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Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it is still incurable as disease progression is not fully understood. To investigate MM and its immune environment, we apply single cell RNA and linked-read whole genome sequencing to profile 29 longitudinal samples at different disease stages from 14 patients. Here, we collect 17,267 plasma cells and 57,719 immune cells, discovering patient-specific plasma cell profiles and immune cell expression changes. Patients with the same genetic alterations tend to have both plasma cells and immune cells clustered together. By integrating bulk genomics and single cell mapping, we track plasma cell subpopulations across disease stages and find three patterns: stability (from precancer to diagnosis), and gain or loss (from diagnosis to relapse). In multiple patients, we detect “B cell-featured” plasma cell subpopulations that cluster closely with B cells, implicating their cell of origin. We validate AP-1 complex differential expression (JUN and FOS) in plasma cell subpopulations using CyTOF-based protein assays, and integrated analysis of single-cell RNA and CyTOF data reveals AP-1 downstream targets (IL6 and IL1B) potentially leading to inflammation regulation. Our work represents a longitudinal investigation for tumor and microenvironment during MM progression and paves the way for expanding treatment options. Clonal evolution in multiple myeloma (MM) needs to be understood in both the tumor and its microenvironment. Here the authors perform single-cell multi-omics profiling of samples from MM patients at different stages, finding transitions in the immune cell composition throughout progression.

Advances in mass-spectrometry have generated increasingly large-scale proteomics datasets containing tens of thousands of phosphorylation sites (phosphosites) that require prioritization. We develop a bioinformatics tool called HotPho and systematically discover 3D co-clustering of phosphosites and cancer mutations on protein structures. HotPho identifies 474 such hybrid clusters containing 1255 co-clustering phosphosites, including RET p.S904/Y928, the conserved HRAS/KRAS p.Y96, and IDH1 p.Y139/IDH2 p.Y179 that are adjacent to recurrent mutations on protein structures not found by linear proximity approaches. Hybrid clusters, enriched in histone and kinase domains, frequently include expression-associated mutations experimentally shown as activating and conferring genetic dependency. Approximately 300 co-clustering phosphosites are verified in patient samples of 5 cancer types or previously implicated in cancer, including CTNNB1 p.S29/Y30, EGFR p.S720, MAPK1 p.S142, and PTPN12 p.S275. In summary, systematic 3D clustering analysis highlights nearly 3,000 likely functional mutations and over 1000 cancer phosphosites for downstream investigation and evaluation of potential clinical relevance. Dysregulated phosphorylation is well-known in cancers, but it has largely been studied in isolation from mutations. Here the authors introduce HotPho, a tool that can discover spatial interactions between phosphosites and mutations, which are associated with activating mutation and genetic dependencies in cancer.

Therapy targeting the BRAF-MEK cascade created a treatment revolution for patients with BRAF mutant advanced melanoma. Unfortunately, 80% patients treated will progress by 5 years follow-up. Thus, it is imperative we study mechanisms of melanoma progression and therapeutic resistance. We created a scRNA (single cell RNA) atlas of 128,230 cells from 18 tumors across the treatment spectrum, discovering melanoma cells clustered strongly by transcriptome profiles of patients of origins. Our cell-level investigation revealed gains of 1q and 7q as likely early clonal events in metastatic melanomas. By comparing patient tumors and their derivative cell lines, we observed that PD1 responsive tumor fraction disappears when cells are propagated in vitro . We further established three anti-BRAF-MEK treatment resistant cell lines using three BRAF mutant tumors. ALDOA and PGK1 were found to be highly expressed in treatment resistant cell populations and metformin was effective in targeting the resistant cells. Our study suggests that the investigation of patient tumors and their derivative lines is essential for understanding disease progression, treatment response and resistance.

