Evidence of a Hardening in the Cosmic Ray Proton Spectrum at around 166 TeV Observed by the GRAPES-3 Experiment.

We present the measurement of the cosmic ray proton spectrum from 50 TeV to 1.3 PeV using 7.81×10^{6} extensive air shower events recorded by the ground-based GRAPES-3 experiment between 1 January 2014 and 26 October 2015 with a live time of 460 day. Our measurements provide an overlap with direct observations by satellite and balloon-based experiments. The electromagnetic and muon components in the shower were measured by a dense array of plastic scintillator detectors and a tracking muon telescope, respectively. The relative composition of the proton primary from the air shower data containing all primary particles was extracted using the multiplicity distribution of muons which is a sensitive observable for mass composition. The observed proton spectrum suggests a spectral hardening at ∼166 TeV and disfavors a single power law description of the spectrum up to the Knee energy (∼3 PeV).

Social cognition and social motivation in schizophrenia and bipolar disorder: are impairments linked to the disorder or to being socially isolated?

BACKGROUND: People with schizophrenia on average are more socially isolated, lonelier, have more social cognitive impairment, and are less socially motivated than healthy individuals. People with bipolar disorder also have social isolation, though typically less than that seen in schizophrenia. We aimed to disentangle whether the social cognitive and social motivation impairments observed in schizophrenia are a specific feature of the clinical condition v. social isolation generally. METHODS: We compared four groups (clinically stable patients with schizophrenia or bipolar disorder, individuals drawn from the community with self-described social isolation, and a socially connected community control group) on loneliness, social cognition, and approach and avoidance social motivation. RESULTS: Individuals with schizophrenia (n = 72) showed intermediate levels of social isolation, loneliness, and social approach motivation between the isolated (n = 96) and connected control (n = 55) groups. However, they showed significant deficits in social cognition compared to both community groups. Individuals with bipolar disorder (n = 48) were intermediate between isolated and control groups for loneliness and social approach. They did not show deficits on social cognition tasks. Both clinical groups had higher social avoidance than both community groups. CONCLUSIONS: The results suggest that social cognitive deficits in schizophrenia, and high social avoidance motivation in both schizophrenia and bipolar disorder, are distinct features of the clinical conditions and not byproducts of social isolation. In contrast, differences between clinical and control groups on levels of loneliness and social approach motivation were congruent with the groups' degree of social isolation.

Ceftazidime-avibactam alone or in combination with Aztreonam versus Polymyxins in the management of carbapenem-Resistant Klebsiella pneumoniae nosocomial Infections (CAPRI study): a retrospective cohort study from South India.

INTRODUCTION: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections commonly cause hospital-acquired infections. The study aimed to compare the outcomes of CRKP infections between patients receiving ceftazidime avibactam +/- aztreonam and polymyxins in a hospital setting with a high prevalence of New Delhi Metallo Beta Lactamase production. METHODS: We conducted a retrospective cohort study from January 2020 to September 2022 in critically ill adult patients admitted to a non-COVID-19 medical intensive care unit with CRKP infection. The patients were followed up for a total of 30 days or death, whichever was later. RESULTS: Of a total of 106 patients included in the study, 65 patients received polymyxins and 41 patients received ceftazidime-avibactam +/- aztreonam. Higher 30-day mortality was noted in the polymyxin group (56.9% vs. 29.2%, P = 0.005). The mean time to event (mortality) in ceftazidime-avibactam +/- aztreonam was 23.9 + 1.5 days which was significantly higher compared to polymyxins (17.9 + 1.2 days, p = 0.006). On Cox regression analysis, after adjusting for the covariates, the hazard ratio for time to event with the use of polymyxin was 2.02 (95% CI: 1.03-3.9). CONCLUSION: Ceftazidime-avibactam + aztreonam is possibly associated with better clinical outcomes in patients infected with CRKP.

Kisspeptin stimulates sheep ovarian follicular development in vitro through homologous receptors.

