Treatment challenges and outcomes of older patients with acute myeloid leukemia from India.

Globally, overall survival (OS) of older patients with AML continues to be suboptimal with very little data from India. In a multicenter registry analysis, we evaluated 712 patients with AML older than 55 years. Only 323 (45.3%) underwent further treatment, of which 239 (74%) received HMAs, and 60 (18%) received intensive chemotherapy (IC). CR was documented in 39% of those receiving IC and 42% after HMAs. Overall, 100 (31%) patients died within 60 days of diagnosis, most commonly due to progressive disease (47%) or infections (30%). After a median follow-up of 176 days, 228 (76%) of patients had discontinued treatment. At one year from diagnosis, 211 (65%) patients had died, and the median OS was 186 days (IQR, 137-234). Only 12 (3.7%) patients underwent stem cell transplantation. Survival was significantly lower for those older than 60 years (p < 0.001). Patients who died had a higher median age (p = .027) and baseline WBC counts (p = .006). Our data highlights suboptimal outcomes in older AML patients, which are evident from 55 years of age onwards, making it necessary to evaluate HMA and targeted agent combinations along with novel consolidation strategies to improve survival in this high-risk population.

Frequency-tuned selectivity enhancement of Mg@ZnO-TiO2 nanoflake-based heterojunction sensor devices.

Selectivity improvement by the frequency tuning of Mg@ZnO-TiO2 nanoflake-based heterojunction devices under exposure to different volatile organic compounds is the prime focus of the present paper. The synthesis of Mg@ZnO-TiO2 nanoflakes was carried out using a solution process followed by a low-cost hydrothermal method. A capacitive measurement approach was used to find the resonant frequencies of the device in 2-butanone, acetone, 2-propanol, ethanol, and methanol environments in the frequency range from 0.001 to 220 kHz. A Cole-Cole plot derived from impedance measurements suggested that the device impedance consisted of capacitance (Cz = 2.01 pF and CT = 2.17 pF) and resistance (Rz = 13 552.2 kΩ and RT = 3500.574 kΩ) from the ZnO nanoflake layer and TiO2 thin film layer, respectively. The maximum capacitive responses to 2-butanone (C4H8O), acetone (C3H6O), 2-propanol (C3H8O), ethanol (C2H5OH), and methanol (CH3OH) were recorded at resonant frequencies of 1.000 kHz, 0.791 kHz, 0.702 kHz, 0.319 kHz and 0.103 kHz, respectively, at the corresponding temperature of 125 °C, 100 °C, 100 °C, 75 °C, and 75 °C, respectively. The device offered optimum capacitive responses of 221.32%, 242.65%, 317.09%, 373.96%, and 401.24% to 100 ppm of 2-butanone, acetone, 2-propanol, ethanol, and methanol, respectively. Experimental observation confirmed that the capacitive response inversely varied with the resonant frequency. Such an inverse relation was correlated with the dielectric variation at the junction interface, change in the molecular weights of VOCs, and their sticking coefficient. An equivalent circuit diagram with the help of adsorption-desorption isotherms and an energy band model is illustrated to correlate the device optimum capacitive response at the tuned frequencies under different VOC media.

Molecular characterization of DNAH6 and ATPase6 (Mitochondrial DNA) genes in asthenozoospermia patients in the northern region of India.

BACKGROUND: Male infertility due to spermatogenesis defects affects millions of men worldwide. However, the genetic etiology of the vast majority remains unclear. The present study was undertaken to assess the association of DNAH6 and ATPase6 genes in asthenozoospermia patients in the northern region of India. METHODS: A total of 60 semen samples were collected for the study, of which 30 were from the case group and 30 were from the control group. The semen samples for the case group (asthenozoospermia) and control groups were collected from IVF and Reproductive Biology Centre, Maulana Azad Medical College, New Delhi. Sperm count and motility were classified as per World Health Organization (WHO 2021) protocol. A total genomic DNA was extracted as per the stranded TRIZOL method with little modification. RESULTS: In-vitro molecular characterizations of DNAH6 and ATPase6 genes in both groups were checked by Polymerase Chain Reaction (PCR). The 675 bp and 375 bp amplicons were amplified using PCR for ATPase6 and DNAH6 genes. Our study results showed a significant (P ≤ 0.05) null deletion of DNAH6 and ATPase6 genes in asthenozoospermia patients as compared to the control. We found the significant null deletion of DNAH6 in case 45.0%, and the control group was 11.7%. However, in the case of APTase6, it was 26.7% and 10.0%, respectively. CONCLUSIONS: Our study concluded that the presence of DHAH6 and ATPase6 genes had a significant impact on male infertility.

