Evaluation of GPT Large Language Model Performance on RSNA 2023 Case of the Day Questions.

Background GPT-4V (GPT-4 with vision, ChatGPT; OpenAI) has shown impressive performance in several medical assessments. However, few studies have assessed its performance in interpreting radiologic images. Purpose To assess and compare the accuracy of GPT-4V in assessing radiologic cases with both images and textual context to that of radiologists and residents, to assess if GPT-4V assistance improves human accuracy, and to assess and compare the accuracy of GPT-4V with that of image-only or text-only inputs. Materials and Methods Seventy-two Case of the Day questions at the RSNA 2023 Annual Meeting were curated in this observer study. Answers from GPT-4V were obtained between November 26 and December 10, 2023, with the following inputs for each question: image only, text only, and both text and images. Five radiologists and three residents also answered the questions in an "open book" setting. For the artificial intelligence (AI)-assisted portion, the radiologists and residents were provided with the outputs of GPT-4V. The accuracy of radiologists and residents, both with and without AI assistance, was analyzed using a mixed-effects linear model. The accuracies of GPT-4V with different input combinations were compared by using the McNemar test. P < .05 was considered to indicate a significant difference. Results The accuracy of GPT-4V was 43% (31 of 72; 95% CI: 32, 55). Radiologists and residents did not significantly outperform GPT-4V in either imaging-dependent (59% and 56% vs 39%; P = .31 and .52, respectively) or imaging-independent (76% and 63% vs 70%; both P = .99) cases. With access to GPT-4V responses, there was no evidence of improvement in the average accuracy of the readers. The accuracy obtained by GPT-4V with text-only and image-only inputs was 50% (35 of 70; 95% CI: 39, 61) and 38% (26 of 69; 95% CI: 27, 49), respectively. Conclusion The radiologists and residents did not significantly outperform GPT-4V. Assistance from GPT-4V did not help human raters. GPT-4V relied on the textual context for its outputs. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Katz in this issue.

Integrating PARP Inhibitors in mCRPC Therapy: Current Strategies and Emerging Trends.

Metastatic castrate-resistant prostate cancer (mCRPC) is associated with poor prognosis. DNA damage response (DDR) genes are commonly altered in mCRPC rendering them as promising therapeutic targets. Poly (ADP ribose) polymerase inhibitors (PARPi) demonstrated antitumor activity in mCRPC patients with DDR gene mutations through synthetic lethality. Multiple clinical trials with PARPi monotherapy exhibited encouraging clinical outcomes in selected patients with mCRPC. More recently, three Phase III randomized clinical trials (RCTs) combining PARPi with androgen receptor signaling inhibitors (ARSIs) demonstrated improved antitumor activity compared to ARSI monotherapy in mCRPC patients as the first-line therapy. Clinical benefit was more pronounced in patients harboring DDR alterations, specifically BRCA1/2. Interestingly, antitumor activity was also observed irrespective of DDR gene mutations, highlighting BRCAness phenotype with androgen receptor blockade resulting in synergistic activity between ARSIs and PARPi. In this review, we discuss the clinical efficacy and safety data of the combination of PARPi plus ARSI in all Phase 3 randomized controlled trials (RCTs), emphasizing strategies for patient selection and highlighting emerging trends based on clinical trial data.

Comorbidity of Depression and Diabetes: A Literature Review on Systemic Flaws in Healthcare and the Benefits of Collaborative Diagnosis and Treatment in Primary Care Settings.

BACKGROUND: The increasing specialization and dispersion of healthcare systems have led to a shortage of resources to address comorbidities. Patients with coexisting mental and physical conditions are disadvantaged, as medical providers often only focus on the patient's mental illness while neglecting their physical needs, resulting in poorer health outcomes. OBJECTIVE: This study aimed to shed light on the systemic flaws in healthcare systems that contribute to suboptimal health outcomes in individuals with comorbid diseases, including depression and diabetes. This paper also discusses the clinical and economic benefits of collaborative methods for diagnosing and treating depressive disorders in primary care settings. METHODS: A comprehensive literature review of the relationship between depression and diabetes was conducted. The outcomes of the literature review were carefully analyzed. Several databases were searched using keywords such as "diabetes," "depression," "comorbidity," "prevalence," "epidemiology," and "risk factors" using Google Scholar and PubMed as search engines. The review and research papers written between 1961 and 2023 were our main focus. RESULTS: This study revealed improved depressive symptoms and better blood sugar and blood pressure control. Additionally, individuals with comorbid depression and diabetes have higher direct and secondary medical costs. Antidepressants and psychological interventions are equally effective in treating depressive symptoms in patients with diabetes, although they have conflicting effects on glycemic control. For individuals with comorbid diabetes and depression, clear care pathways, including a multidisciplinary team, are essential for achieving the best medical and mental health outcomes. CONCLUSION: Coordinated healthcare solutions are necessary to reduce the burden of illness and improve therapeutic outcomes. Numerous pathophysiological mechanisms interact with one another and may support the comorbidities of T2DM, and depressive disorders could exacerbate the course of both diseases.