The present study was conducted to elucidate (1) the influence of kisspeptin (KP) on the in vitro development of preantral follicles (PFs) and (2) evolution of KP receptor gene (KISS1R) expression during ovarian follicular development in sheep. Kisspeptin was supplemented (0-100 µg/ml) in the culture medium of PFs for 6 days. The cumulus-oocyte complexes (COCs) from cultured PFs were subsequently matured to metaphase II (MII) for an additional 24 h. The proportions of PFs exhibiting growth, antrum formation, average increase in diameter, and maturation of oocytes to MII stage were the indicators of follicular development in vitro. The expression of the kisspeptin receptor gene at each development stages of in vivo developed (preantral, early antral, antral, large antral and COCs from Graafian follicles) and in vitro cultured PFs supplemented with KP was assessed using a real-time polymerase chain reaction. The best development in all the parameters under study was elicited with 10 µg/ml of KP. Supplementation of KP (10 µg/ml) in a medium containing other growth factors (insulin-like growth factor-I) and hormones (growth hormone, thyroxine, follicle-stimulating hormone) resulted in better PF development. The KISS1R gene was expressed in follicular cells and oocytes at all the development stages of both in vivo developed and in vitro cultured follicles. Higher KISS1R gene expression was supported by culture medium containing KP along with other hormones and growth factors. Accordingly, it is suggested that one of the mechanisms through which KP and other growth factors and hormones influence the ovarian follicular development in mammals is through the upregulation of expression of the KP receptor gene.

Fabrication and Characterization Techniques of In Vitro 3D Tissue Models.

The culturing of cells in the laboratory under controlled conditions has always been crucial for the advancement of scientific research. Cell-based assays have played an important role in providing simple, fast, accurate, and cost-effective methods in drug discovery, disease modeling, and tissue engineering while mitigating reliance on cost-intensive and ethically challenging animal studies. The techniques involved in culturing cells are critical as results are based on cellular response to drugs, cellular cues, external stimuli, and human physiology. In order to establish in vitro cultures, cells are either isolated from normal or diseased tissue and allowed to grow in two or three dimensions. Two-dimensional (2D) cell culture methods involve the proliferation of cells on flat rigid surfaces resulting in a monolayer culture, while in three-dimensional (3D) cell cultures, the additional dimension provides a more accurate representation of the tissue milieu. In this review, we discuss the various methods involved in the development of 3D cell culture systems emphasizing the differences between 2D and 3D systems and methods involved in the recapitulation of the organ-specific 3D microenvironment. In addition, we discuss the latest developments in 3D tissue model fabrication techniques, microfluidics-based organ-on-a-chip, and imaging as a characterization technique for 3D tissue models.

Organocatalytic Selective [3 + 2] Cycloadditions: Synthesis of Functionalized 5-Arylthiomethyl-1,2,3-triazoles and 4-Arylthio-1,2,3-triazoles.

An organocatalytic azide-ketone [3 + 2] cycloaddition (OrgAKC) of a variety of 1-aryl-3-(arylthio)propan-2-ones and 1-alkyl-3-(arylthio)propan-2-ones with different aryl/vinyl/alkyl azides is reported under ambient conditions to furnish the medicinally important 1,4-disubstituted-5-arylthiomethyl-1,2,3-triazoles and 1,5-disubstituted-4-arylthio-1,2,3-triazoles, respectively, in a regioselective manner with high yields/rates. With controlled and online NMR experiments, we proved that the reaction path is following the organocatalytic enolization through selective deprotonation followed by a [1,3]-H shift. Surprisingly, the [3 + 2] cycloaddition of aryl/vinyl/alkyl azides with the in situ-generated equilibrated thermodynamic ↔ kinetic enolates furnished the highly regioselective functionally rich 1,2,3-triazoles by discriminating their reactivities. This is the first report on the investigation of a selective OrgAKC with the regiomers of enolates generated in situ from the unsymmetrical carbonyl compounds. The reaction sustainability is explained with a few controlled experiments, mechanistic studies, and applications.

Utilization of banana crop residue as an agricultural bioresource for the production of acetone-butanol-ethanol by Clostridium beijerinckii YVU1.

