The Physiology of Homeoprotein Transduction.

The homeoprotein family comprises ~300 transcription factors and was long seen as primarily involved in developmental programs through cell autonomous regulation. However, recent evidence reveals that many of these factors are also expressed in the adult where they exert physiological functions not yet fully deciphered. Furthermore, the DNA-binding domain of most homeoproteins contains two signal sequences allowing their secretion and internalization, thus intercellular transfer. This review focuses on this new-found signaling in cell migration, axon guidance, and cerebral cortex physiological homeostasis and speculates on how it may play important roles in early arealization of the neuroepithelium. It also describes the use of homeoproteins as therapeutic proteins in mouse models of diseases affecting the central nervous system, in particular Parkinson disease and glaucoma.

Engrailed homeoprotein blocks degeneration in adult dopaminergic neurons through LINE-1 repression.

LINE-1 mobile genetic elements have shaped the mammalian genome during evolution. A minority of them have escaped fossilization which, when activated, can threaten genome integrity. We report that LINE-1 are expressed in substantia nigra ventral midbrain dopaminergic neurons, a class of neurons that degenerate in Parkinson's disease. In Engrailed-1 heterozygotes, these neurons show a progressive degeneration that starts at 6 weeks of age, coinciding with an increase in LINE-1 expression. Similarly, DNA damage and cell death, induced by an acute oxidative stress applied to embryonic midbrain neurons in culture or to adult midbrain dopaminergic neurons in vivo, are accompanied by enhanced LINE-1 expression. Reduction of LINE-1 activity through (i) direct transcriptional repression by Engrailed, (ii) a siRNA directed against LINE-1, (iii) the nucleoside analogue reverse transcriptase inhibitor stavudine, and (iv) viral Piwil1 expression, protects against oxidative stress in vitro and in vivo We thus propose that LINE-1 overexpression triggers oxidative stress-induced DNA strand breaks and that an Engrailed adult function is to protect mesencephalic dopaminergic neurons through the repression of LINE-1 expression.

The story of a deformed leprous foot.

Eccrine syringofibroadenoma (ESFA) is a rare adnexal tumour of eccrine ductal proliferation. A 50 year old treated case of leprosy presented with a chronic non healing ulcer of 5 years duration on the deformity laden right foot. Multiple verrucous papules and plaques were seen surrounding the ulcer which showed histopathological findings consistent with ESFA. Although ESFA constitutes a rare association with leprosy, considering the load of treated cases in our country and elsewhere, it may represent an under-reported entity which requires more attention in the post elimination era.

Neuroprotective Transcription Factors in Animal Models of Parkinson Disease.

A number of transcription factors, including En1/2, Foxa1/2, Lmx1a/b, Nurr1, Otx2, and Pitx3, with key roles in midbrain dopaminergic (mDA) neuron development, also regulate adult mDA neuron survival and physiology. Mouse models with targeted disruption of some of these genes display several features reminiscent of Parkinson disease (PD), in particular the selective and progressive loss of mDA neurons in the substantia nigra pars compacta (SNpc). The characterization of these animal models has provided valuable insights into various mechanisms of PD pathogenesis. Therefore, the dissection of the mechanisms and survival signalling pathways engaged by these transcription factors to protect mDA neuron from degeneration can suggest novel therapeutic strategies. The work on En1/2-mediated neuroprotection also highlights the potential of protein transduction technology for neuroprotective approaches in PD.

Progressive nigrostriatal terminal dysfunction and degeneration in the engrailed1 heterozygous mouse model of Parkinson's disease.