Unlocking the Immunomodulatory Potential of Rosmarinic Acid Isolated from Punica granatum L. using Bioactivity-Guided Approach: In Silico, In Vitro, and In Vivo Approaches.

BACKGROUND: Punica granatum L. is well-known for its multifaceted therapeutic potential, including anti-inflammatory and immunomodulatory activities. AIM: This study aimed to characterize an immunomodulatory compound isolated from Punica granatum L. using a bioactivity-guided approach. METHODS: Chromatographic techniques were adopted for isolation and purification of secondary metabolites. In silico, in vitro, and in vivo methods were performed to characterize the therapeutic potential of the isolated compound. RESULTS: Using preparative thin-layer chromatography, rosmarinic acid was isolated from F4 (column chromatography product obtained from a butanolic fraction of the extract). The impact of rosmarinic acid was assessed in rats using the neutrophil adhesion test, DTH response, and phagocytic index. In immunized rats, rosmarinic acid demonstrated significant immunomodulatory potential. Computational experiments, like molecular docking and molecular dynamics, were also conducted against two targeted receptors, Cereblon (PDB ID: 8AOQ) and human CD22 (PDB ID: 5VKM). Computational studies suggested that an increase in phagocytic index by rosmarinic acid could be attributed to inhibiting Cereblon and CD22. Pharmacokinetics and toxicity prediction also suggested the drug-likeness of rosmarinic acid. CONCLUSION: Rosmarinic acid is a potential candidate, but extensive research needs to be done to translate this molecule from bench to bedside.

Efficient production of an antitumor precursor actinocin and other medicinal molecules from kynurenine pathway in Escherichia coli.

Kynurenine pathway has a potential to convert L-tryptophan into multiple medicinal molecules. This study aims to explore the biosynthetic potential of kynurenine pathway for the efficient production of actinocin, an antitumor precursor selected as a proof-of-concept target molecule. Kynurenine pathway is first constructed in Escherichia coli by testing various combinations of biosynthetic genes from four different organisms. Metabolic engineering strategies are next performed to improve the production by inhibiting a competing pathway, and enhancing intracellular supply of a cofactor S-adenosyl-L-methionine, and ultimately to produce actinocin from glucose. Metabolome analysis further suggests additional gene overexpression targets, which finally leads to the actinocin titer of 719 mg/L. E. coli strain engineered to produce actinocin is further successfully utilized to produce 350 mg/L of kynurenic acid, a neuroprotectant, and 1401 mg/L of 3-hydroxyanthranilic acid, an antioxidant, also from glucose. These competitive production titers demonstrate the biosynthetic potential of kynurenine pathway as a source of multiple medicinal molecules. The approach undertaken in this study can be useful for the sustainable production of molecules derived from kynurenine pathway, which are otherwise chemically synthesized.

Facile Hydrogenolysis of Sugars to 1,2-Glycols by Ru@PPh3/OPPh3 Confined Large-Pore Mesoporous Silica.

Tandem hydrogenation vis-à-vis hydrogenolysis of xylose to 1,2-glycols remains a major challenge. Although one-pot conversion of xylose to 1,2-glycols requires stringent conditions, a sustainable approach would be quite noteworthy. We have developed a microwave route for the one-pot conversion of pentose (C5) and hexose (C6) sugars into glycol and hexitol, without pressurized hydrogen reactors. A pronounced hydrogenolysis of sugars to glycols is observed by Ru single atom (SA) on triphenylphosphine/phosphine oxide-modified silica (Ru@SiP), in contrast to Ru SA on pristine (Ru@SiC) and 3-aminopropyl-modified silica (Ru@SiN). A promising "ligand effect" was observed through phosphine modification of silica that presents a 70% overall yield of all reduced sugars (xylitol + glycols) from a 99% conversion of xylose with Ru@SiP. A theoretical study by DFT depicts an electronic effect on Ru-SA by triphenylphosphine that promotes the catalytic hydrogenolysis of sugars under mild conditions. Hence, this research represents an important step for glycols from biomass-derived sources.

Catalytic Inhibition of Base-Mediated Reactivity by a Self-Assembled Metal-Ligand Host.