This study aimed to produce acetone-butanol-ethanol (ABE) using lignocellulosic crop residues as renewable bioresources. Butanol production from banana crop residue (BCR) was studied using a newly isolated solventogenic Clostridium beijerinckii YVU1. BCR is one of the abundant lignocellulosic substrates available in tropical countries containing 4·3 ± 3·5% cellulose, 28·5 ± 3·0% hemicellulose and 20·3 ± 2·6% lignin. The sequential dilute alkali and acid pretreatments solubilized 69% of lignin and 73% of hemicellulose. Ten percent (w/v) of pretreated substrate was subjected to enzymatic saccharification with cellulase, and it was found to release 0·481 ± 0·035 g glucose per g pretreated biomass. In the batch fermentation process, 20·5 g l-1 ABE (14·0 g l-1 of butanol, 5·4 g l-1 of acetone and 1·1 g l-1 of ethanol) was obtained. The executed fermentation process yielded 0·39 g ABE per g hydrolysate with 0·14 g l-1  h-1 of volumetric productivity. On the basis of the results, we believe that sequential alkali and acid pretreatment on the enzymatic hydrolysis for butanol production is indeed a technology with the potential to be applied and newly isolated. C. beijerinckii YVU1 is also a potential candidate organism for butanol production agricultural residues. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates that a banana crop residue (BCR) can be successfully utilized as an inexpensive and alternative bioresource for the production of acetone-butanol-ethanol (ABE). The sequential pretreatment of BCR with alkali and acid solubilized lignin and hemicellulose leading to high glucose release during enzymatic hydrolysis. A newly isolated Clostridium beijerinckii YVU1 was able to produce comparable amount of ABE with previous reports. Therefore, we can state that the utilization of BCR as substrate for C. beijerinckii YVU1 leads to an economical bioprocess for the microbial production of ABE.

Endothelial progenitor/stem cells in engineered vessels for vascular transplantation.

BACKGROUND: Dysfunction of blood vessel leads to aneurysms, myocardial infarction and other thrombosis conditions. Current treatment strategies are transplantation of blood vessels from one part of the body to other dysfunction area, or allogenic, synthetic. Due to shortage of the donor, painful dissection, and lack of efficacy in synthetic, there is a need for alternative to native blood vessels for transplantation. METHODS: Human umbilical-cord tissue obtained from the hospital with the informed consent. Umbilical-cord blood vessels were isolated for decellularization and to establish endothelial cell culture. Cultured cells were characterized by immunophenotype, gene expression and in vitro angiogenesis assay. Decellularized blood vessels were recellularized with the endothelial progenitors and Wharton jelly, CL MSCs (1:1), which was characterized by MTT, biomechanical testing, DNA content, SEM and histologically. Bioengineered vessels were transplanted into the animal models to evaluate their effect. RESULTS: Cultured cells express CD31 and CD14 determining endothelial progenitor cells (EPCs). EPCs expresses various factors such as angiopoitin1, VWF, RANTES, VEGF, BDNF, FGF1, FGF2, HGF, IGF, GDNF, NGF, PLGF, NT3, but fail to express NT4, EGF, and CNTF. Pro and anti-inflammatory cytokine expressions were noticed. Functionally, these EPCs elicit in vitro tube formation. Negligible DNA content and intact ECM confirms the efficient decellularization of tissue. The increased MTT activity in recellularized tissue determines proliferating cells and biocompatibility of the scaffolds. Moreover, significant (P < 0.05) increase in maximum force and tensile of recellularized biomaterial as compared to the decellularized scaffolds. Integration of graft with host tissue, suggesting biocompatible therapeutic biomaterial with cells. CONCLUSION: EPCs with stem cells in engineered blood vessels could be therapeutically applicable in vascular surgery.

Acute Intermittent Porphyria Presenting with Posterior Reversible Encephalopathy Syndrome: A Rare Cause of Abdominal Pain and Seizures.

