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Genome wide analysis revealed conserved domains involved in the effector discrimination of bacterial type VI secretion system

Type VI secretion systems (T6SS) inject protein effectors directly into the cytoplasm of target cells. The T6SS is important for activities as diverse as bacterial pathogenicity, symbiosis, and inter-bacterial competition. Nevertheless, questions remain as to how the so many diverse toxins can be selected for injection by the T6SS. This study presents a searchable online database of all examples of a specific critical component of all T6SS, VgrG. This protein is a “spike” that allows the system to puncture host membranes and deliver the effector. An additional “adapter” protein is required to link the effector to the VgrG. Our database allowed us to determine six domain families encoded within vgrG loci important in the selection process. This work should facilitate other researchers in the field to better understand what effector proteins they use and how they are selected by the T6SS. Read the paper here.Link opens in a new window

Fri 25 Oct 2024, 12:56 | Tags: BMS BMS_newpub

Policy Brief - Dr Katy Stokes, graduate of the MRC DTP programme

Congratulations to Dr Katy Stokes, a graduate of the MRC DTP programme, who recently published a policy brief with Baroness Natalie Bennett urging the responsible use of biocides in consumer goods.

This briefingLink opens in a new windowLink opens in a new window will accompany the introduction of a Consumer Products (Control of Biocides) Bill in the House of Lords, which focuses on safeguarding public health and the environment. To achieve this Katy undertook an internship with the British Society of Antimicrobial Chemotherapy (BASC)’s Parliamentary Internship Programme.

 

Wed 23 Oct 2024, 11:35 | Tags: BMS

Detailed Analysis of Electrogram Peak Frequency to guide Centricular Tachycardia Substrate Mapping

Professor Tarvinder Dhanjal, Professor of Cardiology, has had their latest manuscript published in EP Europace journal. The project was a multi-centre, international, mechanistic VT mapping study including UHCW, Brighton and Barcelona.

Abstract:
Differentiating near-field (NF) and far-field (FF) electrograms (EGMs) is crucial in identifying critical arrhythmogenic substrate during Ventricular Tachycardia (VT) ablation. A novel algorithm annotates NF fractionated signals enabling EGM Peak Frequency (PF) determination using wavelet transformation. This study evaluated the algorithms effectiveness in identifying critical components of the VT circuit during substrate mapping.
Read the paper here.

Fri 11 Oct 2024, 12:38 | Tags: BMS BMS_newpub

Insight into the emerging insect to human pathogen Photorhabdus revealing geographic differences in immune cell tropism

In this study, we investigate the differences between the pathogenic activities of P. asymbiotica isolates from different geographic locations. Pathogenicity was analysed using infection assays with both cultured cell lines (THP-1, CHO, and HEK cells) and primary immune cells, and peripheral blood mononuclear cells (PBMCs) isolated from human blood.

Read the paper here.

Fri 04 Oct 2024, 10:10 | Tags: BMS BMS_newpub

Single-cell analysis identifies distinct macrophage phenotypes associated with prodisease and proresolving functions in the endometriotic niche

Endometriosis negatively impacts the health-related quality of life of 190 million women worldwide. Novel advances in nonhormonal treatments for this debilitating condition are desperately needed. Macrophages play a vital role in the pathophysiology of endometriosis and represent a promising therapeutic target. In the current study, we revealed the full transcriptomic complexity of endometriosis-associated macrophage subpopulations using single-cell analyses in a preclinical mouse model of experimental endometriosis. We have identified two key lesion-resident populations that resemble i) tumor-associated macrophages (characterized by expression of Folr2, Mrc1, Gas6, and Ccl8+) that promoted expression of Col1a1 and Tgfb1 in human endometrial stromal cells and increased angiogenic meshes in human umbilical vein endothelial cells, and ii) scar-associated macrophages (Mmp12, Cd9, Spp1, Trem2+) that exhibited a phenotype associated with fibrosis and matrix remodeling. We also described a population of proresolving large peritoneal macrophages that align with a lipid-associated macrophage phenotype (Apoe, Saa3, Pid1) concomitant with altered lipid metabolism and cholesterol efflux. Gain of function experiments using an Apoe mimetic resulted in decreased lesion size and fibrosis, and modification of peritoneal macrophage populations in the preclinical model. Using cross-species analysis of mouse and human single-cell datasets, we determined the concordance of peritoneal and lesion-resident macrophage subpopulations, identifying key similarities and differences in transcriptomic phenotypes. Ultimately, we envisage that these findings will inform the design and use of specific macrophage-targeted therapies and open broad avenues for the treatment of endometriosis.
Read the paper here.Link opens in a new window