Spacious M4 L6 tetrahedra can act as catalytic inhibitors for base-mediated reactions. Upon adding only 5 % of a self-assembled Fe4 L6 cage complex, the conversion of the conjugate addition between ethylcyanoacetate and ß-nitrostyrene catalyzed by proton sponge can be reduced from 83 % after 75 mins at ambient temperature to <1 % under identical conditions. The mechanism of the catalytic inhibition is unusual: the octacationic Fe4 L6 cage increases the acidity of exogenous water in the acetonitrile reaction solvent by favorably binding the conjugate acid of the basic catalyst. The inhibition only occurs for Fe4 L6 hosts with spacious internal cavities: minimal inhibition is seen with smaller tetrahedra or Fe2 L3 helicates. The surprising tendency of the cationic cage to preferentially bind protonated, cationic ammonium guests is quantified via the comprehensive modeling of spectrophotometric titration datasets.

Water quality and health risk assessment of heavy metals in groundwater of Ranbir Singh Pura tehsil of Jammu and Kashmir, India.

Groundwater is one of the important sources available for drinking, agricultural, domestic, and various other purposes in the study area. Study area is having agricultural importance and is famous for Basmati rice production in the world. In order to assess water suitability for irrigation and drinking purposes, 25 sampling sites were selected and water samples were collected from handpumps, borewells and motors from May 2022 to June 2022. Fifteen physico-chemical parameters and water quality index (WQI) was calculated to assess the drinking water suitability. The results obtained then compared with the BIS (2012) and WHO drinking water guidelines. For irrigation water suitability, irrigation water quality index (IWQI) and other indices were calculated. Heavy metal health risk assessment was also evaluated using target hazard quotient (THQ), carcinogenic risks (CR), non-carcinogenic risks, heavy metal pollution index (HPI), etc. Study found 60% of water samples under poor category of WQI. All water samples were found suitable for irrigation purposes according to different indices except for permeability index for which only 32% samples were found suitable. IWQI classifies 52%, 32%, and 12% of water samples under moderate, low, and no restriction category respectively. Groundwater of the study area found to be contaminated with copper (Cu), iron (Fe), lead (Pb), and chromium (Cr) while low contamination of zinc (Zn) and arsenic (As) was found according to heavy metal evaluation index (HEI). High contamination of chromium (HPI= 9740.8) and lead (HPI=188) was recorded as per HPI. HQ value for men, women, and children in case of zinc were found safe while HQ values for copper and lead in all population groups were found at risk. Overall, the study area was found highly contaminated with the lead, copper, and chromium concentrations. Thus, study recommends regular monitoring of the groundwater of study area as well as treatment before using this water for drinking purposes.

Targeting mitochondrial dysfunction to salvage cellular senescence for managing neurodegeneration.

Aging is an inevitable phenomenon that causes a decline in bodily functions over time. One of the most important processes that play a role in aging is senescence. Senescence is characterized by accumulation of cells that are no longer functional but elude the apoptotic pathway. These cells secrete inflammatory molecules that comprise the senescence associated secretory phenotype (SASP). Several essential molecules such as p53, Rb, and p16INK4a regulate the senescence process. Mitochondrial regulation has been found to play an important role in senescence. Reactive oxygen species (ROS) generated from mitochondria can affect cellular senescence by inducing the persistent DNA damage response, thus stabilizing the senescence. Evidently, senescence plays a major contributory role to the development of age-related neurological disorders. In this chapter, we discuss the role of senescence in the progression and onset of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Moreover, we also discuss the efficacy of certain molecules like MitoQ, SkQ1, and Latrepirdine that could be proven therapeutics with respect to these disorders by regulating mitochondrial activity.

Comparative Study of Chromium Phytoremediation by Two Aquatic Macrophytes.

Chromium (Cr) occurs in several oxidation states from trivalent to hexavalent. However, hexavalent forms are more toxic and mainly produced by anthropogenic activities. A hydroponic experiment was conducted to analyse the comparative remediation of Cr by Marsilea minuta and Pistia stratiotes. Plants were exposed to four concentrations of Cr (0.5, 1.0, 1.5, and 2.0 mM) for 3 days. The highest accumulation of Cr was seen at the 1.5 mM concentration after 3 days in Marsilea (11.96 mg/g) and Pistia (18.78 mg/g). Dry weights decreased and malondialdehyde (MDA) levels increased in response to increasing Cr concentrations. Results indicate that both macrophytes are suitable candidates for Cr phytoremediation. Antioxidant-enzyme activity as a function of metal tolerance is imperative for a coherent understanding of plant physiology under metal stress.