Acute intermittent porphyria (AIP) is an acute neurovisceral porphyria caused due to inherited deficiency of porphobilinogen deaminase (also called hydroxymethylbilane synthase) (HMBS) in the heme biosynthesis pathway. AIP is rarely associated with posterior reversible encephalopathy syndrome (PRES), which is a clinicoradiological condition caused by the failure of the posterior circulation to autoregulate, resulting in cerebral edema, headaches, nausea, and seizures. AIP should be considered when a patient presents with unexplained abdominal pain and seizures. This association is important because drugs used in the management of seizures may worsen an attack of AIP. This case report describes a young woman who presented with AIP and PRES with seizures. HOW TO CITE THIS ARTICLE: Sarala Kumari D, Murthy NLN Arumilli, Siva Kumar Reddy L, Nageshwar Reddy D, Motor R. Acute Intermittent Porphyria Presenting with Posterior Reversible Encephalopathy Syndrome: A Rare Cause of Abdominal Pain and Seizures. Indian J Crit Care Med 2020;24(8):724-726.

Measurement of the Electrical Properties of a Thundercloud Through Muon Imaging by the GRAPES-3 Experiment.

The GRAPES-3 muon telescope located in Ooty, India records rapid (∼10 min) variations in the muon intensity during major thunderstorms. Out of a total of 184 thunderstorms recorded during the interval of April 2011-December 2014, the one on December 1, 2014 produced a massive potential of 1.3 GV. The electric field measured by four well-separated (up to 6 km) monitors on the ground was used to help estimate some of the properties of this thundercloud, including its altitude and area that were found to be 11.4 km above mean sea level and ≥380 km^{2}, respectively. A charging time of 6 min to reach 1.3 GV implied the delivery of a power of ≥2 GW by this thundercloud that was moving at a speed of ∼60 km h^{-1}. This work possibly provides the first direct evidence for the generation of gigavolt potentials in thunderclouds that could also possibly explain the production of highest-energy (100 MeV) gamma rays in the terrestrial gamma-ray flashes.

Leaf lipidome and transcriptome profiling of Portulaca oleracea: characterization of lysophosphatidylcholine acyltransferase.

MAIN CONCLUSION: Portulaca leaves serve as an alternative bioresource for edible PUFAs. Transcriptome data provide information to explore Portulaca as a model system for galactolipids, leaf lipid metabolism, and PUFA-rich designer lipids. Poly-unsaturated fatty acids (PUFAs) are gaining importance due to their innumerable health benefits, and hence, understanding their biosynthesis in plants has attained prominence in recent years. The most common source of PUFAs is of marine origin. Although reports have identified Portulaca oleracea (purslane) as a leaf source of omega-3 fatty acids in the form of alpha-linolenic acid (ALA), the mechanism of ALA accumulation and its distribution into various lipids has not been elucidated. Here, we present the lipid profiles of leaves and seeds of several accessions of P. oleracea. Among the nineteen distinct accessions, the RR04 accession has the highest amount of ALA and is primarily associated with galactolipids. In addition, we report the transcriptome of RR04, and we have mapped the potential genes involved in lipid metabolism. Phosphatidylcholine (PC) is the major site of acyl editing, which is catalyzed by lysophosphatidylcholine acyltransferase (LPCAT), an integral membrane protein that plays a major role in supplying oleate to the PC pool for further unsaturation. Our investigations using mass spectrometric analysis of leaf microsomal fractions identified LPCAT as part of a membrane protein complex. Both native and recombinant LPCAT showed strong acyltransferase activity with various acyl-CoA substrates. Altogether, the results suggest that ALA-rich glycerolipid biosynthetic machinery is highly active in nutritionally important Portulaca leaves. Furthermore, lipidome, transcriptome, and mass spectrometric analyses of RR04 provide novel information for exploring Portulaca as a potential resource and a model system for studying leaf lipid metabolism.

Design and synthesis of functionalized piperazin-1yl-(E)-stilbenes as inhibitors of 17α-hydroxylase-C17,20-lyase (Cyp17).