Clinicohistoradiological and surgical outcome in diffuse midline glioma.

PURPOSE: Diffuse Midline Glioma (DMG) with H3K27M mutation is a rare and aggressive midline high grade glioma with a predominant astrocytic differentiation and K27M mutation in either H3F3A or HIST1H3B/C. This tumor is more common in children than in adults. The current study was aimed to determine clinicohistoradiological and surgical outcome of patients who have undergone surgery for DMG and study disease severity of patients with DMG. METHODS: This is an observational study in which 29 DMG patients were evaluated for clinicohistoradiological and surgical outcomes by assessing the pre and postoperative neurological status. RESULT: Survival duration was significantly high in patients with age > 18 years (p = 0.02). Patients who had undergone Radiation Therapy showed higher survival rate (p = 0.05) and the cases with low levels of Ki 67 index had improved post operative outcome (p = 0.002). CONCLUSION: DMG with H3K27M mutation in newly classified Central Nervous System tumor are WHO grade IV Tumors, comprising H3K27M mutation as molecular marker for diagnosis and related with a poor prognosis.

Molecular and genetic diversity in isolates of Trypanosoma evansi from naturally infected horse and dogs by using RoTat 1.2 VSG gene in Madhya Pradesh, India.

BACKGROUND: Trypanosoma evansi is a protozoan parasite that can infect a wide range of animals and is widespread around the world. In this study, we analyzed four fatal cases of T. evansi infection using clinical, parasitological, and molecular approaches. We also explored the genetic diversity, demographic history, and population-genetic structure of T. evansi using available Rode Trypanozoon antigenic type (RoTat) 1.2 gene sequences. METHODS AND RESULTS: Clinical findings of infected animals revealed high fever, anemia, weakness, and anorexia. The animals were treated with diminazene aceturate, which was moderately effective, and hematobiochemical parameters showed changes in hemoglobin and glucose levels. The molecular and genetic diversity of T. evansi was analyzed using the RoTat 1.2 VSG gene. Phylogenetic and haplotype analysis revealed two distinct clusters of T. evansi circulating in India. The genetic diversity indices, neutrality tests, gene flow, and genetic differentiation outcomes confirmed the genetic diversity of the T. evansi population, with a lack of uniformity. The identification of two distinct clusters, exhibiting differential demographic histories and evolutionary forces, implies that the clusters may have undergone independent evolutionary trajectories or experienced different environmental pressures. CONCLUSION: The present findings underlined the need of an early and precise diagnosis in order to treat and control T. evansi infections, and the RoTat 1.2 VSG gene is an important genetic marker for understanding the genetic diversity and evolutionary history of T. evansi. This knowledge can be used to create tailored strategies to control and manage the infection in an endemic region.

Assessment of genetic diversity of Trypanosoma evansi in the domestic animal populations through ITS-1 gene sequence analysis.

