def grow_hyphae(self, iron_min_grow, grow_time, p_branch, spacing):
"""Grow fungal hyphae."""
cells = self.cell_data
conidia_indices = self.alive(
(cells['form'] == FungusCellData.Form.CONIDIA)
& (cells['status'] == FungusCellData.Status.GERMINATED)
& (np.invert(cells['internalized'])))
hyphae_indices = self.alive(
(cells['form'] == FungusCellData.Form.HYPHAE)
& (cells['status'] == FungusCellData.Status.GROWABLE)
& (np.invert(cells['internalized']))
& (cells['iron'] > iron_min_grow)
& (cells['iteration'] > grow_time))
# grow conidia
if len(conidia_indices) != 0:
cells['status'][conidia_indices] = FungusCellData.Status.GROWN
cells['form'][conidia_indices] = FungusCellData.Form.HYPHAE
children = FungusCellData(len(conidia_indices), initialize=True)
children['iron'] = cells['iron'][conidia_indices]
growth = spacing * (rg.random((len(conidia_indices), 3)) * 2 - 1)
children['point'] = cells['point'][conidia_indices] + growth
self.spawn_hypahael_cell(children)
# grow hyphae
if len(hyphae_indices) != 0:
cells['status'][hyphae_indices] = FungusCellData.Status.GROWN
branch_mask = rg.random(len(hyphae_indices)) < p_branch
not_branch_indices = (np.invert(branch_mask)).nonzero()[0]
branch_indices = branch_mask.nonzero()[0]
elongate_children = FungusCellData(len(hyphae_indices),
initialize=True)
branch_children = FungusCellData(len(branch_indices),
initialize=True)
elongate_children['iron'] = cells['iron'][hyphae_indices] / 2
growth = spacing * (rg.random((len(hyphae_indices), 3)) * 2 - 1)
elongate_children[
'point'] = cells['point'][hyphae_indices] + growth
if len(branch_indices) != 0:
elongate_children['iron'][branch_indices] = (
cells['iron'][hyphae_indices[branch_indices]] / 3)
branch_children['iron'] = cells['iron'][
hyphae_indices[branch_indices]] / 3
growth = spacing * (rg.random(
(len(hyphae_indices[branch_indices]), 3)) * 2 - 1)
branch_children['point'] = cells['point'][
hyphae_indices[branch_indices]] + growth
# update iron in orignal cells
cells['iron'][hyphae_indices[not_branch_indices]] /= 2
cells['iron'][hyphae_indices[branch_indices]] /= 3
self.spawn_hypahael_cell(elongate_children)
self.spawn_hypahael_cell(branch_children)
def random_sphere_point() -> np.ndarray:
"""Generate a random point on the unit 2-sphere in R^3 using Marsaglia's method"""
# generate vector in unit disc
u: np.ndarray = 2 * rg.random(size=2) - 1
while np.linalg.norm(u) > 1.0:
u = 2 * rg.random(size=2) - 1
norm_squared_u = float(np.dot(u, u))
return np.array(
[
2 * u[0] * np.sqrt(1 - norm_squared_u),
2 * u[1] * np.sqrt(1 - norm_squared_u),
1 - 2 * norm_squared_u,
],
dtype=np.float64,
)
def recruit_new(self, rec_rate_ph, rec_r, p_rec_r, tissue, grid, cyto):
num_reps = rec_rate_ph # maximum number of macrophages recruited per time step
cyto_index = np.argwhere(
np.logical_and(tissue == TissueType.BLOOD.value, cyto >= rec_r))
if len(cyto_index) == 0:
# nowhere to place cells
return
for _ in range(num_reps):
if p_rec_r > rg.random():
ii = rg.integers(cyto_index.shape[0])
point = Point(
x=grid.x[cyto_index[ii, 2]],
y=grid.y[cyto_index[ii, 1]],
z=grid.z[cyto_index[ii, 0]],
)
