A highly diastereoselective one-pot Ugi/radical spirocyclization/aza-Michael addition sequence.

We hereby report a highly diastereoselective synthesis of chalcogenated azaspirotricycles via a one-pot Ugi/spirocyclization/aza-Michael addition sequence. The reaction proceeds via a key visible light mediated spirocyclization step under mild, metal-free and energy efficient conditions. A variety of complex sulfenylated and selenylated azaspirotricycles were obtained in good yields. The reaction was found to be scalable and preliminary mechanistic studies indicated that the spirocyclization step proceeds via radical intermediates.

Opportunity cost determines free-operant action initiation latency and predicts apathy.

BACKGROUND: Apathy, a disabling and poorly understood neuropsychiatric symptom, is characterised by impaired self-initiated behaviour. It has been hypothesised that the opportunity cost of time (OCT) may be a key computational variable linking self-initiated behaviour with motivational status. OCT represents the amount of reward which is foregone per second if no action is taken. Using a novel behavioural task and computational modelling, we investigated the relationship between OCT, self-initiation and apathy. We predicted that higher OCT would engender shorter action latencies, and that individuals with greater sensitivity to OCT would have higher behavioural apathy. METHODS: We modulated the OCT in a novel task called the 'Fisherman Game', Participants freely chose when to self-initiate actions to either collect rewards, or on occasion, to complete non-rewarding actions. We measured the relationship between action latencies, OCT and apathy for each participant across two independent non-clinical studies, one under laboratory conditions (n = 21) and one online (n = 90). 'Average-reward' reinforcement learning was used to model our data. We replicated our findings across both studies. RESULTS: We show that the latency of self-initiation is driven by changes in the OCT. Furthermore, we demonstrate, for the first time, that participants with higher apathy showed greater sensitivity to changes in OCT in younger adults. Our model shows that apathetic individuals experienced greatest change in subjective OCT during our task as a consequence of being more sensitive to rewards. CONCLUSIONS: Our results suggest that OCT is an important variable for determining free-operant action initiation and understanding apathy.

Imbalanced basal ganglia connectivity is associated with motor deficits and apathy in Huntington's disease.

The gating of movement depends on activity within the cortico-striato-thalamic loops. Within these loops, emerging from the cells of the striatum, run two opponent pathways-the direct and indirect basal ganglia pathways. Both are complex and polysynaptic, but the overall effect of activity within these pathways is thought to encourage and inhibit movement, respectively. In Huntington's disease, the preferential early loss of striatal neurons forming the indirect pathway is thought to lead to disinhibition, giving rise to the characteristic motor features of the condition. But early Huntington's disease is also associated with apathy, a loss of motivation and failure to engage in goal-directed movement. We hypothesized that in Huntington's disease, motor signs and apathy may be selectively correlated with indirect and direct pathway dysfunction, respectively. We used spectral dynamic casual modelling of resting-state functional MRI data to model effective connectivity in a model of these cortico-striatal pathways. We tested both of these hypotheses in vivo for the first time in a large cohort of patients with prodromal Huntington's disease. Using an advanced approach at the group level we combined parametric empirical Bayes and Bayesian model reduction procedures to generate a large number of competing models and compare them using Bayesian model comparison. With this automated Bayesian approach, associations between clinical measures and connectivity parameters emerge de novo from the data. We found very strong evidence (posterior probability > 0.99) to support both of our hypotheses. First, more severe motor signs in Huntington's disease were associated with altered connectivity in the indirect pathway components of our model and, by comparison, loss of goal-direct behaviour or apathy, was associated with changes in the direct pathway component. The empirical evidence we provide here demonstrates that imbalanced basal ganglia connectivity may play an important role in the pathogenesis of some of commonest and disabling features of Huntington's disease and may have important implications for therapeutics.

Neurofilament light-associated connectivity in young-adult Huntington's disease is related to neuronal genes.

