Direct Visualization of 3-Dimensional Force and Energy Map of a Single Molecular Switch

Mechanical properties of molecules adsorbed on materials surfaces are increasingly vital for the applications of molecular thin films. Here, we conduct a fundamental research to induce conformational change mechanically on a single molecule and quantify the driving force needed for such molecular shape switch via a low temperature (~ 5K) Scanning Tunneling Microscope (STM) and Qplus Atomic Force Microscope (Q+AFM). Our measurement maps a three-dimensional landscape for mechanical potential and force at single molecule level with high spatial resolution in all three dimensions of a few angstrom (10-10 m). Molecule TBrPP-Co (a cobalt porphyrin) deposited on an atomically clean gold substrate typically has two of its pentagon rings tilted upward and the other two downward. An atomically sharp tip of the STM/Q+AFM, which vibrates with a high frequency (~ 30kHz), is employed to scan the molecule at different heights with 0.1Å increment and meanwhile record tip-molecule interaction strength in the form of tip frequency change. When tip approaches to the threshold distance to the molecule, mechanical force become large enough and cause pentagon rings flip their direction. Due to the sensitive nature of tip-molecule interaction, the rings flipping can be directly visualized by STM, as rings tilting upward exhibit two bright protrusions in contrast to rings downward in image. By processing frequency change, we obtain a three-dimensional mechanical potential and force map for a single molecule with the resolution of angstrom level in all three dimensions. Our preliminary results indicate that an energy barrier of ~400meV needs to be overcome for rings flipping of TBrPP-Co.https://digitalcommons.odu.edu/gradposters2021_sciences/1015/thumbnail.jp

Performanse višeimpulsno-pozicijske amplitudne modulacije za TH IR-UWB komunikacijske sustave

The multi pulse position amplitude modulation scheme for time-hopping multiple access impulse radio ultrawideband communication systems has been presented in this paper. Multi pulse position amplitude modulation is a hybrid modulation technique, which combines multi pulse position modulation and pulse amplitude modulation. It is shown that multi pulse position amplitude modulation significantly outperforms pulse position modulation with respect to bandwidth efficiency. The multi pulse position amplitude modulation error probability over IEEE 802.15.3a multipath fading channels in multiuser environment is derived. The system analysis shows that the proper selection of modulation parameters can improve the system performance at the cost of hardware complexity (and vice versa).U ovom je radu predstavljena višeimpulsno-pozicijska amplitudna modulacijska shema za impulsne ultraširokopojasne radiokomunikacijske sustave, zasnovana na višekorisničkom pristupu s vremenskim skakanjem. Višeimpulsno-pozicijska amplitudna modulacija je hibridni modulacijski postupak, koji je kombinacija višeimpulsno-pozicijske modulacije i impulsno-amplitudne modulacije. Pokazano je da višeimpulsno-pozicijska amplitudna modulacija značajno nadmašuje impulsno-pozicijsku modulaciju u pogledu pojasne učinkovitosti. Izvedena je vjerojatnost pogreške višeimpulsno-pozicijske amplitudne modulacije u kanalu IEEE 802.15.3a s višestaznim rasprostiranjem i iščezavanjem signala u višekorisničkom okruženju. Analiza sustava pokazuje da odgovaraju ći izbor parametara modulacije može poboljšati performanse sustava uz povećanje složenosti sklopovlja (i obrnuto)

Metastable chaos in the ammonia ring laser

We report experimental studies of metastable chaos in the far-infrared ammonia ring: laser. When the laser pump power is switched from above chaos threshold to slightly below, chaotic intensity pulsations continue for a varying time afterward before decaying to either periodic or cw emission. The behavior is in good qualitative agreement with that predicted by the Lorenz equations, previously used to describe this laser. The statistical distribution of the duration of the chaotic transient is measured and shown to be in excellent agreement with the Lorenz equations in showing a modified exponential distribution. We also give a brief numerical analysis and graphical visualization of the Lorenz equations in phase space illustrating the boundary between the metastable chaotic and the stable fixed point basins of attraction. This provides an intuitive understanding of the metastable dynamics of the Lorenz equations and the experimental system

