in dark matter experiments are analyzed including signals of a low mass Z' resonance and the production of spin zero bosons and their decays into two photons. In this model two types of dark matter candidates emerge which are Majorana and Dirac particles. Predictions are made for a possible simultaneous observation of new physics events in dark matter experiments and at the LHC.Comment: 38 pages, 7 fig

Massive-Scale RNA-Seq Analysis of Non Ribosomal Transcriptome in Human Trisomy 21

Hybridization- and tag-based technologies have been successfully used in Down syndrome to identify genes involved in various aspects of the pathogenesis. However, these technologies suffer from several limits and drawbacks and, to date, information about rare, even though relevant, RNA species such as long and small non-coding RNAs, is completely missing. Indeed, none of published works has still described the whole transcriptional landscape of Down syndrome. Although the recent advances in high-throughput RNA sequencing have revealed the complexity of transcriptomes, most of them rely on polyA enrichment protocols, able to detect only a small fraction of total RNA content. On the opposite end, massive-scale RNA sequencing on rRNA-depleted samples allows the survey of the complete set of coding and non-coding RNA species, now emerging as novel contributors to pathogenic mechanisms. Hence, in this work we analysed for the first time the complete transcriptome of human trisomic endothelial progenitor cells to an unprecedented level of resolution and sensitivity by RNA-sequencing. Our analysis allowed us to detect differential expression of even low expressed genes crucial for the pathogenesis, to disclose novel regions of active transcription outside yet annotated loci, and to investigate a plethora of non-polyadenilated long as well as short non coding RNAs. Novel splice isoforms for a large subset of crucial genes, and novel extended untranslated regions for known genes—possibly novel miRNA targets or regulatory sites for gene transcription—were also identified in this study. Coupling the rRNA depletion of samples, followed by high-throughput RNA-sequencing, to the easy availability of these cells renders this approach very feasible for transcriptome studies, offering the possibility of investigating in-depth blood-related pathological features of Down syndrome, as well as other genetic disorders

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease

A realistic intersecting D6-brane model after the first LHC run

With the Higgs boson mass around 125 GeV and the LHC supersymmetry search constraints, we revisit a three-family Pati-Salam model from intersecting D6-branes in Type IIA string theory on the $\mathbf{T^6/(\Z_2 \times \Z_2)}$ orientifold which has a realistic phenomenology. We systematically scan the parameter space for $\mu0$, and find that the gravitino mass is generically heavier than about 2 TeV for both cases due to the Higgs mass low bound 123 GeV. In particular, we identify a region of parameter space with the electroweak fine-tuning as small as $\Delta_{EW} \sim$ 24-32 (3-4$\%$). In the viable parameter space which is consistent with all the current constraints, the mass ranges for gluino, the first two-generation squarks and sleptons are respectively $[3, ~18]$ TeV, $[3, ~16]$ TeV, and $[2, ~7]$ TeV. For the third-generation sfermions, the light stop satisfying $5\sigma$ WMAP bounds via neutralino-stop coannihilation has mass from 0.5 to 1.2 TeV, and the light stau can be as light as 800 GeV. We also show various coannihilation and resonance scenarios through which the observed dark matter relic density is achieved. Interestingly, the certain portions of parameter space has excellent $t$-$b$-$\tau$ and $b$-$\tau$ Yukawa coupling unification. Three regions of parameter space are highlighted as well where the dominant component of the lightest neutralino is a bino, wino or higgsino. We discuss various scenarios in which such solutions may avoid recent astrophysical bounds in case if they satisfy or above observed relic density bounds. Prospects of finding higgsino-like neutralino in direct and indirect searches are also studied. And we display six tables of benchmark points depicting various interesting features of our model.Comment: 41 pages, 12 figures, 6 table

The binding of the small heat-shock protein αB-crystallin to fibrils of α-synuclein is driven by entropic forces.

Molecular chaperones are key components of the cellular proteostasis network whose role includes the suppression of the formation and proliferation of pathogenic aggregates associated with neurodegenerative diseases. The molecular principles that allow chaperones to recognize misfolded and aggregated proteins remain, however, incompletely understood. To address this challenge, here we probe the thermodynamics and kinetics of the interactions between chaperones and protein aggregates under native solution conditions using a microfluidic platform. We focus on the binding between amyloid fibrils of α-synuclein, associated with Parkinson's disease, to the small heat-shock protein αB-crystallin, a chaperone widely involved in the cellular stress response. We find that αB-crystallin binds to α-synuclein fibrils with high nanomolar affinity and that the binding is driven by entropy rather than enthalpy. Measurements of the change in heat capacity indicate significant entropic gain originates from the disassembly of the oligomeric chaperones that function as an entropic buffer system. These results shed light on the functional roles of chaperone oligomerization and show that chaperones are stored as inactive complexes which are capable of releasing active subunits to target aberrant misfolded species.The research leading to these results has received funding from the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007- 2013) through the ERC grant PhysProt (agreement n◦ 337969) (TS, TPJK). Furthermore, we acknowledge financial support from the Marie Curie fellowship scheme for career development (PA), EPSRC (EP/J01835x/1) (OT,JLPB), BBSRC, the Cambridge Commonwealth, European and International Trust (MMJB), the NIHOxford Cambridge Scholars Programme (MMJB), the Oppenheimer Fellowship (THW), the Frances and Augustus Newman Foundation (TPJK), the Wellcome Trust (094425/Z/10/Z) (CMD, MV, TPJK), the UK Research and Innovation Future Leaders Fellowship (MR/S033947/1) (FAA) and the Alzheimer’s Society, UK (511) (FAA). Furthermore, we thank Eva Klimont for protein preparation and Alexander Büll for helpful discussion