The fractional quantum Hall (FQH) effect plays a prominent role in the study of topological phases of matter and of strongly correlated electron systems in general. FQH systems have been demonstrated to show many interesting novel properties such as fractional charges, and are believed to harbor even more intriguing phenomena such as fractional statistics. However, there remain many interesting questions to be addressed in this regime. The work reported in this thesis aims to push the envelope of our understanding of the low-energy properties of FQH states using microscopic principles. In the first part of the thesis, we present a systematic perturbative approach to study excitations in the thin cylinder/torus limit of the quantum Hall states. The approach is applied to the Haldane-Rezayi and Gaffnian quantum Hall states, which are both expected to have gapless excitations in the usual two-dimensional thermodynamic limit. For the Haldane-Rezayi state, we confirm that gapless excitations are present also in the “one-dimensional” thermodynamic limit of an infinite thin cylinder, in agreement with earlier considerations based on the wave functions alone. In contrast, we identify the lowest excitations of the Gaffnian state in the thin cylinder limit, and conclude that they are gapped, using a combination of perturbative and numerical means. We discuss possible scenarios for the cross-over between the two-dimensional and the one-dimensional thermodynamic limit in this case. In the second part of the thesis, we study the low energy spectral properties of positive center-of-mass conserving two-body Hamiltonians as they arise in models of FQH states. Starting from the observation that positive many-body Hamiltonians must have ground state energies that increase monotonously in particle number, we explore what general additional constraints can be obtained for two-body interactions with “center-of-mass conservation” symmetry, both in the presence and absence of particle-hole symmetry. We find general bounds that constrain the evolution of the ground state energy with particle number, and in particular constrain the chemical potential at T=0. Special attention is given to Hamiltonians with zero modes, in which case similar bounds on the first excited state are also obtained, using a duality property. In this case, in particular an upper bound on the charge gap is also obtained. We further comment on center-of-mass and relative-decomposition in disk geometry within the framework of second quantization.

We present a systematic perturbative approach to study excitations in the thin cylinder/torus limit of the quantum Hall states. The approach is applied to the Haldane-Rezayi and Gaffnian quantum Hall states, which are both expected to have gapless excitations in the usual two-dimensional thermodynamic limit. For the Haldane-Rezayi state, we confirm that gapless excitations are present also in the \"one-dimensional\" thermodynamic limit of an infinite thin cylinder, in agreement with earlier considerations based on the wave functions alone. In contrast, we identify the lowest excitations of the Gaffnian state in the thin cylinder limit, and conclude that they are gapped, using a combination of perturbative and numerical means. We discuss possible scenarios for the cross-over between the two-dimensional and the one-dimensional thermodynamic limit in this case.

Somatic mutation phasing informs our understanding of cancer-related events, like driver mutations. We generated linked-read whole genome sequencing data for 23 samples across disease stages from 14 multiple myeloma (MM) patients and systematically assigned somatic mutations to haplotypes using linked-reads. Here, we report the reconstructed cancer haplotypes and phase blocks from several MM samples and show how phase block length can be extended by integrating samples from the same individual. We also uncover phasing information in genes frequently mutated in MM, including , , , , and , phasing 79.4% of 20,705 high-confidence somatic mutations. In some cases, this enabled us to interpret clonal evolution models at higher resolution using pairs of phased somatic mutations. For example, our analysis of one patient suggested that two hotspot mutations occurred on the same haplotype but were independent events in different subclones. Given sufficient tumor purity and data quality, our framework illustrates how haplotype-aware analysis of somatic mutations in cancer can be beneficial for some cancer cases.

We study the low-energy spectral properties of positive center-of-mass conserving two-body Hamiltonians as they arise in models of fractional quantum Hall states. Starting from the observation that positive many-body Hamiltonians must have ground-state energies that increase monotonously in particle number, we explore what general additional constraints can be obtained for two-body interactions with \"center-of-mass conservation\" symmetry, both in the presence and absence of particle-hole symmetry. We find general bounds that constrain the evolution of the ground-state energy with particle number, and in particular, constrain the chemical potential at \\(T=0\\). Special attention is given to Hamiltonians with zero modes, in which case similar bounds on the first excited state are also obtained, using a duality property. In this case, in particular, an upper bound on the charge gap is also obtained. We further comment on center of mass and relative decomposition in disk geometry within the framework of second quantization.