Examining the immunological effects of COVID-19 vaccination in patients with conditions potentially leading to diminished immune response capacity – the OCTAVE trial

SARS-COV-2 vaccines have been shown to be efficacious primarily in healthy volunteer populations and population level studies. Immune responses following SARS-CoV-2 vaccination are less well characterised in potentially immune vulnerable patient groups, including those with immune-mediated inflammatory and chronic diseases (inflammatory arthritis [IA] incorporating rheumatoid arthritis [RA] and psoriatic arthritis [PsA]; ANCA-Associated Vasculitis [AAV]; inflammatory bowel disease [IBD]); hepatic disease (HepD), end stage kidney disease requiring haemodialysis (HD) without or with immunosuppression (HDIS); solid cancers (SC) and haematological malignancies (HM), and those that have undergone haemopoietic stem cell transplant (HSCT). The OCTAVE trial is a multi-centre, multi-disease, prospective cohort that will comprehensively assess SARS-CoV-2 vaccine responses within and between the abovementioned disease cohorts using common analytical platforms in patients recruited across the United Kingdom (UK). The majority of subjects received either COVID-19 mRNA Vaccine BNT162b2 (Pfizer/BioNTech) or ChAdOx1 Vaccine (AstraZeneca formerly AZD1222) as part of the UK National COVID19 vaccination programme. As of 13 th August 2021; 2,583 patients have been recruited. We report herein the humoral and T cell immune response results from the first 600 participants recruited where serology data are available at baseline, pre-second vaccine dose (boost) and/or 4 weeks post second dose. We also include in the analysis, data obtained from 231 healthy individuals from the PITCH (Protective Immunity from T cells in Healthcare workers) study. Overall, in comparison to PITCH where 100% of tested individuals (n=93) generated anti-Spike antibodies after vaccine doses, 89% of patients within OCTAVE seroconverted 4 weeks after second vaccine dose. By corollary, approximately 11% of patients across all disease cohorts fail to generate antibodies that react to SARS-CoV-2 spike 4 weeks after two vaccines. Failure to generate spike reactive antibodies was found at a higher proportion in some specific patient subgroups, particularly AAV (72.4%), HD-IS (16.7%) and HepD (16.7%). Importantly, all recruited AAV patients had received Rituximab; a targeted B cell depletion therapy. Furthermore, even in those who seroconverted, 40% of patients across disease cohorts generate lower levels of SARS-CoV-2 antibody reactivity compared to healthy subjects after two SARS-CoV-2 vaccines; the functional significance of these findings in providing protection from subsequent SARS-CoV-2 exposure is not currently known. In contrast to the observed serological response, evaluation of the Spike-specific T cell response revealed that across all patient sub-groups (including AAV) a response similar to healthy individuals was generated. Our data argue strongly for further vaccination strategies to optimise humoral immune responses against SARS-CoV-2 in patients with chronic diseases and/or patients on immune suppressive therapies. Trial Registration: The trial is registered on ISRCTN 12821688.Funding: This work was supported by the Medical Research Council COVID-19 Immunity – National Core Study (IMM-NCS) [grant number MC-PC-20031]. Staff at the Cancer Research UK Clinical Trials Unit (CRCTU) are supported by a core funding grant from Cancer Research UK (C22436/A25354). PK and EB are supported by the NIHR Birmingham Biomedical Research Centres at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham Biomedical Research Centres. EB and PK are supported by an NIHR Senior Investigator award. PK is funded by WT109965MA. SJD is funded by an NIHR Global Research Professorship (NIHR300791). TdS is funded by a Wellcome Trust Intermediate Clinical Fellowship (110058/Z/15/Z). DS is supported by the NIHR Academic Clinical Lecturer programme in Oxford. LT is supported by the Wellcome Trust (grant number 205228/Z/16/Z), the U.S. Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085. and the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. The PITCH (Protective Immunity from T cells to Covid-19 in Health workers) Consortium, is funded by the UK Department of Health and Social Care with contributions from UKRI/NIHR through the UK Coronavirus Immunology Consortium (UKCIC), the Huo Family Foundation and The National Institute for Health Research (UKRIDHSC COVID-19 Rapid Response Rolling Call, Grant Reference Number COV19-RECPLAS).Declaration of Interest: None to declare. Ethical Approval: This study was approved by the UK Medicines and Healthcare Products Regulatory Agency on the 5th February 2021 and the London and Chelsea Research Ethics Committee (REC Ref:21/HRA/0489) on 12th February 2021, with subsequent amendments approved on 3rd March 2021, 19th April 2021 and 26th April 2021)