Trypanosoma evansi infects domestic animals, causing a debilitating and occasionally fatal disease. The disease leads to significant economic losses to farmers and poses a substantial impediment to the growth of livestock production in developing nations, including India. Considering the challenges associated with managing this infection, there is an urgent need to enhance our understanding of the molecular and genetic diversity of T. evansi. Therefore, this study was planned to analyze the genetic diversity of T. evansi using available internal transcribed spacer-1 (ITS-1) gene sequences from India and compare them with sequences from around the globe. Blood samples used in this study were collected from naturally infected animals including dogs, cattle, and buffaloes in the Indian state of Madhya Pradesh. Using the ITS-1 gene, we amplified a 540 base pairs (bp) segment using polymerase chain reaction (PCR), sequenced it, and identified intra-specific variations. Phylogenetic analysis of 90 sequences, including 27 from India, revealed three distinct clusters with high bootstrap support values. A haplotype network analysis identified 34 haplotypes, with H7 being the most prevalent, indicating a complex evolutionary history involving multiple countries. The genetic analysis of the Indian population revealed distinct characteristics. Despite low nucleotide diversity, there was high haplotype diversity in comparison to other populations. Tajima's D, Fu and Li's D, and Fu and Li's F exhibited non-significant negative values, indicating potential stability. Additionally, the slightly positive values in Fu's Fs, Raggedness (r), and Ramos-Onsins and Rozas (R2) statistics suggested a lack of recent significant selective pressures or population expansions. Furthermore, the presence of genetic differentiation and gene flow among T. evansi populations highlighted ongoing evolutionary processes. These findings collectively depicted a complex genetic landscape, suggesting both stability and ongoing evolutionary dynamics within the Indian population of T. evansi. The findings of this study are important for understanding the evolutionary history and population dynamics of T. evansi, and they may help us develop effective control strategies.

Molecular investigation of bovine tropical theileriosis outbreak in an organized dairy cattle farm in Madhya Pradesh, India.

The present study aimed to investigate an outbreak of Theileria annulata (T. annulata) infection in an organized dairy cattle farm in Madhya Pradesh, India, using clinical and molecular techniques. Following the deaths of two crossbred cattle in March 2021, 43 blood samples were collected from infected and apparently healthy animals and examined by blood smear and polymerase chain reaction (PCR) techniques. The blood smear examination showed that 23.25% of samples were positive for Theileria organisms, while conventional PCR targeting the 18S ribosomal RNA (18S rRNA) and T. annulata merozoite surface antigen-1 (TAMS-1) genes revealed that 32.55% of samples were positive for T. annulata. PCR targeting cytochrome b (Cytb) gene showed 46.51% of samples were positive for T. annulata. Haematological analysis confirmed clinical signs of infection in affected animals, which were treated with buparvaquone @ 2.5 mg/kg body weight intramuscularly along with supportive medicine. Two 18S rRNA gene amplicons were sequenced and analysed in a phylogenetic tree and haplotype network with 54 Indian and 38 foreign sequences. The phylogenetic tree revealed two groups with a high posterior probability and bootstrap value, while the haplotype network revealed 35 haplotypes, with haplotype 1 (H1) being the most abundant and several single haplotypes clustering around it, indicating fast and widespread expansion. Genetic diversity indices and neutrality tests confirmed that the population was expanding. These studies highlight the significance of prompt and precise diagnosis and management of T. annulata outbreaks and provide insights into its evolutionary history and population dynamics of T. annulata in India, which could aid improving disease preventive and control strategies.

Real-world experience of anti-D immunoglobulin in immune thrombocytopenia.

In developing countries, anti-D has been used in immune thrombocytopenia (ITP) as a cheaper alternative to human immunoglobulin. We aim to analyze the response and safety profile of anti-D in patients with severe ITP. A retrospective study was conducted at a tertiary care hospital in Northern India. Patients received a single intravenous infusion of 75 µg/kg anti-D. In total, 36 patients (20 females) were included in this study. The median duration from ITP diagnosis to anti-D therapy was 235 days (range 1-1613 days). Four (11.1%) patients received anti-D as an upfront treatment. The patients' platelet counts rose significantly by the end of day three and continued to be significantly high until day 30 of receiving anti-D (p ≤ 0.001). The overall response rate (ORR) by day seven was 88.89%. There was no effect of age, sex, duration of disease, prior therapy, and platelet count on the ORR. Patients were followed up for a median duration of 52 days (longest follow-up: 3080 days). Six (6/36, 16.67%) patients continued to be in remission till the last follow-up. The hemoglobin fall was statistically significant on day three and day seven (p < 0.001 and p = 0.001) and got normalized by day 30. We observed equally good ORR in mixed populations and different phases of ITP along with long-term sustained response. The study demonstrates a quick and high response rate along with good safety profile to anti-D in all forms of ITP.

