The Flexible Ends of CENP-A Nucleosome Are Required for Mitotic Fidelity.

CENP-A is a histone variant, which replaces histone H3 at centromeres and confers unique properties to centromeric chromatin. The crystal structure of CENP-A nucleosome suggests flexible nucleosomal DNA ends, but their dynamics in solution remains elusive and their implication in centromere function is unknown. Using electron cryo-microscopy, we determined the dynamic solution properties of the CENP-A nucleosome. Our biochemical, proteomic, and genetic data reveal that higher flexibility of DNA ends impairs histone H1 binding to the CENP-A nucleosome. Substituting the 2-turn αN-helix of CENP-A with the 3-turn αN-helix of H3 results in compact particles with rigidified DNA ends, able to bind histone H1. In vivo replacement of CENP-A with H3-CENP-A hybrid nucleosomes leads to H1 recruitment, delocalization of kinetochore proteins, and significant mitotic and cytokinesis defects. Our data reveal that the evolutionarily conserved flexible ends of the CENP-A nucleosomes are essential to ensure the fidelity of the mitotic pathway.

Effect of dietary supplementation of wildCumin (Bunium persicum) seeds on performance, nutrient digestibility and circulating metabolites in broiler chicks during the finisher phase.

The objective of the present study was to evaluate the impact of inclusion of wild cumin seeds (WCS) on performance, nutrient digestibility and blood profile in broilers during the finisher phase. For this purpose, 360, 14 days old chicks were randomly divided into four groups designated as CONT (control), 0.5WCS, 1.0WCS and 1.5WCS with 5 replicates, which were supplemented with WCS at the rate of 0, 0.5, 1, and 1.5% respectively. On the overall, feed intake was significantly (p < 0.01) higher in the CONT compared to the 1.0WCS. At the end of the finisher phase, and overall basis, body weight and feed conversion ratio were significantly (p < 0.05) higher in 0.5WCS. Crude protein apparent digestibility in the ileum was significantly (p < 0.05) higher in 0.5WCS compared to the CONT, while crude fat digestibility was significantly (p < 0.01) higher in 0.5WCS and 1.5WCS compared to the control. Similarly, serum triglyceride was significantly (p < 0.05) lower in 0.5WC but high density lipoprotein was significantly (p < 0.05) higher in the same group. It was concluded that wild Cumin at the rate of 0.5% was superior compared to the other treatments in the diet to improve the performance, nutrient digestibility and blood metabolites in broiler during the finisher phase.

Variation and succession of microbial communities under the conditions of persistent heavy metal and their survival mechanism.

This review summarizes the recent papers published about the microbial communities under the conditions of persistent heavy metals around the world. Many microbial communities' study has demonstrated intense changes in the community composition, and microbial diversity caused by heavy metals, environmental pollution as well as adaptation processes allowing survival of microbes in metal-polluted ecosystems. The effect of heavy metals such as Cu, Pb, Hg, Ni, Cd, Zn, and As on soil microbial communities in mediated soil are reviewed. The different sensitivity measurement, toxicity of metals, relative toxicity is discussed. In recent years, industrial activities have a significant influence on the environment. Especially, heavy metals such as Hg, Cr, Pb, Mn, and As, have induced seriously affected the soil microbial communities, cause diseases and even death of organisms through contaminated soils, although heavy metals in trace amounts are beneficial even significant to organisms. The effect of heavy metals on soil microbial communities is still poorly understood. That how microbial communities respond to environmental changes is a key issue in ecology. In the future further work needed to understand the microbial community under persistent heavy metals, their effects, how to reduce and decrease the microbial diversity, and resistance of specific bacterial species to heavy metals.

Biallelic ZNF407 mutations in a neurodevelopmental disorder with ID, short stature and variable microcephaly, hypotonia, ocular anomalies and facial dysmorphism.

We describe five members of a consanguineous Pakistani family (Family I) plus two affected children from families of different ethnic origins presenting with neurodevelopmental disorders with overlapping features. All affected individuals from families have intellectual disability (ID), ranging from mild to profound, and reduced motor and cognitive skills plus variable features including short stature, microcephaly, developmental delay, hypotonia, dysarthria, deafness, visual problems, enuresis, encopresis, behavioural anomalies, delayed pubertal onset and facial dysmorphism. We first mapped the disease locus in the large family (Family I), and by exome sequencing identified homozygous ZNF407 c.2814_2816dup (p.Val939dup) in four affected members where DNA samples were available. By exome sequencing we detected homozygous c.2405G>T (p.Gly802Val) in the affected member of Family II and compound heterozygous variants c.2884C>G (p.Arg962Gly) and c.3642G>C (p.Lys1214Asn) in the affected member of Family III. Homozygous c.5054C>G (p.Ser1685Trp) has been reported in two brothers with an ID syndrome. Affected individuals we present did not exhibit synophrys, midface hypoplasia, kyphosis, 5th finger camptodactyly, short 4th metatarsals or limited knee mobility observed in the reported family.

