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The number of biomedical articles published is increasing rapidly over the years. Currently there are about 30 million articles in PubMed and over 25 million mentions in Medline. Among these fundamentals, Biomedical Named Entity Recognition (BioNER) and Biomedical Relation Extraction (BioRE) are the most essential in analysing the literature. In the biomedical domain, Knowledge Graph is used to visualize the relationships between various entities such as proteins, chemicals and diseases. Scientific publications have increased dramatically as a result of the search for treatments and potential cures for the new Coronavirus, but efficiently analysing, integrating, and utilising related sources of information remains a difficulty. In order to effectively combat the disease during pandemics like COVID-19, literature must be used quickly and effectively. In this paper, we introduced a fully automated framework consists of BERT-BiLSTM, Knowledge graph, and Representation Learning model to extract the top diseases, chemicals, and proteins related to COVID-19 from the literature. The proposed framework uses Named Entity Recognition models for disease recognition, chemical recognition, and protein recognition. Then the system uses the Chemical - Disease Relation Extraction and Chemical - Protein Relation Extraction models. And the system extracts the entities and relations from the CORD-19 dataset using the models. The system then creates a Knowledge Graph for the extracted relations and entities. The system performs Representation Learning on this KG to get the embeddings of all entities and get the top related diseases, chemicals, and proteins with respect to COVID-19.

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Although co-occurring methamphetamine (meth) use and HIV amplify the risk for neuropsychiatric comorbidities, the underlying neuroimmune mechanisms are not well characterized. We examined whether a detectable viral load and dysregulated metabolism of amino acid precursors for neurotransmitters predicted subsequent levels of sexual compulsivity and sexual sensation seeking. This 15-month longitudinal study enrolled 110 sexual minority men (SMM) living with HIV who had biologically confirmed meth use (i.e., reactive urine or hair toxicology results). Peripheral venous blood samples collected at baseline, 6 months, 12 months, and 15 months were used to measure a detectable viral load (> 40 copies/mL), the kynurenine/tryptophan (K/T) ratio, and the phenylalanine/tyrosine (P/T) ratio. The K/T and P/T ratios index dysregulated serotonin and catecholamine (e.g., dopamine) synthesis, respectively. In a cross-lagged panel model, a detectable viral load at 6 months predicted greater sexual compulsivity at 12 months after adjusting for prior levels of sexual compulsivity and recent stimulant use (ß = 0.26, p = 0.046). A greater P/T ratio at baseline predicted decreased sexual sensation seeking at 6 months (ß = - 0.25, p = 0.004) after adjusting for baseline sexual sensation seeking and recent stimulant use. Taken together, HIV replication and dysregulated catecholamine synthesis could potentiate sexual compulsivity while decreasing sexual pleasure in SMM who use meth.

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BACKGROUND: Overweight and obesity are common features of the rare disease Bardet-Biedl syndrome (BBS). Sleep and physical activity are behaviors that might impact overweight and obesity and thus may play a key role in the health and well-being of people with BBS. Objectively-measured sleep and physical activity patterns in people with BBS are not well known. We evaluated objectively-measured sleep and physical activity patterns in the largest cohort to date of people with BBS. RESULTS: Short sleep duration, assessed using wrist-worn accelerometers, was common in both children and adults with BBS. Only 7 (10%) of adults and 6 (8%) of children met age-specific sleep duration recommendations. Most adults 64 (90%) achieved recommended sleep efficiency. The majority of children 26 (67%) age 6-12 years achieved recommended sleep efficiency, but among children age 13-18, only 18 (47%). In both adults and children, sleep duration was significantly negatively correlated with duration of prolonged sedentary time. In children age 6-12 sleep duration was also significantly related to total activity score, children with lower sleep duration had lower total activity scores. CONCLUSIONS: Insufficient sleep duration is very common in people with BBS. Prolonged sedentary time and short sleep duration are both potentially important health-related behaviors to target for intervention in people with BBS.

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A number of simian and simian human immunodeficiency viruses (SIV and SHIV, respectively) have been used to assess the efficacy of HIV-1 vaccine strategies. Among these, SIVmac239 is considered among the most stringent because, unlike SHIV models, its full genome has coevolved in its macaque host and its tier 3 envelope glycoprotein (Env) is exceptionally hard to neutralize. Here, we investigated the ability of eCD4-Ig, an antibody-like entry inhibitor that emulates the HIV-1 and SIV receptor and coreceptor, to prevent SIVmac239 infection. We show that rh-eCD4-IgI39N expressed by recombinant adeno-associated virus (AAV) vectors afforded four rhesus macaques complete protection from high-dose SIVmac239 challenges that infected all eight control macaques. However, rh-eCD4-IgI39N-expressing macaques eventually succumbed to serial escalating challenge doses that were 2, 8, 16, and 32 times the challenge doses that infected the control animals. Despite receiving greater challenge doses, these macaques had significantly lower peak and postpeak viral loads than the control group. Virus isolated from three of four macaques showed evidence of strong immune pressure from rh-eCD4-IgI39N, with mutations located in the CD4-binding site, which, in one case, exploited a point-mutation difference between rh-eCD4-IgI39N and rhesus CD4. Other escape pathways associated with clear fitness costs to the virus. Our data report effective protection of rhesus macaques from SIVmac239.