THERMOD: Development of a Cost Effective Solution for Integrated Sensing and Logging.

With the outbreak of the Covid-19 pandemic, vaccination has become mandatory. Further, for effective results, the vaccines should be stored within the recommended temperature range, typically between 2°C to 8°C, transported safely without any mishandling and temperature excursion. In order to assure vaccine potency, it is essential to have detailed information on the entire temperature data recorded at user-defined intervals. In this paper, we develop functionality interaction to bring different sensors, memory, and processing units to an integrated platform, providing a compact, power-efficient, and low-cost commercial TemperatuRE, Humidity, and MOvement Data-logger (THERMOD). Moreover, the THERMOD hardware is packed with interactive algorithms that address the aforementioned concerns and log the real-time temperature and jerks (3-dimensional movement) encountered throughout the journey, and the logged data can be retrieved by plugging THERMOD into the host computer/laptop. The THERMOD hardware formulation and algorithm embedding have been done in the institution lab, which enables end-to-end storage and monitoring. Also, the proposed design is built with the defined standards by health organizations, e.g., WHO. Further, to validate the proficiency of the proposed design, comparative analysis has been done; a) a cost analysis has been done to state the cost efficiency of the proposed solution, b) real-time power performance graphs have been plotted which depict that THERMOD outperforms the existing solutions. Moreover, a number of experiments were performed for the validation of the proposed design.

"Shunt pumping test": detecting its efficacy through an experimental model.

PURPOSE: Shunt pumping test has often been used clinically to detect functional status of ventriculoperitoneal (VP) shunt. Its ability to correctly predict the status is not reliably known. Ethical dilemmas make it difficult to perform any studies in patients with blocked shunts, and hence, a requirement of devising an experimental model was felt. METHOD: An experimental model was devised using a Chhabra Slit N Spring shunt. The pressures were maintained in the proximal and distal chamber by real-time monitoring and maintained similar to intra-ventricular and intra-abdominal pressures. Three such models with scenarios of proximal block (PB), distal block (DB), and a functional shunt (BO) were created. Twenty-five participants were tested using these models to assess the efficacy of shunt pumping test. RESULTS: The experimental model could be used successfully to perform the test. The sensitivity of the test to detect a shunt with block on any side (AB) was found to be 0.79 (95% confidence interval 0.72-0.85) and specificity to be 0.69 (95% confidence interval 0.59-0.80). Its ability to detect the side of block was also evaluated. Absolute correctness value, odds ratio, and interpersonal heterogeneity were also evaluated. Pressure changes in proximal and distal catheter on compressing the chamber in various scenarios were recorded. CONCLUSION: The shunt pumping test has moderate ability to predict a blocked shunt and can aid clinical assessment of shunt block. It has only limited ability to detect the side of block. Pressure changes in the proximal and distal catheters on chamber compression are commensurate with the rationale of "shunt pumping test."

"Shunt Pumping Test": role of practice on an experimental model.

PURPOSE: To ascertain the benefits of practicing shunt pumping test on a validated experimental model. METHODS: A validated experimental model of shunt was used and 25 medical professionals were asked to assess the block in the model where artificial blocks were created. The assessment was repeated after the participants had practiced on the same model. The performance of participants before and after practice was compared and statistically evaluated. RESULTS: The ability to predict the status of shunt showed an improvement in all scenarios after practice. The odds ratio for predicting a blocked shunt before and after practice was 7.25 (95% credible interval: 1.50-21.01). The odds ratio for predicting a functional shunt before and after practice was 8.81 (95% credible interval of 1.64 to 13.65). CONCLUSION: Practicing on the experimental model significantly improves the ability to predict the status of shunt. Training of primary caregivers on similar shunt models based on the shunts used in respective centers can improve an early detection of shunt block and reduce reliance on more invasive and expensive evaluation modalities.