Upregulation of functional network connectivity in the presence of structural degeneration is seen in the premanifest stages of Huntington's disease (preHD) 10-15 years from clinical diagnosis. However, whether widespread network connectivity changes are seen in gene carriers much further from onset has yet to be explored. We characterized functional network connectivity throughout the brain and related it to a measure of disease pathology burden (CSF neurofilament light, NfL) and measures of structural connectivity in asymptomatic gene carriers, on average 24 years from onset. We related these measurements to estimates of cortical and subcortical gene expression. We found no overall differences in functional (or structural) connectivity anywhere in the brain comparing control and preHD participants. However, increased functional connectivity, particularly between posterior cortical areas, correlated with increasing CSF NfL level in preHD participants. Using the Allen Human Brain Atlas and expression-weighted cell-type enrichment analysis, we demonstrated that this functional connectivity upregulation occurred in cortical regions associated with regional expression of genes specific to neuronal cells. This relationship was validated using single-nucleus RNAseq data from post-mortem Huntington's disease and control brains showing enrichment of neuronal-specific genes that are differentially expressed in Huntington's disease. Functional brain networks in asymptomatic preHD gene carriers very far from disease onset show evidence of upregulated connectivity correlating with increased disease burden. These changes occur among brain areas that show regional expression of genes specific to neuronal GABAergic and glutamatergic cells.

A fungal epidemic amidst a viral pandemic: Risk factors for development of COVID-19 associated rhino-orbital-cerebral mucormycosis in India.

PURPOSE: To study the risk factors for development of COVID-19 associated rhino-orbital-cerebral mucormycosis (ROCM) during the COVID-19 pandemic in India. METHODS: Multi-centric retrospective case-control study conducted from October 2020 to May 2021. Cases comprised of consecutive patients of COVID-19-associated ROCM (CA-ROCM) presenting at the participating ophthalmic institutes. Controls comprised of COVID-19-positive or COVID-19-recovered patients who did not develop ROCM. Comparative analysis of demographic, COVID-19 infection, treatment parameters and vaccination status between cases and controls performed. Clinical and imaging features of CA-ROCM analyzed. RESULTS: There were 179 cases and 361 controls. Mean age of presentation in cases was 52.06 years (p = .001) with male predominance (69.83%, p = .000011). Active COVID-19 infection at the time of presentation of ROCM (57.54%, p < .0001), moderate to severe COVID-19 (p < .0001), steroid administration (OR 3.63, p < .00001), uncontrolled diabetes (OR 32.83, p < .00001), random blood sugar >178 mg/dl were associated with development of CA-ROCM. Vaccination showed a protective effect (p = .0049). In cases with intracranial or cavernous sinus extension there was history of steroid administration (OR 2.89, p = .024) and orbital apex involvement on imaging (OR 6.202, p = .000037) compared to those with only rhino-orbital disease. CONCLUSION: Male gender, active COVID-19 infection, moderate or severe COVID-19, uncontrolled diabetes, steroid administration during COVID-19 treatment are risk factors for developing rhino-orbital-cerebral mucormycosis. Vaccination is protective. Random blood sugar of >178 mg/dl in COVID-19 positive or recovered patients should warrant close observation and early detection of ROCM. Presence of ophthalmoplegia, blepharoptosis at first clinical presentation and orbital apex involvement on imaging are associated with intracranial extension in ROCM.

Molecular basis of priming-induced acquired tolerance to multiple abiotic stresses in plants.

The growth, survival, and productivity of plants are constantly challenged by diverse abiotic stresses. When plants are exposed to stress for the first time, they can capture molecular information and store it as a form of memory, which enables them to competently and rapidly respond to subsequent stress(es). This process is referred to as a priming-induced or acquired stress response. In this review, we discuss how (i) the storage and retrieval of the information from stress memory modulates plant physiological, cellular, and molecular processes in response to subsequent stress(es), (ii) the intensity, recurrence, and duration of priming stimuli influences the outcomes of the stress response, and (iii) the varying responses at different plant developmental stages. We highlight current understanding of the distinct and common molecular processes manifested at the epigenetic, (post-)transcriptional, and post-translational levels mediated by stress-associated molecules and metabolites, including phytohormones. We conclude by emphasizing how unravelling the molecular circuitry underlying diverse priming-stimuli-induced stress responses could propel the use of priming as a management practice for crop plants. This practice, in combination with precision agriculture, could aid in increasing yield quantity and quality to meet the rapidly rising demand for food.