Current research on Parkinson's disease (PD) pathogenesis requires relevant animal models that mimic the gradual and progressive development of neuronal dysfunction and degeneration that characterizes the disease. Polymorphisms in engrailed 1 (En1), a homeobox transcription factor that is crucial for both the development and survival of mesencephalic dopaminergic neurons, are associated with sporadic PD. This suggests that En1 mutant mice might be a promising candidate PD model. Indeed, a mouse that lacks one En1 allele exhibits decreased mitochondrial complex I activity and progressive midbrain dopamine neuron degeneration in adulthood, both features associated with PD. We aimed to further characterize the disease-like phenotype of these En1(+/-) mice with a focus on early neurodegenerative changes that can be utilized to score efficacy of future disease modifying studies. We observed early terminal defects in the dopaminergic nigrostriatal pathway in En1(+/-) mice. Several weeks before a significant loss of dopaminergic neurons in the substantia nigra could be detected, we found that striatal terminals expressing high levels of dopaminergic neuron markers TH, VMAT2, and DAT were dystrophic and swollen. Using transmission electron microscopy, we identified electron dense bodies consistent with abnormal autophagic vacuoles in these terminal swellings. In line with these findings, we detected an up-regulation of the mTOR pathway, concurrent with a downregulation of the autophagic marker LC3B, in ventral midbrain and nigral dopaminergic neurons of the En1(+/-) mice. This supports the notion that autophagic protein degradation is reduced in the absence of one En1 allele. We imaged the nigrostriatal pathway using the CLARITY technique and observed many fragmented axons in the medial forebrain bundle of the En1(+/-) mice, consistent with axonal maintenance failure. Using in vivo electrochemistry, we found that nigrostriatal terminals in the dorsal striatum were severely deficient in dopamine release and reuptake. Our findings support a progressive retrograde degeneration of En1(+/-) nigrostriatal neurons, akin to what is suggested to occur in PD. We suggest that using the En1(+/-) mice as a model will provide further key insights into PD pathogenesis, and propose that axon terminal integrity and function can be utilized to estimate dopaminergic neuron health and efficacy of experimental PD therapies.

Engrailed homeoprotein recruits the adenosine A1 receptor to potentiate ephrin A5 function in retinal growth cones.

Engrailed 1 and engrailed 2 homeoprotein transcription factors (collectively Engrailed) display graded expression in the chick optic tectum where they participate in retino-tectal patterning. In vitro, extracellular Engrailed guides retinal ganglion cell (RGC) axons and synergises with ephrin A5 to provoke the collapse of temporal growth cones. In vivo disruption of endogenous extracellular Engrailed leads to misrouting of RGC axons. Here we characterise the signalling pathway of extracellular Engrailed. Our results show that Engrailed/ephrin A5 synergy in growth cone collapse involves adenosine A1 receptor activation after Engrailed-dependent ATP synthesis, followed by ATP secretion and hydrolysis to adenosine. This is, to our knowledge, the first evidence for a role of the adenosine A1 receptor in axon guidance. Based on these results, together with higher expression of the adenosine A1 receptor in temporal than nasal growth cones, we propose a computational model that illustrates how the interaction between Engrailed, ephrin A5 and adenosine could increase the precision of the retinal projection map.

Evolving pattern of platelet P2Y12 inhibition in patients with acute coronary syndromes.

Dual antiplatelet therapy consisting of clopidogrel in addition to aspirin has previously been the standard of care for patients with acute coronary syndromes (ACS) but international guidelines have been evolving over the last 4 years with the introduction of prasugrel and ticagrelor. In October 2009, prasugrel was approved in the UK by the National Institute of Health and Clinical Excellence (NICE) for use in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI), diabetic patients with non-ST-elevation (NSTE) ACS undergoing PCI and patients with stent thrombosis while other ACS patients were to continue receiving clopidogrel. Ticagrelor was approved in October 2011 by NICE for use in patients with moderate-to-high risk NSTE ACS and STEMI undergoing primary PCI and was recommended in preference to clopidogrel in European guidelines. These recommendations were adopted in our region, constituting a population of 1.8 million. We studied the effect of changing patterns of P2Y12 inhibitor usage on levels of platelet inhibition during maintenance therapy. Patients admitted to Northern General Hospital, Sheffield, with NSTE ACS or STEMI managed with primary PCI were enrolled over two periods of time: May 2010 to November 2011 (T1); and October 2012 to February 2013 (T2). Venous blood samples were obtained at 1 month after the onset of ACS. Light transmittance aggregometry (LTA) was performed and maximum aggregation response to ADP 20 µM was determined. A total of 116 patients were enrolled in T1 of whom 82 were receiving clopidogrel and 34 were receiving prasugrel. Twenty-nine patients were enrolled in T2, all of whom were receiving ticagrelor. Mean LTA results according to treatment with clopidogrel, prasugrel and ticagrelor were 57 ± 18%, 41 ± 20%, and 31 ± 12%, respectively. Prasugrel was associated with significantly lower platelet aggregation responses than clopidogrel (p < 0.001) and ticagrelor was associated with significantly lower platelet aggregation responses than both prasugrel (p = 0.015) and clopidogrel (p < 0.001). We conclude that international guidelines and NICE approval have led to increasing levels of P2Y12 inhibition in ACS patients in this UK centre between May 2010 and February 2013. Ticagrelor was associated with significantly greater P2Y12 inhibition than both clopidogrel and prasugrel during maintenance therapy.

Ferroelectric FET-based context-switching FPGA enabling dynamic reconfiguration for adaptive deep learning machines.

Field programmable gate array (FPGA) is widely used in the acceleration of deep learning applications because of its reconfigurability, flexibility, and fast time-to-market. However, conventional FPGA suffers from the trade-off between chip area and reconfiguration latency, making efficient FPGA accelerations that require switching between multiple configurations still elusive. Here, we propose a ferroelectric field-effect transistor (FeFET)-based context-switching FPGA supporting dynamic reconfiguration to break this trade-off, enabling loading of arbitrary configuration without interrupting the active configuration execution. Leveraging the intrinsic structure and nonvolatility of FeFETs, compact FPGA primitives are proposed and experimentally verified. The evaluation results show our design shows a 63.0%/74.7% reduction in a look-up table (LUT)/connection block (CB) area and 82.7%/53.6% reduction in CB/switch box power consumption with a minimal penalty in the critical path delay (9.6%). Besides, our design yields significant time savings by 78.7 and 20.3% on average for context-switching and dynamic reconfiguration applications, respectively.

Forensic analysis of fabricated long bone fractures for gain.

BACKGROUND: Self-inflicting injury is a recognised psychiatric disorder. Such cases are regularly seen in the emergency department, with a false history of assault. Most of these are easily detected by a forensic medicine expert as they present as described in literature but are difficult to explain if altered by professionals for nefarious reasons. METHOD: This was a prospective study carried out at a tertiary centre. The data was collected and analysed from the office records of medico-legal reports prepared at our institute between 25 February 2022 and 25 February 2023. RESULTS: 21 cases were recorded, that met with our criteria. Most involved males (90.5%). Minimum age was 27 years and maximum age 66 years with a mean of 48.6 years and a standard deviation of ±11 years. Most offenders were unemployed (38.1%). Most fractured bone was tibia (47.6%). Left-sided fractures were more common (61.9%). Injuries corresponded with the findings on clothes in three cases (14.3%). DISCUSSION: Fabricated wounds will reflect the intentions of the fabricator and may range from superficial wounds to grievous injury. Only a critical analysis of all medico-legal cases will identify them, and they will have similarities of presentation. CONCLUSION: Such findings have rarely been reported in other parts of India. A diligently prepared medico-legal report and profiling of all cases can help establish patterns of such injuries.

Severity-Based Hierarchical ECG Classification Using Neural Networks.

Timely detection of cardiac arrhythmia characterized by abnormal heartbeats can help in the early diagnosis and treatment of cardiovascular diseases. Wearable healthcare devices typically use neural networks to provide the most convenient way of continuously monitoring heart activity for arrhythmia detection. However, it is challenging to achieve high accuracy and energy efficiency in these smart wearable healthcare devices. In this work, we provide architecture-level solutions to deploy neural networks for cardiac arrhythmia classification. We have created a hierarchical structure after analyzing various neural network topologies where only required network components are activated to improve energy efficiency while maintaining high accuracy. In our proposed architecture, we introduce a severity-based classification approach to directly help the users of the wearable healthcare device as well as the medical professionals. Additionally, we have employed computation-in-memory based hardware to improve energy efficiency and area consumption by leveraging in-situ data processing and scalability of emerging memory technologies such as resistive random access memory (RRAM). Simulation experiments conducted using the MIT-BIH arrhythmia dataset show that the proposed architecture provides high accuracy while consuming average energy of 0.11 µJ per heartbeat classification and 0.11 mm2 area, thereby achieving 25× improvement in average energy consumption and 12× improvement in area compared to the state-of-the-art.

Efficacy and In-Use Tolerance of Venusia Baby Moisturizer for Skin Hydration in Babies With Dry and/or Normal Skin.

Introduction Skin hydration is important for maintaining adequate skin barrier function. After delivery, the baby's skin faces the most difficult challenge as they are exposed to the exterior world's environmental changes, friction, and microorganisms. The management is further complicated by the availability of a large range of infant skin-care products with varying claims. The first-ever Indian study on babies was done to analyze the test product (Venusia baby moisturizer; Dr. Reddy's Laboratories Ltd., Hyderabad, India) in order to bring scientific clarity to consumers. This product is devoid of parabens, alcohol, and animal origin (Dr. Reddy's Laboratories Ltd., Hyderabad, India) and is designed for skin hydration and in-use tolerance in babies with dry and/or normal skin. The endpoints were hydration and clinical evaluation of the skin, evaluated using a moisture meter scale (MMSC; Delfin Technologies Ltd., Kuopio, Finland) and parent self-assessment questionnaire, respectively. Material and methods A total of 136 healthy babies aged between six months to two years were enrolled in a four-group, monocentric, non-randomized, evaluator-blinded study: Group 1 (Venusia baby cream for dry skin), Group 2 (Venusia baby lotion for Dry Skin), Group 3 (Venusia baby cream for normal skin), and Group 4 (Venusia baby lotion for normal skin). The endpoints were hydration and clinical evaluation of the skin, evaluated using an MMSC and parent self-assessment questionnaire, respectively. Results In babies with dry skin, skin hydration was improved with Venusia baby cream (37.50%) and Venusia baby lotion (66.40%). Additionally, 66.66% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby cream; 76.47% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby lotion. In babies with normal skin, skin hydration was improved with Venusia baby cream (12.20%) and Venusia baby lotion (7.20%); 59.37% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby cream; and 84.84% of participants strongly agreed that the baby's skin became softer and smoother after the application of Venusia baby lotion. Conclusion Significant improvement was seen in skin hydration using Venusia baby cream and Venusia baby lotion in babies with dry skin and normal skin. No skin intolerances and product-related adverse or serious adverse events were clinically observed or reported during the study duration. Venusia baby lotion had the highest effect (66.4%) on skin hydration in babies with dry skin, where there was a significant shift from dry skin to normal skin range.

Powering Disturb-Free Reconfigurable Computing and Tunable Analog Electronics with Dual-Port Ferroelectric FET.

Single-port ferroelectric FET (FeFET) that performs write and read operations on the same electrical gate prevents its wide application in tunable analog electronics and suffers from read disturb, especially in the high-threshold voltage (VTH) state as the retention energy barrier is reduced by the applied read bias. To address both issues, we propose to adopt a read disturb-free dual-port FeFET where the write is performed on the gate featuring a ferroelectric layer and the read is done on a separate gate featuring a nonferroelectric dielectric. Combining the unique structure and the separate read gate, read disturb is eliminated as the applied field is aligned with polarization in the high-VTH state, thus improving its stability, while it is screened by the channel inversion charge and exerts no negative impact on the low-VTH state stability. Comprehensive theoretical and experimental validation has been performed on fully depleted silicon-on-insulator (FDSOI) FeFETs integrated on a 22 nm platform, which intrinsically has dual ports with its buried oxide layer acting as the nonferroelectric dielectric. Novel applications that can exploit the proposed dual-port FeFET are proposed and experimentally demonstrated for the first time, including FPGA that harnesses its read disturb-free feature and tunable analog electronics (e.g., frequency tunable ring oscillator in this work) leveraging the separated write and read paths.

Engrailed signaling in axon guidance and neuron survival.

Several homeoproteins can function in a direct cell non-autonomous fashion to control various biological processes. In the developing nervous system, this mode of signaling has been well documented for Engrailed in the guidance of retinal ganglion cell axons and retino-tectal patterning. Engrailed is also a key factor for mesencephalic dopaminergic (mDA) neurons, not only during development but also in the adult. Haplodeficiency for Engrailed1 leads to progressive adult-onset loss of mDA neurons and several phenotypic alterations reminiscent of Parkinson's disease (PD). Thanks to its transduction properties, Engrailed has been shown to confer neuroprotection in several experimental models of PD. Study of the mechanisms underlying these two Engrailed-mediated effects has revealed a key role of the translation regulation by Engrailed and uncovered an unsuspected link between a homeoprotein and mitochondrial activity. These studies highlight the crucial role of cellular energetic metabolism in neuron development, survival and neurodegeneration, and may help to identify novel therapeutic targets.

Ant bite artefacts: A series of cases reported over a year.

Artefacts are postmortem findings that often complicate an investigation into death. The police and relatives may be bewildered by them, and forensic pathologists need to be well versed with the intricacies that they can pose. We studied postmortem records over a year and report three cases of ant bite artefacts which led the relatives and the police to suspect the manner of death. A thorough postmortem examination endorsed the findings as ant bite artefacts and so correctly advised the police investigation.