Sphingosine kinases negatively regulate the expression of matrix metalloproteases (MMP1 and MMP3) and their inhibitor TIMP3 genes via sphingosine 1-phosphate in extravillous trophoblasts.

PURPOSE: Extracellular matrix remodeling is essential for extravillous trophoblast (EVT) cell migration and invasion during placental development and regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteases (TIMPs). Sphingosine kinases (SPHK1 and SPHK2) synthesize sphingosine-1-phosphate (S1P), which works either intracellularly or extracellularly via its receptors S1PR1-5 in an autocrine or paracrine manner. The role of SPHKs/S1P in regulating the expression of MMPs and TIMPs in EVT is mostly unknown and forms the primary objective of the study. METHODS: HTR-8/SVneo cells were used as a model of EVT. To inhibit the expression of SPHKs, cells were treated with specific inhibitors, SK1-I and SKI-II, or gene-specific siRNAs. The expressions of MMPs and TIMPs were estimated by qPCR. RESULTS: We demonstrated that SPHK1, MMP1-3, and TIMP1-3 were highly expressed in HTR-8/SVneo cells. We found that treatment of cells with SK1-I, SKI-II, and knockdown of SPHK1 or SPHK2 increased the expression of MMP1, MMP3, and TIMP3. The addition of extracellular S1P inhibits the upregulation of MMPs and TIMPs in treated cells. CONCLUSIONS: SPHKs negatively regulate the expression of MMP1, MMP3, and TIMP3. The level of intracellular S1P acts as a negative feedback switch for MMP1, MMP3, and TIMP3 expression in EVT cells.

Understanding COVID-19 transmission through Bayesian probabilistic modeling and GIS-based Voronoi approach: a policy perspective.

Originating from Wuhan, China, COVID-19 is spreading rapidly throughout the world. The transmission rate is reported to be high for this novel strain of coronavirus, called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as compared to its predecessors. Major strategies in terms of clinical trials of medicines and vaccines, social distancing, use of personal protective equipment (PPE), and so on are being implemented in order to control the spread. The current study concentrates on lockdown and social distancing policy followed by the Indian Government and evaluates its effectiveness using Bayesian probability model (BPM). The change point analysis (CPA) done through the above approach suggests that the states which implemented the lockdown before the exponential rise of cases are able to control the spread of the disease in a much better and efficient way. The analysis has been done for states of Maharashtra, Gujarat, Madhya Pradesh, Rajasthan, Tamil Nadu, West Bengal, Uttar Pradesh, and Delhi as union territory. The highest value of Δ (delta) is reported for Gujarat and Madhya Pradesh with a value of 9.6 weeks, while the lowest value is 4.7, evidently for Maharashtra which is the worst affected. All of the states indicate a significant correlation (p < 0.05, tstat > tcritical) for Δ, i.e., the difference in the time period of CPA and lockdown with cases per population (CPP) and cases per unit area (CPUA), while weak correlation (p < 0.1 and tstat < tcritical) is exhibited by delta and cases per unit population density (CPD). For both CPP and CPUA, tstat > tcritical indicating a significant correlation, while Pearson's correlation indicates the direction to be negative. Further analysis in terms of identification of high-risk areas has been studied from the Voronoi approach of GIS based on the inputs from BPM. All the states follow the above pattern of high population, high case scenario, and the boundaries of risk zones can be identified by Thiessen polygon (TP) constructed therein. The findings of the study help draw strategic and policy-driven response for India, toward tackling COVID-19 pandemic.

Extended-spectrum beta-lactamase (ESBL) producing and multidrug-resistant Escherichia coli in street foods: a public health concern.