Visible-Light Mediated Arbuzov-Like Reaction with Thiophenols.

We hereby disclose, a visible light mediated addition of sulfenyl radicals to trialkyl phosphites to access functionalized phosphorothioates. The use of cheap and readily available Eosin Y as a photocatalyst under mild energy efficient conditions bypassing the use of external oxidants forms the chief highlight of the work. The protocol is scalable and mechanistic studies indicate that the reaction proceeds through an ionic-Arbuzov like pathway from phosphoranyl radicals.

Peripunctal Mass Lesions: Clinicopathological Analysis and Surgical Outcomes-A Multicentric Series.

PURPOSE: To report the epidemiology, histopathological spectrum, and surgical outcomes of peripunctal mass lesions. METHODS: Multicentric retrospective case series involving 6 centers in India. All cases of peripunctal masses with histopathological diagnoses and minimum follow up of 3 months were included. Demographic data, clinical photographs, objective assessments of clinical improvement were assessed before and after treatment. RESULTS: A total of 50 patients were included. The mean age was 46.4 years (range: 12-76 years). The mean duration of complaints was 27.4 months (range: 1-120 months) and mean follow-up period after surgery was 15.8 months (range: 3-120 months). The most common presenting complaints were a mass lesion/cosmetic concern (82%), followed by epiphora (48%) and foreign body sensation (16%). The most common lesion was melanocytic nevus (19/50; 38%), followed by squamous papilloma (8/50; 16%), hidrocystoma (7/50; 14%), and epidermoid cyst (7/50; 14%). Three cases of malignant tumors were diagnosed: 2 cases of sebaceous gland carcinoma and 1 case of squamous cell carcinoma. In all, 21 of 50 (42%) cases underwent excision with the placement of a Mini-Monoka stent, whereas the remaining 29 cases underwent only excision. At final follow up, a healed punctal opening was visible in 46 of 50 (92%) of the cases; 2 (4%) cases had a slit-like punctum and in 1 case (2%), a stenosed punctum was visible. However, only 1 case (2%) reported epiphora at follow up. CONCLUSIONS: Peripunctal masses are largely benign and present most commonly on the lower eyelid. Melanocytic nevus is the most common peripunctal mass lesion. In the series, stent placement did not play a significant role in the functional outcome.

Elastically flexible molecular crystals.

The discovery of molecular single crystals that display interesting elastic behaviour has generated excitement regarding their potential applications as it has upended the common perception of crystals as brittle objects. In order to design new functional materials based on molecular crystals, a comprehensive understanding of how these materials respond to deformation on a molecular-level is required. An introduction to the underlying mechanical theory and how it may be applied to single crystals is provided, along with a comprehensive discussion on how these mechanical properties can be characterised. While this field has already presented a large number of elastically flexible crystals, there is a lack of detailed mechanical characterisation data and some contention regarding the atomic-scale mechanism of elasticity. Due to the discrepancies and contradictions between theories proposed in the literature, it is not yet understood why some crystals are elastic while others shatter under applied force. To dispel ambiguity and guide future research, a set of criteria are proposed to define an elastically flexible crystal, so that these materials may find applications among future technologies.

Transcutaneous retrobulbar injection of amphotericin B in rhino-orbital-cerebral mucormycosis: a review.

Mucormycosis is an aggressive and potentially fatal invasive fungal infection. The most common form of mucormycosis is rhino-orbital-cerebral mucormycosis (ROCM). While it is commonly seen in immunocompromised patients, it is also known to affect healthy individuals. The global disease burden of ROCM has increased significantly following the surge in cases during the COVID-19 pandemic. Endoscopic sinus debridement, systemic antifungal therapy, and control of the underlying immunosuppressive condition are essential for the management of ROCM. Orbital involvement, however, presents a challenge to clinicians. Intervention strategies that have been described to treat orbital disease include orbital exenteration, conservative orbital debridement with or without irrigation with amphotericin B and transcutaneous retrobulbar injection of amphotericin B (TRAMB). Currently, there is a lack of clarity regarding the indications and outcomes of TRAMB as a treatment modality. In this review, the drug formulations used, the complications, and outcomes of previously described cases that have used TRAMB in cases of ROCM are discussed. Favorable outcomes following TRAMB depend on appropriate patient selection and radiological evidence of the orbital burden of the disease. This review aims to familiarize clinicians with objective parameters for patient selection for TRAMB, namely the extent of the disease, the clinical features, and radiological findings; viz. the clinical interpretation of areas of contrast uptake and those of necrosis. TRAMB can be considered as a viable option in select cases of orbital mucormycosis where exenteration or debridement are not indicated, or when there is limited orbital disease.