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Adeno-associated virus (AAV) delivery of potent and broadly neutralizing antibodies (bNAbs is a promising approach for the prevention of HIV-1 infection. The immunoglobulin G (IgG)1 subtype is usually selected for this application, because it efficiently mediates antibody effector functions and has a somewhat longer half-life. However, the use of IgG1-Fc has been associated with the generation of anti-drug antibodies (ADAs) that correlate with loss of antibody expression. In contrast, we have shown that expression of the antibody-like molecule eCD4-Ig bearing a rhesus IgG2-Fc domain showed reduced immunogenicity and completely protected rhesus macaques from simian-HIV (SHIV)-AD8 challenges. To directly compare the performance of the IgG1-Fc and the IgG2-Fc domains in a prophylactic setting, we compared AAV1 expression of rhesus IgG1 and IgG2 forms of four anti-HIV bNAbs: 3BNC117, NIH45-46, 10-1074, and PGT121. Interestingly, IgG2-isotyped bNAbs elicited significantly lower ADA than their IgG1 counterparts. We also observed significant protection from two SHIV-AD8 challenges in macaques expressing IgG2-isotyped bNAbs, but not from those expressing IgG1. Our data suggest that monoclonal antibodies isotyped with IgG2-Fc domains are less immunogenic than their IgG1 counterparts, and they highlight ADAs as a key barrier to the use of AAV1-expressed bNAbs.

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OBJECTIVE: To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. METHODS: A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation. RESULTS: We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable. CONCLUSIONS: Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.

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UNLABELLED: The HIV-1 envelope glycoprotein (Env) is a trimer of gp120/gp41 heterodimers that mediates viral entry. Env binds cellular CD4, an association which stabilizes a conformation favorable to its subsequent association with a coreceptor, typically CCR5 or CXCR4. The CD4- and coreceptor-binding sites serve as epitopes for two classes of HIV-1-neutralizing antibodies: CD4-binding site (CD4bs) and CD4-induced (CD4i) antibodies, respectively. Here we observed that, at a fixed total concentration, mixtures of the CD4i antibodies (E51 or 412d) and the CD4bs antibody VRC01 neutralized the HIV-1 isolates 89.6, ADA, SG3, and SA32 more efficiently than either antibody alone. We found that E51, and to a lesser extent 412d and 17b, promoted association of four CD4bs antibodies to the Env trimer but not to monomeric gp120. We further demonstrated that the binding of the sulfotyrosine-binding pocket by CCR5mim2-Ig was sufficient for promoting CD4bs antibody binding to Env. Interestingly, the relationship is not reciprocal: CD4bs antibodies were not as efficient as CD4-Ig at promoting E51 or 412d binding to Env trimer. Consistent with these observations, CD4-Ig, but none of the CD4bs antibodies tested, substantially increased HIV-1 infection of a CD4-negative, CCR5-positive cell line. We conclude that the ability of CD4i antibodies to promote VRC01 association with Env trimers accounts for the increase potency of VRC01 and CD4i antibody mixtures. Our data further suggest that potent CD4bs antibodies avoid inducing Env conformations that bind CD4i antibodies or CCR5. IMPORTANCE: Potent HIV-1-neutralizing antibodies can prevent viral transmission and suppress an ongoing infection. Here we show that CD4-induced (CD4i) antibodies, which recognize the conserved coreceptor-binding site of the HIV-1 envelope glycoprotein (Env), can increase the association of Env with potent broadly neutralizing antibodies that recognize the CD4-binding site (CD4bs antibodies). We further show that, unlike soluble forms of CD4, CD4bs antibodies poorly induce envelope glycoprotein conformations that efficiently bind CCR5. This study provides insight into the properties of potent CD4bs antibodies and suggests that, under some conditions, CD4i antibodies can improve their potency. These observations may be helpful to the development of vaccines designed to elicit specific antibody classes.