# Do we really want these things to always be in the exact center of the voxel?
# No we do not. Should not have any effect on model, but maybe some on
# visualization.
perturbation = rg.multivariate_normal(mean=[0.0, 0.0, 0.0],
cov=[[0.25, 0.0, 0.0],
[0.0, 0.25, 0.0],
[0.0, 0.0, 0.25]])
perturbation_magnitude = np.linalg.norm(perturbation)
perturbation /= max(1.0, perturbation_magnitude)
point += perturbation
self.append(MacrophageCellData.create_cell(point=point))
def internalize_conidia(self, m_det, max_spores, p_in, grid,
fungus: FungusCellList):
for i in self.alive():
cell = self[i]
vox = grid.get_voxel(cell['point'])
# Moore neighborhood, but order partially randomized. Closest to furthest order, but
# the order of any set of points of equal distance is random
neighborhood = list(
itertools.product(tuple(range(-1 * m_det, m_det + 1)),
repeat=3))
shuffle(neighborhood)
neighborhood = sorted(neighborhood,
key=lambda v: v[0]**2 + v[1]**2 + v[2]**2)
for dx, dy, dz in neighborhood:
zi = vox.z + dz
yj = vox.y + dy
xk = vox.x + dx
if grid.is_valid_voxel(Voxel(x=xk, y=yj, z=zi)):
index_arr = fungus.get_cells_in_voxel(
Voxel(x=xk, y=yj, z=zi))
for index in index_arr:
if (fungus[index]['form']
== FungusCellData.Form.CONIDIA
and not fungus[index]['internalized']
and p_in > rg.random()):
fungus[index]['internalized'] = True
self.append_to_phagosome(i, index, max_spores)
def advance(self, state: State, previous_time: float) -> State:
"""Advance the state by a single time step."""
from nlisim.modules.macrophage import MacrophageState
hepcidin: HepcidinState = state.hepcidin
macrophage: MacrophageState = state.macrophage
voxel_volume: float = state.voxel_volume
# interaction with macrophages
activated_voxels = zip(*np.where(
activation_function(
x=hepcidin.grid,
k_d=hepcidin.k_d,
h=self.time_step / 60, # units: (min/step) / (min/hour)
volume=voxel_volume,
b=1,
) > rg.random(size=hepcidin.grid.shape)))
for z, y, x in activated_voxels:
for macrophage_cell_index in macrophage.cells.get_cells_in_voxel(
Voxel(x=x, y=y, z=z)):
macrophage_cell = macrophage.cells[macrophage_cell_index]
macrophage_cell['fpn'] = False
macrophage_cell['fpn_iteration'] = 0
# Degrading Hepcidin is done by the "liver"
# hepcidin does not diffuse
return state
def change_status(self, p_internal_swell: float, rest_time: int,
swell_time: int):
cells = self.cell_data
indices = self.alive(cells['form'] != FungusCellData.Form.HYPHAE, )
internalized_indices = (cells['internalized'][indices]).nonzero()[0]
not_internalized_indices = (np.invert(
cells['internalized'][indices])).nonzero()[0]
internalized_rest_indices = np.logical_and(
cells['status'][internalized_indices] ==
FungusCellData.Status.RESTING,
cells['iteration'][internalized_indices] >= rest_time,
).nonzero()[0]
internalized_swollen_indices = np.logical_and(
cells['status'][internalized_indices] ==
FungusCellData.Status.SWOLLEN,
cells['iteration'][internalized_indices] >= swell_time,
).nonzero()[0]
# internal fungus with REST status
swall_mask = rg.random(
len(internalized_rest_indices)) < p_internal_swell
internalized_rest_indices = swall_mask.nonzero()[0]
cells['status'][
internalized_rest_indices] = FungusCellData.Status.SWOLLEN
cells['iteration'][internalized_rest_indices] = 0
# internal fungus with SWOLLEN status
cells['status'][
internalized_swollen_indices] = FungusCellData.Status.GERMINATED
cells['iteration'][internalized_swollen_indices] = 0
rest_indices = np.logical_and(
cells['status'][not_internalized_indices] ==
FungusCellData.Status.RESTING,
cells['iteration'][not_internalized_indices] >= rest_time,
).nonzero()[0]
swollen_indices = np.logical_and(
cells['status'][not_internalized_indices] ==
FungusCellData.Status.SWOLLEN,
cells['iteration'][not_internalized_indices] >= swell_time,
).nonzero()[0]
# free fungus with REST status
cells['status'][rest_indices] = FungusCellData.Status.SWOLLEN
cells['iteration'][rest_indices] = 0
# free fungus with SWOLLEN status
cells['status'][swollen_indices] = FungusCellData.Status.GERMINATED
cells['iteration'][swollen_indices] = 0
def generate_branch_direction(cell_vec: np.ndarray) -> np.ndarray:
"""
Generate a direction vector for branches.