Immunopathology of COVID-19 and its implications in the development of rhino-orbital-cerebral mucormycosis: a major review.

PURPOSE: To present a literature review on various immunopathologic dysfunctions following COVID-19 infection and their potential implications in development of rhino-orbital-cerebral mucormycosis (ROCM). METHODS: A literature search was performed via Google Scholar and PubMed with subsequent review of the accompanying references. Analogies were drawn between the immune and physiologic deviations caused by COVID-19 and the tendency of the same to predispose to ROCM. RESULTS: Sixty-two articles were reviewed. SARS-CoV-2 virus infection leads to disruption of epithelial integrity in the respiratory passages, which may be a potential entry point for the ubiquitous Mucorales to become invasive. COVID-19 related GRP78 protein upregulation may aid in spore germination and hyphal invasion by Mucorales. COVID-19 causes interference in macrophage functioning by direct infection, a tendency for hyperglycemia, and creation of neutrophil extracellular traps. This affects innate immunity against Mucorales. Thrombocytopenia and reduction in the number of natural killer (NK) cells and infected dendritic cells is seen in COVID-19. This reduces the host immune response to pathogenic invasion by Mucorales. Cytokines released in COVID-19 cause mitochondrial dysfunction and accumulation of reactive oxygen species, which cause oxidative damage to the leucocytes. Hyperferritinemia also occurs in COVID-19 resulting in suppression of the hematopoietic proliferation of B- and T-lymphocytes. CONCLUSIONS: COVID-19 has a role in the occurrence of ROCM due to its effects at the entry point of the fungus in the respiratory mucosa, effects of the innate immune system, creation of an environment of iron overload, propagation of hyperglycemia, and effects on the adaptive immune system.

Concomitant adult onset xanthogranuloma and IgG4-related orbital disease: a rare occurrence.

Adult onset xanthogranulomatous disease is a rare orbital disease. IgG4-related disease is a systemic disease that can often manifest in the orbit. In this communication, we present the case of a patient with a xanthelasma-like lesion on the upper eyelid, and an enlarged lacrimal gland, which on biopsy was diagnosed as an orbital xanthogranuloma. Detailed serological workup showed that the patient was found to have elevated serum IgG4 levels. The orbital specimen was re-stained and found to be positive for IgG4. The patient was treated with oral steroids with partial resolution of the lesion. This is an interesting case of both histopathological adult onset xanthogranuloma (AOX) and IgG4-related orbital disease (IgG4-ROD). The early evidence suggests that the diagnosis of one of these disorders should point the physician to investigate for the presence of the other, especially if xanthogranulomatous disease is diagnosed first.

Clinical Presentations, Management and Outcomes of Rhino-Orbital-Cerebral Mucormycosis (ROCM) Following COVID-19: A Multi-Centric Study.