Antimicrobial resistance (AMR) pattern and virulence genes of extended-spectrum beta-lactamase (ESBL) producing Escherichia coli from foods of animal origin were evaluated. Based on combination disc method and ESBL E test, 42 of the 213 E. coli isolates were confirmed as ESBL producers where a high presence was observed in raw foods (60.62%), environmental samples (46.73%) and ready to eat foods (42.99%) of which 31(26.49%), 3(6.97%) and 7(15.21%) samples harbored ESBL E. coli, respectively. Higher contamination rates were observed in samples collected from meat vendors (54.36%), milk vendors (48.88%) and egg vendors (45.20%) of which 16.1%, 11.11% and 2.05%, respectively were ESBL E. coli. Among the 42 ESBL isolates, 85.71% (36/42) were multidrug-resistant. On polymerase chain reaction (PCR) analysis, expression of beta-lactamase genes viz., blaCTXM was noted in 69.04% (29/42) ESBL isolates, blaTEM in 66.66% (28/42) and blaOXA-1 in 19.04% (8/42) isolates, while blaSHV was not detected in any of the isolates. Other AMR genes viz., blaAmpC, sul1, sul2, tet(A), tet(B), catI, dhfrI, aac(3)-IIa(aacC2), aph(3')-Ia(aphA1), qnrB, qnrS were detected by PCR in 39, 28, 29, 3, 9, 5, 17, 11, 6, 6 and 33 isolates, respectively. None of the isolates harbored chloramphenicol (floR) and plasmid-mediated quinolone resistance (PMQR) (qnrA) genes. However, 21 isolates were positive for class I integron (int1), 5 for EPEC (eae) and 9 for ETEC (lt) while none were carrying bfp or stII genes. All ESBL producing isolates formed a single group when subjected to enterobacterial repetitive intergenic consensus (ERIC PCR) genotyping. The presence of multidrug-resistant ESBL E. coli in street foods of animal origin raises the issues of food safety and public health.

The development of early pioneer neurons in the annelid Malacoceros fuliginosus.

BACKGROUND: Nervous system development is an interplay of many processes: the formation of individual neurons, which depends on whole-body and local patterning processes, and the coordinated growth of neurites and synapse formation. While knowledge of neural patterning in several animal groups is increasing, data on pioneer neurons that create the early axonal scaffold are scarce. Here we studied the first steps of nervous system development in the annelid Malacoceros fuliginosus. RESULTS: We performed a dense expression profiling of a broad set of neural genes. We found that SoxB expression begins at 4 h postfertilization, and shortly later, the neuronal progenitors can be identified at the anterior and the posterior pole by the transient and dynamic expression of proneural genes. At 9 hpf, the first neuronal cells start differentiating, and we provide a detailed description of axonal outgrowth of the pioneer neurons that create the primary neuronal scaffold. Tracing back the clonal origin of the ventral nerve cord pioneer neuron revealed that it is a descendant of the blastomere 2d (2d221), which after 7 cleavages starts expressing Neurogenin, Acheate-Scute and NeuroD. CONCLUSIONS: We propose that an anterior and posterior origin of the nervous system is ancestral in annelids. We suggest that closer examination of the first pioneer neurons will be valuable in better understanding of nervous system development in spirally cleaving animals, to determine the potential role of cell-intrinsic properties in neuronal specification and to resolve the evolution of nervous systems.

Acaricide resistance in Rhipicephalus microplus collected from selected districts of Madhya Pradesh, Uttar Pradesh and Punjab states of India.

The isolates of Rhipicephalus microplus collected from Madhya Pradesh (MP), Punjab (PJB) and Uttar Pradesh (UP) states of India were characterized using laboratory standardized adult immersion test (AIT) against macrocyclic lactone (ivermectin), synthetic pyrethroids (cypermethrin and deltamethrin), organophosphates (coumaphos and diazinon) and phenylpyrazole compounds (fipronil). Out of the six isolates tested, five isolates except MTH were resistant to deltamethrin and cypermethrin at level II with RF ranging from 16.4 to 24.02 and 7.05 to 13.2, respectively. In case of organophosphates, coumaphos was less effective showing resistance level II (RF 8.52-11.2) in all the six populations compared with diazinon to which three isolates (MHW, RWA and AGS) were resistant at level II. Except MTH, other five isolates were categorized at level I with RF ranging from 1.53 to 3.02 against ivermectin. The phenylpyrazole compound however was found effective, and none of the isolates could survive at a discriminating concentration. The possible strategy for the management of multi-acaricide-resistant ticks in the surveyed districts was discussed in the present study.