ABSTRACT Advances in mass-spectrometry have generated increasingly large-scale proteomics datasets containing tens of thousands of phosphorylation sites (phosphosites) that require prioritization. We develop a bioinformatics tool called HotPho and systematically discover 3D co-clustering of phosphosites and cancer mutations on protein structures. HotPho identifies 474 such hybrid clusters containing 1,255 co-clustering phosphosites, including RET p.S904/Y928, the conserved HRAS/KRAS p.Y96, and IDH1 p.Y139/IDH2 p.Y179 that are adjacent to recurrent mutations on protein structures not found by linear proximity approaches. Hybrid clusters, enriched in histone and kinase domains, frequently include expression-associated mutations experimentally shown as activating and conferring genetic dependency. Approximately 300 co-clustering phosphosites are verified in patient samples of 5 cancer types or previously implicated in cancer, including CTNNB1 p.S29/Y30, EGFR p.S720, MAPK1 p.S142, and PTPN12 p.S275. In summary, systematic 3D clustering analysis highlights nearly 3,000 likely functional mutations and over 1,000 cancer phosphosites for downstream investigation and evaluation of potential clinical relevance. Competing Interest Statement The authors have declared no competing interest.

Microorganisms, inhabiting various ecological niches, exhibit a capacity to produce a diverse array of pigments with different shades. These colorful microbial pigments may also potentially possess beneficial bioactivities. This dual functionality together with the ease of mass production and downstream processing has shifted the global attention towards the use of microbially-derived pigments as bioactive colorants in different industries. Therefore, the present study was conducted with the aim of characterizing the pigments from Kocuria flava and identifying their potential biotechnological applications. The bacterium, PUTS1_3, was isolated using the surface sediment samples from the Puttalam mangrove ecosystem, Sri Lanka and it was identified as Kocuria flava using 16S rRNA gene sequencing. The yellow, intracellular pigment of PUTS1_3 was obtained by treating the cell pellet with methanol. Characterization of the pigment extract using UV-visible spectroscopy, TLC, and HPLC confirmed the presence of three carotenoid compounds, including β-carotene. The pigment extract also demonstrated antibacterial activity, against Gram positive bacteria tested. Antioxidant properties were observed with an IC 50 value of 181.95 ± 4.57 µg/ml in the DPPH free radical scavenging assay. Although its sun protection factor was comparatively low (SPF 7.69 ± 0.01), the pigment showed promising results as a textile dye demonstrating good color performance and stability in washing and pH stability tests. Moreover, fabrics dyed with the pigment extract displayed antibacterial activity against Staphylococcus aureus (ATCC 25923). These findings suggest the potential use of the yellow pigments of K. flava PUTS1_3 for various biotechnological applications.

Microorganisms, inhabiting various ecological niches, exhibit a capacity to produce a diverse array of pigments with different shades. These colorful microbial pigments may also potentially possess beneficial bioactivities. This dual functionality together with the ease of mass production and downstream processing has shifted the global attention towards the use of microbially-derived pigments as bioactive colorants in different industries. Therefore, the present study was conducted with the aim of characterizing the pigments from Kocuria flava and identifying their potential biotechnological applications. The bacterium, PUTS1₃, was isolated using the surface sediment samples from the Puttalam mangrove ecosystem, Sri Lanka and it was identified as Kocuria flava using 16S rRNA gene sequencing. The yellow, intracellular pigment of PUTS1₃ was obtained by treating the cell pellet with methanol. Characterization of the pigment extract using UV-visible spectroscopy, TLC, and HPLC confirmed the presence of three carotenoid compounds, including β-carotene. The pigment extract also demonstrated antibacterial activity, against Gram positive bacteria tested. Antioxidant properties were observed with an IC50 value of 181.95 ± 4.57 µg/ml in the DPPH free radical scavenging assay. Although its sun protection factor was comparatively low (SPF 7.69 ± 0.01), the pigment showed promising results as a textile dye demonstrating good color performance and stability in washing and pH stability tests. Moreover, fabrics dyed with the pigment extract displayed antibacterial activity against Staphylococcus aureus (ATCC 25923). These findings suggest the potential use of the yellow pigments of K. flava PUTS1₃ for various biotechnological applications.