αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation.

Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases (αKGDDs), and prior work has shown that changes in αKGDD affect demethylases. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that Trimethyllysine Hydroxylase Epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation, while histone methylation was affected but dispensable. The increase in histone acetylation via αKG-dependent carnitine synthesis promoted HR-mediated DNA repair through site- and substrate-specific histone acetylation. These data demonstrate for the first time that HR-proficiency is mediated through αKG directly influencing histone acetylation via carnitine synthesis and provide a metabolic avenue to induce HR-deficiency and sensitivity to DNA damaging agents.

Brown fat ATP-citrate lyase links carbohydrate availability to thermogenesis and guards against metabolic stress.

Brown adipose tissue (BAT) engages futile fatty acid synthesis-oxidation cycling, the purpose of which has remained elusive. Here, we show that ATP-citrate lyase (ACLY), which generates acetyl-CoA for fatty acid synthesis, promotes thermogenesis by mitigating metabolic stress. Without ACLY, BAT overloads the tricarboxylic acid cycle, activates the integrated stress response (ISR) and suppresses thermogenesis. ACLY's role in preventing BAT stress becomes critical when mice are weaned onto a carbohydrate-plentiful diet, while removing dietary carbohydrates prevents stress induction in ACLY-deficient BAT. ACLY loss also upregulates fatty acid synthase (Fasn); yet while ISR activation is not caused by impaired fatty acid synthesis per se, deleting Fasn and Acly unlocks an alternative metabolic programme that overcomes tricarboxylic acid cycle overload, prevents ISR activation and rescues thermogenesis. Overall, we uncover a previously unappreciated role for ACLY in mitigating mitochondrial stress that links dietary carbohydrates to uncoupling protein 1-dependent thermogenesis and provides fundamental insight into the fatty acid synthesis-oxidation paradox in BAT.

High-Resolution CT Chest Findings in Suspected COVID-19 Pneumonia Patients With Negative Real-Time Polymerase Chain Reaction Assay.

Objective The study was conducted with the objective of describing High-resolution computed tomography (HRCT) chest findings of clinically suspected COVID-19 patients having a negative real-time polymerase chain reaction (RT-PCR) assay as well as prevalence and distribution of the HRCT chest manifestations consistent with the diagnosis of COVID-19 pneumonia. Methods This descriptive cross-sectional study was conducted prospectively on a total of 48 patients with high clinical suspicion for COVID-19 and a negative RT-PCR assay that was presented to the Diagnostic Radiology Department of Capital Hospital, Islamabad from July 2020 to December 2020. These patients were included via non-probability consecutive sampling, had a positive history of contact with a known COVID-19 patient and/or any two of the following signs and symptoms; fever, cough, malaise, body aches, arthralgia, new-onset loss of taste and smell, and dyspnea or oxygen saturation less than 85%. A detailed history was sought after informed consent and all these patients underwent non-contrast HRCT chest scans that were reported by an experienced consultant radiologist. The scans showing positive features for COVID-19 pneumonia were assessed for the nature and distribution of the disease. Results Amongst 48 suspects with negative RT-PCR assay, 38 (79.2%) showed ground-glass opacities, a hallmark feature of COVID-19 pneumonia. A total of 22 (57.89%) of these 38 patients had ground-glass opacities with a crazy-paving pattern, nine (23.68%) mixed ground-glass opacities with consolidation, and seven (18.42%) had pure ground-glass opacities. Among these 79.2% suspects, ground-glass opacities were multifocal in 37 (97.37%), bilateral in 35 (92.10%), peripheral in 36 (94.74%), and dorsally located in 32 (81.6%) cases. Subpleural atelectatic bands were seen in 18 (47.36%) of these, bronchovascular markings were prominent in 15 (39.47%), and reverse halo sign was positive in nine (23.68%) cases. Out of the rest of the cases, three were diagnosed as interstitial lung disease, two as chronic lung disease, and one as active pulmonary tuberculosis. Conclusion The majority of clinically suspected cases for COVID-19 showed hallmark findings on non-contrast HRCT chest scans in keeping with coronavirus disease regardless of a negative RT-PCR assay.

An audio-visual motor training improves audio spatial localization skills in individuals with scotomas due to retinal degenerative diseases.

Several studies have shown that impairments in a sensory modality can induce perceptual deficits in tasks involving the remaining senses. For example, people with retinal degenerative diseases like Macular Degeneration (MD) and with central scotoma show biased auditory localization abilities towards the visual field's scotoma area. This result indicates an auditory spatial reorganization of cross-modal processing in people with scotoma when the visual information is impaired. Recent works showed that multisensory training could be beneficial to improve spatial perception. In line with this idea, here we hypothesize that audio-visual and motor training could improve people's spatial skills with retinal degenerative diseases. In the present study, we tested this hypothesis by testing two groups of scotoma patients in an auditory and visual localization task before and after a training or rest performance. The training group was tested before and after multisensory training, while the control group performed the two tasks twice after 10 min of break. The training was done with a portable device positioned on the finger, providing spatially and temporally congruent audio and visual feedback during arm movement. Our findings show improved audio and visual localization for the training group and not for the control group. These results suggest that integrating multiple spatial sensory cues can improve the spatial perception of scotoma patients. This finding ignites further research and applications for people with central scotoma for whom rehabilitation is classically focused on training visual modality only.

Audio-Visual Thumble (AVT): A low-vision rehabilitation device using multisensory feedbacks.

Since the 70s sensory substitution devices have been used for blind individuals to compensate for the lack of vision and enable them to perceive environment through intact sensory modalities. In this study, we present a rehabilitation device called Audio Visual Thumble (AVT), which is a small ring-like device with LED and buzzer, that can be worn on pharynx. We focus on a unique group of low-vision individuals with a black spot or scotoma in their visual field due to a disease called Macular Degeneration. The visual localization abilities of these individuals are highly impaired due to developing scotoma. We recently showed that also their audio localization skills are impaired [9]. Rehabilitation techniques developed so far for Macular Degeneration focus on visual modality only. Since audition can also be used to improve their spatial skills, we developed the AVT device. It permits to associate the multisensory information (audio and visual feedbacks) coming from the device with the own movement (proprioceptive feedback). We propose that the AVT has the potential to help people with visual dysfunctions to improve in the identification of audio and visual targets outside or at the edge of the residual visual field. AVT could be used for a wide range of applications combined with classical rehabilitation techniques in Macular Degeneration patients.Clinical relevance- This device can be an effective addition for low-vision rehabilitation experts and can be used combined with classical rehabilitation methods.

The Sound of Scotoma: Audio Space Representation Reorganization in Individuals With Macular Degeneration.

Blindness is an ideal condition to study the role of visual input on the development of spatial representation, as studies have shown how audio space representation reorganizes in blindness. However, how spatial reorganization works is still unclear. A limitation of the study on blindness is that it is a "stable" system and it does not allow for studying the mechanisms that subtend the progress of this reorganization. To overcome this problem here we study, for the first time, audio spatial reorganization in 18 adults with macular degeneration (MD) for which the loss of vision due to scotoma is an ongoing progressive process. Our results show that the loss of vision produces immediate changes in the processing of spatial audio signals. In individuals with MD, the lateral sounds are "attracted" toward the central scotoma position resulting in a strong bias in the spatial auditory percept. This result suggests that the reorganization of audio space representation is a fast and plastic process occurring also later in life, after vision loss.