The synthesis of steroid hormones is critical to human physiology and improper regulation of either the synthesis of these key molecules or activation of the associated receptors can lead to disease states. This has led to intense interest in developing compounds capable of modulating the synthesis of steroid hormones. Compounds capable of inhibiting Cyp19 (Aromatase), a key enzyme in the synthesis of estrogens, have been successfully employed as breast cancer therapies, while inhibitors of Cyp17 (17α-hydroxylase-17,20-lyase), a key enzyme in the synthesis of glucocorticoids, mineralocorticoids and steroidal sex hormones, are a key component of prostate cancer therapy. Inhibition of CYP17 has also been suggested as a possible target for the treatment of Cushing Syndrome and Metabolic Syndrome. We have identified two novel series of stilbene based CYP17 inhibitors and demonstrated that exemplary compounds in these series have pharmacokinetic properties consistent with orally delivered drugs. These findings suggest that compounds in these classes may be useful for the treatment of diseases and conditions associated with improper regulation of glucocorticoids synthesis and glucocorticoids receptor activation.

Tetraphenylethylene conjugated p-hydroxyphenacyl: fluorescent organic nanoparticles for the release of hydrogen sulfide under visible light with real-time cellular imaging.

Hydrogen sulfide (H2S) behaves like a two-edged sword, at low concentrations it has beneficial and cytoprotective effects, while at higher concentrations it exhibits toxicity. Hence there is a keen interest in developing light responsive H2S donors with a spatio-temporal controlled release. Herein, we report visible light activatable tetraphenylethylene conjugated p-hydroxyphenacyl (TPE-pHP-H2S) nanoparticles for the release of hydrogen sulfide (H2S) with a real time monitoring ability. Our newly designed photoresponsive single component organic nanoparticle based H2S donor is built by integrating the tetraphenylethylene (TPE) moiety and p-hydroxyphenacyl (pHP) group so that it can display both aggregation-induced emission (AIE) and excited state intramolecular proton transfer (ESIPT) properties. Aggregation-induced emission enhancement was exhibited by our TPE-pHP-H2S NP donor, which was then explored for the cellular imaging application. The ESIPT by the pHP moiety provided unique advantages to our TPE-pHP-H2S NP donor which include (i) the excitation wavelength extended to >410 nm (ii) a large Stokes shift (iii) a low inner filter effect and (iv) real-time monitoring of H2S release by a simple fluorescent colour change. In vitro studies showed that the TPE-pHP-H2S NP donor presents excellent properties like real-time monitoring, photoregulated H2S release and biocompatibility.

Impact of Thermal Decomposition on Thermal Desorption Instruments: Advantage of Thermogram Analysis for Quantifying Volatility Distributions of Organic Species.

We present results from a high-resolution chemical ionization time-of-flight mass spectrometer (HRToF-CIMS), operated with two different thermal desorption inlets, designed to characterize the gas and aerosol composition. Data from two field campaigns at forested sites are shown. Particle volatility distributions are estimated using three different methods: thermograms, elemental formulas, and measured partitioning. Thermogram-based results are consistent with those from an aerosol mass spectrometer (AMS) with a thermal denuder, implying that thermal desorption is reproducible across very different experimental setups. Estimated volatilities from the detected elemental formulas are much higher than from thermograms since many of the detected species are thermal decomposition products rather than actual SOA molecules. We show that up to 65% of citric acid decomposes substantially in the FIGAERO-CIMS, with ∼20% of its mass detected as gas-phase CO2, CO, and H2O. Once thermal decomposition effects on the detected formulas are taken into account, formula-derived volatilities can be reconciled with the thermogram method. The volatility distribution estimated from partitioning measurements is very narrow, likely due to signal-to-noise limits in the measurements. Our findings indicate that many commonly used thermal desorption methods might lead to inaccurate results when estimating volatilities from observed ion formulas found in SOA. The volatility distributions from the thermogram method are likely the closest to the real distributions.

A unique squalenoylated and nonpegylated doxorubicin nanomedicine with systemic long-circulating properties and anticancer activity.