Deciphering the role of cytoplasmic domain of Channelrhodopsin in modulation of the interactome and SUMOylome of Chlamydomonas reinhardtii.

Translocation of channelrhodopsins (ChRs) is mediated by the intraflagellar transport (IFT) machinery. However, the functional role of the network involving photoreceptors, IFT and other proteins in controlling algal ciliary motility is still not fully delineated. In the current study, we have identified two important motifs at the C-terminus of ChR1, VXPX and LKNE. VXPX is a known ciliary targeting sequence in animals, and LKNE is a well-known SUMOylation motif. To the best of our knowledge, this study gives prima facie insight into the role of SUMOylation in Chlamydomonas. We prove that VMPS of ChR1 is important for interaction with GTPase CrARL11. We show that SUMO motifs are present in the C-terminus of putative ChR1s from green algae. Performing experiments with n-Ethylmaleimide (NEM) and Ubiquitin-like protease 1 (ULP-1), we show that SUMOylation may modulate ChR1 protein in Chlamydomonas. Experiments with 2D08, a known sumoylation blocker, increased the concentration of ChR1 protein. Finally, we show the endogenous SUMOylated proteins (SUMOylome) of C. reinhardtii, identified by using immunoprecipitation followed by nano-LC-MS/MS detection. This report establishes a link between evolutionarily conserved SUMOylation and ciliary machinery for the maintenance and functioning of cilia across the eukaryotes. Our enriched SUMOylome of C. reinhardtii comprehends the proteins related to ciliary development and photo-signaling, along with the orthologue(s) associated to human ciliopathies as SUMO targets.

Role of calcium sensor protein module CBL-CIPK in abiotic stress and light signaling responses in green algae.

Ca2+ signaling is an important biological process that enable to perceive and communicate information in the cell. Our current understanding of the signaling system suggests that plants and animals have certain differences in signal-sensing mechanisms. The Ca2+-mediated CBL-CIPK module has emerged as a major sensor responder network for Ca2+ signaling and has been speculated to be involved in plant terrestrial life adaptation. This module has previously been reported in Archaeplastids, Chromalveolates, and Excavates. In our experimental analysis of Chlamydomonas reinhardtii CBLs, we proved that the CrCBL1 protein interacts with Phototropin and Channelrhodopsin, and the expression of CrCBLs is modulated by light. Further analysis using chlorophyte and streptophyte algal sequences allowed us to identify the differences that have evolved in CBL and CIPK proteins since plants have progressed from aquatic to terrestrial habitats. Moreover, an investigation of Klebsormidium CBL and CIPK genes led us to know that they are abiotic stress stimuli-responsive, indicating that their role was defined very early during terrestrial adaptations. Structure-based prediction and Ca2+-binding assays indicated that the KnCBL1 protein in Klebsormidium showed a typical Ca2+-binding pocket. In summary, the results of this study suggest that these stress-responsive proteins enable crosstalk between Ca2+ and light signaling pathways very early during plant adaptation from aquatic to terrestrial habitats.

Synthetic amino acids-based short amphipathic peptides exhibit antifungal activity by targeting cell membrane disruption.

Availability of a limited number of antifungal drugs created a necessity to develop new antifungals with distinct mode of action. Investigation on a new series of peptides led us to identify Boc-His-Trp-His[1-(4-tert-butylphenyl)] (10g) as the most promising inhibitor exhibiting IC50 value of 4.4 µg/mL against Cryptococcus neoformans. Analog 10g exhibit high selectivity to fungal cells and was nonhemolytic and noncytotoxic at its minimum inhibitory concentration. 10g produced fungicidal effect on growing cryptococcal cells and displayed synergistic effect with amphotericin B. Overall cationic character of 10g resulted in interaction with negatively charged fungal membrane while hydrophobicity enhanced penetration inside the cryptococcal cells causing hole(s) formation and disruption to the membrane as evident by the scanning electron microscopy, transmission electron microscopy, and confocal laser scanning microscopy analyses. Flow cytometric investigation revealed rapid death of fungal cells by apopotic pathway.

Anticryptococcal activity and mechanistic studies of short amphipathic peptides.

Cryptococcus neoformans, an opportunistic fungal pathogen, causes cryptococcosis in immunocompromised persons. A series of modified L-histidines-containing peptides are synthesized that exhibit promising activity against C. neoformans. Analog 11d [L-His(2-adamantyl)-L-Trp-L-His(2-phenyl)-OMe] produced potency with an IC50 of 3.02 µg/ml (MIC = 5.49 µg/ml). This peptide is noncytotoxic and nonhaemolytic at the MIC and displays synergistic effects with amphotericin B at subinhibitory concentration. Mechanistic investigation of 11d using microscopic tools indicates cell wall and membrane disruption of C. neoformans, while flow cytometric analysis confirms cell death by apoptosis. This study indicates that 11d exhibits antifungal potential and acts via the rapid onset of action.

