Passive immunotherapy against Aβ in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage

BACKGROUND: Anti-Aβ immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Aβ antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-Aβ antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. RESULTS: After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Aβ immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. CONCLUSIONS: The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage

Contemplative Science: An Insider's Prospectus

This chapter describes the potential far‐reaching consequences of contemplative higher education for the fields of science and medicine

Drumming To Communicate Emotion: Dual-Brain Imaging Informs An Intervention In A Carceral Setting

Drumming is an ancient nonverbal communication modality for expression of emotion. However, there has been limited exploration of its possible applications in clinical settings. Further, the underlying neural systems engaged during live communication with drumming have not been identified. We investigated the neural response to live, natural communication of emotion via drumming using a novel dual-brain neuroimaging paradigm to discover its unique neurophysiological mechanisms related to drum behavior and cross-brain coherence, and as compared to talking. We then investigated the application of a drumming intervention in an incarcerated, halfway house population to characterize intervention feasibility, elucidate the phenomenology of social and emotional effects of group drumming, and identify its possible benefits for treatment engagement and community reintegration. For neural response investigation, hemodynamic signals were acquired using whole-head functional near infrared spectroscopy. Dyads of 36 subjects participated in two conditions, drumming and talking, alternating between “sending” (drumming or talking to partner) and “receiving” (listening to partner) in response to emotionally salient images from the International Affective Picture System. Results indicated that increased frequency and amplitude of drum strikes was behaviorally correlated with higher arousal and lower valence measures, and neurally correlated with temporoparietal junction (TPJ) activation in the listener. Contrast comparisons of drumming greater than talking also revealed neural activity in right TPJ. For the interventional investigation, a group drumming program was implemented once a week for eight weeks for incarcerated participants in a halfway house. Twenty-eight participants were randomized to either the drum group or treatment as usual. Interviews and a focus group were conducted to assess the experienced benefits of the group drumming intervention, and halfway house retention rates were compared across groups. Retention rate was significantly higher in the drum group than in the treatment as usual group. Qualitative analysis elicited three themes: group drumming 1) functions therapeutically as a method of coping with difficulty, 2) offers opportunity for connection through building relationship and experiencing communion in a setting where isolation is the norm, and 3) provides an environment for personal growth, particularly toward re-humanization and self-empowerment. Neural findings suggest that emotional content communicated by drumming engages right TPJ mechanisms in an emotionally and behaviorally sensitive fashion; interventional findings suggest significant therapeutic potential in social and emotional domains that can have quantifiable impact on recovery process. Together, findings suggest that drumming may provide access to neural mechanisms with known sensitivity to social and emotional conditions that facilitates therapeutic aims. Informed by this research, drumming may provide novel, effective clinical approaches for treating social-emotional psychopathology

Computational Resources to Filter Gravitational Wave Data with P-approximant Templates

The prior knowledge of the gravitational waveform from compact binary systems makes matched filtering an attractive detection strategy. This detection method involves the filtering of the detector output with a set of theoretical waveforms or templates. One of the most important factors in this strategy is knowing how many templates are needed in order to reduce the loss of possible signals. In this study we calculate the number of templates and computational power needed for a one-step search for gravitational waves from inspiralling binary systems. We build on previous works by firstly expanding the post-Newtonian waveforms to 2.5-PN order and secondly, for the first time, calculating the number of templates needed when using P-approximant waveforms. The analysis is carried out for the four main first-generation interferometers, LIGO, GEO600, VIRGO and TAMA. As well as template number, we also calculate the computational cost of generating banks of templates for filtering GW data. We carry out the calculations for two initial conditions. In the first case we assume a minimum individual mass of $1 M_{\odot}$ and in the second, we assume a minimum individual mass of $5 M_{\odot}$. We find that, in general, we need more P-approximant templates to carry out a search than if we use standard PN templates. This increase varies according to the order of PN-approximation, but can be as high as a factor of 3 and is explained by the smaller span of the P-approximant templates as we go to higher masses. The promising outcome is that for 2-PN templates the increase is small and is outweighed by the known robustness of the 2-PN P-approximant templates.Comment: 17 pages, 8 figures, Submitted to Class.Quant.Gra

Suprasellar Ganglioglioma: Expanding the Differential Diagnosis

This case study describes a young man with symptoms suggestive of the presence of a space-occupying lesion within the cranial cavity. Imaging studies confirmed a lesion in the suprasellar region and surgical intervention to remove the tumor yielded an unexpected diagnosis. Neuroimaging characteristics and histopathology including immunohistochemistry are described. Gangliogliomas are uncommon CNS neoplasms and are most commonly found in the temporal and frontal lobes of young, male adults. They are rarely seen in the suprasellar region and only a handful of cases have been reported to date. The differential diagnoses associated with these suprasellar region lesions can be dependent on the age of the patient and neuroimaging characteristics. The present report highlights the importance of histopathological examination and the need to consider a wide range of diagnostic entities in the differential diagnosis of lesions in this topographic distribution, including rarely encountered tumors such as gangliogliomas

Communication of emotion via drumming: dual-brain imaging with functional near-infrared spectroscopy