We identified that the chemical linkage of the anticancer drug doxorubicin onto squalene, a natural lipid precursor of the cholesterol's biosynthesis, led to the formation of squalenoyl doxorubicin (SQ-Dox) nanoassemblies of 130-nm mean diameter, with an original "loop-train" structure. This unique nanomedicine demonstrates: (i) high drug payload, (ii) decreased toxicity of the coupled anticancer compound, (iii) improved therapeutic response, (iv) use of biocompatible transporter material, and (v) ease of preparation, all criteria that are not combined in the currently available nanodrugs. Cell culture viability tests and apoptosis assays showed that SQ-Dox nanoassemblies displayed comparable antiproliferative and cytotoxic effects than the native doxorubicin because of the high activity of apoptotic mediators, such as caspase-3 and poly(ADP-ribose) polymerase. In vivo experiments have shown that the SQ-Dox nanomedicine dramatically improved the anticancer efficacy, compared with free doxorubicin. Particularly, the M109 lung tumors that did not respond to doxorubicin treatment were found inhibited by 90% when treated with SQ-Dox nanoassemblies. SQ-Dox nanoassembly-treated MiaPaCa-2 pancreatic tumor xenografts in mice decreased by 95% compared with the tumors in the saline-treated mice, which was significantly higher than the 29% reduction achieved by native doxorubicin. Concerning toxicity, SQ-Dox nanoassemblies showed a fivefold higher maximum-tolerated dose than the free drug, and moreover, the cardiotoxicity study has evidenced that SQ-Dox nanoassemblies did not cause any myocardial lesions, such as those induced by the free doxorubicin treatment. Taken together, these findings demonstrate that SQ-Dox nanoassemblies make tumor cells more sensitive to doxorubicin and reduce the cardiac toxicity, thus providing a remarkable improvement in the drug's therapeutic index.

Evaluation of biomedical waste management in primary health care centres in Saudi Arabia: a knowledge, attitudes and practices study.

Awareness and knowledge of biomedical waste practices is very important for any health care setting. This study aimed to determine the knowledge, attitudes and practices (KAP) about biomedical waste among health professionals in primary health care centres in Hail City, Saudi Arabia. The study included 135 of 155 professionals who dealt with biomedical waste from 16 out of 26 primary health care centres. Data were collected using a structured questionnaire. Overall 54.8%, 48.9% and 49.6% of the participants had good knowledge, attitudes and practices scores respectively. Profession, education and age were significantly associated with KAP level (P < 0.01): doctors, those with a degree and older respondents had better KAP scores. There was a strong correlation between knowledge and attitudes, knowledge and practices, and attitudes and practices (P ˂ 0.05). Training is recommended to enhance the knowledge of the professionals dealing with biomedical waste in the primary health care centres.

Advances in Recurrent Respiratory Papillomatosis Treatment: Adjuvant Intralesional Bevacizumab's Impact, Potential and Insights from a Case Series Study.

Recurrent respiratory papillomatosis is an aggressive benign disease characterised by the repeated growth of multiple warts involving the larynx as well as other parts of the respiratory tract. Recurrent respiratory papillomatosis is most commonly caused by human papillomaviruses 6 and 11. It requires multiple surgical procedures for tumour debulking.Our study aims to evaluate the impact and potential of adjuvant intralesional bevacizumab in the treatment of recurrent respiratory papillomatosis while providing valuable insights based on a case series analysis.A prospective study of a total of 13 patients with Recurrent respiratory papillomatosis attending a tertiary care hospital with ages ranging from 3 to 30 years was conducted from February 2018 to February 2023 by intralesional bevacizumab 1 ml with a concentration of 2.5 mg/ml per dose, 3 injections, each once every 4 weeks by calculating the number of operative procedures per year, duration of time between procedures, calculating the Derkay score before 1 year of the first injection and after 1 year of the last dose injection of bevacizumab treatment. Inclusion criteria are ages between 3 and 30 years with recurrent respiratory papillomatosis who underwent at least 4 or more surgical procedures with no adjuvant therapies. In all our cases, the affected area was the larynx.Adjuvant therapy with intralesional bevacizumab increases the duration of time between surgical procedures and reduces the number of operative procedures each year with an overall improvement in the Derkay score. No adverse drug effects have been reported in our study.Intralesional Bevacizumab is an effective and safe adjuvant treatment option for recurrent respiratory papillomatosis. It increases the duration of time between surgical procedures and decreases the number of procedures per year with an overall improvement in the Derkay score.

