SYF2 suppression mitigates neurodegeneration in models of diverse forms of ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by many diverse genetic etiologies. Although therapeutics that specifically target causal mutations may rescue individual types of ALS, such approaches cannot treat most patients since they have unknown genetic etiology. Thus, there is a critical need for therapeutic strategies that rescue multiple forms of ALS. Here, we combine phenotypic chemical screening on a diverse cohort of ALS patient-derived neurons with bioinformatic analysis of large chemical and genetic perturbational datasets to identify broadly effective genetic targets for ALS. We show that suppressing the gene-encoding, spliceosome-associated factor SYF2 alleviates TDP-43 aggregation and mislocalization, improves TDP-43 activity, and rescues C9ORF72 and causes sporadic ALS neuron survival. Moreover, Syf2 suppression ameliorates neurodegeneration, neuromuscular junction loss, and motor dysfunction in TDP-43 mice. Thus, suppression of spliceosome-associated factors such as SYF2 may be a broadly effective therapeutic approach for ALS.

Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons.

An intronic GGGGCC repeat expansion in C9ORF72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the pathogenic mechanism of this repeat remains unclear. Using human induced motor neurons (iMNs), we found that repeat-expanded C9ORF72 was haploinsufficient in ALS. We found that C9ORF72 interacted with endosomes and was required for normal vesicle trafficking and lysosomal biogenesis in motor neurons. Repeat expansion reduced C9ORF72 expression, triggering neurodegeneration through two mechanisms: accumulation of glutamate receptors, leading to excitotoxicity, and impaired clearance of neurotoxic dipeptide repeat proteins derived from the repeat expansion. Thus, cooperativity between gain- and loss-of-function mechanisms led to neurodegeneration. Restoring C9ORF72 levels or augmenting its function with constitutively active RAB5 or chemical modulators of RAB5 effectors rescued patient neuron survival and ameliorated neurodegenerative processes in both gain- and loss-of-function C9ORF72 mouse models. Thus, modulating vesicle trafficking was able to rescue neurodegeneration caused by the C9ORF72 repeat expansion. Coupled with rare mutations in ALS2, FIG4, CHMP2B, OPTN and SQSTM1, our results reveal mechanistic convergence on vesicle trafficking in ALS and FTD.

Motion tracking in infrared imaging for quantitative medical diagnostic applications.

In medical applications, infrared (IR) thermography is used to detect and examine the thermal signature of skin abnormalities by quantitatively analyzing skin temperature in steady state conditions or its evolution over time, captured in an image sequence. However, during the image acquisition period, the involuntary movements of the patient are unavoidable, and such movements will undermine the accuracy of temperature measurement for any particular location on the skin. In this study, a tracking approach using a template-based algorithm is proposed, to follow the involuntary motion of the subject in the IR image sequence. The motion tacking will allow to associate a temperature evolution to each spatial location on the body while the body moves relative to the image frame. The affine transformation model is adopted to estimate the motion parameters of the template image. The Lucas-Kanade algorithm is applied to search for the optimized parameters of the affine transformation. A weighting mask is incorporated into the algorithm to ensure its tracking robustness. To evaluate the feasibility of the tracking approach, two sets of IR image sequences with random in-plane motion were tested in our experiments. A steady-state (no heating or cooling) IR image sequence in which the skin temperature is in equilibrium with the environment was considered first. The thermal recovery IR image sequence, acquired when the skin is recovering from 60-s cooling, was the second case analyzed. By proper selection of the template image along with template update, satisfactory tracking results were obtained for both IR image sequences. The achieved tracking accuracies are promising in terms of satisfying the demands imposed by clinical applications of IR thermography.

Involuntary motion tracking for medical dynamic infrared thermography using a template-based algorithm.

In medical applications, Dynamic Infrared (IR) Thermography is used to detect the temporal variation of the skin temperature. Dynamic Infrared Imaging first introduces a thermal challenge such as cooling on the human skin, and then a sequence of hundreds of consecutive frames is acquired after the removal of the thermal challenge. As a result, by analyzing the temporal variation of the skin temperature over the image sequence, the thermal signature of skin abnormality can be examined. However, during the acquisition of dynamic IR imaging, the involuntary movements of patients are unavoidable, and such movements will undermine the accuracy of diagnosis. In this study, based on the template-based algorithm, a tracking approach is proposed to compensate the motion artifact. The affine warping model is adopted to estimate the motion parameter of the image template, and then the Lucas-Kanade algorithm is applied to search for the optimized parameters of the warping function. In addition, the weighting mask is also incorporated in the computation to ensure the robustness of the algorithm. To evaluate the performance of the approach, two sets of IR image sequences of a subject's hand are analyzed: the steady-state image sequence, in which the skin temperature is in equilibrium with the environment, and the thermal recovery image sequence, which is acquired after cooling is applied on the skin for 60 seconds. By selecting the target region in the first frame as the template, satisfactory tracking results were obtained in both experimental trials, and the robustness of the approach can be effectively ensured in the recovery trial.