Design, synthesis, and applications of ring-functionalized histidines in peptide-based medicinal chemistry and drug discovery.

Modified and synthetic α-amino acids are known to show diverse applications. Histidine, which possesses numerous applications when subjected to synthetic modifications, is one such amino acid. The utility of modified histidines varies widely from remarkable biological activities to catalysis, and from nanotechnology to polymer chemistry. This renders histidine residue an important place in scientific research. Histidine is a well-studied scaffold and constitutes the active site of various enzymes catalyzing important reactions in the biological systems. A rational modification in histidine structure with a distinctly developed protocol extensively changes its physical and chemical properties. The utilization of modified histidines in search of potent, target selective and proteostable scaffolds is vital in the development of bioactive peptides with enhanced drug-likeliness. This review is a compilation and analysis of reported side-chain ring modifications at histidine followed by applications of ring-modified histidines in the synthesis of various categories of bioactive peptides and peptidomimetics.

Peptide-based drug discovery: Current status and recent advances.

The progressive development of peptides from reaction vessels to life-saving drugs via rigorous preclinical and clinical assessments is fascinating. Peptide therapeutics have gained momentum with the evolution of techniques in peptide chemistry, such as microwave irradiation in solid- and solution-phase synthesis, ligation chemistry, recombinant synthesis, and amalgamation with synthetic tools, including metal catalysis. Diverse emerging technologies, such as DNA-encoded libraries (DELs) and display techniques, are changing the status quo in the discovery of peptide therapeutics. In this review, we analyzed US Food and Drug Administration (FDA)-approved peptide drugs and those in clinical trials, highlighting recent advances in peptide-based drug discovery.

Synthetic amino acids-derived peptides target Cryptococcus neoformans by inducing cell membrane disruption.

We investigated synthetic amino acid-based approach to design short peptide-based antibiotics. Tautomerically restricted, amphiphilic 1-aryl-l-histidines along with hydrophobic tryptophan were utilized to synthesize the designed peptides. l-Trp-l-His(1-biphenyl)-NHBzl (12e, IC50 = 1.91 µg/mL; MIC = 3.46 µg/mL) and l-His[1-(4-n-butylphenyl)]-l-Trp-l-His[1-(4-n-butylphenyl)]-NHBzl (16d, IC50 = 1.36 µg/mL; MIC = 2.46 µg/mL) produced potency against Cryptococcus neoformans. Peptides with moderate antibacterial activities (IC50s = 4.40-8.80 µg/mL) were also identified. The mechanism of action and cellular changes revealed that membrane disruption due to interactions of the positively charged peptides with the negatively charged membrane of the cryptococcal cells result in permeabilization, leading to pore formation. The internal localization of the peptides instigated the interactions with DNA causing fragmentation of the genetic material, which together with membrane disruption led to cell death. Flow cytometric analysis points to cells death by apoptotic pathway. Time kill kinetics and synergistic study confirmed the fungicidal nature and synergism with amphotericin B.

Chickpea (Cicer arietinum L.) Biology and Biotechnology: From Domestication to Biofortification and Biopharming.

Chickpea (Cicer arietinum L.), the world's second most consumed legume crop, is cultivated in more than 50 countries around the world. It is a boon for diabetics and is an excellent source of important nutrients such as vitamins A, C, E, K, B1-B3, B5, B6, B9 and minerals (Fe, Zn, Mg and Ca) which all have beneficial effects on human health. By 2050, the world population can cross 9 billion, and in order to feed the teaming millions, chickpea production should also be increased, as it is a healthy alternative to wheat flour and a boon for diabetics. Moreover, it is an important legume that is crucial for food, nutrition, and health security and the livelihood of the small-scale farmers with poor resources, in developing countries. Although marvelous improvement has been made in the development of biotic and abiotic stress-resistant varieties, still there are many lacunae, and to fulfill that, the incorporation of genomic technologies in chickpea breeding (genomics-assisted breeding, high-throughput and precise-phenotyping and implementation of novel breeding strategies) will facilitate the researchers in developing high yielding, climate resilient, water use efficient, salt-tolerant, insect/pathogen resistant varieties, acceptable to farmers, consumers, and industries. This review focuses on the origin and distribution, nutritional profile, genomic studies, and recent updates on crop improvement strategies for combating abiotic and biotic stresses in chickpea.