Antioxidant potential and chemical characterization of bioactive compounds from a medicinal plant Colebrokea oppositifolia Sm.

Colebrookea oppositifolia is a highly used medicinal plant and an enriched source of essential oils. Therefore, the present study was designed with the aim to extract the chemical constituents and to evaluate its antioxidant potential. Fresh plant parts were subjected to the extraction of volatile chemical constituents by maceration using n-hexane as the menstruum. The resulting n-hexane fractions were purified and then subjected to GC-MS and FTIR analysis. In-vitro antioxidant abilities were evaluated by, DPPH, total phenolic content (TPC), total flavonoid content (TFC) method against the standard solutions of (Gallic acid, Quercetin) as a positive control. The GC-MS analysis of leaves, stem and inflorescence showed a total of 100, 98 and 48 components out of which 47, 16 and 17 peaks were identified representing the 67.64 %, 73.16 % and 61.93 % of the total oily fractions, respectively. The FTIR spectrum indicated the presence of various functional groups. In-vitro antioxidant results exhibited that leaves showed the highest antioxidant potential by DPPH (3.365 ± 0.002), and the highest total phenolic content by FC method (203.00 ± 0.091). Foliar micromorphological features were found significant in the authentication of C. oppositifolia. Further pharmacognostic studies of this plant are recommended to evaluate its therapeutic potential.

The death-associated protein DAXX is a novel histone chaperone involved in the replication-independent deposition of H3.3.

The histone variant H3.3 marks active chromatin by replacing the conventional histone H3.1. In this study, we investigate the detailed mechanism of H3.3 replication-independent deposition. We found that the death domain-associated protein DAXX and the chromatin remodeling factor ATRX (alpha-thalassemia/mental retardation syndrome protein) are specifically associated with the H3.3 deposition machinery. Bacterially expressed DAXX has a marked binding preference for H3.3 and assists the deposition of (H3.3-H4)(2) tetramers on naked DNA, thus showing that DAXX is a H3.3 histone chaperone. In DAXX-depleted cells, a fraction of H3.3 was found associated with the replication-dependent machinery of deposition, suggesting that cells adapt to the depletion. The reintroduced DAXX in these cells colocalizes with H3.3 into the promyelocytic leukemia protein (PML) bodies. Moreover, DAXX associates with pericentric DNA repeats, and modulates the transcription from these repeats through assembly of H3.3 nucleosomes. These findings establish a new link between the PML bodies and the regulation of pericentric DNA repeat chromatin structure. Taken together, our data demonstrate that DAXX functions as a bona fide histone chaperone involved in the replication-independent deposition of H3.3.

Pharmacological profile of the aerial parts of Rubus ulmifolius Schott.

BACKGROUND: As aerial parts of Rubus ulmifolius contains phytochemicals like flavonoids and tannins. And whereas flavonoids and tannins have antioxidant and antipyretic activity, hence, current work is carried out to screen crude methanolic extract of aerial parts of Rubus ulmifolius (Ru.Cr) and crude flavonoids rich extract of Rubus ulmifolius (Ru.F) for possible antioxidant and antipyretic activity. Ru.Cr and Ru.F are also tested for brine shrimps lethality bioassay. Ru.F is tested for the first time for possible antioxidant and antipyretic activity. METHODS: Preliminary phytochemical screening of Ru.Cr and Ru.F was performed as it provides rapid finger printing for targeting a pharmacological activity. Acute toxicity and Brine shrimps' cytotoxicity studies of Ru.Cr and Ru.F were performed to determine its safe dose range. Antioxidant and antipyretic studies were also performed as per reported procedures. RESULTS: Ru.Cr tested positive for presence of tannins, alkaloids, flavonoids and steroids. Ru.Cr is safe up to 6 g/kg following oral doses for acute toxicity study. Ru.Cr is safe up to 75 µg/kg (p.o), LC50 for Ru.Cr and Ru.F are 16.7 ± 1.4 µg/ml 10.6 ± 1.8 µg/ml, respectively (n = 3). Both Ru.Cr and Ru.F demonstrated comparable antioxidant activity using vitamin C as standard (p ≤ 0.05). In test dose of 300 mg of Ru.Cr, rectal temperature was reduced by 74% (p ≤ 0.05) on 4th hour of the administration. More, Ru.F produced 72% reduction in pyrexia (p ≤ 0.05) on 4th hour of administration of paracetamol in Westar rats. CONCLUSIONS: The current work confirms that aerial parts of Rubus ulmifolius contain flavonoids that are safe up to 6 g/kg (p.o). Crude methanolic extract and flavonoids rich fraction of Rubus ulmifolius have significant antioxidant and antipyretic activity. Further work is required to isolate the pharmacologically active substances for relatively safe and effective antipyretics and antioxidants.