Fri 20 Sep 2024, 11:48 | Tags: BMS BMS_newpub

Single molecule dynamics in a virtual cell combining a 3-dimensional matrix model with random walks

Professor Justin Molloy has a new paper in the journal "Scientific Reports" in collaboration with Gregory I. Mashanov of the Francis Crick institute, London.
The paper describes a multiscale computer model that simulates the dynamics of individual molecules within the complex architecture of a living cell.

The motivation for this work was to develop computational tools to validate and test hypotheses resulting from recent technical advances that allow biologists to directly visualise individual molecules within living cells using video microscopy.

Biological molecules show dynamic changes in structure and position over a very wide range of time and length scales - from nanoseconds to tens of seconds and nanometres to tens of micrometres. These dynamic ranges can be difficult to capture, simulate and model. We present a multiscale modelling environment that helps to bridge the gap between time and length scales and model experimental data sets using relatively simple physical-chemical understandings of molecular interactions and thermal forces.

Read the paper here

Fri 13 Sep 2024, 13:33 | Tags: BMS BMS_newpub

Retirement: Prof Lawrence Young

After 12 years at the University of Warwick and an academic career spanning more than 40 years, Professor Lawrence Young retired at the end of July 2024.

Thu 29 Aug 2024, 11:34 | Tags: BMS

Receptor binding and tortuosity explain morphogen local-to-global diffusion coefficient transition

In this work, we explored how molecules (e.g., morphogens) move within biologically realistic domains. Our Singapore-based collaborators (Wohland lab) generated subcellular resolution maps of the developing zebrafish hindbrain using electron microscopy. Yi Ting Loo, a MathSys PhD student in the Saunders lab, built a simulation environment to explore how molecules would move within these maps. We accounted for tortuosity, dead-ends and receptor binding. Our results reveal how measurement techniques such as FCS and FRAP can lead to very different estimations of dynamic parameters (e.g., the diffusivity). Hopefully, this work provides a framework for properly accounting for biologically complex environments in estimating dynamics in living organisms.
Read the paper here.Link opens in a new window

Fri 16 Aug 2024, 10:39 | Tags: BMS BMS_newpub

Cryopreserved Kidney Epithelial (Vero) Cell Monolayers for Rapid Viral Quantification, Enabled by a Combination of Macromolecular Cryoprotectants

We demonstrate the cryopreservation of vero-cells in assay ready format using macromolecular cryoprotectants and induce ice nucleation.

Thu 01 Aug 2024, 14:31 | Tags: BMS BMS_newpub

Kinetic investigation of photoiniferter-RAFT polymerization in continuous flow using inline NMR analysis

Photo reversible deactivation radical polymerization and, in particular, photoiniferter-reversible addition–fragmentation chain transfer (PI-RAFT) polymerization have become popular approaches to polymer synthesis in recent years. There is, however, a lack of fundamental investigations concerning the mechanism and kinetics of such reactions.

Wed 31 Jul 2024, 12:07 | Tags: BMS BMS_newpub

CAMDU receives Technician Commitment Award for Outstanding Achievement - Team Award

CAMDU are pictured receiving their award from Professor Stuart Croft, Vice-Chancellor and President of Warwick.

CAMDU provides researchers with access, support and training on state-of-the-art light microscopes. In addition they input into research with highly specialised knowledge and train the next generation of scientists.

Congratulations to the outstanding team - Maelle, Laura, David and Tim.

CAMDU Team

Tue 30 Jul 2024, 10:06 | Tags: BMS

Technician Commitment Awards for Outstanding Achievement - Matthew Rosser highly commended in the individual award

Matthew Rosser

Tue 30 Jul 2024, 10:03 | Tags: BMS

New paper about the force generating mechanism of kinesin molecular motors

Sumiyoshi et al. is a collaboration addressing a question Robert Cross and Jun Yajima first asked themselves almost 20 years ago – would monomeric kinesin molecular motors tethered via surface loops still drive microtubule gliding? It turns out yes! Scanning a dsDNA tether across all exposed loops reveals a core mechanical cycle of the kinesin-1 motor domain that underlies, and is amplified by, linker docking.

