Microdeletion of target sites for insulator protein CTCF in a chromosome 11p15 imprinting center in Beckwith-Wiedemann syndrome and Wilms' tumor

We have analyzed several cases of Beckwith-Wiedemann syndrome (BWS) with Wilms' tumor in a familial setting, which give insight into the complex controls of imprinting and gene expression in the chromosome 11p15 region. We describe a 2.2-kbp microdeletion in the H19/insulin-like growth factor 2 (IGF2)-imprinting center eliminating three target sites of the chromatin insulator protein CTCF that we believe here is necessary, but not sufficient, to cause BWS and Wilms' tumor. Maternal inheritance of the deletion is associated with IGF2 loss of imprinting and up-regulation of IGF2 mRNA. However, in at least one affected family member a second genetic lesion (a duplication of maternal 11p15) was identified and accompanied by a further increase in IGF2 rnRNA levels 35-fold higher than control values. Our results suggest that the combined effects of the H19//GF2-imprinting center microdeletion and 11p15 chromosome duplication were necessary for manifestation of BWS

COMBREX: a project to accelerate the functional annotation of prokaryotic genomes

COMBREX (http://combrex.bu.edu) is a project to increase the speed of the functional annotation of new bacterial and archaeal genomes. It consists of a database of functional predictions produced by computational biologists and a mechanism for experimental biochemists to bid for the validation of those predictions. Small grants are available to support successful bids.National Institute of General Medical Sciences (U.S.) (Go grant 1RC2GM092602-01

Huntington’s Disease iPSC-Derived Brain Microvascular Endothelial Cells Reveal WNT-Mediated Angiogenic and Blood-Brain Barrier Deficits

Brain microvascular endothelial cells (BMECs) are an essential component of the blood-brain barrier (BBB) that shields the brain against toxins and immune cells. While BBB dysfunction exists in neurological disorders, including Huntington's disease (HD), it is not known if BMECs themselves are functionally compromised to promote BBB dysfunction. Further, the underlying mechanisms of BBB dysfunction remain elusive given limitations with mouse models and post-mortem tissue to identify primary deficits. We undertook a transcriptome and functional analysis of human induced pluripotent stem cell (iPSC)-derived BMECs (iBMEC) from HD patients or unaffected controls. We demonstrate that HD iBMECs have intrinsic abnormalities in angiogenesis and barrier properties, as well as in signaling pathways governing these processes. Thus, our findings provide an iPSC-derived BBB model for a neurodegenerative disease and demonstrate autonomous neurovascular deficits that may underlie HD pathology with implications for therapeutics and drug delivery.American Heart Association (12PRE10410000)American Heart Association (CIRMTG2-01152)National Institutes of Health (U.S.) (NIHNS089076

Technology-assisted stroke rehabilitation in Mexico: a pilot randomized trial comparing traditional therapy to circuit training in a Robot/technology-assisted therapy gym

Background Stroke rehabilitation in low- and middle-income countries, such as Mexico, is often hampered by lack of clinical resources and funding. To provide a cost-effective solution for comprehensive post-stroke rehabilitation that can alleviate the need for one-on-one physical or occupational therapy, in lower and upper extremities, we proposed and implemented a technology-assisted rehabilitation gymnasium in Chihuahua, Mexico. The Gymnasium for Robotic Rehabilitation (Robot Gym) consisted of low- and high-tech systems for upper and lower limb rehabilitation. Our hypothesis is that the Robot Gym can provide a cost- and labor-efficient alternative for post-stroke rehabilitation, while being more or as effective as traditional physical and occupational therapy approaches. Methods A typical group of stroke patients was randomly allocated to an intervention (n = 10) or a control group (n = 10). The intervention group received rehabilitation using the devices in the Robot Gym, whereas the control group (n = 10) received time-matched standard care. All of the study subjects were subjected to 24 two-hour therapy sessions over a period of 6 to 8 weeks. Several clinical assessments tests for upper and lower extremities were used to evaluate motor function pre- and post-intervention. A cost analysis was done to compare the cost effectiveness for both therapies. Results No significant differences were observed when comparing the results of the pre-intervention Mini-mental, Brunnstrom Test, and Geriatric Depression Scale Test, showing that both groups were functionally similar prior to the intervention. Although, both training groups were functionally equivalent, they had a significant age difference. The results of all of the upper extremity tests showed an improvement in function in both groups with no statistically significant differences between the groups. The Fugl-Meyer and the 10 Meters Walk lower extremity tests showed greater improvement in the intervention group compared to the control group. On the Time Up and Go Test, no statistically significant differences were observed pre- and post-intervention when comparing the control and the intervention groups. For the 6 Minute Walk Test, both groups presented a statistically significant difference pre- and post-intervention, showing progress in their performance. The robot gym therapy was more cost-effective than the traditional one-to-one therapy used during this study in that it enabled therapist to train up to 1.5 to 6 times more patients for the approximately same cost in the long term. Conclusions The results of this study showed that the patients that received therapy using the Robot Gym had enhanced functionality in the upper extremity tests similar to patients in the control group. In the lower extremity tests, the intervention patients showed more improvement than those subjected to traditional therapy. These results support that the Robot Gym can be as effective as traditional therapy for stroke patients, presenting a more cost- and labor-efficient option for countries with scarce clinical resources and funding. Trial registration ISRCTN98578807