Surgical repair of partial atrioventricular septal defect.

OBJECTIVE: To review the results of surgical correction of partial atrioventricular septal defect and associated cardiac comorbidities. METHODS: Retrospective case analysis of electronic database of department of paediatrics cardiac surgery, CPEIC, Multan was done. Forty consecutive patients operated for partial atrioventricular septal defect repair from September 2011 to October 2016 were included. Mean age was 14.67±7.96 years. 60% (24) patients were male. Regarding echocardiographic findings, pre-operatively 40% (n=16) had mild, 47.5% (19) had moderate and 12.5% (n=5) had severe mitral valve regurgitation. There were 25% (n=10) patients having moderate tricuspid valve regurgitation. Pulmonary hypertension was moderate in 57.5% (n=23) cases and severe in 7.5% (n=3) cases. Among other associated lesions 10% (n=4) patients had secundum ASD, pulmonary artery stenosis was seen in 5% (n=2) patients. Another 5.0% (n=2) patients had bilateral SVCS. While one patient had PDA and one patient had associated common atrium. RESULTS: Post-operatively there were 19 cases (47.5%) having no mitral valve regurgitation while 18 (45%) patients showed mild and 7.5% (n=3) had moderate mitral valve regurgitation. Only one case had moderate tricuspid valve regurgitation post-operatively, while 22.5% (n=9) cases had mild tricuspid regurgitation. Complete heart block and left sided brain infarct developed in one case. There was no mortality, reoperation, residual atrial shunt or left ventricular outflow tract obstruction. CONCLUSION: Repair of partial AV canal carries good overall results with minimal mortality however earlier repair is suggested to reduce post- operative morbidity further.

Phosphorylation of the CENP-A amino-terminus in mitotic centromeric chromatin is required for kinetochore function.

The role of the mitotic phosphorylation of the amino (NH2) terminus of Centromere Protein A (CENP-A), the histone variant epigenetic centromeric marker, remains elusive. Here, we show that the NH2 terminus of human CENP-A is essential for mitotic progression and that localization of CENP-C, another key centromeric protein, requires only phosphorylation of the CENP-A NH2 terminus, and is independent of the CENP-A NH2 terminus length and amino acid sequence. Mitotic CENP-A nucleosomal complexes contain CENP-C and phosphobinding 14-3-3 proteins. In contrast, mitotic nucleosomal complexes carrying nonphosphorylatable CENP-A-S7A contained only low levels of CENP-C and no detectable 14-3-3 proteins. Direct interactions between the phosphorylated form of CENP-A and 14-3-3 proteins as well as between 14-3-3 proteins and CENP-C were demonstrated. Taken together, our results reveal that 14-3-3 proteins could act as specific mitotic "bridges," linking phosphorylated CENP-A and CENP-C, which are necessary for the platform function of CENP-A centromeric chromatin in the assembly and maintenance of active kinetochores.

Sexual Health of Prison Inmates: A Case Study of Kano Central Prison, North Western Nigeria.

Sexual and reproductive health of prison inmates suffers from serious neglect in Nigeria. This mixed method study examined prison officials and 160 inmates on prison law and administration, and sexual health of inmates. Most of the inmates examined (82.5%) reported having frequent sexual desire. Wet dreams (46.2%) and watching others' nakedness (25.0%) were the common means by which inmates manifest sexual desire. Majority relieve sexual desire through anal sex (72.0%) and masturbation (69.7%). Common forms of sexual violence observed include forceful fondling with genitalia (47.4%) and forceful insertion of finger/object in the anus (21.0%) in males and rape (15.8%) in females. All victims were younger inmates (18 - 34 years). There is a need for legislation on sexual violence and exploring the practice of conjugal visits or furloughs as practiced in some countries.