Parameters
----------
cell_vec : np.ndarray
a unit 3-vector
Returns
-------
np.ndarray
a random unit 3-vector at a 45 degree angle to `cell_vec`, sampled from the
uniform distribution
"""
# norm should be approx 1, can delete for performance
cell_vec /= np.linalg.norm(cell_vec)
# create orthogonal basis adapted to cell's direction
# get first orthogonal vector
u: np.ndarray
epsilon = 0.1
e1 = np.array([1.0, 0.0, 0.0], dtype=np.float64)
e2 = np.array([0.0, 1.0, 0.0], dtype=np.float64)
# if the cell vector isn't too close to +/- e1, generate the orthogonal vector using the cross
# product with e1. otherwise use e2. (we can't be too close to both)
u = (
np.cross(cell_vec, e1)
if (np.linalg.norm(cell_vec - e1) > epsilon and np.linalg.norm(cell_vec + e1) > epsilon)
else np.cross(cell_vec, e2)
)
u /= np.linalg.norm(u) # unlike the other normalizations, this is non-optional
# get second orthogonal vector, orthogonal to both the cell vec and the first orthogonal vector
v = np.cross(cell_vec, u)
# norm should be approx 1, can delete for performance
v /= np.linalg.norm(v)
# change of coordinates matrix
p_matrix = np.array([cell_vec, u, v]).T
# form a random unit vector on a 45 degree cone
theta = rg.random() * 2 * np.pi
branch_direction = p_matrix @ np.array([1.0, np.cos(theta), np.sin(theta)]) / np.sqrt(2)
# norm should be approx 1, can delete for performance
branch_direction /= np.linalg.norm(branch_direction)
return branch_direction
def fungus_macrophage_interaction(
afumigatus: AfumigatusState,
afumigatus_cell: AfumigatusCellData,
afumigatus_cell_index: int,
macrophage: 'MacrophageState',
macrophage_cell: 'MacrophageCellData',
macrophage_cell_index: int,
iron: IronState,
grid: RectangularGrid,
):
from nlisim.modules.macrophage import PhagocyteStatus
probability_of_interaction = (
afumigatus.pr_ma_hyphae
if afumigatus_cell['status'] == AfumigatusCellStatus.HYPHAE
else afumigatus.pr_ma_phag
)
# return if they do not interact
if rg.random() >= probability_of_interaction:
return
# now they interact
interact_with_aspergillus(
phagocyte_cell=macrophage_cell,
phagocyte_cell_index=macrophage_cell_index,
phagocyte_cells=macrophage.cells,
aspergillus_cell=afumigatus_cell,
aspergillus_cell_index=afumigatus_cell_index,
phagocyte=macrophage,
phagocytize=afumigatus_cell['status'] != AfumigatusCellStatus.HYPHAE,
)
# unlink the fungal cell from its tree
if (
afumigatus_cell['status'] == AfumigatusCellStatus.HYPHAE
and macrophage_cell['status'] == PhagocyteStatus.ACTIVE
):
Afumigatus.kill_fungal_cell(
afumigatus, afumigatus_cell, afumigatus_cell_index, iron, grid
)
def branch(
afumigatus_cell: AfumigatusCellData,
afumigatus_cell_index: int,
pr_branch: float,
afumigatus: AfumigatusState,
):
if (
afumigatus_cell['next_branch'] != -1 # if it already has a branch
or afumigatus_cell['status'] != AfumigatusCellStatus.HYPHAE
or not afumigatus_cell['boolean_network'][NetworkSpecies.LIP]
):
return
hyphal_length: float = afumigatus.hyphal_length
if rg.random() < pr_branch:
# now we branch
branch_vector = generate_branch_direction(cell_vec=afumigatus_cell['vec'])
branch_center_point = (
afumigatus_cell['point']
+ (hyphal_length / 2) * afumigatus_cell['vec']
+ (hyphal_length / 2) * branch_vector
) # center of new branch is offset by rest (half) of this septa and half of the new septa
# create the new septa
next_branch: CellData = AfumigatusCellData.create_cell(
point=Point(
