Cold Spring Harbor perspectives in biology最新文献

Calcium signaling is a key controller of numerous cellular events and is intricately linked to many processes that are critical pathways in cancer progression. This review revisits the calcium signaling toolkit in cancer, with a focus on calcium regulation of processes that go beyond the originally defined "classic" hallmarks of cancer such as those associated with proliferation, metastasis, and resistance to cell death pathways. We will consider calcium signaling in the context of the more recently proposed hallmarks of cancer, emerging hallmarks, and cancer-enabling characteristics. This broader examination of calcium signaling and its toolkit members will encompass processes such as metabolic reprogramming, evasion of immune destruction, cellular phenotypic plasticity, senescence, genome instability, and nonmutational epigenetic reprogramming. These cancer features and their interactions with calcium signaling will frequently be analyzed through the lenses of therapy resistance and the complexities of the tumor microenvironment.

Cancers that rely on activation of the alternative lengthening of telomeres (ALT) pathway predominantly affect children and adolescents, and are associated with catastrophic outcomes due to a lack of clinically effective, targeted therapeutics. The exponential rise in our understanding of the ALT mechanism in recent years has led to the identification of many therapeutic targets and strategies for patients suffering from these cancers. These include targeting replication fork remodelers and DNA damage response pathways to exacerbate telomere-specific replication stress, inhibiting ALT-mediated telomere synthesis to induce telomere dysfunction, and using oncolytic viruses to selectively kill ALT cancer cells. Herein we will evaluate the advantages and shortfalls of these therapeutic strategies, and discuss current diagnostic opportunities that are a necessary accompaniment to direct ALT therapeutics to patients.

Recent years have seen significant breakthroughs at the intersection of machine learning and protein science. Tools such as AlphaFold have revolutionized protein structure prediction. They are also enabling variant effect prediction and functional annotation of proteins, as well as opening up new possibilities for protein design. However, these technological advances must be balanced with sustainable computing practices.

A protein is defined by its amino acid sequence. This sequence and environmental factors shape a protein's 3D structural landscape, which is crucial for the protein's function and activity. Protein design aims to develop novel protein sequences or modify existing ones to perform specific functions or have desired protein properties. The protein sequence space is exponentially large, making protein sequence design a tough problem. This problem can be simplified by considering a backbone conditional protein sequence design that factorizes the design problem into two parts: protein backbone design and backbone-dependent sequence design. This allows for a more efficient search over the sequence space for desired structural features. In this review, we discuss when backbone conditional sequence design is possible and how to assess the performance of different design methods, training data, symmetric design, and the combination of unconditional and conditional sequence models.

The actin cytoskeleton plays a major role in locomotion of amoeboid cells. The extending pseudopod contains predominantly branched F-actin nucleated by actin-related protein 2/3 (Arp2/3) that is oriented toward the membrane, while the side/back of the cell contains predominantly linear F-actin nucleated by formins that is arranged parallel to the membrane in a contractile network using cross-linkers, membrane anchors, and myosin filaments. During cell movement, branched and linear F-actin have opposite functions: Elongation of branched F-actin filaments leads to pseudopod growth in the front, whereas pseudopod formation is strongly inhibited in areas of the contractile network. On the other hand, branched and linear F-actin also collaborate to optimize locomotion and navigation. Assembly of branched F-actin to induce a new pseudopod in the front also activates linear F-actin in the rest of the cell to inhibit a second pseudopod. Furthermore, linear F-actin at the side/back of the cell and branched F-actin each provide a memory of direction that is highly synergistic to mediate strong persistence of cell movement and sensitive chemotaxis.

Neural crest cells are among the most migratory cells in the vertebrate embryo. They initially arise within the forming neural tube, the precursor to the brain and spinal cord, but then migrate away by undergoing an epithelial-to-mesenchymal transition (EMT). Different neural crest populations exist along the body axis that differ in their flavor of EMT, migratory pathways, and cell types into which they differentiate. In the head region, neural crest cells interact with ectodermal placodal cells, another migratory cell type unique to vertebrates, that form sensory structures of the head. Here, we focus on select neural crest and placodal populations, highlighting how their region-specific migrations may be linked to cell fate choices and discuss how neural crest-placode interactions influence each other's behavior and derivative formation.

Cytosolic Ca²⁺ plays a crucial role as a second messenger in cell signaling, regulating a wide range of cellular processes. Hence, studying its spatiotemporal dynamics has emerged as a key area of research, and fluorescence imaging has become an indispensable method. The first attempt to visualize Ca²⁺ in living specimens was made in the 1960s by microinjecting the bioluminescent Ca²⁺-binding protein aequorin. However, the true breakthrough in Ca²⁺ imaging is often considered to be the development of Ca²⁺ chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) and its derivatives such as quin2, Fura-2, and Fluo-3, which allowed us to visualize Ca²⁺ responses in living cells by fluorescence microscopy. While these organic sensors are widely used in biological applications, they have notable drawbacks, including uncontrolled cellular localization and challenges in loading into living animals. The advent of genetically encoded Ca²⁺ indicators (GECIs) has overcome these limitations. In this review, we focus on GECIs, tracing their development and comparing them with organic sensors.

Calcium (Ca²⁺) is vital in hepatocyte metabolism and plays a dual role in liver mitochondrial function: Physiological Ca²⁺ stimulates respiration and mitochondrial dynamics-processes crucial for proper metabolic functioning. However, Ca²⁺ overload can be catastrophic, leading to mitochondrial dysfunction and the halt of metabolic processes. This dichotomy plays out in liver diseases such as metabolic dysfunction-associated steatohepatitis (MASH) and alcoholic liver disease (ALD), where excess lipid and alcohol, respectively, result in pathological changes in this precarious Ca²⁺ balance, impairing liver function and contributing to liver failure. In this review, we discuss the complex processes of Ca²⁺ signaling in hepatic mitochondria and how these processes are altered or fail in liver disease states.

Telomeric repeats recruit the shelterin complex to prevent activation of the double-strand break response at chromosome ends. Thousands of TTAGGG repeats are present at each chromosome end to ensure telomere function. This abundance of G-rich repeats comes with the propensity to generate unusual DNA structures. The telomere loop (t-loop) structure, generated by strand invasion of the 3' overhang in the internal repeats, contributes to telomere function. G4-DNA is promoted by the stretches of G-rich repeats in a single-stranded form and may affect telomere replication and elongation by telomerase. The intramolecular homology can lead to the formation of internal loops (i-loops) via intramolecular recombination at sites of telomeric damage, which can promote the excision of telomeric repeats as extrachromosomal circular DNA. Shelterin promotes t-loops, counteracting the accumulation of pathological structures either directly or via the recruitment of specialized helicases. Here, we will discuss the current evidence for the formation of unusual DNA structures at telomeres and possible implications for telomere function.

Mitochondria are the masters of evolutionary tinkering, which can be exemplified by both the remarkable variability of the mitochondrial genome architectures and numerous noncanonical features involved in the mitochondrial gene expression. Evolutionary experimentation in these living test tubes is facilitated by their polyploid nature and resulted in a number of surprising oddities identified in various eukaryotic lineages. Excellent examples of these peculiarities are provided by mitochondrial genetic systems of unicellular fungi classified as the budding yeasts. Perhaps the most perplexing eccentricity found in yeast mitochondria are the bypassing elements (byps) residing in the reading frames of protein-coding genes. Ribosomes ignore byps during translation by means of programmed translational bypassing. Massive occurrence of these coding gaps in certain yeast species raises the questions on their evolutionary origin and mobility as well as the molecular mechanism of translational bypassing.