Chaperoning the histone H3 family.

Chromatin is a highly dynamic nucleoprotein structure, which orchestrates all nuclear process from DNA replication to DNA repair, fromtranscription to recombination. The proper in vivo assembly of nucleosome, the basic repeating unit of chromatin, requires the deposition of two H3-H4 dimer pairs followed by the addition of two dimers of H2A and H2B. Histone chaperones are responsible for delivery of histones to the site of chromatin assembly and histone deposition onto DNA, histone exchange and removal. Distinct factors have been found associated with different histone H3 variants, which facilitate their deposition. Unraveling the mechanism of histone depositionby specific chaperones is of key importance to epigenetic regulation. In this review, we focus on histoneH3 variants and their deposition mechanisms. This article is part of a Special Issue entitled: Histone chaperones and Chromatin assembly.

Study of non-syndromic thumb aplasia in six independent cases.

OBJECTIVES: To report on six independent and isolated cases demonstrating thumb aplasia as an essentially limb-specific phenotype. METHODS: The subjects were ascertained during 2011-2013 from six different geographic regions of Pakistan, and underwent detailed clinical and phenotypic examination. RESULTS: The affected arms of patients had complete absence of first digital rays, medial inclinations of second and fifth fingers, narrowing of palms, missing carpals, and shortening of zeugopod. All the subjects were presented with isolated and sporadic limb deficiencies, and five had no family history of limb or any other malformation. Parental consanguinity was denied in majority of the cases. We present detailed phenotypic manifestation of thumb apalsia in these subjects. CONCLUSION: Thumb aplasia markedly impairs the normal function of affected hand. Surgical procedures like pollicisation of the index finger should be employed to improve the quality of life of these subjects. There is so far no specific genetic factor known for isolated thumb aplasia, compromising an accurate genetic counseling. Collection of patients with similar phenotypic presentations could be useful in further molecular genetic investigations.

HJURP binds CENP-A via a highly conserved N-terminal domain and mediates its deposition at centromeres.

The human histone H3 variant, CENP-A, replaces the conventional histone H3 in centromeric chromatin and, together with centromere-specific DNA-binding factors, directs the assembly of the kinetochore. We purified the prenucelosomal e-CENP-A complex. We found that HJURP, a member of the complex, was required for cell cycle specific targeting of CENP-A to centromeres. HJURP facilitated efficient deposition of CENP-A/H4 tetramers to naked DNA in vitro. Bacterially expressed HJURP binds at a stoichiometric ratio to the CENP-A/H4 tetramer but not to the H3/H4 tetramer. The binding occurred through a conserved HJURP short N-terminal domain, termed CBD. The novel characteristic identified in vertebrates that we named TLTY box of CBD, was essential for formation of the HJURP-CENP-A/H4 complex. Our data identified HJURP as a vertebrate CENP-A chaperone and dissected its mode of interactions with CENP-A.

The Chemical Composition of Soyhulls and Their Effect on Amino Acid and Nutrient Digestibility in Laying Hens during the Peak of Production.

This study investigates the chemical composition of soyhulls (SHs) as an alternative feed ingredient and their effect on nutrient and amino acid (AA) digestibility in laying hens during peak production. A total of 200 golden brown hens (28 weeks old) were subjected to random allocation across 5 dietary treatments: a corn-soybean meal (SBM) reference diet and 4 test diets with 25% SHs from different mills (SH1, SH2, SH3, and SH4). Each treatment was replicated four times with ten birds per replicate. Digesta samples were collected during three phases (28-32, 32-36, and 36-40 weeks of age) to measure apparent metabolizable energy (AME), the apparent ileal digestibility (AID) of nutrients, and the standard ileal digestibility (SID) of AAs. The SBM diet had 30.0% crude protein (CP) and 3.78% crude fiber (CF), while the SH diets had 21.0 to 21.5% CP and 11.6% CF. The findings revealed that the AME was lower (p < 0.05) with SH diets (2404 kcal/kg) compared to the SBM diet (2627 kcal/kg) in all three phases. The SH diets had a lower AID of dry matter (DM), crude protein (CP), ash, ether extract (EE), and crude fiber (CF) than the SBM diet by an average of 2.88, 2.25, 4.93, 4.99, and 3.36%, respectively. The AID of nitrogen-free extract (NFE) was higher in the SH diets than the SBM diet by 3.42% in all three phases (p < 0.05). The SH diets had lower uric acid excretion (about 66.93 mg/100 mL) than the SBM diet (about 76.43 mg/100 mL) on average in all three phases. The SH diets had a lower SID of arginine, histidine, isoleucine, lysine, cysteine, valine, and tyrosine than the SBM diet by 2 to 10%, while the SID of methionine was higher in the SH diets than the SBM diet by 2.2% on average in all three phases (p < 0.05). The SH from Sadiq Brother Feed (SH1) had the highest AME and AID of DM, ash, CP, EE, CF, and the SID of AA among the SH diets. These results indicate that SH can partially replace SBM in laying hen diets, but the source and quality of SH should be considered.