PURPOSE: To report clinical presentations and factors affecting outcomes in rhino-orbital-cerebral mucormycosis following COVID-19. METHODS: Retrospective multi-centric interventional case series of 58 eyes with rhino-orbital-cerebral mucormycosis. Demography, clinical parameters and management outcomes were noted. Factors affecting outcome and mortality were analyzed. Outcome was defined as favorable when complete resolution or stabilization without further progression of the infection was noted at last visit. RESULTS: Mean age was 55 ± 11 years (median 56). The mean HbA1c value was 10.44 ± 2.84 mg% (median 10.5). The duration between the diagnosis of COVID-19 and rhino-orbital-cerebral mucormycosis was 16 ± 21 days (median: 8 days). Thirty-six eyes (62%) had no vision at presentation. Imaging revealed paranasal sinus involvement (100%), orbital apex involvement (41%), cavernous sinus involvement (30%), and central nervous system (CNS) involvement (33%). All the patients were treated with systemic Liposomal amphotericin-B and sinus debridement. Twenty-two eyes (38%) underwent exenteration. One eye underwent transcutaneous retrobulbar amphotericin-B. The mean follow-up duration was 5.62 ± 0.78 months (median 6). Favorable outcome was seen in 35 (60%) cases. Presence of uncontrolled diabetes (p = 0.001), orbital apex involvement (p = 0.04), CNS involvement (p = 0.04), and history of steroid use (p < 0.0001) resulted in unfavorable outcome. CNS involvement was the only factor predicting mortality (p = 0.03). Mortality was seen in 20 (34%) patients. CONCLUSION: Over a third of patients with rhino-orbital-cerebral mucormycosis following COVID-19 have an unfavorable clinical outcome. Uncontrolled diabetes mellitus at presentation, involvement of the orbital apex, CNS, and the usage of steroids were associated with poorer outcomes. CNS involvement was a factor determining mortality.

Rhino-orbital mucormycosis following COVID-19 in previously non-diabetic, immunocompetent patients.

PURPOSE: To report a series of 13 immunocompetent patients who developed new-onset uncontrolled diabetes mellitus (DM) following COVID-19 infection and presented as rhino-orbital mucormycosis (ROM). METHOD: Retrospective study. RESULTS: A total of 127 patients of COVID-19 Associated Mucormycosis (CAM) were evaluated at four centres in India. All patients underwent endoscopic sinus debridement surgery and received systemic amphotericin-B therapy. Five patients (5/13; 38.4%) received retrobulbar amphotericin-B injections. Orbital exenteration was performed in advanced orbital involvement or progression of orbital disease in spite of maximal medical therapy. In his cohort, 13/127 (10.2%) patients presented with new onset DM, where one patient had bilateral disease. The mean age was 35.9 years (range: 20-51 years) and the mean duration from diagnosis of COVID-19 to the diagnosis of mucormycosis was 14.2 days. While 7/13 (53.8%) of the patients received systemic corticosteroids during the course of their treatment for COVID-19, six patients received no steroids or immunomodulators. The mean follow-up period was 9.2 weeks (range: 3-18 weeks) following discharge. Life salvage was possible in 100% of the cases. While overall globe salvage was possible in 42.8% (6/14 eyes), the globe could be preserved in 4/5 patients who received retrobulbar amphotericin-B injections. CONCLUSIONS: Those involved in the care of COVID-19 patients should be aware about the possibility of recent-onset DM, even in patients without a history of corticosteroid therapy. Rarely, recent-onset DM following COVID-19 may present as rhino-orbital mucormycosis, which requires aggressive surgical and medical intervention.

Cobalt-Catalyzed C8-Dienylation of Quinoline-N-Oxides.

An efficient Cp*CoIII -catalyzed C8-dienylation of quinoline-N-oxides was achieved by employing allenes bearing leaving groups at the α-position as the dienylating agents. The reaction proceeds by CoIII -catalyzed C-H activation of quinoline-N-oxides and regioselective migratory insertion of the allene followed by a ß-oxy elimination, leading to overall dienylation. Site-selective C-H activation was achieved with excellent selectivity under mild reaction conditions, and 30 mol % of a NaF additive was found to be crucial for the efficient dienylation. The methodology features high stereoselectivity, mild reaction conditions, and good functional-group tolerance. C8-alkenylation of quinoline-N-oxides was achieved in the case of allenes devoid of leaving groups as coupling partners. Furthermore, gram-scale preparation and preliminary mechanistic experiments were carried out to gain insights into the reaction mechanism.

Apathy Associated With Impaired Recognition of Happy Facial Expressions in Huntington's Disease.