CURVATURE EFFECT QUANTIFICATION FOR IN-VIVO IR THERMOGRAPHY.

Medical Infrared (IR) Imaging has become an important diagnostic tool over recent years. However, one underlying problem in medical diagnostics is associated with accurate quantification of body surface temperatures. This problem is caused by the artifacts induced by the curvature of objects, which leads to inaccurate temperature mapping and biased diagnostic results. Therefore, in our study, an experiment-based analysis is conducted to address the curvature effects toward the 3D temperature reconstruction of the IR thermography image. For quantification purposes, an isothermal copper plate with flat surface, and a cylindrical metal container filled with water are imaged. For the flat surface, the tilting angle measured from camera axis was varied incrementally from 0° to 60 °, such that the effects of surface viewing angle and travel distance on the measured temperature can be explored. On the cylindrical curved surface, the points viewed from 0° to 90° with respect to the camera axis are simultaneously imaged at different temperature levels. The experimental data obtained for the flat surface indicate that both viewing angle and distance effects become noticeable for angles over 40 °. The travel distance contributes a minor change when compared with viewing angle. The experimental results from the curved surface indicate that the curvature effect becomes pronounced when the viewing angle is larger than 60 °. The measurement error on the curved surface is compared with the simulation using the non-dielectric model, and the normalized temperature difference relative to 0° viewing angle was analyzed at six temperature levels. These results indicate that the linear formula associated with directional emissivity is a reasonable approximation for the measurement error, and the normalized error curves change consistently with viewing angle at various temperatures. Therefore, the analysis in this study implies that the directional emissivity based on the non-dielectric model can be applied for the calibration of measurement error. The normalized error curve serves as a consistent basis to correct the measurement error due to curvature artifacts.

Split-focused ultrasound transducer with multidirectional heating for breast tumor thermal surgery.

This study investigated the feasibility of using a split-focused ultrasound transducer to perform thermal surgery on breast tumors, based on a multidirectional heating scheme. The transducer is a square section of a sphere with a radius of 10 cm. The transducer was tilted such that its acoustic beam was 45 degrees relative to the rib surface, and its focal zone was arranged by a shift of 6 mm away from the center of the planning target volume. The multifocus switching technique was employed to enhance the heating efficiency. When a single transducer was used, the transducer sonicated from a certain position for a given duration, and then rotated sequentially to continue the heating. Computer simulations and in vitro phantom experiments have been studied for this heating system. Both simulation and experimental results demonstrated that the system based on a multidirectional heating scheme is capable of generating a proper thermal lesion within 8 min. Meanwhile, from the simulation results, the rib heating was effectively alleviated by tilting the transducer to induce the total reflection at the muscle/bone interface. While using multiple ultrasound transducers, an appropriate arrangement was designed to have the same configuration of acoustic beams as is used for a single-transducer strategy. The simulation results from the four-transducer strategy indicated that the heating results could be further improved. This study revealed that it is very promising to have an appropriate arrangement of a single split-focused ultrasound transducer with mechanical rotation, or to have multiple split-focused transducers that use multidirectional heating for breast tumor thermal therapy.

Thermal therapy for breast tumors by using a cylindrical ultrasound phased array with multifocus pattern scanning: a preliminary numerical study.

The purpose of this study is to investigate the feasibility of using a 1 MHz cylindrical ultrasound phased array with multifocus pattern scanning to produce uniform heating for breast tumor thermal therapy. The breast was submerged in water and surrounded by the cylindrical ultrasound phased array. A multifocus pattern was generated and electrically scanned by the phased array to enlarge the treatment lesion in single heating. To prevent overheating normal tissues, a large planning target volume (PTV) would be divided into several planes with several subunits on each plane and sequentially treated with a cooling phase between two successive heatings of the subunit. Heating results for different target temperatures (T(tgt)), blood perfusion rates and sizes of the PTV have been studied. Furthermore, a superficial breast tumor with different water temperatures was also studied. Results indicated that a higher target temperature would produce a slightly larger thermal lesion, and a higher blood perfusion rate would not affect the heating lesion size but increase the heating time significantly. The acoustic power deposition and temperature elevations in ribs can be minimized by orienting the acoustic beam from the ultrasound phased array approximately parallel to the ribs. In addition, a large acoustic window on the convex-shaped breast surface for the proposed ultrasound phased array and the cooling effect of water would prevent the skin overheating for the production of a lesion at any desired location. This study demonstrated that the proposed cylindrical ultrasound phased array can provide effective heating for breast tumor thermal therapy without overheating the skin and ribs within a reasonable treatment time.