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Long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. Adeno-associated virus (AAV) vectors can stably express HIV-1 broadly neutralizing antibodies (bNAbs). However, even the best bNAbs neutralize 10-50% of HIV-1 isolates inefficiently (80% inhibitory concentration (IC80) > 5 µg ml(-1)), suggesting that high concentrations of these antibodies would be necessary to achieve general protection. Here we show that eCD4-Ig, a fusion of CD4-Ig with a small CCR5-mimetic sulfopeptide, binds avidly and cooperatively to the HIV-1 envelope glycoprotein (Env) and is more potent than the best bNAbs (geometric mean half-maximum inhibitory concentration (IC50) < 0.05 µg ml(-1)). Because eCD4-Ig binds only conserved regions of Env, it is also much broader than any bNAb. For example, eCD4-Ig efficiently neutralized 100% of a diverse panel of neutralization-resistant HIV-1, HIV-2 and simian immunodeficiency virus isolates, including a comprehensive set of isolates resistant to the CD4-binding site bNAbs VRC01, NIH45-46 and 3BNC117. Rhesus macaques inoculated with an AAV vector stably expressed 17-77 µg ml(-1) of fully functional rhesus eCD4-Ig for more than 40 weeks, and these macaques were protected from several infectious challenges with SHIV-AD8. Rhesus eCD4-Ig was also markedly less immunogenic than rhesus forms of four well-characterized bNAbs. Our data suggest that AAV-delivered eCD4-Ig can function like an effective HIV-1 vaccine.

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In the title compound, C23H24F2O3, the central pyran ring has a flat-boat conformation, whereas the two fused cyclo-hexenone rings adopt envelope conformations, with the C atom bearing the dimethyl substituent being the flap atom in each case. The pyran ring mean plane and the di-fluoro-phenyl ring are almost normal to each other, making a dihedral angle of 87.55 (4)°. In the crystal, mol-ecules are linked by pairs of C-H⋯O hydrogen bonds, forming inversion dimers with an R 2 (2)(8) ring motif. The F atom at position 2 on the di-fluoro-phenyl ring is disordered over the 2- and 6-positions, and has a refined occupancy ratio of 0.932 (3):0.068 (3).

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In the title compound, C18H17FN2O, the imidazole ring makes dihedral angles of 68.81 (6) and 25.20 (8)° with the meth-oxy-phenyl and fluoro-phenyl rings, respectively. The dihedral angle between the meth-oxy-phenyl and fluoro-phenyl ring is 71.89 (6)°. In the crystal, mol-ecules are linked into inversion dimers with an R 2 (2)(8) graph-set motif by pairs of weak C-H⋯F inter-actions.

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The asymmetric unit of the title compound, C22H23F2NO, contains two independent mol-ecules, A and B. The bicyclic system adopts a twin-chair conformation in both mol-ecules. The dihedral angles between the fluoro-phenyl rings are 55.27 (8) and 56.37 (7)° in mol-ecules A and B, respectively. The NH groups are not involved in hydrogen bonding due to the steric hindrance of fluoro-phenyl groups. The crystal structure features weak C-H⋯O inter-actions.

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The interferon-induced transmembrane (IFITM) proteins are a family of small membrane proteins that inhibit the cellular entry of several genera of viruses. These proteins had been predicted to adopt a two-pass, type III transmembrane topology with an intracellular loop, two transmembrane helices (TM1 and TM2), and extracellular N and C termini. Recent work, however, supports an intramembrane topology for the helices with cytosolic orientation of both termini. Here we determined the topology of murine Ifitm3. We found that the N terminus of Ifitm3 could be stained by antibodies at the cell surface but that this conformation was cell type-dependent and represented a minority of the total plasma membrane pool. In contrast, the C terminus was readily accessible to antibodies at the cell surface and extracellular C termini comprised most or all of those present at the plasma membrane. The addition of a C-terminal KDEL endoplasmic reticulum retention motif to Ifitm3 resulted in sequestration of Ifitm3 in the ER, demonstrating an ER-luminal orientation of the C terminus. C-terminal, but not N-terminal, epitope tags were also degraded within lysosomes, consistent with their luminal orientation. Furthermore, epitope-tagged Ifitm3 TM2 functioned as a signal anchor sequence when expressed in isolation. Collectively, our results demonstrate a type II transmembrane topology for Ifitm3 and will provide insight into its interaction with potential targets and cofactors.

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In the title compound, C18H18N2O, the imidazole ring makes dihedral angles of 68.26 (7) and 22.45 (9)° with the meth-oxy-phenyl and phenyl rings, respectively. The dihedral angle between the meth-oxy-phenyl and phenyl ring is 71.86 (7)°. In the crystal, weak inter-molecular C-H⋯O and C-H⋯N hydrogen bonds link the mol-ecules into columns propagated in [101].

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In the title compound, C18H21NO3, the bicyclic ring system adopts a twin-chair conformation. The two methyl groups attached to the bicycle are in an equatorial orientation for both rings. One of the furan rings is disordered over two orientations with an occupancy ratio of 0.686 (6):0.314 (6). In the crystal, very long N-H⋯O hydrogen bonds connect the mol-ecules into a chain perpendicular to the ac plane.