COMBREX: a project to accelerate the functional annotation of prokaryotic genomes

COMBREX (http://combrex.bu.edu) is a project to increase the speed of the functional annotation of new bacterial and archaeal genomes. It consists of a database of functional predictions produced by computational biologists and a mechanism for experimental biochemists to bid for the validation of those predictions. Small grants are available to support successful bids.National Institute of General Medical Sciences (U.S.) (Go grant 1RC2GM092602-01

Nearfield Summary and Statistical Analysis of the Second AIAA Sonic Boom Prediction Workshop

A summary is provided for the Second AIAA Sonic Boom Workshop held 8-9 January 2017 in conjunction with AIAA SciTech 2017. The workshop used three required models of increasing complexity: an axisymmetric body, a wing body, and a complete configuration with flow-through nacelle. An optional complete configuration with propulsion boundary conditions is also provided. These models are designed with similar nearfield signatures to isolate geometry and shock/expansion interaction effects. Eleven international participant groups submitted nearfield signatures with forces, pitching moment, and iterative convergence norms. Statistics and grid convergence of these nearfield signatures are presented. These submissions are propagated to the ground, and noise levels are computed. This allows the grid convergence and the statistical distribution of a noise level to be computed. While progress is documented since the first workshop, improvement to the analysis methods for a possible subsequent workshop are provided. The complete configuration with flow-through nacelle showed the most dramatic improvement between the two workshops. The current workshop cases are more relevant to vehicles with lower loudness and have the potential for lower annoyance than the first workshop cases. The models for this workshop with quieter ground noise levels than the first workshop exposed weaknesses in analysis, particularly in convective discretization

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

MicroRNA-135b Regulates Leucine Zipper Tumor Suppressor 1 in Cutaneous Squamous Cell Carcinoma

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin malignancy and it presents a therapeutic challenge in organ transplant recipient patients. Despite the need, there are only a few targeted drug treatment options. Recent studies have revealed a pivotal role played by microRNAs (miRNAs) in multiple cancers, but only a few studies tested their function in cSCC. Here, we analyzed differential expression of 88 cancer related miRNAs in 43 study participants with cSCC; 32 immunocompetent, 11 OTR patients, and 15 non-lesional skin samples by microarray analysis. Of the examined miRNAs, miR-135b was the most upregulated (13.3-fold, 21.5-fold; p=0.0001) in both patient groups. Similarly, the miR-135b expression was also upregulated in three cSCC cell lines when evaluated by quantitative real-time PCR. In functional studies, inhibition of miR-135b by specific anti-miR oligonucleotides resulted in upregulation of its target gene LZTS1 mRNA and protein levels and led to decreased cell motility and invasion of both primary and metastatic cSCC cell lines. In contrast, miR-135b overexpression by synthetic miR-135b mimic induced further down-regulation of LZTS1 mRNA in vitro and increased cancer cell motility and invasiveness. Immunohistochemical evaluation of 67 cSCC tumor tissues demonstrated that miR-135b expression inversely correlated with LZTS1 staining intensity and the tumor grade. These results indicate that miR-135b functions as an oncogene in cSCC and provide new understanding into its pathological role in cSCC progression and invasiveness