Enhancing medical ultrasound imaging through fractional mathematical modeling of ultrasound bubble dynamics.

The classical mathematical modeling of ultrasound acoustic bubble is so far using to improve the medical imaging quality. A clear and visible medical ultrasound image relies on bubble's diameter, wavelength and intensity of the scattered sound. A bubble with diameter much smaller than the sound wavelength is regarded as highly efficient source of sound scattering. The dynamical equation for a medical ultrasound bubble is primarily modeled in classical integer-order differential equation. Then a reduction of order technique is used to convert the modeled dynamic equation for the bubble surface into a system of incommensurate fractional-orders. The incommensurate fractional-order values are calculated directly, by using Riemann stability region. On the basis of stability the convergence and accuracy of the numerical scheme is also discussed in detail. It has been found that the system will remain stable and chaotic for the incommensurate values α1<0.737 and α2<2.80, respectively.

Volumetric thermo-convective casson fluid flow over a nonlinear inclined extended surface.

The thermophysical features of Casson fluid flow caused by a nonlinear permeable stretchable surface are assessed in the present study. The computational model of Casson fluid is used to define viscoelasticity, which is quantified rheologically in the momentum equation. Exothermic chemical reactions, heat absorption/generation, magnetic field and nonlinear volumetric thermal/mass expansion over the stretched surface are also considered. The proposed model equations are lessened by the similarity transformation to the dimensionless system of ODEs. The obtained set of differential equations are numerically computed through parametric continuation approach. The results are displayed and discussed via figures and tables. The outcomes of the proposed problem are compared to the existing literature and bvp4c package for the validity and accuracy purposes. It has been perceived that the energy and mass transition rate of Casson fluid increased with the flourishing trend of heat source parameter and chemical reaction respectively. Casson fluid velocity can be elevated by the rising effect of thermal, mass Grashof number and nonlinear thermal convection.

Impact of the SARS-CoV-2 nucleocapsid 203K/204R mutations on the inflammatory immune response in COVID-19 severity.

BACKGROUND: The excessive inflammatory responses provoked by SARS-CoV-2 infection are critical factors affecting the severity and mortality of COVID-19. Previous work found that two adjacent co-occurring mutations R203K and G204R (KR) on the nucleocapsid (N) protein correlate with increased disease severity in COVID-19 patients. However, links with the host immune response remain unclear. METHODS: Here, we grouped nasopharyngeal swab samples of COVID-19 patients into two cohorts based on the presence and absence of SARS-CoV-2 nucleocapsid KR mutations. We performed nasopharyngeal transcriptome analysis of age, gender, and ethnicity-matched COVID-19 patients infected with either SARS-CoV-2 with KR mutations in the N protein (KR patients n = 39) or with the wild-type N protein (RG patients n = 39) and compared to healthy controls (n = 34). The impact of KR mutation on immune response was further characterized experimentally by transcriptomic and proteomic profiling of virus-like-particle (VLP) incubated cells. RESULTS: We observed markedly elevated expression of proinflammatory cytokines, chemokines, and interferon-stimulated (ISGs) genes in the KR patients compared to RG patients. Using nasopharyngeal transcriptome data, we found significantly higher levels of neutrophils and neutrophil-to-lymphocyte (NLR) ratio in KR patients than in the RG patients. Furthermore, transcriptomic and proteomic profiling of VLP incubated cells confirmed a similar hyper-inflammatory response mediated by the KR variant. CONCLUSIONS: Our data demonstrate an unforeseen connection between nucleocapsid KR mutations and augmented inflammatory immune response in severe COVID-19 patients. These findings provide insights into how mutations in SARS-CoV-2 modulate host immune output and pathogenesis and may contribute to more efficient therapeutics and vaccine development.