Read the paper here.

Fri 19 Jul 2024, 10:49 | Tags: BMS BMS_newpub

Scientists make breakthrough in development of fridge-free storage for vital medicines

Scientists have developed a new approach to store and distribute crucial protein therapeutics without the need for fridges or freezers.

The breakthrough, published in the journal Nature, could significantly improve accessibility of essential protein-based drugs in developing countries where cold storage infrastructure may be lacking, helping efforts to diagnose and treat more people with serious health conditions.

The researchers, from the Universities of Manchester, Glasgow and Warwick, have designed a hydrogel – a material mostly made of water – that stabilises proteins, protecting its properties and functionality at temperatures as high as 50°C.

Thu 18 Jul 2024, 14:30 | Tags: BMS BMS_newpub

Enteric nervous system regeneration and functional cure of experimental digestive Chagas disease with trypanocidal chemotherapy

nervous system of the gastrointestinal tract, causing problems with peristalsis. Using an experimental model, Khan et al show that if the infection is successfully treated early enough then the damage can be reversed via a repair mechanism involving regeneration of nerve cells in the colon.
Read the paper here.Link opens in a new window

Thu 11 Jul 2024, 11:43 | Tags: BMS BMS_newpub

Dynamics of Trypanosoma cruzi infection in hamsters and novel association with progressive motor dysfunction

Much of our knowledge about how T. cruzi causes Chagas disease comes from studies of infections in mice, but the data do not capture the full range of clinical outcomes seen in humans. In this paper, we developed a hamster model of T. cruzi infection with two striking features – almost exclusive restriction of chronic infection to a skin tissue niche and a progressive gait dysfunction resembling cerebral palsy.
Read the paper here.Link opens in a new window

Wed 10 Jul 2024, 08:28 | Tags: BMS BMS_newpub

A panel of phenotypically and genotypically diverse bioluminescent: fluorescent Trypanosoma cruzi strains as a resource for Chagas disease research

The Chagas disease drug discovery pipeline has been focused on a few model T. cruzi strains, but this does not reflect the parasite’s genetic diversity present across the millions of infected people. Here we present an expanded panel of strains engineered to express dual bioluminescent-fluorescent fusion reporter genes that can be used to ensure candidate compounds have in vivo activity across the species before being advanced into clinical testing.
Read the paper here.Link opens in a new window

Tue 09 Jul 2024, 08:06 | Tags: BMS BMS_newpub

Hub stability in the calcium calmodulin-dependent protein kinase II

In this paper we use a combination of cryo-electron microscopy (CryoEM) and total internal reflection fluorescence microscopy (TIRFM) to investigate structural plasticity of the multi-subunit protein kinase called CaMKII. CaMKII plays a critical role in synaptic transmission by neuronal cells and the fact we observe intrinsic variation in stoichiometry and pleomorphology of the complex is important because subunit number is thought to play a critical role in alteration of dendritic spine anatomy, which underlies the structural basis of learning.
Read the paper here.Link opens in a new window

Mon 08 Jul 2024, 15:19 | Tags: BMS BMS_newpub

Structural characterization and inhibition of the interaction between ch-TOG and TACC3

In this paper we describe the structure of the interaction between TACC3 and ch-TOG. A single helix from ch-TOG, normally bound to two hairpins, pops out and binds to the coiled-coil of TACC3. We then isolated Affimers (non-antibody binders) that inhibit this interaction in vitro. Moving into cells, we could express the Affimers to inhibit the ch-TOG–TACC3 interaction and found a new function for these two proteins in stabilizing the pericentriolar material.
Read the paper here.Link opens in a new window

Mon 10 Jun 2024, 09:05 | Tags: BMS BMS_newpub

Non-disruptive inducible labeling of ER-membrane contact sites using the Lamin B Receptor

Laura Downie has invented a new way of labelling ER-Membrane Contact Sites in live cells on-demand. It uses the Lamin B Receptor so we called it “LaBeRling”. Unlike other methods, LaBeRling doesn’t distort existing contacts. It can label many different contacts between ER and other organelles (plasma membrane, mitochondria, lysosomes, endosomes, lipid droplets). Here, Laura uses LaBeRling to look at ER-Golgi contact sites in mitosis for the first time.
Read the paper hereLink opens in a new window.