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In the title compound, C(24)H(23)FN(2)O(3), the cyclo-hexene ring adopts a screw-boat conformation. The fluorobenzene ring attached to the cyclo-hexene ring and the phenyl ring attached to the indazole moiety are inclined to one another by 57.77 (13)°. In the crystal, mol-ecules are linked by O-H⋯N and C-H⋯O hydrogen bonds, forming chains with C(5) and C(10) graph-set motifs. There are also C-H⋯π inter-actions present. The isopropoxycarbonyl group undergoes considerable thermal motion.

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In the title compound, C(22)H(28)N(2)O(2)·H(2)O, rings B and C adopt chair conformations. Ring A adopts an envelope conformation, with the non-fused C atom adjacent to the fused C atom bearing a methyl group as the flap atom. Ring D also adopts an envelope conformation, with the fused C atom not bearing a methyl group as the flap atom. The water mol-ecule links the mol-ecules via O-H⋯O and O-H⋯N hydrogen bonds, forming zigzag chains which run parallel to the c axis. Weak C-H⋯O inter-actions also occur.

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In the title compound, C(17)H(19)NO(8) [systematic name = dimethyl 4-hydroxy-4-methyl-2-(3-nitrophenyl)-6-oxocyclohexane-1,3-dicarboxylate], the cyclo-hexa-none ring exhibits a chair conformation. The meth-oxy-carbonyl groups are oriented in opposite directions with respect to the cyclo-hexa-none ring. In the crystal, O-H⋯O hydrogen bonds links the mol-ecules into chains running parallel to the a axis. These chains are connected by weak C-H⋯O hydrogen bonds, forming sheets parallel to the ab plane.

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Thiosemicarbazide hydrochloride (TSCHCL) was synthesized by mixing thiosemicarbazide and hydrochloride in 1:1 molar ratio in double distilled water. Single crystals of TSCHCL were grown by slow evaporation at room temperature and were characterized by single crystal X-ray diffraction study to determine the molecular structure and by FT-IR, (1)H and (13)C NMR spectral analyses to confirm the synthesized compound. Thermogravimetric and differential thermal analyses reveal the thermal stability of the crystal. The transmission spectrum of TSCHCL showed that the crystal is transparent in the wavelength range 380-1100 nm. High resolution X-ray diffractometry (HRXRD) was employed to evaluate the perfection of the grown crystal. Mechanical properties of the grown crystal were studied using Vickers microhardness test. Second harmonic generation efficiency of the powdered TSCHCL was tested using Nd:YAG laser and is ∼1.5 times that of potassium dihydrogen orthophosphate.

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There are not many studies on long term follow up of children following surgery for posterior urethral valve in India. This study was done to assess the growth and renal function of children who had completed five years after surgery for posterior urethral valve at our hospital. Thirty children were included in this study. They were assessed retrospectively for the age and pattern of presentation, time of surgery and outcome. Outcomes measured were stunting, renal failure (GFR, tubular functions) and bladder functions. Fifty per cent of children were symptomatic five years after surgery with enuresis, dribbling, polyuria and recurrent urinary tract infection (UTI). GFR was <60 ml/m/1.73 m(2) in 33%. Growth failure, according to the World Health Organization (WHO) definition, was present in one-third of children. A low GFR was associated with growth failure. Poor bladder function evidenced by history of dribbling and significant residual urine was seen in one-third of patients. Residual hydronephrosis was seen in 74%. The most common presenting symptoms of PUV were poor urinary stream followed by recurrent UTI, poor weight gain, renal failure and abdominal mass. Eighty per cent of the study population had undergone surgery in infancy. Five years after surgery, 50% children were symptomatic; 30% had stunting. 33% had a GFR <60 ml/m/1.73 m(2) and a significantly greater degree of stunting than those with GFR >60 ml/m/1.73 m(2). Sonologically normal kidneys on follow-up were associated with a GFR above 60 ml/m/1.73 m(2). Poor bladder function was present in 30% of the children. Univariate analysis showed that statistically significant risk factors for decline in GFR in this study are oligohydramnios and surgery beyond the neonatal period.

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Synthesis, growth, X-ray crystal structure and characterization of a novel third order nonlinear optical material, 4-methoxy-4'-dimethylamino-benzylidene aniline (MDMABA), are reported for the first time. The asymmetric unit of MDMABA compound contains two crystallographically independent molecules (A and B), and they exist in the E-configuration. The structural perfection of the grown crystal is analyzed by high-resolution X-ray diffraction rocking curve analysis. The functional groups present in MDMABA are investigated by FTIR and FT-Raman spectral analyses. The placement of the protons is determined using HNMR spectrum. The range and percentage of optical transmission were ascertained by recording UV-vis-NIR spectrum. Thermal and mechanical properties are reported. Dielectric study shows that the dielectric constant of the crystal varies with frequency and temperature. The third order nonlinear optical absorption coefficient of the MDMABA crystal is determined by the Z-scan technique.

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