Stochastic averaging using elliptic functions to study nonlinear stochastic systems

In this paper, a new scheme of stochastic averaging using elliptic functions is presented that approximates nonlinear dynamical systems with strong cubic nonlinearities in the presence of noise by a set of Itô differential equations. This is an extension of some recent results presented in deterministic dynamical systems. The second order nonlinear differential equation that is examined in this work can be expressed as % MathType!MTEF!2!1!+-% feaafiart1ev1aaatCvAUfeBSjuyZL2yd9gzLbvyNv2CaerbuLwBLn% hiov2DGi1BTfMBaeXatLxBI9gBaerbd9wDYLwzYbItLDharqqtubsr% 4rNCHbGeaGqiVu0Je9sqqrpepC0xbbL8F4rqqrFfpeea0xe9Lq-Jc9% vqaqpepm0xbba9pwe9Q8fs0-yqaqpepae9pg0FirpepeKkFr0xfr-x% fr-xb9adbaqaaeGaciGaaiaabeqaamaabaabaaGcbaWexLMBb50ujb% qeguuDJXwAKbacfiGaf8hEaGNbamaacqGHRaWkcaWGJbadcaaIXaGc% cqWF4baEcqGHRaWkcaWGJbadcaaIZaGccqWF4baEdaahaaWcbeqaai% aaiodaaaGccqGHRaWkcqaH1oqzcaWGMbGaaiikaiab-Hha4jaacYca% cqWFGaaicuWF4baEgaGaaiaacMcacqGHRaWkcqaH1oqzdaahaaWcbe% qaaiaaigdacaGGVaGaaGOmaaaaruWrL9MCNLwyaGGbcOGaa43zaiaa% cIcacqWF4baEcaGGSaGae8hiaaIaf8hEaGNbaiaacaGGSaGae8hiaa% IaeqOVdGNaaeikaiaadshacaqGPaGaaiykaiabg2da9iaaicdaaaa!645D![ddot x + c1x + c3x^3 + varepsilon f(x, dot x) + varepsilon ^{1/2} g(x, dot x, xi {text{(}}t{text{)}}) = 0] where c 1 and c 3 are given constants, ξ( t ) is stationary stochastic process with zero mean and ε≪1 is a small parameter. This method involves the laborious manipulation of Jacobian elliptic functions such as cn, dn and sn rather than the usual trigonometric functions. The use of a symbolic language such as Mathematica reduces the computational effort and allows us to express the results in a convenient form. The resulting equations are Markov approximations of amplitude and phase involving integrals of elliptic functions. Finally, this method was applied to study some standard second order systems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/43328/1/11071_2004_Article_BF00120672.pd

Antibody-mediated enhancement aggravates chikungunya virus infection and disease severity