An open-source, automated, and cost-effective platform for COVID-19 diagnosis and rapid portable genomic surveillance using nanopore sequencing.

The COVID-19 pandemic, caused by SARS-CoV-2, has emphasized the necessity for scalable diagnostic workflows using locally produced reagents and basic laboratory equipment with minimal dependence on global supply chains. We introduce an open-source automated platform for high-throughput RNA extraction and pathogen diagnosis, which uses reagents almost entirely produced in-house. This platform integrates our methods for self-manufacturing magnetic nanoparticles and qRT-PCR reagents-both of which have received regulatory approval for clinical use-with an in-house, open-source robotic extraction protocol. It also incorporates our "Nanopore Sequencing of Isothermal Rapid Viral Amplification for Near Real-time Analysis" (NIRVANA) technology, designed for tracking SARS-CoV-2 mutations and variants. The platform exhibits high reproducibility and consistency without cross-contamination, and its limit of detection, sensitivity, and specificity are comparable to commercial assays. Automated NIRVANA effectively identifies circulating SARS-CoV-2 variants. Our in-house, cost-effective reagents, automated diagnostic workflows, and portable genomic surveillance strategies provide a scalable and rapid solution for COVID-19 diagnosis and variant tracking, essential for current and future pandemic responses.

DNA-binding protein PfAP2-P regulates parasite pathogenesis during malaria parasite blood stages.

Malaria-associated pathogenesis such as parasite invasion, egress, host cell remodelling and antigenic variation requires concerted action by many proteins, but the molecular regulation is poorly understood. Here we have characterized an essential Plasmodium-specific Apicomplexan AP2 transcription factor in Plasmodium falciparum (PfAP2-P; pathogenesis) during the blood-stage development with two peaks of expression. An inducible knockout of gene function showed that PfAP2-P is essential for trophozoite development, and critical for var gene regulation, merozoite development and parasite egress. Chromatin immunoprecipitation sequencing data collected at timepoints matching the two peaks of pfap2-p expression demonstrate PfAP2-P binding to promoters of genes controlling trophozoite development, host cell remodelling, antigenic variation and pathogenicity. Single-cell RNA sequencing and fluorescence-activated cell sorting revealed de-repression of most var genes in Δpfap2-p parasites. Δpfap2-p parasites also overexpress early gametocyte marker genes, indicating a regulatory role in sexual stage conversion. We conclude that PfAP2-P is an essential upstream transcriptional regulator at two distinct stages of the intra-erythrocytic development cycle.

PfAP2-MRP DNA-binding protein is a master regulator of parasite pathogenesis during malaria parasite blood stages.

Malaria pathogenicity results from the parasite's ability to invade, multiply within and then egress from the host red blood cell (RBC). Infected RBCs are remodeled, expressing antigenic variant proteins (such as PfEMP1, coded by the var gene family) for immune evasion and survival. These processes require the concerted actions of many proteins, but the molecular regulation is poorly understood. We have characterized an essential Plasmodium specific Apicomplexan AP2 (ApiAP2) transcription factor in Plasmodium falciparum (PfAP2-MRP; Master Regulator of Pathogenesis) during the intraerythrocytic developmental cycle (IDC). An inducible gene knockout approach showed that PfAP2-MRP is essential for development during the trophozoite stage, and critical for var gene regulation, merozoite development and parasite egress. ChIP-seq experiments performed at 16 hour post invasion (h.p.i.) and 40 h.p.i. matching the two peaks of PfAP2-MRP expression, demonstrate binding of PfAP2-MRP to the promoters of genes controlling trophozoite development and host cell remodeling at 16 h.p.i. and antigenic variation and pathogenicity at 40 h.p.i. Using single-cell RNA-seq and fluorescence-activated cell sorting, we show de-repression of most var genes in Δpfap2-mrp parasites that express multiple PfEMP1 proteins on the surface of infected RBCs. In addition, the Δpfap2-mrp parasites overexpress several early gametocyte marker genes at both 16 and 40 h.p.i., indicating a regulatory role in the sexual stage conversion. Using the Chromosomes Conformation Capture experiment (Hi-C), we demonstrate that deletion of PfAP2-MRP results in significant reduction of both intra-chromosomal and inter-chromosomal interactions in heterochromatin clusters. We conclude that PfAP2-MRP is a vital upstream transcriptional regulator controlling essential processes in two distinct developmental stages during the IDC that include parasite growth, chromatin structure and var gene expression.