Mon 10 Jun 2024, 09:03 | Tags: BMS BMS_newpub

Bariatric surgery for spontaneous ovulation in women living with polycystic ovary syndrome: the BAMBINI multicentre, open-label, randomised controlled trial

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Obesity exacerbates the reproductive complications of PCOS; however, the management of obesity in women with PCOS remains a large unmet clinical need. Observational studies have indicated that bariatric surgery could improve the rates of ovulatory cycles and prospects of fertility; however, the efficacy of surgery on ovulation rates has not yet been compared with behavioural modifications and medical therapy in a randomised trial. The aim of this study was to compare the safety and efficacy of bariatric surgery versus medical care on ovulation rates in women with PCOS, obesity, and oligomenorrhoea or amenorrhoea.
Read the paper hereLink opens in a new window.

Tue 28 May 2024, 10:24 | Tags: BMS BMS_newpub

Interdisciplinary Biomedical Research Building awarded RIBA West Midlands Building of the Year

Our Interdisciplinary Biomedical Research Building, which we share with the School of Life Sciences, has been awarded the West Midlands Building of the Year award from the Royal Institute of British Architects.

Mon 13 May 2024, 11:37 | Tags: news BMS

Global spread of Salmonella enterica due to centralised industrialisation of pig farming

In a collaboration between Soochow (China), Institut Pasteur (Shanghai), CDC (China), Liverpool, Georgia (US), and Warwick we investigated the host-specificity of S. enterica based on 362,931 publically accessible genomes in EnteroBase (a database of sequenced enteric bacteria genomes hosted and developed at Warwick). We detected the presence of nine populations that are enriched in pigs and observed frequent intercontinental transmission of genetically almost identical strains in these pig-enriched populations, which cannot be explained solely by natural causes. Therefore, we focused on one population enriched in pigs, serovar Choleraesuis, reconstructing the historical fluctuations in this population, accumulation of antimicrobial-resistant genes, and international transmissions. We revealed a 2-stage expansion in the population of this serovar, the first associated with the development of intensive pig farming in the early 20th century and the second due to the increased frequency of antimicrobial resistance after the 1960s. Additionally, we found that Europe and the USA contributed the most to international transmissions of this serovar.
Read the paper hereLink opens in a new window.
Read the press release here.Link opens in a new window

Mon 13 May 2024, 09:26 | Tags: BMS BMS_newpub

Professor Robert Cross awarded Biochemical Society Award for Sustained Excellence 2025

Professor Robert Cross, Warwick Medical School has been awarded the Biochemical Society Award for Sustained Excellence 2025.

The work and contribution of fifteen eminent bioscientists, outstanding educators and exceptional early career researchers has been acknowledged in the annual Biochemical Society Awards following a record year of nominations - Find out more and read the full article here

Thu 04 Apr 2024, 10:56 | Tags: news BMS

Long-range formation of the Bicoid gradient requires multiple dynamic modes that spatially vary across the embryo

Morphogen gradients provide essential positional information to gene networks through their spatially heterogeneous distribution, yet how they form is still hotly contested, with multiple models proposed for different systems. Here, we focus on the transcription factor Bicoid (Bcd), a morphogen that forms an exponential gradient across the anterior-posterior (AP) axis of the early Drosophila embryo. Using fluorescence correlation spectroscopy we find there are spatial differences in Bcd diffusivity along the AP axis, with Bcd diffusing more rapidly in the posterior. We establish that such spatially varying differences in Bcd dynamics are sufficient to explain how Bcd can have a steep exponential gradient in the anterior half of the embryo and yet still have an observable fraction of Bcd near the posterior pole. In the nucleus, we demonstrate that Bcd dynamics are impacted by binding to DNA. Addition of the Bcd homeodomain to eGFP::NLS qualitatively replicates the Bcd concentration profile, suggesting this domain regulates Bcd dynamics. Our results reveal how a long-range gradient can form while retaining a steep profile through much of its range. Read the paper here.

Tue 12 Mar 2024, 08:45 | Tags: BMS BMS_newpub

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