OBJECTIVES: Previous research has demonstrated an association between emotion recognition and apathy in several neurological conditions involving fronto-striatal pathology, including Parkinson's disease and brain injury. In line with these findings, we aimed to determine whether apathetic participants with early Huntington's disease (HD) were more impaired on an emotion recognition task compared to non-apathetic participants and healthy controls. METHODS: We included 43 participants from the TRACK-HD study who reported apathy on the Problem Behaviours Assessment - short version (PBA-S), 67 participants who reported no apathy, and 107 controls matched for age, sex, and level of education. During their baseline TRACK-HD visit, participants completed a battery of cognitive and psychological tests including an emotion recognition task, the Hospital Depression and Anxiety Scale (HADS) and were assessed on the PBA-S. RESULTS: Compared to the non-apathetic group and the control group, the apathetic group were impaired on the recognition of happy facial expressions, after controlling for depression symptomology on the HADS and general disease progression (Unified Huntington's Disease Rating Scale total motor score). This was despite no difference between the apathetic and non-apathetic group on overall cognitive functioning assessed by a cognitive composite score. CONCLUSIONS: Impairment of the recognition of happy expressions may be part of the clinical picture of apathy in HD. While shared reliance on frontostriatal pathways may broadly explain associations between emotion recognition and apathy found across several patient groups, further work is needed to determine what relationships exist between recognition of specific emotions, distinct subtypes of apathy and underlying neuropathology. (JINS, 2019, 25, 453-461).

Visible-light mediated sulfonylation of thiols via insertion of sulfur dioxide.

A simple and efficient visible-light mediated synthesis of thiosulfonates via a radical-radical coupling of sulfenyl radicals and arylsulfonyl radicals was developed. The reaction of thiols, aryldiazonium tetrafluoroborates and DABSO proceeded at room temperature using 5 mol% eosin Y. The reaction displayed wide functional group tolerance and delivered the unsymmetrical thiosulfonates in good to excellent yields.

Patient perceptions regarding the use of smart devices for medical photography: results of a patient-based survey.

AIM: To assess patient perceptions regarding medical photography and the use of smart devices, namely mobile phones and tablets for medical photography. METHODS: A questionnaire-based survey was conducted among 280 consecutive adult patients who presented to the oculoplastics clinic at a tertiary eye care centre. The responses were tabulated and analysed. RESULTS: Of the 280 patients surveyed, 68% felt that medical photography had a positive impact on their understanding of their illnesses and 72% felt that the use of smartphones for medical photography was acceptable. Respondents below the age of 40 years were more likely to approve of the use of mobile phones for photography as compared to those over 40. Most patients (74%) preferred a doctor to be the person photographing them. While a majority approved of doctors and trainee physicians having access to their photographs, they felt non-physician healthcare personnel should not have access to clinical photographs. Also, 72% of the respondents felt that the patient's consent should be taken before using their photographs. It was noted that patient identification and breach of confidentiality could be some of the potential issues with using smart devices as cameras in the clinic. CONCLUSIONS: Clinical photography in general and, specifically, using smart devices for clinical photographs have gained acceptance among patients. The outcomes of this study may be utilized to create policy guidelines for the use of smart devices as photography tools in the clinics. The findings of this survey can also help to create standardized, uniform patient consent forms for clinical photography.

Congenital Dermal Facial Temporal Sinus: Rare Presentation of Intraorbital Dermoid in Children.

We present a rare case of an intraorbital dermoid which was associated with a small temporal region dermal sinus in a 3-year-old child. This got infected and the child presented with orbital cellulitis. Definitive surgery involved excision of all the dermal elements using a superficial and intraorbital approach. We stress the need to evaluate, apparently benign lateral facial dermal sinuses as they may be the pointers of the underlying pathological deep dermoid cysts to avoid complications.

Organogels composed of trifluoromethyl anthryl cyanostyrenes: enhanced emission and self-assembly.

A series of α-cyanostyrenes bearing anthracene and electron withdrawing trifluoromethyl units were designed and synthesized. The α-cyanostyrene skeleton favors aggregation induced enhanced emission behavior due to the restriction of intramolecular rotations. Remarkably, the anthryl cyanostyrenes bearing simple trifluoromethyl (CF3) substituents form stable organogels with enhanced fluorescence emission compared to their solution state. In water, the CF3 substituted anthrylstyrenes self-assemble into entangled fibrous nano/microstructures through intermolecular H-bonding, π-π stacking and cyano substituent interactions. The morphological features of the aggregates and the gels were substantiated using scanning electron microscopy, TEM, and powder XRD measurements. The stability of the gels was assessed using rheology investigations.