x=branch_center_point[2], y=branch_center_point[1], z=branch_center_point[0]
),
vec=branch_vector,
growth_iteration=-1,
iron_pool=0,
status=AfumigatusCellStatus.HYPHAE,
state=afumigatus_cell['state'],
is_root=False,
)
next_branch_id: int = afumigatus.cells.append(next_branch)
# link them together
afumigatus_cell['next_branch'] = next_branch_id
next_branch['previous_septa'] = afumigatus_cell_index
def cell_self_update(
afumigatus: AfumigatusState,
afumigatus_cell: AfumigatusCellData,
afumigatus_cell_index: int,
) -> None:
afumigatus_cell['activation_iteration'] += 1
process_boolean_network(
afumigatus_cell=afumigatus_cell,
steps_to_eval=afumigatus.steps_to_bn_eval,
afumigatus=afumigatus,
)
# resting conidia become swelling conidia after a number of iterations
# (with some probability)
if (
afumigatus_cell['status'] == AfumigatusCellStatus.RESTING_CONIDIA
and afumigatus_cell['activation_iteration'] >= afumigatus.iter_to_swelling
and rg.random() < afumigatus.pr_aspergillus_change
):
afumigatus_cell['status'] = AfumigatusCellStatus.SWELLING_CONIDIA
afumigatus_cell['activation_iteration'] = 0
elif (
afumigatus_cell['status'] == AfumigatusCellStatus.SWELLING_CONIDIA
and afumigatus_cell['activation_iteration'] >= afumigatus.iter_to_germinate
):
afumigatus_cell['status'] = AfumigatusCellStatus.GERM_TUBE
afumigatus_cell['activation_iteration'] = 0
# TODO: verify this, 1 turn on internalizing then free?
if afumigatus_cell['state'] in {
AfumigatusCellState.INTERNALIZING,
AfumigatusCellState.RELEASING,
}:
afumigatus_cell['state'] = AfumigatusCellState.FREE
# Distribute iron evenly within fungal tree.
# Note: called for every cell, but a no-op on non-root cells.
diffuse_iron(afumigatus_cell_index, afumigatus)
def lip_activation(afumigatus: AfumigatusState, iron_pool: float) -> bool:
molar_concentration = iron_pool / afumigatus.hyphae_volume
activation = 1 - np.exp(-molar_concentration / afumigatus.kd_lip)
return bool(rg.random() < activation)
def chemotaxis(
self,
molecule,
drift_lambda,
drift_bias,
tissue,
grid: RectangularGrid,
):
# 'molecule' = state.'molecule'.concentration
# prob = 0-1 random number to determine which voxel is chosen to move
# 1. Get cells that are alive
for index in self.alive():
prob = rg.random()
# 2. Get voxel for each cell to get molecule in that voxel
cell = self[index]
vox = grid.get_voxel(cell['point'])
# 3. Set prob for neighboring voxels
p = []
vox_list = []
p_tot = 0.0
i = -1
# calculate individual probability
for x in [0, 1, -1]:
for y in [0, 1, -1]:
for z in [0, 1, -1]:
p.append(0.0)
vox_list.append([x, y, z])
i += 1
zk = vox.z + z
yj = vox.y + y
xi = vox.x + x
if grid.is_valid_voxel(Voxel(x=xi, y=yj, z=zk)):
if tissue[zk, yj, xi] in [
TissueType.SURFACTANT.value,
TissueType.BLOOD.value,
TissueType.EPITHELIUM.value,
TissueType.PORE.value,
]:
p[i] = logistic(molecule[zk, yj, xi],
drift_lambda, drift_bias)
p_tot += p[i]
# scale to sum of probabilities
if p_tot:
for i in range(len(p)):
p[i] = p[i] / p_tot
# chose vox from neighbors
cum_p = 0.0
for i in range(len(p)):
cum_p += p[i]
if prob <= cum_p:
cell['point'] = Point(
x=random.uniform(grid.xv[vox.x + vox_list[i][0]],
grid.xv[vox.x + vox_list[i][0] + 1]),
y=random.uniform(grid.yv[vox.y + vox_list[i][1]],
grid.yv[vox.y + vox_list[i][1] + 1]),
z=random.uniform(grid.zv[vox.z + vox_list[i][2]],
grid.zv[vox.z + vox_list[i][2] + 1]),
)
self.update_voxel_index([index])
break