Perturbed DNA methylation by Gadd45b induces chromatin disorganization, DNA strand breaks and dopaminergic neuron death.

Age is a major risk factor for neurodegenerative diseases like Parkinson's disease, but few studies have explored the contribution of key hallmarks of aging, namely DNA methylation changes and heterochromatin destructuration, in the neurodegenerative process. Here, we investigated the consequences of viral overexpression of Gadd45b, a multifactorial protein involved in DNA demethylation, in the mouse midbrain. Gadd45b overexpression induced global and stable changes in DNA methylation, particularly in introns of genes related to neuronal functions, as well as on LINE-1 transposable elements. This was paralleled by disorganized heterochromatin, increased DNA damage, and vulnerability to oxidative stress. LINE-1 de-repression, a potential source of DNA damage, preceded Gadd45b-induced neurodegeneration, whereas prolonged Gadd45b expression deregulated expression of genes related to heterochromatin maintenance, DNA methylation, or Parkinson's disease. Our data indicates that aging-related alterations contribute to dopaminergic neuron degeneration with potential implications for Parkinson's disease.

Transposable elements as new players in neurodegenerative diseases.

Neurodegenerative diseases (NDs), including the most prevalent Alzheimer's disease and Parkinson disease, share common pathological features. Despite decades of gene-centric approaches, the molecular mechanisms underlying these diseases remain widely elusive. In recent years, transposable elements (TEs), long considered 'junk' DNA, have gained growing interest as pathogenic players in NDs. Age is the major risk factor for most NDs, and several repressive mechanisms of TEs, such as heterochromatinization, fail with age. Indeed, heterochromatin relaxation leading to TE derepression has been reported in various models of neurodegeneration and NDs. There is also evidence that certain pathogenic proteins involved in NDs (e.g., tau, TDP-43) may control the expression of TEs. The deleterious consequences of TE activation are not well known but they could include DNA damage and genomic instability, altered host gene expression, and/or neuroinflammation, which are common hallmarks of neurodegeneration and aging. TEs might thus represent an overlooked pathogenic culprit for both brain aging and neurodegeneration. Certain pathological effects of TEs might be prevented by inhibiting their activity, pointing to TEs as novel targets for neuroprotection.

Retrotransposons as a Source of DNA Damage in Neurodegeneration.

The etiology of aging-associated neurodegenerative diseases (NDs), such as Parkinson's disease (PD) and Alzheimer's disease (AD), still remains elusive and no curative treatment is available. Age is the major risk factor for PD and AD, but the molecular link between aging and neurodegeneration is not fully understood. Aging is defined by several hallmarks, some of which partially overlap with pathways implicated in NDs. Recent evidence suggests that aging-associated epigenetic alterations can lead to the derepression of the LINE-1 (Long Interspersed Element-1) family of transposable elements (TEs) and that this derepression might have important implications in the pathogenesis of NDs. Almost half of the human DNA is composed of repetitive sequences derived from TEs and TE mobility participated in shaping the mammalian genomes during evolution. Although most TEs are mutated and no longer mobile, more than 100 LINE-1 elements have retained their full coding potential in humans and are thus retrotransposition competent. Uncontrolled activation of TEs has now been reported in various models of neurodegeneration and in diseased human brain tissues. We will discuss in this review the potential contribution of LINE-1 elements in inducing DNA damage and genomic instability, which are emerging pathological features in NDs. TEs might represent an important molecular link between aging and neurodegeneration, and a potential target for urgently needed novel therapeutic disease-modifying interventions.

Acne fulminans in a young man with granulomatosis with polyangiitis (Wegener's granulomatosis): A chance association or marker of serious systemic disease?

A 19-year-old man with granulomatosis with polyangiitis (Wegener's disease) presented with hemorrhagic facial nodules mimicking severe inflammatory acne (acne fulminans) as one of the first symptoms of the disease. The lesions were earlier treated as nodulocystic acne with isotretinoin without any benefit. Complete resolution was seen with pulsed methylprednisolone and oral prednisolone and mycophenolate mofetil thereafter. He also developed acute onset of severe pustular eruption of the face and a destructive ulcer of the auricle on two separate occasions. Facial lesions mimicking severe inflammatory acne, not responsive to standard treatment, may be a marker for more severe systemic disease such as Wegener's disease/granulomatosis with polyangiitis.