Erythropoietin and ferritin response in native highlanders aged 4-19 years from the Leh-Ladakh region of India.

The pivotal role of erythropoietin (EPO) in hypoxic adaptation has led to various studies assessing the EPO and ferritin response in native highlanders from Andes and Tibet. We assessed the relationship between EPO, haemoglobin and ferritin in 335 native highlanders (172 boys and 163 girls, aged 4 to 19 years) from Leh-Ladakh, India, who had no history of travel to lowland areas. Complete blood counts, serum EPO and ferritin levels were measured. We stratified study subjects based on age, gender, pubertal status and analysed the EPO and ferritin levels between the stratified groups respectively. The mean EPO level in boys was lower than girls. The mean ferritin level in boys was significantly higher (P = 0·013) than in girls. There was no significant variation in the EPO and ferritin levels amongst the various age groups in our study. Near normal EPO levels since childhood with a negative correlation with haemoglobin is suggestive of a robust adaptive mechanism to high altitude from the early years of life. Low ferritin levels are indicative of decreased iron stores in these native highlanders.

Differentiation and molecular heterogeneity of inhibitory and excitatory neurons associated with midbrain dopaminergic nuclei.

Local inhibitory GABAergic and excitatory glutamatergic neurons are important for midbrain dopaminergic and hindbrain serotonergic pathways controlling motivation, mood, and voluntary movements. Such neurons reside both within the dopaminergic nuclei, and in adjacent brain structures, including the rostromedial and laterodorsal tegmental nuclei. Compared with the monoaminergic neurons, the development, heterogeneity, and molecular characteristics of these regulatory neurons are poorly understood. We show here that different GABAergic and glutamatergic subgroups associated with the monoaminergic nuclei express specific transcription factors. These neurons share common origins in the ventrolateral rhombomere 1, where the postmitotic selector genes Tal1, Gata2 and Gata3 control the balance between the generation of inhibitory and excitatory neurons. In the absence of Tal1, or both Gata2 and Gata3, the GABAergic precursors adopt glutamatergic fates and populate the glutamatergic nuclei in excessive numbers. Together, our results uncover developmental regulatory mechanisms, molecular characteristics, and heterogeneity of central regulators of monoaminergic circuits.

The mechanism of phosphatidylcholine-induced interference of PAP (248-286) aggregation.

Seminal amyloids are well known for their role in enhancing HIV infection. Among all the amyloidogenic peptides identified in human semen, PAP248-286 was found to be the most active and was termed as semen-derived enhancer of viral infection (SEVI). Although amyloidogenic nature of the peptide is mainly linked with enhancement of the viral infection, the most active physiological conformation of the aggregated peptide remains inconclusive. Lipids are known to modulate aggregation pathway of a variety of proteins and peptides and constitute one of the most abundant biomolecules in human semen. PAP248-286 significantly differs from the other known amyloidogenic peptides, including Aß and IAPP, in terms of critical concentration, surface charge, fibril morphology, and structural transition during aggregation. Hence, in the present study, we aimed to assess the effect of a lipid, 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), on PAP248-286 aggregation and the consequent conformational outcomes. Our initial observation suggested that the presence of the lipid considerably influenced the aggregation of PAP248-286 . Further, ZDOCK and MD simulation studies of peptide multimerization have suggested that the hydrophobic residues at C-terminus are crucial for PAP248-286 aggregation and are anticipated to be major DOPC-interacting partners. Therefore, we further assessed the aggregation behaviour of C-terminal (PAP273-286 ) fragment of PAP248-286 and observed that DOPC possesses the ability to interfere with the aggregation behaviour of both the peptides used in the current study. Mechanistically, we propose that the presence of DOPC causes considerable inhibition of the peptide aggregation by interfering with the peptide's disordered state to ß-sheet transition.