Disease modeling and pharmacological rescue of autosomal dominant retinitis pigmentosa associated with RHO copy number variation.

Retinitis pigmentosa (RP), a heterogenous group of inherited retinal disorder, causes slow progressive vision loss with no effective treatments available. Mutations in the rhodopsin gene (RHO) account for ~25% cases of autosomal dominant RP (adRP). In this study, we describe the disease characteristics of the first-ever reported mono-allelic copy number variation (CNV) in RHO as a novel cause of adRP. We (a) show advanced retinal degeneration in a male patient (68 years of age) harboring four transcriptionally active intact copies of rhodopsin, (b) recapitulated the clinical phenotypes using retinal organoids, and (c) assessed the utilization of a small molecule, Photoregulin3 (PR3), as a clinically viable strategy to target and modify disease progression in RP patients associated with RHO-CNV. Patient retinal organoids showed photoreceptors dysgenesis, with rod photoreceptors displaying stunted outer segments with occasional elongated cilia-like projections (microscopy); increased RHO mRNA expression (quantitative real-time PCR [qRT-PCR] and bulk RNA sequencing); and elevated levels and mislocalization of rhodopsin protein (RHO) within the cell body of rod photoreceptors (western blotting and immunohistochemistry) over the extended (300 days) culture time period when compared against control organoids. Lastly, we utilized PR3 to target NR2E3, an upstream regulator of RHO, to alter RHO expression and observed a partial rescue of RHO protein localization from the cell body to the inner/outer segments of rod photoreceptors in patient organoids. These results provide a proof-of-principle for personalized medicine and suggest that RHO expression requires precise control. Taken together, this study supports the clinical data indicating that RHO-CNV associated adRPdevelops as a result of protein overexpression, thereby overloading the photoreceptor post-translational modification machinery.

Using machine learning to understand social isolation and loneliness in schizophrenia, bipolar disorder, and the community.

Social disconnection, including objective social isolation and subjective loneliness, is linked to substantial health risks. Yet, little is known about the predictors of social disconnection in individuals with mental illness. Here, we used machine learning to identify predictors of social isolation and loneliness in schizophrenia (N = 72), a psychiatric condition associated with social disconnection. For comparison, we also included two other groups: a psychiatric comparison sample of bipolar disorder (N = 48) and a community sample enriched for social isolation (N = 151). We fitted statistical models of social isolation and loneliness within and across groups. Each model included five candidate predictors: social avoidance motivation, depression, nonsocial cognition, social anhedonia, and social cognition. The results showed that social anhedonia explained unique variance in social isolation and loneliness in all samples, suggesting that it contributes to social isolation and loneliness broadly. However, nonsocial cognition explained unique variance in social isolation only within schizophrenia. Thus, social anhedonia could be a potential intervention target across populations, whereas nonsocial cognition may play a unique role in determining social disconnection in schizophrenia.

Human iPSC-derived photoreceptor transplantation in the cone dominant 13-lined ground squirrel.

Several retinal degenerations affect the human central retina, which is primarily comprised of cones and is essential for high acuity and color vision. Transplanting cone photoreceptors is a promising strategy to replace degenerated cones in this region. Although this approach has been investigated in a handful of animal models, commonly used rodent models lack a cone-rich region and larger models can be expensive and inaccessible, impeding the translation of therapies. Here, we transplanted dissociated GFP-expressing photoreceptors from retinal organoids differentiated from human induced pluripotent stem cells into the subretinal space of damaged and undamaged cone-dominant 13-lined ground squirrel eyes. Transplanted cell survival was documented via noninvasive high-resolution imaging and immunohistochemistry to confirm the presence of human donor photoreceptors for up to 4 months posttransplantation. These results demonstrate the utility of a cone-dominant rodent model for advancing the clinical translation of cell replacement therapies.