The arthropod-transmitted chikungunya virus (CHIKV) causes a flu-like disease that is characterized by incapacitating arthralgia. The re-emergence of CHIKV and the continual risk of new epidemics have reignited research in CHIKV pathogenesis. Virus-specific antibodies have been shown to control virus clearance, but antibodies present at sub-neutralizing concentrations can also augment virus infection that exacerbates disease severity. To explore this occurrence, CHIKV infection was investigated in the presence of CHIKV-specific antibodies in both primary human cells and a murine macrophage cell line, RAW264.7. Enhanced attachment of CHIKV to the primary human monocytes and B cells was observed while increased viral replication was detected in RAW264.7 cells. Blocking of specific Fc receptors (FcγRs) led to the abrogation of these observations. Furthermore, experimental infection in adult mice showed that animals had higher viral RNA loads and endured more severe joint inflammation in the presence of sub-neutralizing concentrations of CHIKV-specific antibodies. In addition, CHIKV infection in 11 days old mice under enhancing condition resulted in higher muscles viral RNA load detected and death. These observations provide the first evidence of antibody-mediated enhancement in CHIKV infection and pathogenesis and could also be relevant for other important arboviruses such as Zika virus

A Novel Docetaxel-Loaded Poly (ε-Caprolactone)/Pluronic F68 Nanoparticle Overcoming Multidrug Resistance for Breast Cancer Treatment

Multidrug resistance (MDR) in tumor cells is a significant obstacle to the success of chemotherapy in many cancers. The purpose of this research is to test the possibility of docetaxel-loaded poly (ε-caprolactone)/Pluronic F68 (PCL/Pluronic F68) nanoparticles to overcome MDR in docetaxel-resistance human breast cancer cell line. Docetaxel-loaded nanoparticles were prepared by modified solvent displacement method using commercial PCL and self-synthesized PCL/Pluronic F68, respectively. PCL/Pluronic F68 nanoparticles were found to be of spherical shape with a rough and porous surface. The nanoparticles had an average size of around 200 nm with a narrow size distribution. The in vitro drug release profile of both nanoparticle formulations showed a biphasic release pattern. There was an increased level of uptake of PCL/Pluronic F68 nanoparticles in docetaxel-resistance human breast cancer cell line, MCF-7 TAX30, when compared with PCL nanoparticles. The cytotoxicity of PCL nanoparticles was higher than commercial Taxotere®in the MCF-7 TAX30 cell culture, but the differences were not significant (p > 0.05). However, the PCL/Pluronic F68 nanoparticles achieved significantly higher level of cytotoxicity than both of PCL nanoparticles and Taxotere®(p < 0.05), indicating docetaxel-loaded PCL/Pluronic F68 nanoparticles could overcome multidrug resistance in human breast cancer cells and therefore have considerable potential for treatment of breast cancer

Coevolution between a Family of Parasite Virulence Effectors and a Class of LINE-1 Retrotransposons

Parasites are able to evolve rapidly and overcome host defense mechanisms, but the molecular basis of this adaptation is poorly understood. Powdery mildew fungi (Erysiphales, Ascomycota) are obligate biotrophic parasites infecting nearly 10,000 plant genera. They obtain their nutrients from host plants through specialized feeding structures known as haustoria. We previously identified the AVRk1 powdery mildew-specific gene family encoding effectors that contribute to the successful establishment of haustoria. Here, we report the extensive proliferation of the AVRk1 gene family throughout the genome of B. graminis, with sequences diverging in formae speciales adapted to infect different hosts. Also, importantly, we have discovered that the effectors have coevolved with a particular family of LINE-1 retrotransposons, named TE1a. The coevolution of these two entities indicates a mutual benefit to the association, which could ultimately contribute to parasite adaptation and success. We propose that the association would benefit 1) the powdery mildew fungus, by providing a mechanism for amplifying and diversifying effectors and 2) the associated retrotransposons, by providing a basis for their maintenance through selection in the fungal genome

Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes

BACKGROUND: Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers. METHODS: A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry. RESULTS: During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56). CONCLUSION: Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers