Re-wiring the brain: Increased functional connectivity within primary somatosensory cortex following synchronous co-activation

AbstractThe primary somatosensory cortex shows precise topographical organisation, but can be quickly modified by alterations to sensory inputs. Temporally correlated sensory inputs to the digits can result in the merging of digit representations on the cortical surface. Underlying mechanisms driving these changes are unclear but the strengthening of intra-cortical synaptic connections via Hebbian mechanisms has been suggested. We use fMRI measures of temporal coherence to infer alterations in the relative strength of neuronal connections between digit regions 2 and 4 following 3hours of synchronous and asynchronous co-activation. Following synchronous co-activation we find a 20% increase in temporal coherence of the fMRI signal (p=0.0004). No significant change is seen following asynchronous co-activation suggesting that temporal coincidence between the two digit inputs during co-activation is driving this coherence change. In line with previous work we also find a trend towards reduced separation of the digit representations following synchronous co-activation and significantly increased separation for the asynchronous case. Increased coherence is significantly correlated with reduced digit separation for the synchronous case. This study shows that passive synchronous stimulation to the digits strengthens the underlying cortical connections between the digit regions in only a few hours, and that this mechanism may be related to topographical re-organisation

Routine versus As-Needed Bevacizumab with 12-Weekly Assessment Intervals for Neovascular Age-Related Macular Degeneration 92-Week Results of the GMAN Trial

PurposeTo evaluate the efficacy and safety of intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA) in patients with neovascular age-related macular degeneration (nAMD) using 2 different treatment regimens in which patients were assessed clinically at up to 12-week intervals.DesignRandomized, controlled, noninferiority trial.ParticipantsA total of 331 patients with nAMD.MethodsPatients were treated with 1.25 mg intravitreal bevacizumab and followed up to 92 weeks. They were randomized into 2 arms. All patients received 3 loading doses 4 weeks apart and thereafter were assessed every 12 weeks until the end of the study. One arm received a routine treatment at each 12-week assessment, and the other arm was treated at these assessments on an as-needed basis. After the loading doses, patients in either arm who showed signs of disease activity had an additional assessment after 6 weeks and at that visit had top-up treatments on an as-needed basis.Main Outcome MeasuresMean best-corrected visual acuity (BCVA) at 92 weeks.ResultsAt 92 weeks, patients who had treatments every 12 weeks had superior BCVA to those treated on an as-needed basis every 12 weeks (P = 0.008), with the regular treatment arm gaining a mean BCVA of 5.5 letters and the as-needed treatment arm gaining 0.6 letters. The regular treatment arm of the study showed significantly improved outcomes with respect to 5-, 10-, and 15-letter changes in BCVA from baseline compared with the as-needed treatment arm, as well as superior reading speed. In patients who completed the study, up to but not including week 92, the mean number of treatments was 10.8 for the regular treatment arm and 9.1 for the as-needed treatment arm.ConclusionsA treatment regimen with regular bevacizumab injections every 12 weeks after loading doses supplemented with as-needed top-up treatments produced a stable improvement in BCVA from baseline. The improvement in BCVA was broadly similar to that obtained in other studies using anti-vascular endothelial growth factor drugs with more frequent assessments and treatments

Interactive audio-tactile maps for visually impaired people

International audienceVisually impaired people face important challenges related to orientation and mobility. Indeed, 56% of visually impaired people in France declared having problems concerning autonomous mobility. These problems often mean that visually impaired people travel less, which influences their personal and professional life and can lead to exclusion from society. Therefore this issue presents a social challenge as well as an important research area. Accessible geographic maps are helpful for acquiring knowledge about a city's or neighborhood's configuration, as well as selecting a route to reach a destination. Traditionally, raised-line paper maps with braille text have been used. These maps have proved to be efficient for the acquisition of spatial knowledge by visually impaired people. Yet, these maps possess significant limitations. For instance, due to the specificities of the tactile sense only a limited amount of information can be displayed on a single map, which dramatically increases the number of maps that are needed. For the same reason, it is difficult to represent specific information such as distances. Finally, braille labels are used for textual descriptions but only a small percentage of the visually impaired population reads braille. In France 15% of blind people are braille readers and only 10% can read and write. In the United States, fewer than 10% of the legally blind people are braille readers and only 10% of blind children actually learn braille. Recent technological advances have enabled the design of interactive maps with the aim to overcome these limitations. Indeed, interactive maps have the potential to provide a broad spectrum of the population with spatial knowledge, irrespective of age, impairment, skill level, or other factors. To this regard, they might be an efficient means for providing visually impaired people with access to geospatial information. In this paper we give an overview of our research on making geographic maps accessible to visually impaired people

Two-loop effective potential for a general renormalizable theory and softly broken supersymmetry

I compute the two-loop effective potential in the Landau gauge for a general renormalizable field theory in four dimensions. Results are presented for the \bar{MS} renormalization scheme based on dimensional regularization, and for the \bar{DR} and \bar{DR}' schemes based on regularization by dimensional reduction. The last of these is appropriate for models with softly broken supersymmetry, such as the Minimal Supersymmetric Standard Model. I find the parameter redefinition which relates the \bar{DR} and \bar{DR}' schemes at two-loop order. I also discuss the renormalization group invariance of the two-loop effective potential, and compute the anomalous dimensions for scalars and the beta function for the vacuum energy at two-loop order in softly broken supersymmetry. Several illustrative examples and consistency checks are included.Comment: 38 pages. Typos in equations (3.5), (3.11), and (6.3) are fixed. Explicit claim of renormalization group invariance in the general case of softly-broken supersymmetry is added. Additional discussion of cases of multiple simple or U(1) groups. Equations in Appendix B rewritten in a more useful for

Two-Loop Renormalization Group Equations for Soft Supersymmetry-Breaking Couplings

We compute the two-loop renormalization group equations for all soft supersymmetry-breaking couplings in a general softly broken N=1 supersymmetric model. We also specialize these results to the Minimal Supersymmetric Standard Model.Comment: 26 pages. [v4: Signs of equations (4.2) and (4.3) are fixed.

Activation of STING-Dependent Innate Immune Signaling By S-Phase-Specific DNA Damage in Breast Cancer

Background: Previously we identified a DNA damage response–deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. Methods: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype. Isogenic cell lines, which represent DDRD-positive and -negative, were used to study the effects of chemokine release on peripheral blood mononuclear cell (PBMC) migration and the mechanism of immune signaling activation. Finally, we studied the association between the DDRD subtype and expression of the immune-checkpoint protein PD-L1 as detected by IHC. All statistical tests were two-sided. Results: We found that DDRD breast tumors were associated with CD4+ and CD8+ lymphocytic infiltration (Fisher’s exact test P < .001) and that DDRD cells expressed the chemokines CXCL10 and CCL5 3.5- to 11.9-fold more than DNA damage response–proficient cells (P < .01). Conditioned medium from DDRD cells statistically significantly attracted PBMCs when compared with medium from DNA damage response–proficient cells (P < .05), and this was dependent on CXCL10 and CCL5. DDRD cells demonstrated increased cytosolic DNA and constitutive activation of the viral response cGAS/STING/TBK1/IRF3 pathway. Importantly, this pathway was activated in a cell cycle–specific manner. Finally, we demonstrated that S-phase DNA damage activated expression of PD-L1 in a STING-dependent manner. Conclusions: We propose a novel mechanism of immune infiltration in DDRD tumors, independent of neoantigen production. Activation of this pathway and associated PD-L1 expression may explain the paradoxical lack of T-cell-mediated cytotoxicity observed in DDRD tumors. We provide a rationale for exploration of DDRD in the stratification of patients for immune checkpoint–based therapies

GABA Modulates Frequency-Dependent Plasticity in Humans

Frequency-dependent reorganization of the primary somatosensory cortex, together with perceptual changes, arises following repetitive sensory stimulation. Here, we investigate the role of GABA in this process. We co-stimulated two finger tips and measured GABA and Glx using magnetic resonance (MR) spectroscopy at the beginning and end of the stimulation. Participants performed a perceptual learning task before and after stimulation. There were 2 sessions with stimulation frequency either at or above the resonance frequency of the primary somatosensory cortex (23 and 39 Hz, respectively). Perceptual learning occurred following above resonance stimulation only, while GABA reduced during this condition. Lower levels of early GABA were associated with greater perceptual learning. One possible mechanism underlying this finding is that cortical disinhibition “unmasks” lateral connections within the cortex to permit adaptation to the sensory environment. These results provide evidence in humans for a frequency-dependent inhibitory mechanism underlying learning and suggest a mechanism-based approach for optimizing neurostimulation frequency

Health and wellbeing amongst older people research in Northamptonshire

The Ageing Research Centre of the University of Northampton (2014-current), in collaboration with the East Midlands Research into Ageing Network (EMRAN) is pleased to compile this brochure on research activity associated with older people across the county of Northamptonshire. This provides a comprehensive overview of activity that is relevant and of value to practice, identifying research outcomes that have real significance to age-related health and wellbeing. The brochure provides a summary of research activity over the last five years from academic, clinical and professional colleagues and demonstrates cross sector networks of collaboration around the common agenda of aging. Such collaboration will enhance the capacity of research understanding across the county and provide information and support for the needs of older people, their families and carers. The translation of research outcomes into practice is essential if we are to promote wellness, independence and healthy aging within the county and beyond and I would like to thank all contributors for their commitment and hard work in the production of this brochure