Nonverbal communication of emotion is essential to human interaction and relevant to many clinical applications, yet it is an understudied topic in social neuroscience. Drumming is an ancient nonverbal communication modality for expression of emotion that has not been previously investigated in this context. We investigate the neural response to live, natural communication of emotion via drumming using a novel dual-brain neuroimaging paradigm. Hemodynamic signals were acquired using whole-head functional near-infrared spectroscopy (fNIRS). Dyads of 36 subjects participated in two conditions, drumming and talking, alternating between 'sending' (drumming or talking to partner) and 'receiving' (listening to partner) in response to emotionally salient images from the International Affective Picture System. Increased frequency and amplitude of drum strikes was behaviorally correlated with higher arousal and lower valence measures and neurally correlated with temporoparietal junction (TPJ) activation in the listener. Contrast comparisons of drumming greater than talking also revealed neural activity in right TPJ. Together, findings suggest that emotional content communicated by drumming engages right TPJ mechanisms in an emotionally and behaviorally sensitive fashion. Drumming may provide novel, effective clinical approaches for treating social-emotional psychopathology

Proposal of RT-PCReBased Mass Population Screening for Severe Acute Respiratory Syndrome Coronavirus 2 (Coronavirus Disease 2019)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing has lagged in many countries because of test kit shortages and analytical process bottlenecks. This study investigated the feasibility and accuracy of a sample pooling approach for wide-scale population screening for coronavirus disease 2019. A total of 940 nasopharyngeal swab samples (934 negative and 6 positive) previously tested for SARS-CoV-2 were deidentified and assigned random numbers for analysis, and 94 pools of 10 samples each were generated. Automated RNA extraction, followed by RT-PCR, was performed in a 96-well plate. Positive pools were identified, and the individual samples were reanalyzed. Of the 94 pools/wells, four were positive [Ct values: N (22.7 to 28.3), ORF1ab (23.3 to 27.2), and internal control (34.4 to 35.4)]. The 40 samples comprising the four pools were identified and reanalyzed individually; six samples were positive, with Ct values of N gene, ORF1ab, and internal control comparable to their respective wells. Additional experiments were performed on samples with high Ct values, and overall results showed 91.6% positive and 100% negative agreement compared with individual testing approach. Thus, 940 samples were tested in 148 reactions compared with 940 reactions in routine screening. The sample pooling strategy may help catch up with testing needs and minimal turnaround times and facilitate enormous savings on laboratory supplies, extraction, and PCR kits currently in short supply

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

Human matrix metalloproteinases (MMPs) belong to the M10 family of the MA clan of endopeptidases. They are ubiquitarian enzymes, structurally characterized by an active site where a Zn(2+) atom, coordinated by three histidines, plays the catalytic role, assisted by a glutamic acid as a general base. Various MMPs display different domain composition, which is very important for macromolecular substrates recognition. Substrate specificity is very different among MMPs, being often associated to their cellular compartmentalization and/or cellular type where they are expressed. An extensive review of the different MMPs structural and functional features is integrated with their pathological role in several types of diseases, spanning from cancer to cardiovascular diseases and to neurodegeneration. It emerges a very complex and crucial role played by these enzymes in many physiological and pathological processes

D4cpv-calsequestrin: a sensitive ratiometric biosensor accurately targeted to the calcium store of skeletal muscle

Current fluorescent monitors of free [Ca2+] in the sarcoplasmic reticulum (SR) of skeletal muscle cells are of limited quantitative value. They provide either a nonratio signal that is difficult to calibrate and is not specific or, in the case of Forster resonant energy transfer (FRET) biosensors, a signal of small dynamic range, which may be degraded further by imperfect targeting and interference from endogenous ligands of calsequestrin. We describe a novel tool that uses the cameleon D4cpv, which has a greater dynamic range and lower susceptibility to endogenous ligands than earlier cameleons. D4cpv was targeted to the SR by fusion with the cDNA of calsequestrin 1 or a variant that binds less Ca2+. “D4cpv-Casq1,” expressed in adult mouse at concentrations up to 22 µmole/liter of muscle cell, displayed the accurate targeting of calsequestrin and stayed inside cells after permeabilization of surface and t system membranes, which confirmed its strict targeting. FRET ratio changes of D4cpv-Casq1 were calibrated inside cells, with an effective KD of 222 µM and a dynamic range [(Rmax − Rmin)/Rmin] of 2.5, which are improvements over comparable sensors. Both the maximal ratio, Rmax, and its resting value were slightly lower in areas of high expression, a variation that was inversely correlated to distance from the sites of protein synthesis. The average [Ca2+]SR in 74 viable cells at rest was 416 µM. The distribution of individual ratio values was Gaussian, but that of the calculated [Ca2+]SR was skewed, with a tail of very large values, up to 6 mM. Model calculations reproduce this skewness as the consequence of quantifiably small variations in biosensor performance. Local variability, a perceived weakness of biosensors, thus becomes quantifiable. It is demonstrably small in D4cpv. D4cpv-Casq1 therefore provides substantial improvements in sensitivity, specificity, and reproducibility over existing monitors of SR free Ca2+ concentration